Book of Abstracts - Ruhr-Universität Bochum
Book of Abstracts - Ruhr-Universität Bochum
Book of Abstracts - Ruhr-Universität Bochum
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ISBOMC ‘10<br />
5th International Symposium on Bioorganometallic Chemistry<br />
July 05 - 09, 2010, <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
© G Gasser<br />
<strong>Book</strong> <strong>of</strong> <strong>Abstracts</strong><br />
RESEARCH DEPARTMENT<br />
INTERFACIAL SYSTEMS CHEMISTRY<br />
DFG-Forschergruppe 630<br />
B i o l o g i c a l f u n c t i o n o f<br />
organometallic compounds
Contents<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Foreword 2<br />
Sponsors 3<br />
Venue and travel directions 4<br />
General Information 6<br />
Conference program 7<br />
Oral presentations 16<br />
Poster presentations 58<br />
List <strong>of</strong> participants 143<br />
1
Foreword<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
We welcome you to the 5 th International Symposium on Bioorganometallic Chemistry<br />
at the <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>. It is our pleasure to host you at one <strong>of</strong> the largest<br />
and most dynamic universities in Germany.<br />
Bioorganometallic Chemistry is a rapidly growing field <strong>of</strong> research at the interface <strong>of</strong><br />
various disciplines. It is firmly routed in synthetic chemistry, but its applications range<br />
from biomedicine to medicinal and environmental analysis, modified enzymes and<br />
enzyme mimetics, structural studies <strong>of</strong> biomolecules and wholly new entities such as<br />
metallo-DNA, RNA and its analogues. The current meeting serves to showcase the<br />
broad variety <strong>of</strong> Bioorganometallic Chemistry, and the overwhelming interest that we<br />
received further underlines the vibrancy <strong>of</strong> the field. Indeed, we received many more<br />
applications for oral contributions than we could possibly accommodate in the<br />
scientific program. This has made the task <strong>of</strong> selecting a diverse and representative<br />
set <strong>of</strong> speakers <strong>of</strong> high scientific quality almost a daunting one, and I thank our<br />
colleagues for their support with this task, and all delegates for their understanding.<br />
We are proud to host the biggest-ever ISBOMC conference in <strong>Bochum</strong>, with > 180<br />
participants from more than 25 countries and all five continents. <strong>Bochum</strong> University is<br />
an ideal place to host such a meeting, and we will do our best to ensure that you will<br />
carry pleasant memories <strong>of</strong> the science as well as the venue home. Surely, this is<br />
only possible with the help <strong>of</strong> many caring hands and minds behind the scene, who<br />
have done a great job in preparing ISBOMC’10, and are ensuring its smooth<br />
operation during the conference. I wish to express my sincere thanks to all those<br />
helpers!<br />
I hope you will enjoy the science and the spirit <strong>of</strong> the symposium, and continue your<br />
efforts to make Bioorganometallic Chemistry an ongoing success story!<br />
<strong>Bochum</strong>, July 2010<br />
Nils Metzler-Nolte<br />
2
Sponsors<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
The <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong> is one <strong>of</strong> Germany’s leading research universities. The<br />
University draws its strengths from both the diversity and the proximity <strong>of</strong> scientific<br />
and engineering disciplines on a single, coherent campus. This highly dynamic<br />
setting enables students and researchers to work across traditional boundaries <strong>of</strong><br />
academic subjects and faculties. Host to 32,600 students and 4,700 staff, the <strong>Ruhr</strong>-<br />
<strong>Universität</strong> is a vital institution in the <strong>Ruhr</strong> area, which has been selected as<br />
European Capital <strong>of</strong> Culture for the year 2010.<br />
Research Department Interfacial Systems Chemistry<br />
The Research Department IFSC is an interdisciplinary community that brings<br />
together chemical and neighbouring disciplines. Researchers collaborate in the open<br />
spirit <strong>of</strong> a Research Department to get a fundamental and systemic understanding <strong>of</strong><br />
the structural and dynamic complexity <strong>of</strong> hierarchically structured assemblies and<br />
complex chemical systems.<br />
3
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Venue and travel directions<br />
The 5 th International Symposium on Bioorganometallic Chemistry (ISBOMC `10) will<br />
take place at the convention center ("Veranstaltungszentrum") <strong>of</strong> the <strong>Ruhr</strong>-<strong>Universität</strong><br />
<strong>Bochum</strong>. The lecture hall (hall 2a) and poster exhibition hall (hall 1) are located in the<br />
convention centre (Veranstaltungszentrum) on the 4 th floor <strong>of</strong> the Mensa Building.<br />
The reception and registration desk is located direct in front <strong>of</strong> room 2a. For entering<br />
the 4 th floor please use the elevator left or right. <strong>Bochum</strong> can conveniently be<br />
reached by train from Frankfurt, Düsseldorf and Dortmund airport. For booking,<br />
reservation and timetable information we recommend the webpage from the<br />
Deutsche Bahn (http://www.bahn.de/i/view/GBR/en/index.shtml). From <strong>Bochum</strong><br />
central station, take the subway train U35 from the basement level bound for<br />
"Hustadt/Querenburg" and get <strong>of</strong>f after about 5 stops and 10 min travel time at the<br />
station "<strong>Ruhr</strong>-<strong>Universität</strong>". During daytime, the subway will go every 5 minutes. When<br />
leaving the platform at "<strong>Ruhr</strong>-<strong>Universität</strong>", turn right and walk past the main university<br />
administration building (UV on the map), the central library (UB on the map), and the<br />
Audimax (big bowl-shaped lecture hall) towards the mensa. You can use your<br />
conference badge as a valid ticket for local transport in <strong>Bochum</strong> during the<br />
conference from 5.7 – 9.7.2010. Please take your conference badge with you<br />
using local transport.<br />
4
Conference Venue<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Convention Centre 4 th floor:<br />
Convention Centre<br />
RUB Mensa<br />
Veranstaltungszentrum<br />
4. Floor<br />
5<br />
U35 subway station<br />
<strong>Ruhr</strong>-<strong>Universität</strong><br />
Bus Stop<br />
Transfer:<br />
- Folkwang<br />
- Zeche Zollverein<br />
- Conference Dinner
General information<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Bus Transfers<br />
The buses for the excursion to the Folkwang Museum and Zeche Zollverein will wait<br />
10 min walk form the convention centre (marked with the red line and red dot in the<br />
map above). We will <strong>of</strong>fer a guided tour to the buses. Departure for the guided walk<br />
to the bus stop is 2:30 pm on Wednesday (Excursion), July 7 th and 6:00 pm on<br />
Thursday (Conference dinner), July 8 th from the reception desk in the convention<br />
centre. After the conference dinner several busses will departure at different times<br />
from conference dinner location Henrichshütte. Departure times and all other<br />
important actual news we will announce on the screen at the reception desk.<br />
Poster Session<br />
Please hang up your posters immediately after arrival, latest till Tuesday before the<br />
morning session and remove them on Thursday before the conference dinner. For<br />
adding your poster please contacts the guides in the poster hall and use the material<br />
delivered at the conferewnce venue. The number <strong>of</strong> the abstract for your poster you<br />
will find on the poster board reserved for you.<br />
Internet connection<br />
You will have access to the internet in the convention centre via WLAN. For getting<br />
connected to the WWW you need a pin number you will get at the reception desk on<br />
demand. This number is personalized and valid for one day. You need a new<br />
number every day.<br />
6
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Conference program<br />
7
Monday, July 5 th 2010<br />
16:00 to 18:00 registration<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
18:00 to 18:15 opening remarks <strong>of</strong> ISBOMC'10<br />
18:15 to 19:00 opening lecture<br />
Pr<strong>of</strong>. Dr. Chris Orvig (OP-1)<br />
Department <strong>of</strong> Chemistry<br />
University <strong>of</strong> British Columbia<br />
Bioorganometallics in Medicinal Inorganic Chemistry<br />
19:00 welcome reception<br />
8
Tuesday, July 6 th 2010<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Session I - Medicinal bioorganometallic chemistry I<br />
09:00 to 09:20 Pr<strong>of</strong>. Dr. Ingo Ott (OP-2)<br />
Institute <strong>of</strong> Pharmaceutical Chemistry<br />
Technische <strong>Universität</strong> Braunschweig<br />
Bioorganometallic Solutions for the Design <strong>of</strong> Novel Gold Anticancer<br />
Metallodrugs<br />
09:20 to 09:40 Dr. Yaw-Kai Yan (OP-3)<br />
Nanyang Technological University, National Institute <strong>of</strong> Education<br />
Natural Sciences & Science Education Department<br />
Rhenium(I) Tricarbonyl Complexes <strong>of</strong> Benzaldehyde and Substituted<br />
Salicylaldehyde Dibenzyl Semicarbazones: Synthesis and<br />
Cytotoxicity Studies<br />
09:40 to 10:00 Pr<strong>of</strong>. Dr. Roman Dembinski (OP-4)<br />
Department <strong>of</strong> Chemistry<br />
Oakland University<br />
Metallo-Nucleosides: Bis(dicobalt hexacarbonyl alkynyl) Derivatives<br />
<strong>of</strong> 2'-Deoxyuridine. Synthesis and Evaluation <strong>of</strong> Antiproliferative<br />
Activity Against Human Breast Cancer Cells<br />
10:00 to 10:20 Pr<strong>of</strong>. Dr. Matthias Tacke (OP-5)<br />
School <strong>of</strong> Chemistry and Chemical Biology<br />
University College Dublin<br />
Novel Metallocene Anticancer Drugs: From Lead to Hit<br />
10:20 to 11:00 c<strong>of</strong>fee break<br />
Session II - Medicinal bioorganometallic chemistry II<br />
11:00 to 11:45 Pr<strong>of</strong>. Dr. Stefan Wölfl (OP-6)<br />
Institute <strong>of</strong> Pharmacy and Molecular Biotechnology<br />
<strong>Universität</strong> Heidelberg<br />
Transcriptional Pr<strong>of</strong>ile <strong>of</strong> HT-29 Cells upon Treatment with Different<br />
Organometallic Compounds<br />
11:45 to 12:05 Nicolas Barry (OP-7)<br />
Institute <strong>of</strong> Chemistry<br />
University <strong>of</strong> Neuchatel<br />
Arene-Ruthenium Metalla-Prisms: New Drug Vectors<br />
12:05 to 12:25 Dr. Christian Gaiddon (OP-8)<br />
UMRS692 Signalisations Moléculaires et Neurodégénérescenc<br />
INSERM - Université de Strasbourg<br />
Design and Characterisation <strong>of</strong> the Anticancer Properties <strong>of</strong><br />
Ruthenium(II) Organometallic Compounds: Chemical Structure<br />
Optimization, Transport and Regulated Signaling Pathways<br />
9
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
12:25 to 12:45 Anusch Arezki (OP-9)<br />
UMR 7223 Organometallic Medicinal Chemistry Group<br />
Ecole Nationale Supérieure de Chimie de Paris<br />
Synthesis and Structure-Activity Relationship <strong>of</strong> Organometallic<br />
Derivatives <strong>of</strong> Curcumin as Anticancer Agents<br />
12:45 to 14:00 lunch break<br />
Session III - Medicinal bioorganometallic chemistry III<br />
14:00 to 14:20 Pr<strong>of</strong>. Dr. Domenico Osella (OP-10)<br />
Department <strong>of</strong> Environmental and Life Sciences<br />
University <strong>of</strong> Piemonte Orientale<br />
Synthesis, characterization and antiproliferative activity <strong>of</strong> a series <strong>of</strong><br />
Pt(IV) complexes: a QSAR approach to their cytotoxicity<br />
14:20 to 14:40 Pr<strong>of</strong>. Dr. Nataliia I. Shtemenko (OP-11)<br />
Department <strong>of</strong> Biophysics and Biochemistry<br />
Dnipropetrovs’k National University<br />
Influence <strong>of</strong> the Rhenium-Platinum antitumor system on tumor<br />
growth and blood antioxidant state<br />
14:40 to 15:00 Daniel Can (OP-12)<br />
Faculty <strong>of</strong> Inorganic Chemistry<br />
University <strong>of</strong> Zurich<br />
The [CpM(CO)3]-Moiety (M = Mn, Tc, Re) as Phenyl Ring analog - a<br />
Promising Strategy Towards New Drugs and Radiopharmaceuticals<br />
15:00 to 15:20 Dr. Elizabeth Hillard (OP-13)<br />
UMR 7223 Organometallic Medicinal Chemistry Group<br />
Ecole Nationale Supérieure de Chimie de Paris<br />
Ferrocenyl Flavonoids: Synthesis and Antiproliferative Effects<br />
15:20 to 16:00 c<strong>of</strong>fee break<br />
16:00 to 18:00 poster session<br />
18:00 BBQ dinner: The BBQ will take place on the ro<strong>of</strong> garden <strong>of</strong> the Bistro<br />
in the Convention centre on floor 1. You can reach the ro<strong>of</strong> garden<br />
with the elevator from the conference hall (1 st semi-final game soccer<br />
world cup 2010 �).<br />
10
Wednesday, July 7 th 2010<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Session IV - Medicinal bioorganometallic chemistry IV<br />
09:00 to 09:20 Dr. Alberta Bergamo (OP-14)<br />
Callerio Foundation Onlus<br />
Preclinical Development <strong>of</strong> Metal-Based Compounds:<br />
Set Up <strong>of</strong> a Plastic Mouse Model<br />
09:20 to 09:40 Dr. Braja G. Bag (OP-15)<br />
Department <strong>of</strong> Chemistry and Chemical Technolgy<br />
Vidyasagar University<br />
Arjunolic acid: The First Renewable-Nano Triterpenoid in<br />
Bioorganometallics<br />
09:40 to 10:00 Dr. Gregory S. Smith (OP-16)<br />
Department <strong>of</strong> Chemistry<br />
University <strong>of</strong> Cape Town<br />
Anticancer Activity <strong>of</strong> Multinuclear Ruthenium-Arene Complexes<br />
Coordinated to Dendritic Poly(propyleneimine) Scaffolds<br />
10:00 to 10:20 Dr. Stephan Niland (OP-17)<br />
Center for Molecular Medicine, Department <strong>of</strong> Vascular Matrix<br />
Biology, <strong>Universität</strong> Frankfurt am Main<br />
Bi<strong>of</strong>unctionalization <strong>of</strong> a Generic Collagenous Triple Helix with the<br />
Integrin α2β1 Binding Site<br />
10:20 to 11:00 c<strong>of</strong>fee break<br />
Session V - Medicinal bioorganometallic chemistry V<br />
11:00 to 11:45 award lecture<br />
Pr<strong>of</strong>. Dr. Paul Dyson (OP-18)<br />
Institut des Sciences et Ingénierie Chimiques<br />
Ecole Polytechnique Fédérale de Lausanne (EPFL)<br />
Organometallic Anticancer Drugs: From Simple Structures to<br />
Rational Drug Design Based on a Mechanistic Approach<br />
11:45 to 12:05 Dr. Frederik H. Kriel (OP-19)<br />
AuTEK Biomed, Mintek<br />
Biological Activity <strong>of</strong> Gold and Silver Bis(Phosphino)Hydrazine<br />
Complexes<br />
12:05 to 12:25 Pr<strong>of</strong>. Dr. Mallayan Palaniandavar (OP-20)<br />
Centre for Bioinorganic Chemistry<br />
School <strong>of</strong> Chemistry, Bharathidasan University<br />
DNA and Protein Binding, Cleavage and Anticancer Activity <strong>of</strong><br />
Organometallic (M = Ru(II), Rh(III) and Ir(III)) Arene Complexes<br />
11
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
12:25 to 12:45 PD Dr. Christian Hartinger (OP-21)<br />
Institute <strong>of</strong> Inorganic Chemistry<br />
University <strong>of</strong> Vienna<br />
Organometallic Pyrone and Pyridone Complexes as Anticancer<br />
Agents<br />
12:45 to 14:00 lunch<br />
14:00 to 18:00 excursions to Folkwang-Museum or Zeche Zollverein<br />
(only by separate registration)<br />
18:00 free evening<br />
(2 nd half-final game soccer world cup 2010 �)<br />
12
Thursday, July 8 th 2010<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Session VI - Enzymes and bioorganometallic supramolecular systems I<br />
09:00 to 09:45 Pr<strong>of</strong>. Dr. Holger Dobbek (OP-22)<br />
Institut für Biologie<br />
Humboldt-<strong>Universität</strong> Berlin<br />
Metalloenzymes in the bacterial life on carbon monoxide:<br />
A view from structural biology<br />
09:45 to 10:05 Pr<strong>of</strong>. Dr. Wolfgang Weigand (OP-23)<br />
Institut für Anorganische und Analytische Chemie<br />
Friedrich-Schiller-<strong>Universität</strong> Jena<br />
Models for the Active Site in [FeFe] Hydrogenase with<br />
Silicon-containing Ligands<br />
10:05 to 10:25 Pr<strong>of</strong>. Dr. Andres Jäschke (OP-24)<br />
Institute <strong>of</strong> Pharmacy and Molecular Biotechnology<br />
<strong>Universität</strong> Heidelberg<br />
DNA-Organometallic Hybrid Catalysts<br />
10:25 to 11:00 c<strong>of</strong>fee break<br />
Session VII - Enzymes and bioorganometallic supramolecular systems II<br />
11:00 to 11:45 Pr<strong>of</strong>. Dr. Yoshihito Watanabe (OP-25)<br />
Graduate School <strong>of</strong> Science, Department <strong>of</strong> Chemistry<br />
Nagoya University<br />
Construction <strong>of</strong> Organometalloenzymes<br />
11:45 to 12:05 Dr. Fabio Zobi (OP-26)<br />
Institute <strong>of</strong> Inorganic Chemistry<br />
University <strong>of</strong> Zürich<br />
CO Releasing Properties <strong>of</strong> cis-trans-[Re II (CO)2Br2L2]n Complexes:<br />
A Feature Modulated by Ligand Variation for a True Chance at<br />
Medicinal Applications<br />
12:05 to 12:25 Dr. João D. G. Correia (OP-27)<br />
Unidade de Ciências Químicas e Radi<strong>of</strong>armacêuticas, ITN<br />
Nitric Oxide Synthase Targeting with 99m Tc(I)/Re(I) Complexes<br />
12:25 to 12:45 Dr. Jason M. Lynam (OP-28)<br />
Department <strong>of</strong> Chemistry<br />
University <strong>of</strong> York<br />
Mechanistic and Synthetic Studies <strong>of</strong> Bio-compatible Carbon<br />
Monoxide-Releasing Molecules<br />
12:45 to 14:00 lunch break<br />
13
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Session VIII - Enzymes and bioorganometallic supramolecular systems III<br />
14:00 to 14:45 Pr<strong>of</strong>. Dr. Morten Meldal (OP-29)<br />
Carlsberg Laboratory<br />
Peptide-carbenes and peptide-phosphines transition metal catalysts<br />
for “Green” solid phase catalysts<br />
14:45 to 15:05 Dr. Pratima Srivastava (OP-30)<br />
UMR 7223 Organometallic Medicinal Chemistry Group<br />
Ecole Nationale Supérieure de Chimie de Paris<br />
Construction <strong>of</strong> an Immunosensor via Copper-Free ‘Click’ Reaction<br />
Between Azido SAMs and Alkynyl Fischer Carbene Complex.<br />
Application to the detection <strong>of</strong> Staphyloccal Enterotoxin A<br />
15:05 to 15:25 Pr<strong>of</strong>. Dr. Toshiyuki Moriuchi (OP-31)<br />
Department <strong>of</strong> Applied Chemistry, Graduate School <strong>of</strong> Engineering<br />
Osaka University<br />
Polypeptides Induced Self-Association and Emission Properties <strong>of</strong><br />
Platinum(II) and Gold(I) Complexes<br />
15:25 to 16:00 c<strong>of</strong>fee break<br />
Session IX - Enzymes and bioorganometallic supramolecular systems IV<br />
16:00 to 16:45 Pr<strong>of</strong>. Dr. Gerard van Koten (OP-32)<br />
Organic Chemistry and Catalysis, Faculty <strong>of</strong> Science<br />
Utrecht University<br />
Homogeneous and Bio-Catalysis in Concert: Hybrids <strong>of</strong> ECE-pincer<br />
Organometallics and Lipases<br />
16:45 to 17:05 Jeremy Zimbron (OP-33)<br />
Department <strong>of</strong> Chemistry<br />
University <strong>of</strong> Basel<br />
Chemo-Genetic Optimization <strong>of</strong> DNA Recognition by Metallodrugs<br />
using a Presenter Protein Strategy<br />
17:05 to 17:25 Dr. Johannes A. Eble (OP-34)<br />
Center for Molecular Medicine, Department <strong>of</strong> Vascular Matrix<br />
Biology, <strong>Universität</strong> Frankfurt am Main<br />
RAPTA-T interacts with �1�1 integrin at the molecular level<br />
18:00 departure for conference dinner at Henrichshütte<br />
14
Friday, July 9 th 2010<br />
Session X - Bioimaging I<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
09:00 to 09:45 Pr<strong>of</strong>. Dr. John Valliant (OP-35)<br />
Department <strong>of</strong> Chemistry<br />
McMaster University<br />
TBA<br />
09:45 to 10:05 Anica Dose (OP-36)<br />
Functional Materials Group, School <strong>of</strong> Physical Science<br />
University <strong>of</strong> Kent<br />
Syntheses <strong>of</strong> New Isomeric Analogues <strong>of</strong> HYNIC for Evaluation<br />
as a Bifunctional Chelator for Technetium-99m<br />
10:05 to 10:25 Pr<strong>of</strong>. Dr. Emanuela Licandro (OP-37)<br />
Dipartimento di Chimica Organica e Industriale<br />
University <strong>of</strong> Milano<br />
Fluorescent Conjugates Between Dinuclear Rhenium(I) Complexes<br />
and Peptide Nucleic Acids (PNA) for Cell imaging and DNA Targeting<br />
10:25 to 11:00 c<strong>of</strong>fee break<br />
Session XI - Bioimaging II<br />
11:00 to 11:45 Pr<strong>of</strong>. Dr. Kenneth Kam-Wing Lo (OP-38)<br />
Department <strong>of</strong> Biology and Chemistry<br />
City University <strong>of</strong> Hong Kong<br />
Design <strong>of</strong> Cyclometalated Iridium(III) Polypyridine Complexes as<br />
Luminescent Biological Labels and Probes<br />
11:45 to 12:05 Dr. Anne Vessières (OP-39)<br />
UMR 7223 Organometallic Medicinal Chemistry Group<br />
Ecole Nationale Supérieure de Chimie de Paris<br />
Subcellular Imaging <strong>of</strong> a Re(CO)3 Complex by Photothermal Infrared<br />
Spectromicroscopy (PTIR)<br />
12:05 to 12:25 Pr<strong>of</strong>. Dr. Edward Rosenberg (OP-40)<br />
Department <strong>of</strong> Chemistry and Biochemistry<br />
University <strong>of</strong> Montana, Missoula<br />
Dynamical Studies <strong>of</strong> Bioconjugated Luminescent Ruthenium<br />
Complexes in Lipid Vesicles<br />
12:25 to 12:45 Dr. Gilles Gasser (OP-41)<br />
Institute <strong>of</strong> Inorganic Chemistry<br />
University <strong>of</strong> Zürich<br />
Multi-Organometallic-Containing Peptide Nucleic Acids: Preparation<br />
and Biological Applications<br />
12:45 to 13:00 closing remarks and announcement <strong>of</strong> ISBOMC'12<br />
15
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Oral presentations<br />
16
OP-1<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Bioorganometallics in Medicinal Inorganic Chemistry<br />
Chris Orvig *a<br />
a Medicinal Inorganic Chemistry Group, Department <strong>of</strong> Chemistry, University <strong>of</strong> British<br />
Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. E-mail: orvig@chem.ubc.ca<br />
Bioorganometallic chemistry was an oxymoron in the 1970s when Pt compounds emerged for cancer<br />
chemotherapy and Tc compounds took flight as nuclear medicine imaging agents. At that time, the<br />
speaker fastidiously avoided working with technetium carbonyl compounds when he was a graduate<br />
student! Now, thanks to the effort <strong>of</strong> this community, bioorganometallic chemistry plays a valuable<br />
role to the larger fields <strong>of</strong> medicinal inorganic chemistry and medicinal chemistry.<br />
Efforts in the speaker's labs to develop organometallic compounds for therapy and diagnosis will be<br />
outlined, focussing on recent results in antimalarial and imaging applications.<br />
17
OP-2<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Bioorganometallic Solutions for the Design<br />
<strong>of</strong> Novel Gold Anticancer Metallodrugs<br />
Ingo Ott, *a Riccardo Rubbiani, a Igor Kitanovic, b Hamed Alborzinia, b Suzan Can, b Stefan Wölfl, b<br />
Liliane A. Onambele, c Aram Prokop c<br />
a Technische <strong>Universität</strong> Braunschweig, Institute <strong>of</strong> Pharmaceutical Chemistry, Beethovenstr. 55,<br />
38106, Braunschweig, Germany, b Ruprecht-Karls-<strong>Universität</strong> Heidelberg, Institut für Pharmazie und<br />
Molekulare Biotechnologie, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany c) Kliniken der<br />
Stadt Köln GmbH; E-mail: ingo.ott@tu-bs.de<br />
Motivated by the success <strong>of</strong> gold species in the treatment <strong>of</strong> rheumatoid arthritis and by the promising<br />
outcome <strong>of</strong> several preclinical studies increasing efforts have been made to develop gold complexes<br />
also for the use in cancer chemotherapy. Concerning the mode <strong>of</strong> drug action thioredoxin reductase<br />
(TrxR), an enzyme closely related to glutathione reductase (GR), is nowadays considered as the most<br />
relevant molecular target based on the high selectivity <strong>of</strong> gold species for this enzyme and its<br />
substantial involvement in tumor growth and progression. 1-3<br />
Here we wish to present our most recent results obtained with gold(I) bioorganometallics featuring Nheterocyclic<br />
carbene (NHC) derived ligands (see the figure below for a relevant example) in<br />
comparison to relevant non organometallic gold(I) phosphine complexes such as auran<strong>of</strong>in.<br />
Promising antiproliferative effects were noted in MCF-7 breast adenocarcinoma as well as HT-29<br />
colon carcinoma cells and the target compounds were found to be strong and selective inhibitors <strong>of</strong><br />
TrxR with an increased stability against glutathione. More detailed studies on a selected gold(I) NHC<br />
complex revealed a strong induction <strong>of</strong> apoptosis and reactive oxygene species (ROS) formation,<br />
antimitochondrial properties, as well as distinct effects on cellular metabolism.<br />
References<br />
N<br />
N<br />
18<br />
Au Cl<br />
Figure: example for a bioactive gold(I) NHC complex<br />
1. I. Ott, Coord. Chem. Rev. 2009, 253, 1670-1681.<br />
2. A. Bindoli, M. P. Rigobello, G. Scutari, C. Gabbiani, A. Casini, L. Messori, Coord. Chem. Rev.<br />
2009, 253, 1692-1707.<br />
3. P. J. Barnard, S. J. Berners-Price, Coord. Chem. Rev. 2007, 251, 1889-1902.
OP-3<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Rhenium(I) Tricarbonyl Complexes <strong>of</strong> Benzaldehyde and Substituted<br />
Salicylaldehyde Dibenzyl Semicarbazones: Synthesis and Cytotoxicity Studies<br />
Yaw-Kai Yan, *a Siti Munira bte Haidad Ali, a and Peng-Foo Peter Lee a<br />
a Nanyang Technological University, National Institute <strong>of</strong> Education, Natural Sciences & Science<br />
Education Department, 1 Nanyang Walk, Singapore 637616. E-mail: yawkai.yan@nie.edu.sg<br />
Semicarbazones and their metal complexes are attracting interest due to their potential medicinal<br />
applications. 1 In particular, metal complexes <strong>of</strong> salicylaldehyde semicarbazones were shown to have in<br />
vitro anti-cancer activity. 2 Since rhenium(I) tricarbonyl complexes <strong>of</strong> bis(diphenylphosphinomethyl)<br />
amines and 2-(dimethylamino)ethoxide also show cytotoxic activity against several murine and human<br />
cancer cell lines, 3 we embarked on a study <strong>of</strong> the cancer cell cytotoxicity <strong>of</strong> rhenium(I) tricarbonyl<br />
complexes <strong>of</strong> N,N-disubstituted salicylaldehyde semicarbazones (SSCs), [ReBr(CO)3(SSC)]. It was<br />
found that these complexes exhibit moderate to high cytotoxicities towards MOLT-4 cells. 4 In this<br />
paper, we report our recent work on the synthesis and cytotoxicity screening <strong>of</strong> benzaldehyde and<br />
substituted salicylaldehyde dibenzyl semicarbazones, and their rhenium(I) tricarbonyl complexes<br />
(Figure). The results show that complexes 2, 3 and 5 are strongly cytotoxic against MOLT-4 cells.<br />
References<br />
1. H. Beraldo, D. Gambino, Minirev. Med. Chem. 2004, 4, 31-39. (b) Z. Afrasiabi, E. Sinn, W. Lin, Y.<br />
Ma, C. Campana, S.B. Padhyé, J. Inorg. Biochem. 2005, 99, 1526-1531. (c) J. Rivadeneira, D.A.<br />
Barrio, G. Arrambide, D. Gambino, L. Bruzzone, S.B. Etcheverry, J. Inorg. Biochem. 2009, 103, 633-<br />
642.<br />
2. (a) J. Patole, S. Padhye, M.S. Moodbidri, N. Shirsat, Eur. J. Med. Chem. 2005, 40, 1052-1055. (b)<br />
P. Noblia, M. Vieites, B. Parajon-Costa, E. Baran, H. Cerecetto, P. Draper, M. Gonzalez, O. Piro, E.<br />
Castellano, A. Azqueta, A. de Cerain, A. Monge-Vega, D. Gambino, J. Inorg. Biochem. 2005, 99,<br />
443-451.<br />
3. (a) J. Zhang, J.J. Vittal, W. Henderson, J. Wheaton, I.H. Hall, T.S.A. Hor, Y.K. Yan, J. Organomet.<br />
Chem. 2002, 650, 123-132. (b) W. Wang, Y.K. Yan, T.S.A. Hor, J.J. Vittal, J.R. Wheaton, I.H. Hall,<br />
Polyhedron 2002, 21, 1991-1999.<br />
4. J. Ho, W. Y. Lee, P. F. P. Lee, Y. K. Yan, J. Inorg. Biochem., submitted.<br />
19
OP-4<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Metallo-Nucleosides: Bis(dicobalt hexacarbonyl alkynyl) Derivatives <strong>of</strong><br />
2'-Deoxyuridine. Synthesis and Evaluation <strong>of</strong> Antiproliferative Activity Against<br />
Human Breast Cancer Cells<br />
Roman Dembinski, *a Przemyslaw Wyrebek. a Agnieszka Mikus. a Adam Sniady,. a Laura Hamel, b<br />
and Ingo Ott *b<br />
a Oakland University, Department <strong>of</strong> Chemistry, 2200 N. Squirrel Rd., 48309-4477, Rochester, MI,<br />
USA. b Technische <strong>Universität</strong> Braunschweig, Institute <strong>of</strong> Pharmaceutical Chemistry, Beethovenstr.<br />
55, 38106 Braunschweig, Germany, E-mail: dembinsk@oakland.edu<br />
In continuation <strong>of</strong> synthetic pursuit <strong>of</strong> metallo-nucleosides, in particular dicobalt<br />
hexacarbonyl 5-alkynyl-2'-deoxyuridines, 1 novel compounds with two alkynyl groups were<br />
synthesized starting from 5-iodo-2'-deoxyuridine (selected example is illustrated below). The<br />
complexes have been examined for their anti-cancer activity in vitro against MCF-7 and<br />
MDA-MB-231 human breast cancer cell lines or HT-29 (colon carcinoma). The results were<br />
compared to activity <strong>of</strong> non-coordinated alkynyl precursors.<br />
References<br />
HO<br />
O<br />
HN<br />
O<br />
OH<br />
O<br />
N<br />
(CO) 3<br />
Co Co(CO) 3<br />
20<br />
H<br />
Co(CO) 3<br />
Co(CO) 3<br />
1. (a) C. D. Sergeant, I. Ott, A. Sniady, S. Meneni, R. Gust, A. L. Rheingold, R. Dembinski, Org.<br />
Biomolec. Chem. 2008, 6, 73-80. (b) I. Ott, B. Kircher, R. Dembinski, R. Gust, Expert Opin.<br />
Therapeutic Pat. 2008, 18, 327-336.
OP-5<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Novel Metallocene Anticancer Drugs: From Lead to Hit<br />
Matthias Tacke a<br />
a Centre for Synthesis and Chemical Biology, Conway Institute<br />
UCD School <strong>of</strong> Chemistry and Chemical Biology, Belfield, Dublin 4, Ireland.<br />
E-mail: matthias.tacke@ucd.ie<br />
Titanocene dichloride derivatives like Titanocene Y were extensively investigated in vitro, in vivo<br />
and ex vivo during the last years. 1-5 In addition, details about the mechanism <strong>of</strong> action became<br />
available, which allowed for choosing renal-cell cancer as one <strong>of</strong> the appropriate targets. More<br />
recently, the successful substitution patterns <strong>of</strong> the titanocenes were transmetallated onto vanadium<br />
which has led to isostructural vanadocene dichloride compounds. 6, 7 These compounds have started<br />
their preclinical evaluation process with respect to their cytotoxicity and anti-angiogenic activity in<br />
vitro and their tumor volume control and toxicity in vivo. The results allow for the first to look at the<br />
direct comparison <strong>of</strong> these two promising classes <strong>of</strong> metallocene compounds; this might allow to<br />
answer the question, which metal is the most promising for further development.<br />
References<br />
1. Bioorganometallic Fulvene-Derived Titanocene Anticancer Drugs, K. Strohfeldt, M. Tacke, Chem.<br />
Soc. Rev., 2008, 37, 1174-1187.<br />
2. In Vitro Anti-Tumor Activity <strong>of</strong> Bridged and Unbridged Benzyl-Substituted Titanocenes, G. Kelter,<br />
N. Sweeney, K. Strohfeldt, H.-H. Fiebig, M. Tacke, Anti-Cancer Drugs, 2005, 16, 1091-1098.<br />
3. Antitumor Activity <strong>of</strong> Titanocene Y in Xenografted Caki-1 Tumors in Mice, I. Fichtner, C.<br />
Pampillón, N. J. Sweeney, K. Strohfeldt, M. Tacke, Anti-Cancer Drugs, 2006, 17, 333-336.<br />
4. Antitumor Activity <strong>of</strong> Titanocene Y in Freshly Explanted Human Breast Tumors and in Xenografted<br />
MCF-7 Tumors in Mice, Anti-Cancer Drugs, 2007, 18, 311-315.<br />
5. Antiproliferative Activity <strong>of</strong> Titanocene Y against Tumor Colony Forming Units, O. Oberschmidt,<br />
A.-R. Hanauske, C. Pampillón, K. Strohfeldt, N. J. Sweeney, M. Tacke, Anti-Cancer Drugs, 2007, 18,<br />
317-321.<br />
6. Novel Benzyl-Substituted Vanadocene Anticancer Drugs, B. Gleeson, J. Claffey, M. Hogan, H.<br />
Müller-Bunz, D. Wallis, M. Tacke, J. Organometal. Chem., 2009, 694, 1369-1374.<br />
7. Synthesis and Cytotoxicity Studies <strong>of</strong> Fluorinated Derivatives <strong>of</strong> Vanadocene Y, B. Gleeson, J.<br />
Claffey, A. Deally, M. Hogan, L. M. Menéndez Méndez, H. Müller-Bunz, S. Patil, D. Wallis, M.<br />
Tacke, Eur. J. Inorg. Chem., 2009, 2804-2810.<br />
Acknowledgement: Support is acknowledged from CESAR, COST, HEA, CSCB and UCD.<br />
21
OP-6<br />
ISBOMC `10 5.7 – 9.7 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Transcriptional Pr<strong>of</strong>ile <strong>of</strong> HT-29 Cells upon Treatment with Different<br />
Organometallic Compounds<br />
Igor Kitanovic, a Ana Kitanovic, a Hamed Alborzinia, a Suzan Can, a Pavlo Holenya, a Elke Lederer, a<br />
Hans-Günther Schmalz, b Annegret Hille, c Ronald Gust, c Ingo Ott, d Aram Prokop, e Melanie Oleszak, f<br />
Yvonne Geldmacher, f William S. Sheldrick, f Gilles Gasser, g Nils Metzler-Nolte h and Stefan Wölfl *a<br />
a Institute <strong>of</strong> Pharmacy and Molecular Biotechnology, University Heidelberg, Germany, b Institute <strong>of</strong><br />
Inorganic Chemistry, University <strong>of</strong> Cologne, Germany, c Institute <strong>of</strong> Pharmacy, Department <strong>of</strong><br />
Pharmaceutical Chemistry, Freie <strong>Universität</strong> Berlin, Germany, d Institute <strong>of</strong> Pharmaceutical<br />
Chemistry, Technische <strong>Universität</strong> Braunschweig, Germany, e Cologne City Hospital, Department <strong>of</strong><br />
Oncology, Cologne, Germany, f Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong> Analytical<br />
Chemistry, University <strong>Bochum</strong>, g Institute <strong>of</strong> Inorganic Chemistry, University <strong>of</strong> Zurich, h Faculty <strong>of</strong><br />
Chemistry and Biochemistry, Department <strong>of</strong> Bioinorganic Chemistry, University <strong>of</strong> <strong>Bochum</strong>. email:<br />
igor.kitanovic@urz.uni-heidelberg.de, wolfl@uni-hd.de<br />
In the past several decades metal compounds containing platinum became an essential part <strong>of</strong> many<br />
clinical protocols for anti-cancer therapy. Considered to be relatively unspecific compounds that block<br />
DNA-replication and cell cycle progression, metal-containing compounds were not in the research<br />
focus <strong>of</strong> medicinal chemistry. New developments in the chemistry <strong>of</strong> (bio-)organometallic compounds<br />
however lead to the discovery <strong>of</strong> several unexpected highly specific activities <strong>of</strong> new organometallic<br />
compounds and opened new important perspectives in this field.<br />
For cancer therapy cancer cell specific toxicity and apoptosis induction are highly desirable features <strong>of</strong><br />
new potential drugs. Within our collaborative network a wide range <strong>of</strong> new (bio-)orgamometallic<br />
compounds were developed that show very distinct cytotoxic properties suggesting that rather than<br />
acting through a common mechanism different cellular targets are responsible for cytotoxicity and cell<br />
death induction.<br />
We will present a comprehensive analysis <strong>of</strong> the cellular response <strong>of</strong> human colorectal<br />
adenocarcinoma cells HT29 with very diverse organometallic compounds: ranging from FeIIsalophenes,<br />
through more classical bioorganometallic compounds to bioorganometallic compounds<br />
derived from established (non-metal containing) drugs. To elucidate their specific activity pr<strong>of</strong>ile,<br />
standard cell based assays were combined with genome wide gene expression pr<strong>of</strong>iling using<br />
affymetrix gene expression arrays. Although the substances represent a wide range <strong>of</strong> different<br />
structures and metal cores, they all are highly cytotoxic and clearly induce apoptosis in HT-29 cells.<br />
For gene expression pr<strong>of</strong>iling concentrations just below the IC50 (cytotoxicity) were chosen to obtain<br />
more compound specific alterations in gene expression rather then common cytotoxicity pr<strong>of</strong>iles, in<br />
addition mRNAs were collected at different time points critical in the cellular response upon<br />
treatment.<br />
The results obtained show similar response characteristics, but also very compound specific changes.<br />
This clearly indicates very distinct biological properties and suggests common response mechanisms<br />
as well as high selectivity and target specificity.<br />
List <strong>of</strong> compounds: Hi41, CoASS (AG Gust), MH1 (AG Scheldrick), MeN69 (AG Schmaltz),<br />
FcOHTAM3, ReGG1 (AG Metzler-Nolte)<br />
This work is supported by the DFG as part <strong>of</strong> the Forschergruppe FOR630.<br />
22
OP-7<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Arene-Ruthenium Metalla-Prisms: New Drug Vectors<br />
Nicolas Barry a and Bruno Therrien *a<br />
a University <strong>of</strong> Neuchatel, Faculty <strong>of</strong> Science, Institute <strong>of</strong> Chemistry, 51 Ave de Bellevaux, 2000,<br />
Neuchatel, Switzerland. E-mail: bruno.therrien@unine.ch<br />
Based on “enhanced permeability and retention” (EPR) effect, passive targeting <strong>of</strong> tumours appears as<br />
a promising solution against the general toxicity, resistance mechanisms and side effects <strong>of</strong> classical<br />
chemotherapeutics. 1 Thus, large drug delivery systems <strong>of</strong>fer in general a better selectivity as compared<br />
to small molecules. Large drug delivery vectors include micelles, nanoparticles and dendrimers;<br />
however, we proposed some years ago a new type <strong>of</strong> water soluble capsule built from arene-ruthenium<br />
units. These intrinsic cytotoxic metalla-prismatic cages allowed encapsulation <strong>of</strong> palladium or<br />
platinum complexes inside their cavities, 2 as well as the encapsulation <strong>of</strong> aromatic molecules. 3<br />
Moreover, the uptake <strong>of</strong> encapsulated molecule into cancer cells via fluorescence microscopy was also<br />
studied. 4<br />
Host-guest properties have been recently observed with a slightly different arene-ruthenium metallaprism,<br />
which does not really change neither the uptake <strong>of</strong> the guest into cancer cells nor the<br />
cytotoxicity. However, fluorescence microscopy assays seem to show a faster release <strong>of</strong> the guest<br />
molecule inside cancer cells, thus opening new perspectives for these metalla-cages. These new results<br />
will be the focus <strong>of</strong> this presentation.<br />
References<br />
1. Y. Matsumura, H. Maeda, Cancer Res. 1986, 46, 6387.<br />
2. B. Therrien, G. Süss-Fink, P. Govindaswamy, A. K. Renfrew, P. J. Dyson, Angew. Chem. Int. Ed.<br />
2008, 47, 3773.<br />
3. J. Mattsson, P. Govindaswamy, J. Furrer, S. Sei, K. Yamaguchi, G. Süss-Fink, B. Therrien,<br />
Organometallics 2008, 27, 4346.<br />
4. O. Zava, J. Mattsson, B. Therrien, P. J. Dyson, Chem. Eur. J. 2010, 16, 1428.<br />
23
OP-8<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Design and Characterisation <strong>of</strong> the Anticancer Properties <strong>of</strong> Ruthenium(II)<br />
Organometallic Compounds: Chemical Structure Optimization, Transport<br />
and Regulated Signaling Pathways<br />
Christian Gaiddon, a* Jenny Marjorie, a Meng Xiangjun, a Leyva L. Mili, b Isabelle Gross, e<br />
Sébastien Harlepp, c Pascal Hébraud, c Anne Boos, d Claude Sirlin, b Michel Pfeffer, b<br />
and Jean-Philippe Loeffler a<br />
aUMRS692 INSERM - Université de Strasbourg, Signalisations Moléculaires et Neurodégénérescence,<br />
11 rue Humann, Strasbourg, France<br />
b UMR 7177 CNRS- Université de Strasbourg, Institut de Chimie, Strasbourg, France<br />
c UMR 7504 CNRS, IPCMS, Strasbourg, France<br />
d UMR 7178 IPHC-DSA, ULP, CNRS, ECPM, Strasbourg France<br />
e UMRS682 INSERM - Université de Strasbourg, Strasbourg, France<br />
gaiddon@unistra.fr<br />
Cisplatin-derived anticancer therapy has been used for three decades despite its side effects. Other<br />
types <strong>of</strong> organometallic complexes, namely some ruthenium-derived compounds (RDCs), which<br />
would display cytotoxicity through different modes <strong>of</strong> action, might represent alternative therapeutic<br />
agents. We have studied both in vitro and in vivo the biological properties <strong>of</strong> a new class <strong>of</strong> RDCs that<br />
contain a covalent bond between a ruthenium(II) atom and a carbon. We showed that these RDC<br />
inhibited the growth <strong>of</strong> various tumors implanted in mice more efficiently than cisplatin. Importantly,<br />
in striking contrast with cisplatin, some <strong>of</strong> these RDCs did not cause severe side effects on the liver,<br />
kidneys, or the neuronal sensory system. We analyzed the mode <strong>of</strong> action <strong>of</strong> these RDC and<br />
demonstrated that they interacted poorly with DNA and induced only limited DNA damages compared<br />
to cisplatin, suggesting alternative transduction pathways. Indeed, we found that target genes <strong>of</strong> the<br />
endoplasmic reticulum (ER) stress pathway, such as Bip, XBP1, PDI, and CHOP, were activated in<br />
RDC-treated cells. Induction <strong>of</strong> the transcription factor CHOP, a crucial mediator <strong>of</strong> ER stress<br />
apoptosis, was also confirmed in tumors treated with RDCs. Activation <strong>of</strong> factor CHOP led to the<br />
expression <strong>of</strong> several <strong>of</strong> its target genes, including pro-apoptotic genes. In addition, the silencing <strong>of</strong><br />
CHOP by RNA interference significantly reduced the cytotoxicity <strong>of</strong> RDCs. Altogether, our results<br />
led us to conclude that RDCs act by an atypical pathway involving CHOP and ER stress, and thus<br />
might provide an interesting alternative for anticancer therapy.<br />
Based on these results, we have now developed new and optimized RDCs with an enhanced<br />
cytotoxicity. We show that they have indeed a greater toxicity in vitro, which is linked to the<br />
activation <strong>of</strong> different signaling pathways. In order to have a better understanding <strong>of</strong> the mode <strong>of</strong><br />
action <strong>of</strong> RDCs, we have analyzed their import into cells and compared the transcriptome regulated by<br />
cisplatin and RDCs. We identified various signaling pathways regulated specifically by RDCs that<br />
allowed us to present an interesting and global hypothesis linking the anticancer effect <strong>of</strong> RDCs, their<br />
redox activity and the alteration <strong>of</strong> the cellular metabolism.<br />
24
OP-9<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis and Structure-Activity Relationship <strong>of</strong> Organometallic Derivatives<br />
<strong>of</strong> Curcumin as Anticancer Agents<br />
Anusch Arezki, Emilie Brulé,* and Gérard Jaouen<br />
Chimie ParisTech (ENSCP), Laboratoire Charles Friedel (UMR 7223),<br />
Organometallic Medicinal Chemistry Group<br />
11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France<br />
E-mail: anusch-arezki@chimie-paristech.fr<br />
Turmeric and especially its main and active constituent curcumin have traditionally been used as a<br />
food preservative, as well as a natural remedy in Ayurvedic and Chinese medicine for centuries. But it<br />
is only within the past few years that modern research has focused on curcumin's biological properties<br />
(antioxidant, anti-inflammatory...) and in particular on the extraordinary actions <strong>of</strong> curcumin in<br />
preventing and fighting cancer. Curcumin has at least a dozen separate ways <strong>of</strong> interfering with cancer<br />
progression, but at the same time preserving normal cells. 1<br />
In our laboratory, we chose different curcuminoids as starting materials to lead to a novel class <strong>of</strong><br />
bioorganometallic anticancer agents by covalently grafting different organometallic ligands to the<br />
curcuminoid skeleton. The synthesis <strong>of</strong> the new ferrocenyl molecules was primarily done by<br />
substitution <strong>of</strong> the central carbon <strong>of</strong> the curcuminoids, 2 which has shown to have a crucial influence on<br />
activity against some cancer cells. 3 The new complexes were tested in vitro on different cancer cell<br />
lines, such as prostate and skin (melanoma), and showed promising cytotoxic effects on all types. For<br />
some <strong>of</strong> the ferrocenyl-curcuminoid derivatives, enhanced cytotoxic activity was observed compared<br />
to the organic curcuminoid analogues, with up to a 3- and 4-fold improvement on prostate and<br />
melanoma cells, respectively.<br />
MeO<br />
HO<br />
OH O<br />
Curcumin<br />
OMe<br />
OH<br />
25<br />
MeO<br />
R 1<br />
OH O<br />
R 2 R 2<br />
R 1 : H, OH, OMe<br />
R 2 : H, OMe<br />
= organic linker<br />
Curcumin and ferrocenyl derivatives <strong>of</strong> several curcuminoids<br />
Due to encouraging results in vitro, the National Institute <strong>of</strong> Health <strong>of</strong> the United States is currently<br />
screening, in collaboration with the National Cancer Institute, one selected ferrocenyl curcuminoid on<br />
60 different cancer cell lines (colon, lung, central nervous system,…). Primary single dose testing<br />
revealed a particular selectivity <strong>of</strong> the compound for certain types <strong>of</strong> cancer in vitro, which has led to<br />
more detailed investigations, presently ongoing.<br />
Acknowledgement to the Gottlieb-Daimler and Carl-Benz Foundation (Germany) and the Association<br />
pour la Recherche sur le Cancer (ARC) (France) for PhD funding.<br />
References<br />
1. A. Goel, A. B. Kunnumakkara, B. B. Aggarwal, Biochem. Pharmacol. 2008, 75, 787-809.<br />
2. A. Arezki, E. Brulé, G. Jaouen, Organometallics 2009, 28, 1606-1609.<br />
3. L. Lin, Q. Shi, A. K. Nyarko, K. F. Bastow et al. J. Med. Chem. 2006, 49, 3963-3972.<br />
4. P. Anand, A. B. Kunnumakkara, R. A. Newman, B. B. Aggarwal, Mol. Pharm. 2007, 4, 804-818.<br />
Fe<br />
OMe<br />
R 1
OP-10<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis, characterization and antiproliferative activity <strong>of</strong> a series <strong>of</strong> Pt(IV)<br />
complexes: a QSAR approach to their cytotoxicity<br />
Domenico Osella, a Paola Gramatica, b Ester Papa, b Mara Luini, b Elena Monti, b Marzia B. Gariboldi, b<br />
Mauro Ravera, a Elisabetta Gabano, a and Luca Gaviglio a<br />
a University <strong>of</strong> Piemonte Orientale “A. Avogadro”, Department <strong>of</strong> Environmental and Life Sciences,<br />
Viale Michel 11, 15121, Alessandria, Italy. b Department <strong>of</strong> Structural and Functional Biology,<br />
University <strong>of</strong> Insubria, Via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. E-mail:<br />
domenico.osella@mfn.unipmn.it<br />
Octahedral Pt(IV) complexes are usually supposed to behave as antitumor pro-drugs: most <strong>of</strong> them can<br />
be reduced by the hypoxic environment <strong>of</strong> the tumour tissue to square planar Pt(II) via a two electron<br />
reduction and loss <strong>of</strong> axial ligands. Both axial and equatorial ligands play an important role in setting<br />
the redox potential into the biological window and modulating the lipophilicity <strong>of</strong> Pt(IV) complexes,<br />
whereas the two carrier groups (N-based) determine the antiproliferative potency <strong>of</strong> the drug.<br />
A large series <strong>of</strong> Pt(IV) complexes containing different ligands was synthesized, characterized<br />
and tested for in vitro antitumor activity against ovarian carcinoma, A2780, and colon<br />
adenocarcinoma, HCT116, cell lines.<br />
A quantitative structure-activity relationship (QSAR) analysis was performed on this series <strong>of</strong> Pt(IV)<br />
complexes to find a relationship among cytotoxicity (IC50), reduction peak potential (Ep), partition<br />
coefficient (log Po/w) and theoretical molecular descriptors. The whole set <strong>of</strong> descriptors was used as<br />
an input set for modeling, in order to identify different structural features <strong>of</strong> Pt(IV) complexes related<br />
to the in vitro cytotoxicity.<br />
In the resulting models, a lipophilic descriptor (i.e log Po/w or number <strong>of</strong> secondary sp 3 carbon atoms,<br />
nCs) plus an electronic descriptor (Ep, number <strong>of</strong> oxygen atoms, nO, or total polar surface area,<br />
TPSA(NO)) is necessary for the optimal modeling. This results support the general findings that the<br />
biological behavior <strong>of</strong> Pt(IV) complexes is related to their uptake, reduction, and structure <strong>of</strong> the<br />
corresponding Pt(II) metabolites.<br />
26
OP-11<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Influence <strong>of</strong> the Rhenium-Platinum antitumor system on tumor growth and blood<br />
antioxidant state<br />
Nataliia I. Shtemenko, a Alexander V. Shtemenko b<br />
a Department <strong>of</strong> Biophysics and Biochemistry, Dnipropetrovs’k National University, 72 Gagarin<br />
avenue, Dnipropetrovs’k 49010, Ukraine, b Department <strong>of</strong> Inorganic Chemistry, Ukrainian State<br />
Chemical Technological University, Gagarin avenue 8, Dnipropetrovs’k 49005, Ukraine. E-mail:<br />
ashtemenko@yahoo.com<br />
The novel antitumor system including cluster rhenium compounds and cisplatin (Re-Pt 4:1 system)<br />
has been recently presented 1 that was effective in the model <strong>of</strong> rat’s specific Guerink carcinoma T8<br />
and in the majority <strong>of</strong> experiments led to disappearance <strong>of</strong> cancer cells. The approach to circumvent<br />
such drawbacks <strong>of</strong> the drugs on the base <strong>of</strong> heavy metal compounds as dose-limiting toxicities<br />
(nephro-, hepato-, neurotoxicity, etc.) by encapsulation <strong>of</strong> the drug into a nanoparticle prevents byside<br />
interactions is a very promising strategy in medicine 2 . Oxidative stress-induced activation <strong>of</strong><br />
NADPH oxidase and peroxisome proliferators-activated receptors, alterations <strong>of</strong> redox state <strong>of</strong><br />
binding proteins, DNA mutations and induction <strong>of</strong> early response genes and hematopoietic activation,<br />
etc. seem to be common elements in the induction <strong>of</strong> hyperplasia, neoplasia, cancer metastasis, and<br />
angiogenesis. In the present work we show application <strong>of</strong> different nano-preparations <strong>of</strong> 20 – 100 nm<br />
size, nanoliposomes and solid nanoparticles loaded with Re-Pt system or with its components in<br />
different ratios in the model <strong>of</strong> tumor growth. The cluster rhenium compounds dichlorotetra-�isobutiratodirhenium(III)<br />
[Re2(i-C3H7CO2)4Cl2] (Re1) and cis-Re2(C10H15COO)2Cl4·2(CH3)2SO (Re2)<br />
tetrachlorodi-µ-adamantylcarboxylatodirhenium(III) with dimethyl sulfoxide as axial ligands were<br />
the matter <strong>of</strong> concern. Parameters <strong>of</strong> oxidative stress in blood <strong>of</strong> experimental animals were<br />
measured. Intensity <strong>of</strong> peroxide oxidation process (POL), activity <strong>of</strong> catalase (C) and superoxide<br />
dismutase (SOD) in plasma and red blood cells were very sensitive to tumor growth and to its<br />
prevention by the system. Introduction <strong>of</strong> the Re-Pt system in nanoliposomes and nanoparticles did<br />
not influence on the inhibition <strong>of</strong> tumor growth, except experiments, where quantity <strong>of</strong> cisplatin in<br />
capsules were lower (1:8). The lowering <strong>of</strong> the size <strong>of</strong> the introduced liposomes and particles did not<br />
influence on the intensity <strong>of</strong> POL: concentration <strong>of</strong> malonic dialdehyde was not changed. Activities<br />
<strong>of</strong> SOD and C in plasma and erythrocytes were higher, especially in experiments with solid<br />
nanoparticles (in 1.8 times in comparison with application <strong>of</strong> ordinary liposomes). This activation <strong>of</strong><br />
the antioxidant enzymes was independent from the size <strong>of</strong> the tumor and remained on the high level<br />
even in those experiments, where ratio <strong>of</strong> introduced Rhenium compound : cisplatin was 1 : 8. In this<br />
work we show also that influence <strong>of</strong> rhenium compounds on the enzymes activity is dependent from<br />
the structure <strong>of</strong> organic radical in the investigated rhenium substance. Encapsulation <strong>of</strong> the rhenium<br />
substances (first component) into lipid coating is effective as in form <strong>of</strong> liposomes, as in form <strong>of</strong><br />
nanoparticles; the Re-Pt system is effective in the form <strong>of</strong> nanoliposomes with mixed composition<br />
inside (encapsulation <strong>of</strong> both components) that opens great opportunities to use medicines with<br />
different properties and in ratio <strong>of</strong> personal inquire in one preparation. Elaboration <strong>of</strong> solid<br />
nanoparticles formulations <strong>of</strong> the Re-Pt requires additional investigations as on this stage <strong>of</strong><br />
development <strong>of</strong> the idea it is clear that only one component <strong>of</strong> the system may be effectively included<br />
into solid lipid coating. Encapsulation <strong>of</strong> both components is promising, but requires additional<br />
procedures warranting prevention <strong>of</strong> the interactions between cisPt and rhenium compounds.<br />
Encapsulation <strong>of</strong> the Re-Pt antitumor system in nanoparticles and nanoliposomes resulted in active<br />
antyhemolytic properties <strong>of</strong> the systems and activated the specific antioxidant defence.<br />
References<br />
1. (a) N. Shtemenko, P. Collery, A. Shtemenko. Anticancer Res. 2007, 27, 2487-2492. (b) A.<br />
Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, et al. Dalton Trans. 2009, 26, 5132 - 5136.<br />
2. (a) C. Medina, M.J Santos-Martinez, A. Radomski. British Journal <strong>of</strong> Pharmacology, 2007, 150,<br />
552-558. (b) K. N. J. Burger, R.W. H. M. Staffhorst. Nat. Med., 2002, 8, 81-84.<br />
27
OP-12<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
The [CpM(CO)3] - Moiety (M = Mn, Tc, Re) as Phenyl Ring analog – a Promising<br />
Strategy Towards New Drugs and Radiopharmaceuticals<br />
D. Can, H.P. N'Dongo, P. Schmutz and R. Alberto*<br />
University <strong>of</strong> Zurich, Faculty <strong>of</strong> Inorganic Chemistry, Winterthurerstrasse 190, 8057 Zurich,<br />
Switzerland.<br />
E-mail: daniel.can@aci.uzh.ch<br />
Structural changes imposed on proteins or nucleic acids by metal cations such as Ca 2+ or Zn 2+ are<br />
essential for the initiation <strong>of</strong> biological processes. Organometallic complexes are comparably rare as<br />
structural recognition site in receptors, whereas exactly this is how most organic molecules and drugs<br />
tend to work 1 .<br />
As early as 1979 Hanzlik et al. studied the interaction <strong>of</strong> �-Ferrocenylalanine with phenylalanine<br />
hydroxylase and phenylalanine decarboxylase and showed that the ferrocene derivative behaved like<br />
phenylalanine analogues 2 . Ongoing investigations by Jaouen et al. showed years later, that substitution<br />
<strong>of</strong> a phenyl ring in tamoxifen by ferrocene similarly kept the biological activity <strong>of</strong> the lead compound<br />
intact 3 .<br />
As 99m Tc is nowadays in the focus <strong>of</strong> the development <strong>of</strong> radiotracers, introducing group 7 transition<br />
metals as [CpM(CO)3] into this analogy opens new directions not only towards new drugs but also<br />
towards very promising radiopharmaceuticals.<br />
O<br />
N<br />
H<br />
Following this strategy we will present the analogy <strong>of</strong> different classes <strong>of</strong> bioactive compounds<br />
containing [CpRe(CO)3]: sulphonamides acting as carbonic anhydrase inhibitors with high binding<br />
affinities 5 , histone deacetylase inhibitors, amino acids transported by the LAT1 transporter and<br />
melanoma imaging agents with melanin afiinity.<br />
Herein we describe the synthesis and characterization <strong>of</strong> "cold" Re-compounds as surrogates to well<br />
known pharmaceuticals and discuss their analogy. For the "hot" molecules, we followed a general<br />
aqueous approach towards 99m Tc(CO)3 labeled � 5 -Cp derivatives from their dimeric Cp species via<br />
metal mediated retro-Diels-Alder reaction 4 and show that the conditions used can be applied to a<br />
variety <strong>of</strong> functional groups.<br />
References<br />
N<br />
OC<br />
Re<br />
O<br />
CO<br />
CO<br />
N<br />
H<br />
N<br />
1. S. J. Lippard, J. M. Berg, Principles <strong>of</strong> Bioinorganic Chemistry, University Science <strong>Book</strong>s, Mill<br />
Valley, CA, 1994<br />
2. R. P. Hanzlik, P. Soine, W. H. Soine, J. Med. Chem., 1979, 22, 424-428<br />
3. G. Jaouen, S. Top, A. Vessière, Bioorganometallics, Wiley-VCH, Weinheim, 2006, p. 65<br />
4. Y. Liu, B. Spingler, P. Schmutz et al, J. Am. Chem. Soc., 2008, 130, 1554-1555<br />
5. C. T. Supuran, Nature, 2008, 7, 168-181<br />
28
OP-13<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Ferrocenyl Flavonoids: Synthesis and Antiproliferative Effects<br />
Elizabeth A. Hillard, a Jean-Philippe Monserrat, a Guy Chabot, b Louis Hamon, c and Gérard Jaouen c<br />
a Chimie ParisTech (Ecole Nationale Supérieure de Chimie de Paris), Laboratoire Charles Friedel,<br />
UMR CNRS 7223, 11 rue Pierre et Marie Curie, 75231 Paris cedex 05, France. b Chimie ParisTech<br />
(Ecole Nationale Supérieure de Chimie de Paris), Département Friedel; Université Paris Descartes,<br />
Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Pharmacologie Chimique,<br />
Génétique et Imagerie (CNRS UMR 8151- INSERM U 1022), 4 avenue de l’Observatoire, 75006<br />
Paris, France. c Institut Parisien de Chimie Moléculaire, UMR CNRS 7201, Université Pierre et Marie<br />
Curie, CC47, 4 Place Jussieu, 75252 Paris Cedex 05, France.<br />
Flavonoids, such as flavanones and flavones, are ubiquitous plant-based polyphenols. Their<br />
importance in health was first reported in 1936, 1 and numerous benefits have been reported for various<br />
conditions including cancer, cardio-vascular diseases, asthma, and viral infections Several pathways<br />
for chemoprevention have been elucidated, particularly protective antioxidant properties. However,<br />
some flavonoids, such as quercetin, are also known to act as prooxidants because they can be<br />
metabolized to o-quinones and quinone methides that subsequently produce ROS, which have been<br />
proposed as a way to stimulate apoptosis in cancer cells. 2 Because <strong>of</strong> the dual antioxidant/prooxidant<br />
actions <strong>of</strong> flavonoids, we therefore became interested in modifying these compounds with redoxactive<br />
ferrocene and screening them against cancer cells.<br />
O<br />
chalcone<br />
O<br />
O<br />
aurone<br />
O<br />
O<br />
flavone<br />
O<br />
O<br />
flavanone<br />
29<br />
HO<br />
O<br />
O<br />
OH<br />
OH O<br />
quercetin<br />
Fe<br />
OH<br />
ferrocenyl chalcone<br />
It is remarkable, that, although ferrocenyl chalcones have been widely studied for over 50 years, 3 there<br />
is, to our knowledge, no report <strong>of</strong> the corresponding ferrocenyl flavones or flavanones. We have<br />
recently discovered a novel reaction which gives easy access to the first ferrocenyl flavones, via a<br />
ferricenium intermediate. 4 The ferrocenyl flavones, furthermore, isomerize under basic conditions to<br />
give access to a class <strong>of</strong> ferrocenyl aurones. We have also been able to graft ferrocene to the flavanone<br />
skeleton via an acid-catalyzed condensation reaction. The synthesis <strong>of</strong> these new compounds and<br />
preliminary in vitro antiproliferative results will be presented.<br />
References<br />
1. S. Rusznyak, A. Szent-Gyorgyi, Nature 1936, 138, 27.<br />
2. H. Pelicano, D. Carney, P. Huang, Drug Resist. Update 2004, 7, 97-110.<br />
3. C. R. Hauser, J. K. Lindsay, J. Org. Chem. 1957, 22, 482-485.<br />
4. J-P Monserrat, G. G. Chabot, L. Hamon, L. Quentin, D. Scherman, G. Jaouen, E. A. Hillard, Chem.<br />
Commun., 2010, in press.<br />
OH
OP-14<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Preclinical Development <strong>of</strong> Metal-Based Compounds:<br />
Set Up <strong>of</strong> a Plastic Mouse Model<br />
A. Bergamo, a V. Vidimar, a D. Gallo, a G. Chiaruttini, a and G. Sava *a,b<br />
a Callerio Foundation Onlus, via A. Fleming 22-31, 34127, Trieste, Italy. b University <strong>of</strong> Trieste,<br />
Faculty <strong>of</strong> Pharmacy, Department <strong>of</strong> Life Sciences, via L. Giorgieri 7, 34127, Trieste, Italy.<br />
E-mail: a.bergamor@callerio.org<br />
Nowadays the main goal <strong>of</strong> solid tumour chemotherapy is the treatment <strong>of</strong> metastases, primary cause<br />
<strong>of</strong> death in most <strong>of</strong> the cancerous diseases. 1,2 The anti-cancer drugs currently used in the clinic have<br />
only limited success: to achieve effective therapeutic approaches, selectivity should be improved and<br />
the new drugs should be designed to hit targets specific <strong>of</strong> metastatic cells. This work arises from the<br />
need to renew the screening’s system <strong>of</strong> the anti-tumour drugs employed for the treatment <strong>of</strong> solid<br />
tumour metastases, a field still lacking <strong>of</strong> a simple, handy, and easily controllable in vitro models to be<br />
used for evaluating and measuring specifically the potential anti-metastatic activity <strong>of</strong> active<br />
principles. This project would contribute to match this unmet need through a biotechnological device,<br />
born from the collaboration between the Callerio Foundation Onlus and the Department <strong>of</strong> Materials<br />
and Natural Resources <strong>of</strong> the University <strong>of</strong> Trieste, able to mimic some physio-pathological<br />
conditions, typical <strong>of</strong> the metastatic process. This system constitutes a “bridge” between the “classic in<br />
vitro study” and the “classic in vivo study”; in the device the tumour cells can migrate, through a<br />
microcircuit, from a well representing the primary tumour, to a well representing the target organ <strong>of</strong><br />
metastases. The model we wish to validate is the metastasis from colo-rectal cancer, a great social<br />
impact disease in western countries, which prognosis and life time expectancy are mainly determined<br />
from the progression <strong>of</strong> the secondary tumours to the liver, and not from the primary tumour itself. 3 In<br />
order to recreate a metastatic colorectal tumour model, human colon adenocarcinoma HT-29 are<br />
chosen as invasive and malignant cells, human non-malignant colon epithelial cell line HCEC is used<br />
to mimic a normal colonic epithelial tissue, and immortalized human hepatocytes IHH to mimic the<br />
healthy hepatic tissue. The first issue <strong>of</strong> this study is to set up the optimal environment to simulate the<br />
physio-pathological process <strong>of</strong> metastatization and liver invasion through the development <strong>of</strong> a coculture<br />
system in which the three cell lines grow together. In parallel the effects <strong>of</strong> three reference<br />
drugs for the treatment <strong>of</strong> colorectal cancer (irinotecan, 5-fluorouracil and oxaliplatin), 4 are studied in<br />
the same system. The results <strong>of</strong> theses series <strong>of</strong> experiments, propaedeutic to the extension <strong>of</strong> the coculture<br />
model in the biotechnological device, will be presented.<br />
Acknowledgements<br />
This work was carried out within the framework <strong>of</strong> COST Action D39.<br />
References<br />
1. P. Cairns, Nat. Rev. Cancer 2006, 7, 531-543.<br />
2. http://www.nlm.nih.gov/medlineplus/cancer.html<br />
3. J.M. McLoughlin, E.H. Jensen, M. Malafa, Cancer Control 2006, 13, 32-41.<br />
4. M. Koopman, C.J. Punt, Eur. J. Cancer 2009, 45 Suppl. 1, 50-56.<br />
30
OP-15<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Arjunolic acid: The First Renewable-Nano Triterpenoid in Bioorganometallics<br />
Braja G. Bag, *a Partha P. Dey, a Rakhi Majumdar, a Shaishab K. Dinda, a and Shib S. Das a<br />
a Vidyasagar University, Department <strong>of</strong> Chemistry and Chemical Technolgy, Midnapore 721 102,<br />
India. E-mail: bgopalbag@yahoo.co.in<br />
Utilization <strong>of</strong> plant metabolites as renewables in various facets <strong>of</strong> bioorganic, bioorganometallic and<br />
organic chemistry research has become significant in recent years because such investigations aim at<br />
the development <strong>of</strong> sustainable chemical feedstocks. 1 Ferrocene moiety has been utilized in the design<br />
<strong>of</strong> peptide analogues, redox-responsive gelators, enhanced antimalarial drugs, etc. 2 However, inspite<br />
<strong>of</strong> the abundance <strong>of</strong> a large variety <strong>of</strong> triterpenoids, having nano-metric dimensions with varied<br />
lengths <strong>of</strong> rigid and flexible parts, 3 according to our knowledge, no ferroceno-triterpenoid has been<br />
reorted so far. Availability <strong>of</strong> arjunolic acid 1, extractable from the heavy wood <strong>of</strong> Terminalia Arjuna<br />
became the first choice for such investigations. 4<br />
Figure 1: (a) A redox-responsive organogel from ferrocenylidene arjunolic acid 2, (b) SEM image<br />
reveals self-assembled fibrillar network having fibers <strong>of</strong> nano-meter diameters, (c) TEM image <strong>of</strong> CdS<br />
nano-particles templated by self-assembled nano-fibers from arjunolic acid derivatives.<br />
The ferrocenylidene arjunolic acid 2, synthesized in one-step from arjunolic acid 1 and formylferrocene<br />
in high yield, self-assembled in various organic media to form s<strong>of</strong>t solid-like materials<br />
(Figure 1a, Table 1). Scanning electron micrographs <strong>of</strong> the s<strong>of</strong>t-solids showed fibrillar net-work<br />
structures having fibers <strong>of</strong> nano-metric dimensions (Figure 1b).<br />
Solvent State Conc.<br />
(g/100 mL)<br />
Toluene Gel 10<br />
o-Xylene Gel 9<br />
m-Xylene Gel 10<br />
p-Xylene Gel 10<br />
Table 1: Gelation Test Results <strong>of</strong> 2<br />
Detailed investigations on the self-assembly <strong>of</strong> arjunolic acid<br />
or its derivatives revealed that most <strong>of</strong> these derivatives selfassemble<br />
in aqueous or organic liquids leading to the<br />
formation <strong>of</strong> fibers <strong>of</strong> nano-metric diameters. 5,6 When H2S<br />
gas was diffused through a gel <strong>of</strong> an arjunolic acid derivative<br />
in ethanol saturated with Cd(OAc)2, then porous CdS<br />
nanoparticles templated by the self-assembled nano-fibers were formed (Figure 1c). Recent results<br />
from our laboratory will be presented describing various approaches towards bioorganometallic<br />
chemistry for the utilization triterpenoids.<br />
Acknowledgements: Financial assistance from AvH foundation Germany and DRDO India are<br />
gratefully acknowledged.<br />
References<br />
1. B.G. Bag, S.K. Dinda, Pure Appl. Chem. 2007, 79, 2031.<br />
2. (a) D.R. van Staveren , N. Metzler-Nolte, Chem. Rev. 2004, 104, 5931; (b) F. Dubar, G. Anquetin,<br />
B. Pradines, D. Dive, J. Khalife, C. Biot, J. Med. Chem. 2009, 52, 7954.<br />
3. B.G. Bag, C. Garai, R. Majumdar, unpublished results.<br />
4. B.G. Bag, P.P. Dey, S.K. Dinda, W.S. Sheldrick, I.M. Oppel, Beil. J. Org. Chem. 2008, 4, 24.<br />
5. B.G. Bag, S.K. Dinda, P.P. Dey, A.V. Mallia, R.G. Weiss, Langmuir 2009, 25, 8663.<br />
6. B.G. Bag, G.C. Maity, S.K. Dinda, Org. Lett. 2006, 8, 5457.<br />
31
OP-16<br />
Ru<br />
N<br />
Cl Cl<br />
N<br />
Ru<br />
Cl Cl<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Anticancer Activity <strong>of</strong> Multinuclear Ruthenium-Arene Complexes Coordinated<br />
to Dendritic Poly(propyleneimine) Scaffolds<br />
R<br />
R<br />
O<br />
N<br />
R<br />
Cl<br />
Ru Cl<br />
N<br />
N<br />
Ru Cl<br />
O<br />
Cl<br />
N<br />
R<br />
N<br />
R<br />
N<br />
Cl<br />
Cl<br />
N<br />
Ru<br />
N<br />
Cl<br />
Cl<br />
R<br />
Gregory S. Smith *a and P. Govender a<br />
a University <strong>of</strong> Cape Town, Faculty <strong>of</strong> Science, Department <strong>of</strong> Chemistry, 7701, Cape Town,<br />
South Africa. E-mail: Gregory.Smith@uct.ac.za<br />
Dendrimers have found potential as molecular tools in biological applications, especially as nanocarriers,<br />
diagnostic agents and as chemotherapeutics. 1-4 An advantage <strong>of</strong> using dendrimers is their<br />
multivalency, which leads to increased interaction between a dendrimer-drug conjugate and a target<br />
bearing multiple receptors, further improving the selectivity to cancer cells. Large macromolecules,<br />
like dendrimers, can also specifically target tumours by exploiting the ‘enhanced permeability and<br />
retention’ (EPR) effect, in which macromolecules can accumulate at the tumour site due to an increase<br />
in blood vessel permeability within diseased tissues compared to normal tissues. 5<br />
In this presentation, we report a series <strong>of</strong> multinuclear ruthenium-arene complexes based on first- and<br />
second-generation poly(propyleneimine) dendritic scaffolds (Fig. 1). Their cytotoxicity against the<br />
A2780 human ovarian cancer cell line will also be discussed.<br />
O<br />
N<br />
Ru<br />
N<br />
O<br />
N<br />
Cl Cl<br />
Ru<br />
N<br />
Cl Cl<br />
N<br />
Ru<br />
N<br />
32<br />
R<br />
R<br />
Cl Cl<br />
N Ru<br />
N<br />
R<br />
R<br />
N<br />
N Ru<br />
Cl Cl<br />
=<br />
N<br />
R<br />
R<br />
N<br />
Ru N<br />
N<br />
Cl Cl<br />
R<br />
N<br />
Ru N<br />
Cl Cl<br />
Fig. 1: Ruthenium-arene metallodendrimers based on a poly(propyleneimine) scaffold.<br />
References<br />
1. (a) U. Boas, J. B. Christensen, P. M. H. Heegaard: Dendrimers in Medicine and Biotechnology:<br />
New Molecular Tools, RSC Publishing (2006). (b) C. C. Lee, J. A. MacKay, J. M. J. Fréchet, F. C.<br />
Szoka, Nature Biotech. 2005, 23, 1517-1526.<br />
2. F. Aulenta, W. Hayes, S. Rannard, Eur. Polym. J. 2003, 39, 1741-1771 and references therein.<br />
3. J. B. Wolinsky, M. W. Grinstaff, Adv. Drug Deliv. Rev. 2008, 60, 1037-1055 and references therein.<br />
4. (a) A. Agarwal, S. Saraf, A. Asthana, U. Gupta, V. Gajbhiye, N. K. Jain, Int. J. Pharm. 2008, 350,<br />
3-13. (b) E. R. Gillies, J. M. J. Fréchet, Drug Discov. Today 2005, 10, 35- 43.<br />
5. D.F. Baban, L.W. Seymour, Adv. Drug Delivery Rev. 1998, 34, 109-119.<br />
4+<br />
O<br />
O H
OP-17<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Bi<strong>of</strong>unctionalization <strong>of</strong> a Generic Collagenous Triple Helix<br />
with the Integrin α2β1 Binding Site<br />
Stephan Niland, a Christoph Westerhausen, b Thilo Bracht, a Alletta Schmidt-Hederich, a Désirée Freund, a<br />
Stephan W. Schneider, c Matthias F. Schneider, d and Johannes A. Eble a<br />
a Goethe University Frankfurt, University Hospital, Center for Molecular Medicine, Department <strong>of</strong><br />
Vascular Matrix Biology, Excellence Cluster Cardio-Pulmonary System, Theodor-Stern-Kai 7, 60590<br />
Frankfurt/Main, Germany. b University <strong>of</strong> Augsburg, Faculty <strong>of</strong> Mathematics and Natural Sciences,<br />
Department <strong>of</strong> Experimental Physics I, Universitaetsstrasse 1, 86135 Augsburg, Germany.<br />
c Heidelberg University, Mannheim University Hospital, Department <strong>of</strong> Experimental Dermatology,<br />
Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. d Boston University, Department <strong>of</strong><br />
Mechanical Engineering, Biological Physics, 590 Commonwealth Avenue, MA 02215, Boston, USA.<br />
E-mail: niland@med.uni-frankfurt.de<br />
Integrin ���� is a major collagen-binding receptor and widely distributed on different tissues. It plays<br />
essential roles in elementary cell functions such as adhesion morphology, migration, proliferation,<br />
gene activation, and differentiation. Therefore, it regulates various (patho)physiological situations,<br />
such as thrombosis, tumor infiltration, and metastasis. It plays an essential role in liver micrometastasis<br />
formation. 1<br />
Integrin ���� recognizes triple-helical collagens, whose quaternary structure consists <strong>of</strong> three lefthanded<br />
polyproline-like chains supercoiled in a right-handed helix about a common axis, yielding a<br />
characteristic triple helical coiled-coil, which provides the framework for the integrin ����<br />
recognition motif (GFOGER)3. Due to these structural requirements, chemical imitation <strong>of</strong> triplehelical<br />
���� integrin recognition site is still a demanding feat. The aim <strong>of</strong> this study was to generate a<br />
recombinant mini-collagen with a single binding site for integrin ���� and to use this collagenmimetic<br />
to characterize the role <strong>of</strong> integrin �����at both molecular and cellular level. Force<br />
spectroscopy was used to determine at the molecular level the binding <strong>of</strong> integrin �����to its triplehelical<br />
recognition motif (GFPGER)3. To define and disclose the role <strong>of</strong> integrin �����in cell biology,<br />
an integrin ����-specific and agonistic recombinant mini-collagen was used, as well as the snake<br />
venom-derived highly specific integrin ���� antagonist rhodocetin. 2<br />
The strong binding <strong>of</strong> integrin �����to its ligand underlines its importance as cellular<br />
mechanotransducer. On a substratum bi<strong>of</strong>unctionalized with integrin binding mini-collagen FC3, cells<br />
behave similar as on collagen I in terms <strong>of</strong> adhesion, spreading and migration. As recombinant minicollagen<br />
FC3 is unhydroxylated, and thus highly specific for integrin ����, this integrin is fully<br />
sufficient to induce this behaviour, while the participation <strong>of</strong> other collagen receptors is at most<br />
ancillary under this conditions. 3<br />
References<br />
1. F. Rosenow, R. Ossig, D. Thormeyer, P. Gasmann, K. Schlüter, G. Brunner, J. Haier, J.A. Eble,<br />
Neoplasia 2008, 10, 168-176.<br />
2. J.A. Eble, S. Niland, T. Bracht, M. Mormann, J. Peter-Katalinic, G. Pohlentz, J. Stetefeld, FASEB J.<br />
2009, 23, 2917-2927l.<br />
3. S. Niland, C. Westerhausen, S.W. Schneider, M.F. Schneider, J.A. Eble, submitted to Biochem J.,<br />
Bio-functionalization <strong>of</strong> a generic collagenous triple helix with the ���� integrin binding site allows<br />
molecular force measurements.<br />
33
OP-18<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Organometallic Anticancer Drugs: From Simple Structures to Rational Drug<br />
Design Based on a Mechanistic Approach<br />
Paul J. Dyson<br />
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH<br />
1015 Lausanne, Switzerland. E-mail: paul.dyson@epfl.ch<br />
Organometallic chemistry has a strong tradition in the rational synthesis <strong>of</strong> compounds with<br />
specific functions, whatever the nature <strong>of</strong> the required function. But how is rational synthesis<br />
<strong>of</strong> organometallic pharmaceutical compounds currently achieved? The first part <strong>of</strong> the<br />
presentation will discuss the relevant issues by considering examples from the literature as<br />
well as from my own laboratory. 1 The presentation then continue with a focus on<br />
organometallic compounds based on the ruthenium(II)-arene unit developed in my laboratory<br />
that exhibit excellent in vivo anticancer activity and overcome certain limitations <strong>of</strong> presently<br />
used drugs. 2 The elements <strong>of</strong> the drug design process and the relevant known drug targets will<br />
be discussed. It will be shown that ligands with specific functions can be introduced into the<br />
drug structure in order to endow the compound with specific properties allowing the metal to<br />
perform a more classical role.<br />
One <strong>of</strong> the overriding features <strong>of</strong> the compounds discussed during the presentation is that<br />
targets other than DNA, i.e. enzyme and protein targets, are crucial for metal drugs, especially<br />
for the ruthenium(II)-arene drugs emanating from my laboratory, and evidence to support this<br />
notion will be provided.<br />
References<br />
1. C. G. Hartinger, P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391–401.<br />
2. W. H. Ang, L. J. Parker, A. De Luca, L. Juillerat-Jeanneret, C. J. Morton, M. Lo Bello, M. W.<br />
Parker, P. J. Dyson, Angew. Chem. Int. Ed., 2009, 48, 3854–3857.<br />
34
OP-19<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Biological Activity <strong>of</strong> Gold and Silver Bis(Phosphino)Hydrazine Complexes<br />
Frederik H. Kriel, *a and Judy Coates a<br />
a AuTEK Biomed, Mintek, Private Bag X3015, Randburg, 2125, South Africa. E-mail:<br />
erikk@mintek.co.za<br />
The anti-tumour potential <strong>of</strong> gold(I) phosphine complexes was first identified at the time when<br />
auran<strong>of</strong>in was shown to kill tumour cells in culture. This sparked the interest <strong>of</strong> Berners-Price et al. 1,2<br />
and led to the development <strong>of</strong> the bis-chelated gold(I) phosphine anti-tumour compound<br />
[Au(bis(diphenylphospino) ethane)2]Cl and later [Au(bis(di-2-pyridalphosphino)ethane)2]Cl. Clinical<br />
development <strong>of</strong> delocalised lipophilic cations has been hindered by severe toxicity, but several classes<br />
<strong>of</strong> these compounds have demonstrated a relationship between anti-tumour selectivity and lipophilichydrophilic<br />
balance. 1,2<br />
Following on the work done by Berners-Price et al.; a series <strong>of</strong> hydrazine-bridged ligands have been<br />
synthesised to modulate the lipophilic-hydrophilic balance <strong>of</strong> the resulting complexes. 3,4 These include<br />
the phenyl, p-methoxyphenyl and p-dimethylaminophenyl derivatives <strong>of</strong> the bis-phosphine. The main<br />
focus <strong>of</strong> the research is on the group 11 transition metals and corresponding gold and silver phosphine<br />
complexes. Here we describe the anti-tumour activity and NCI 60 cell line pr<strong>of</strong>ile <strong>of</strong> these compounds.<br />
Acknowledgements<br />
The authors would like to thank the University <strong>of</strong> Pretoria for use <strong>of</strong> their facilities. Pr<strong>of</strong>. Connie<br />
Medlen, Dr. Gisella Joone and Mrs. Margo Nell for guidance. Pr<strong>of</strong>. Denver Hendricks at the<br />
University <strong>of</strong> Cape Town for reviewing the work. National Research Fund for the funding for training.<br />
The NCI for the 60 cell line screen. AuTEK Biomed (Mintek and Harmony) for permission to publish<br />
the results and financial support.<br />
References<br />
1 S. J. Berners-Price, Chem. Aust., 2004, 71, 10.<br />
2 S. J. Berners-Price, P. J. Sadler, Struc. and Bond., 1988, 70, 27.<br />
3 V. S. Reddy, K. V. Katti, Inorg. Chem., 1994, 33, 2695.<br />
4 F. H. Kriel, M. Layh, H. M. Marques, J Coates, Ph.D. Thesis, University <strong>of</strong> the Witwatersrand,<br />
2007.<br />
35
OP-20<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
DNA and Protein Binding, Cleavage and Anticancer Activity <strong>of</strong> Organometallic<br />
(M = Ru(II), Rh(III) and Ir(III)) Arene Complexes<br />
R. Loganathan, a S. Ramakrishnan, a P. Kumar, c D. S. Pandey, c A. Riyasdeen, b<br />
M. A. Akbarsha, b and Mallayan Palaniandavar* a<br />
a Centre for Bioinorganic Chemistry, School <strong>of</strong> Chemistry, b Department <strong>of</strong> Animal Science,<br />
Bharathidasan University, Tiruchirapalli 620 024, India. c Department <strong>of</strong> Chemistry, Facult <strong>of</strong><br />
Science, Banaras Hindu University, Varanasi 221 005, India.<br />
E-mail: palanim51@yahoo.com<br />
The study <strong>of</strong> organometallic compounds as anticancer agents is receiving much attention now. These<br />
compounds can be tuned by using suitable chelating ligands to facilitate their uptake into the cells or<br />
for selectivity <strong>of</strong> reactions with DNA or proteins. However, the number <strong>of</strong> such studies is very limited.<br />
This is because <strong>of</strong> the low solubility and instability in water and poor uptake by the cells. The<br />
ruthenium complexes NAMI-A and KP1019, which show prominent anticancer activity, are currently<br />
in clinical trials for the treatment <strong>of</strong> metastasis and colorectal cancers, respectively. Very recently, we<br />
have shown that non-covalent interactions <strong>of</strong> certain water soluble Ru(II) complexes 1,2 with DNA<br />
enhances the cytotoxicity against several cancer cell lines. It is noteworthy that a family <strong>of</strong><br />
ruthenium(II)–arene complexes developed by Sadler, and Dyson et al. exhibits high in vitro and in<br />
vivo anticancer activity. The titanocene dichloride has already completed phase II clinical trials and<br />
ferrocifen, which is a ferrocenyl derivative <strong>of</strong> tamoxifen, appears set to enter clinical trials soon. More<br />
recently, increasing interest has been focused on organometallic-arene compounds, which show<br />
excellent antiproliferative properties in vitro and in vivo. In this work a series <strong>of</strong> water soluble<br />
organometallic complexes <strong>of</strong> the type [{Ru(η 6 -arene)(L)Cl}](BF4)2 (arene = benzene; 1 and p-cymene;<br />
2) and [{(η 5 - C10Me5)M(L)Cl}](BF4)2, (M = Rh; 3 and Ir; 4 and L = benzyl-di-pyridin-2-yl-amine) has<br />
been isolated and the structures <strong>of</strong> 3 and 4 have been determined by X-ray crystallography. The<br />
bidentate benzyl-di-pyridin-2-ylamine ligand is designed to provide hydrophobicity. Also, the present<br />
compounds are equipped with a chloride leaving group in order to enable covalent interaction <strong>of</strong> the<br />
complexes with biological targets. Further, the arene ligand provides hydrophobicity thus tuning the<br />
DNA- and protein-binding and DNA- and protein-cleaving properties <strong>of</strong> the complexes. The<br />
interactions <strong>of</strong> these metal complexes with CT DNA have been explored by using absorption,<br />
emission and CD spectroscopy and electrochemical and viscosity measurements. DNA and protein<br />
cleavage reactions have also been studied using agarose and polyacrylamide gel electrophoresis<br />
respectively. The anticancer activities and the mode <strong>of</strong> cell death have also been established. The<br />
results <strong>of</strong> our systematic investigations will be presented and discussed.<br />
References<br />
N3<br />
N2<br />
N1<br />
Cl<br />
Rh<br />
1. V. Rajendiran, M. Murali, E. Suresh, S. Sinha, K. Somasundaram, M. Palaniandavar Dalton Trans.<br />
2008, 148-163.<br />
2. V. Rajendiran, M. Murali, E. Suresh, M. Palaniandavar, V.S. Periasamy, M.A. Akbarsha<br />
Dalton Trans. 2008, 2157-2170.<br />
36<br />
N3<br />
N2<br />
N1<br />
Cl<br />
Ir
OP-21<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Organometallic Pyrone and Pyridone Complexes as Anticancer Agents<br />
Christian G. Hartinger, *a Wolfgang Kandioller, a Muhammad Hanif, a Andrea Kurzwernhart, a<br />
Helena Henke, a Robert Trondl, a Caroline Bartel, a Gerhard Mühlgassner, a Michael A. Jakupec, a<br />
Maria G. Mendoza-Ferri, a Alexey A. Nazarov, a,b Bernhard K. Keppler a<br />
a University <strong>of</strong> Vienna, Institute <strong>of</strong> Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, Austria.<br />
b Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL),<br />
CH-1015 Lausanne, Switzerland. E-mail: christian.hartinger@univie.ac.at<br />
Organometallic compounds have received growing interest as potential chemotherapeutics for the<br />
treatment <strong>of</strong> cancer. Ru(II) compounds bearing ligands such as 1,3,5-triaza-7-phosphaadamantane,<br />
ethylene-1,2-diamine or maltol-derived ligands have shown promising anticancer properties with in<br />
vitro or in vivo anticancer activity comparable to or in some cases superior to cisplatin. 1 Some <strong>of</strong> the<br />
compounds are even active in cisplatin-resistant cell lines, probably due to different modes <strong>of</strong> action,<br />
and potentially provide a means to overcome drug resistance. 2<br />
Organometallic Ru–arene compounds bearing a maltol ligand were shown to be nearly inactive in<br />
vitro. 3 In order to study their biological properties, compounds with different substitution pattern [e.g.<br />
3-hydroxy-2-pyr(id)one vs. 3-hydroxy-4-pyr(id)one] <strong>of</strong> the pyrone-derived ligands were prepared, or<br />
an oxygen donor <strong>of</strong> the chelating moiety was replaced by sulphur. Furthermore, polynuclear<br />
compounds were obtained by linking pyridone moieties via aliphatic chains. The chemical properties<br />
<strong>of</strong> the obtained compounds are very different from that <strong>of</strong> the parent maltolato complex with regard to<br />
stability in aqueous solution, lipophilicity and, depending on the metal centre, reactivity with<br />
biomolecules. For example, reactions with amino acids demonstrate higher stability <strong>of</strong> thiopyrone than<br />
<strong>of</strong> pyrone complexes, which may explain their activity against human tumour cells. In general, the<br />
compounds show affinity to nucleobases, but the polynuclear compounds form extremely rare types <strong>of</strong><br />
DNA and protein adducts and are efficient cross-linkers. 4 Anticancer potencies <strong>of</strong> the arene complexes<br />
are as divergent as their chemical behaviour, from compounds active in the low μM range to inactive<br />
compounds. Based on the chemical and biological data, structure-activity relationships have been<br />
elucidated, and further directions <strong>of</strong> development will be discussed.<br />
References<br />
1. G. Süss-Fink, Dalton Transactions 2010, 1673-1688.<br />
2. (a) W. H Ang, P. J. Dyson, Eur. J. Inorg. Chem. 2006, 4003-4018. (b) A. F. A. Peacock, P. J.<br />
Sadler, Chem. Asian J. 2008, 3, 1890-1899.<br />
3. A. F. A. Peacock, M. Melchart, R. J. Deeth, A. Habtemariam, S. Parsons, P. J. Sadler, Chem. Eur. J.<br />
2007, 13, 2601-2613.<br />
4. O. Nováková, A. A. Nazarov, C. G. Hartinger, B. K. Keppler, V. Brabec, Biochem. Pharmacol.<br />
2009, 77, 364-374.<br />
37
OP-22<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Metalloenzymes in the bacterial life on carbon monoxide:<br />
A view from structural biology<br />
Holger Dobbek,* and Jae-Hun Jeoung<br />
Humboldt-<strong>Universität</strong> zu Berlin, Institute <strong>of</strong> Biology, Structural Biology/Biochemistry, Unter den<br />
Linden 6, 10099, Berlin, Germany. E-mail: holger.dobbek@biologie.hu-berlin.de<br />
The biological conversions <strong>of</strong> small substrates like N2, H2, and CO2 are vital for the biogeochemical<br />
cycle and are typically catalyzed by metalloenzymes with complex iron-sulfur clusters. However, only<br />
little is known about how these metalloclusters activate their substrates.<br />
Carbon monoxide dehydrogenases (CODHases) catalyze the reversible oxidation <strong>of</strong> carbon monoxide<br />
with water, to carbon dioxide, two protons and two electrons. Two principal types <strong>of</strong> CODHases have<br />
been described, which differ in activity, metal composition, amino acid sequence and stability in the<br />
presence <strong>of</strong> oxygen. The Ni, Fe-containing CODHases found in anaerobic microorganisms have a<br />
unique Ni- and Fe-containing metal cluster called cluster C. 1 A Cu- and Mo-containing metal site is<br />
found in CODHases isolated from aerobic microorganisms. 1<br />
We used a crystallographic approach to gain further insights into the reaction mechanism <strong>of</strong> Ni, Fe-<br />
CODHases. Structural analysis <strong>of</strong> CODHII from Carboxydothermus hydrogen<strong>of</strong>ormans in several<br />
different states showed how substrates are activated by cluster C. 2 Water is bound by an<br />
asymmetrically coordinated Fe(II)-ion and carbon dioxide has been shown to act as a bridging ligand<br />
between Ni and the Fe(II)-ion. Amino acids in the direct vicinity <strong>of</strong> the cluster may contribute to<br />
catalysis by fast proton transfers and the stabilization <strong>of</strong> negatively charged intermediates. We further<br />
tested the reactivity <strong>of</strong> cluster C with inhibitors 3 and slow substrates, whose binding mode was<br />
resolved at atomic resolution. The structural analysis <strong>of</strong> ligand binding to cluster C presents a<br />
complementary approach to spectroscopic methods describing the electronic changes <strong>of</strong> cluster C<br />
during catalysis. Both approaches converge to a mechanism in which substrate activation and catalysis<br />
is mediated by a binuclear Ni-Fe sub site <strong>of</strong> cluster C.<br />
References<br />
1. S. W. Ragsdale, Crit. Rev. Biochem. Mol. Biol. 2004, 39, 165-195.<br />
2. J.-H. Jeoung, H. Dobbek, Science 2007, 318, 1461-1464.<br />
3. J.-H. Jeoung, H. Dobbek, J. Am. Chem. Soc. 2009, 131, 9922-9923.<br />
38
OP-23<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Models for the Active Site in [FeFe] Hydrogenase with Silicon-containing Ligands<br />
Ulf-Peter Apfel, a Dennis Troegel, b Yvonne Halpin, c Stefanie Tschierlei, d Ute Uhlemann, d Helmar Görls, a<br />
Michael Schmitt, d Jürgen Popp, d P. Dunne, e M. Venkatesan, e Michael Coey, e,* Manfred Rudolph, a,*<br />
Johannes G. Vos, c,* Reinhold Tacke, b,* Wolfgang Weigand a,*<br />
a Institut für Anorganische und Analytische Chemie, Friedrich-Schiller-<strong>Universität</strong> Jena, August-Bebel-<br />
Straße 2, D-07743 Jena, Germany,wolfgang.weigand@uni-jena.de. b Institut für Anorganische Chemie,<br />
<strong>Universität</strong> Würzburg, Am Hubland, D-97074 Würzburg, Germany. c Solar Energy Conversion SRC,<br />
School <strong>of</strong> Chemical Sciences, Dublin City University, Dublin 9, Ireland. d Institut für Physikalische<br />
Chemie, Friedrich-Schiller-<strong>Universität</strong> Jena, Helmholtzweg 4, D-07743 Jena, Germany. e SFI-Trinity<br />
Nanoscience Laboratory, Physics Department, Trinity College, Dublin 2, Ireland.<br />
A series <strong>of</strong> multifunctional (mercaptomethyl)silanes <strong>of</strong> the general formula type RnSi(CH2SH)4−n (n = 0–2;<br />
R = organyl) was synthesized, starting from the corresponding (chloromethyl)silanes. They were used as<br />
multidentate ligands for the conversion <strong>of</strong> dodecacarbonyltriiron, Fe3(CO)12, into iron carbonyl complexes<br />
in which the deprotonated (mercaptomethyl)silanes act as m-bridging ligands. These complexes can be<br />
regarded as models for the [FeFe] hydrogenase. They were characterized by elemental analyses (C, H, S),<br />
NMR studies ( 1 H, 13 C, 29 Si), and single-crystal X-ray diffraction. Their electrochemical properties were<br />
investigated by cyclic voltammetry to disclose a new mechanism for the formation <strong>of</strong> dihydrogen<br />
catalyzed by these compounds, whereby one sulfur atom was protonated in the catalytic cycle. The<br />
reaction <strong>of</strong> the tridentate ligand MeSi(CH2SH)3 with Fe3(CO)12 yielded a tetranuclear cluster compound. A<br />
detailed investigation by X-ray diffraction, electrochemical, Raman, Mössbauer, and susceptibility<br />
techniques indicates that for this compound initially a [Fe2{MeSi(CH2S)2CH2SH}(CO)6] is formed. This<br />
dinuclear complex is however slowly transformed into the tetranuclear species<br />
[Fe4{MeSi(CH2S)3}2(CO)8].<br />
39
OP-24<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
DNA-Organometallic Hybrid Catalysts<br />
Andres Jäschke, * Pierre Fournier, a Michaela Caprioara, a and Matthias Höhne a<br />
a Heidelberg University, Institute <strong>of</strong> Pharmacy and Molecular Biotechnology, Im Neuenheimer Feld<br />
364, 69120 Heidelberg, Germany. E-mail: jaeschke@uni-hd.de<br />
Hybrid catalysis combines homogeneous chemical catalysts with biopolymers to develop selective<br />
catalysts for organic reactions. While proteins have been used as hosts for various transition metal<br />
complexes, 1 only few published examples are based on nucleic acids. 2 In these reports high<br />
stereoselectivities were obtained in Diels-Alder reactions, Michael additions and fluorinations, with<br />
DNA as sole source <strong>of</strong> chirality, but all these systems relied on Lewis acid catalysis by Cu II ions. Our<br />
goal is the application <strong>of</strong> DNA-conjugated transition metal complexes in organometallic catalysis, as<br />
this kind <strong>of</strong> catalysis is widespread among synthetically useful reactions.<br />
We recently presented DNA-based systems that use Ir I -diene chemistry to catalyze an allylic<br />
substitution in aqueous medium. 3 Towards this end, we covalently attach transition metal ligands, like<br />
phosphinoxazoline and diene ligands, to specific positions <strong>of</strong> oligonucleotides. 4<br />
Our approach is based on a modular design where a 19mer oligodeoxynucleotide carrying a transition<br />
metal ligand is combined with different DNA or RNA counterstrands, thereby forming perfect and<br />
imperfect duplexes that provide subtle changes in the environment <strong>of</strong> the metal center. The covalent<br />
attachment <strong>of</strong> the ligand guarantees its specific, reproducible positioning on nucleic acid structures.<br />
We demonstrate that catalysis occurs in the presence <strong>of</strong> DNA and its numerous functional groups, and<br />
that the structure <strong>of</strong> the DNA modulates the stereochemical outcome <strong>of</strong> the reaction. 3<br />
Recent work will be presented on the extension <strong>of</strong> our approach to other reactions, metals, and ligands,<br />
and about rational and combinatorial strategies for improvement <strong>of</strong> performance and stereoselectivity.<br />
References<br />
Iridium(I)-catalyzed allylic amination using DNA-based ligands<br />
1. (a) J. Steinreiber, T. R. Ward, Coord. Chem. Rev. 2008, 252, 751. (b) M. E. Wilson, G. M.<br />
Whitesides, J. Am. Chem. Soc. 1978, 100, 306. (c) M. T. Reetz, M. Rentzsch, A. Pletsch, M. Maywald,<br />
P. Maiwald, J. J. P. Peyralans, A. Maichele, Y. Fu, N. Jiao, F. Hollmann, R. Mondiere, A. Taglieber,<br />
Tetrahedron 2007, 63, 6404. (d) A. Pordea, M. Creus, J. Panek, C. Duboc, D. Mathis, M. Novic, T. R.<br />
Ward, J. Am. Chem. Soc. 2008, 130, 8085.<br />
2. (a) G. Roelfes, B. L. Feringa, Angew. Chem. Int. Ed. 2005, 44, 3230. (b) N. S. Oltra, G. Roelfes,<br />
Chem. Comm. 2008, 6039. (c) D. Coquière, Ben L. Feringa, G. Roelfes, Angew. Chem. Int. Ed. 2007,<br />
46, 9308. (d) N. Shibata, H. Yasui, S. Nakamura, T. Toru, Synlett 2007, 1153.<br />
3. P. Fournier, R. Fiammengo, A. Jäschke, Angew. Chem. Int. Ed. 2009, 48, 4226.<br />
4. M. Caprioara, R. Fiammengo, M. Engeser, A. Jäschke, Chem. Eur. J. 2007, 13, 2089.<br />
40
OP-25<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Construction <strong>of</strong> Organometalloenzymes<br />
Yoshihito Watanabe a<br />
a Nagoya University, Graduate School <strong>of</strong> Science, Department <strong>of</strong> Chemistry, Chikusa, 464-8602,<br />
Nagoya, Japan. E-mail: yoshi@nucc.cc.nagoya-u.ac.jp<br />
A variety <strong>of</strong> protein structures are employed in nature as frameworks for the deposition <strong>of</strong> metal<br />
c<strong>of</strong>actors to provide metalloenzymes. Very recently, we have designed a myoglobin mutant as a<br />
model for a substrate bound form <strong>of</strong> cytochrome P450 and site<br />
specific aromatic hydroxylation was found to proceed by a<br />
stochiometric amount <strong>of</strong> H 2 O 2 in a few seconds. 1 As an<br />
extension <strong>of</strong> our efforts for the construction <strong>of</strong><br />
organometalloproteins, we have replaced the heme prosthetic<br />
group with a series <strong>of</strong> M(salophen) complexes, Rh(Phebox) (Fig<br />
1), and Cu complexes. 2 Instead <strong>of</strong> these small protein cavities,<br />
we have also employed a protein having a large cavity, i.e., apo-<br />
ferritin (apo-Fr). Ferritin is an iron storage protein and its ap<strong>of</strong>orm<br />
has been employed as nano-reactors. We have also<br />
prepared a zero-valent palladium cluster by chemical reduction<br />
<strong>of</strong> palladium ions in the apo-ferritin cage and examined its catalytic hydrogenation activity. The<br />
palladium clusters catalyzes size-selective olefin hydrogenation because substrates must penetrate into<br />
the ferritin cavity through the size restricted channels. 3 Through the Pd•apo-Feritin study, we have<br />
found that there are Pd ion binding sites in the apo-ferritin to capture as many as 300 Pd ions. Thus,<br />
we have examined crystal structures <strong>of</strong> apo-ferritin containing various amounts <strong>of</strong> Pd ions. The crystal<br />
structures <strong>of</strong> Pd•apo-Fr has been refined to 1.65Å resolution (Fig 2). 4 We have further found that<br />
Pd II (allyl) ion utilizes<br />
different binding sites<br />
bearing different<br />
coordination structures<br />
(Fig 3). The Pd(allyl)•<br />
apo-Fr composites show<br />
catalytic activities for the<br />
Suzuki coupling reaction<br />
as shown below. 5<br />
References<br />
1) T. D. Pfister, et al., J. Biol. Chem. 280, 12858 (2005). 2) M. Koshiyama, et al., J. Am. Chem. Soc.<br />
127, 6556 (2005). 3) M. Suzuki, et al., Angew. Chem. Int. Ed. 43, 2527 (2004). 4) T. Ueno, et al., J.<br />
Am. Chem. Soc. 131, 2094 (2009). 5) T. Ueno, et al., J. Am. Chem. Soc. 130, 10512 (2008).<br />
41<br />
Fig.1 Apo-Mb•Rh(Phebox) composite<br />
structure.<br />
Fig.2 The crystal structure <strong>of</strong> apo-Fr•Pd. Fig.3 The crystal structure <strong>of</strong> apo-Fr•Pd(allyl).
OP-26<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
CO Releasing Properties <strong>of</strong> cis-trans-[Re II (CO)2Br2L2] n Complexes: A Feature<br />
Modulated by Ligand Variation for a True Chance at Medicinal Applications.<br />
Fabio Zobi* a and Alois Degonda a<br />
a University <strong>of</strong> Zürich, Institute <strong>of</strong> Inorganic Chemistry, Winterthurerstr. 190, CH-8057, Zürich,<br />
Switzerland. E-mail: fzobi@aci.uzh.ch<br />
In recent years carbon monoxide (CO) has been acknowledged as a fundamental small-molecule<br />
messenger in humans. 1 The tissue specific distribution <strong>of</strong> heme oxigenases and their action-derived<br />
CO have been linked to several effects. For example, carbon monoxide acts as a signaling molecule in<br />
the inducible defensive system against stressful stimuli. 1 It plays a fundamental role in the circulatory<br />
system by improving vasorelaxation and cardiac blood supply and it suppresses arteriosclerotic lesions<br />
associated with chronic graft rejection. 1,2 As the importance <strong>of</strong> CO is been increasingly recognized,<br />
there is a steadily growing interest in the in pharmacological and medicinal applications <strong>of</strong> CO. Direct<br />
inhalation <strong>of</strong> carbon monoxide has been viewed as a novel therapeutic approach but reports on<br />
tolerance to CO exposure are contradictory.<br />
An alternative approach to the administration <strong>of</strong> carbon monoxide is the use <strong>of</strong> CO-releasing<br />
molecules (CORMs). An obvious choice for CORMs are transition metal carbonyl complexes with<br />
one or more CO ligands. Several complexes have been evaluated to date, but the pioneering work <strong>of</strong><br />
Motterlini and Mann has resulted in the discovery <strong>of</strong> the fac-[RuCl(glycinato)(CO)3] complex<br />
(CORM-3) as the most promising compound for the CO release in vivo. 3<br />
In here we show that complexes <strong>of</strong> the type cis-trans-[Re II (CO)2Br2L2] n (where L = monodentate<br />
ligand) 4 act as CO-releasing molecules and that under physiologically relevant conditions the rate <strong>of</strong><br />
CO release is comparable to that <strong>of</strong> CORM-3. The complexes represent a first example <strong>of</strong> metal-based<br />
CORMs in which the central metal ion is not found in a d 6 or d 8 configuration. The open shell d 5<br />
configuration <strong>of</strong> the Re system herein described represents an advantage over the more robust d 6 or d 8<br />
systems for which physical stimuli (e.g. UV radiation) are <strong>of</strong>ten needed in order to elicit dissociation<br />
<strong>of</strong> carbon monoxide from the metal core. The rate <strong>of</strong> CO release <strong>of</strong> cis-trans-[Re II (CO)2Br2L2] n<br />
complexes is pH dependent and can be modulated by ligand variation. These features <strong>of</strong>fer a true<br />
chance for the application <strong>of</strong> these molecules in medicinal chemistry.<br />
References<br />
1. Wu, L.; Wang, R., Pharmacol. Rev. 2005, 57, 585-630.<br />
2. Otterbein, L. E.; Zuckerbraun, B. S.; Haga, M.; Liu, F.; Song, R. P.; Usheva, A.; Stachulak, C.;<br />
Bodyak, N.; Smith, R. N.; Csizmadia, E.; Tyagi, S.; Akamatsu, Y.; Flavell, R. J.; Billiar, T. R.; Tzeng,<br />
E.; Bach, F. H.; Choi, A. M. K.; Soares, M. P., Nature Med. 2003, 9, 183-190.<br />
3. Foresti, R.; Bani-Hani, M. G.; Motterlini, R., Intensive Care Med. 2008, 34, 649-658.<br />
4. Zobi, F.; Kromer, L.; Spingler, B.; Alberto, R., Inorg. Chem. 2009, 48, 8965-8970.<br />
42
OP-27<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Nitric Oxide Synthase Targeting with 99m Tc(I)/Re(I) Complexes<br />
João D. G. Correia,* a Bruno L. Oliveira, a Filipa Mendes, a Paula D. Raposinho, a Isabel Santos, a<br />
António Ferreira, b Carlos Cordeiro, b Ana P. Freire b<br />
a ITN, Unidade de Ciências Químicas e Radi<strong>of</strong>armacêuticas, Estrada Nacional 10, 2686-953<br />
Sacavém, Portugal. b Universidade de Lisboa, Faculdade de Ciências, Departamento de Química e<br />
Bioquímica, Lisbon, Portugal. E-mail: jgalamba@itn.pt<br />
Nitric oxide (NO), a key signaling mammalian mediator in several physiophatolological processes, is<br />
biosynthesized in vivo by oxidation <strong>of</strong> L-arginine to L-citrulline catalalyzed by Nitric Oxide Synthase<br />
(NOS). 1 This enzyme has two constitutive is<strong>of</strong>orms (neuronal, nNOS; endothelial, eNOS) and one<br />
inducible is<strong>of</strong>orm (iNOS). Noninvasive imaging <strong>of</strong> NOS expression in vivo by nuclear techniques,<br />
namely by Single Photon Emission Tomography (SPECT) or Positron Emission Tomography (PET),<br />
holds great potential for providing new insights in understanding NO/NOS-related diseases, and may<br />
facilitate the development <strong>of</strong> novel therapeutic approaches. 2,3 Aiming to find 99m Tc(CO)3-based tracers<br />
for probing NOS levels in vivo, we will report on the synthesis and characterization <strong>of</strong> novel<br />
Re(I)/ 99m Tc(I) organometallic complexes containing pendant bioactive units for recognition <strong>of</strong> NOS<br />
active site. 4 The enzymatic studies with isolated murine iNOS have shown that some Re(I) compounds<br />
could inhibit the enzyme, being the first examples <strong>of</strong> organometallic complexes able to inhibit NOS.<br />
Such effect was also observed in LPS-stimulated murine macrophages. Interestingly, a few complexes<br />
could also be used as NOS substrates by the same cell model. The biological assessment <strong>of</strong> the 99m Tccomplexes<br />
in different cell lines and in mice will also be presented.<br />
References<br />
1. S. Moncada, R. M. J. Palmer, E. A. Higgs, Pharmacol. Rev. 1991, 43, 109-142.<br />
2. D. Zhou, H. Lee, J. M. Rothfuss, D. L. Chen, D. E. Ponde, M. J. Welch,R. H. Mach, J. Med.<br />
Chem.2009, 52, 2443–2453.<br />
3. H. Hong, J. Sun, W. Cai, Free Radic. Biol. Med. 2009, 47, 684–698.<br />
4. B. L. Oliveira, J. D. G. Correia, P. D. Raposinho, I. Santos, A. Ferreira, C. Cordeiro, A. P. Freire,<br />
Dalton Trans. 2009, 1, 152-162.<br />
Acknowledgements<br />
We thank the Fundação para a Ciência e Tecnologia (FCT) for financial support (POCI/SAU-<br />
FCF/58855/2004). Mallinkrodt-Tyco Inc. is acknowledged for providing the IsoLink® kits. B. L. O.<br />
thanks FCT for a BD grant (SFRH/BD/38753/2007). J. Marçalo is acknowledged for the ESI-MS<br />
analyses, which were run on a QITMS instrument (FCT Contract REDE/1503/REM/2005 - ITN).<br />
43
OP-28<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Mechanistic and Synthetic Studies <strong>of</strong> Bio-compatible<br />
Carbon Monoxide-Releasing Molecules<br />
Anthony J. Atkin, a Ian J. S. Fairlamb, a Jason M. Lynam, *a and Wei-Qiang Zhang a<br />
Department <strong>of</strong> Chemistry, University <strong>of</strong> York, Heslington, York, YO10 5DD, UK<br />
E-mail: jml12@york.ac.uk<br />
Carbon monoxide – releasing molecules (CO-RMs) have become an exciting target for therapeutic<br />
intervention. 1 CO generated in mammals is responsible for a variety <strong>of</strong> important physiological<br />
functions and is a fundamental signalling mediator. CO gas also elicits a range <strong>of</strong> beneficial<br />
therapeutic effects, although the associated toxicity and inherent poor selectivity <strong>of</strong> CO in its naked<br />
form is clearly not ideal. The method <strong>of</strong> choice for taking advantage <strong>of</strong> the beneficial role <strong>of</strong> CO is to<br />
utilise a CO-RM, such as a metal carbonyl complex, which act as a source <strong>of</strong> CO in biological<br />
systems.<br />
Although the biological effects <strong>of</strong> CO (and CO-RMs) are now well established, there is little<br />
understanding <strong>of</strong> the precise requirements needed for transition metal carbonyl compounds to act as<br />
effective therapeutic agents. We have therefore undertaken a systematic study in order to elucidate the<br />
factors that may control CO-release. 2 This has allowed us to determine which metal-carbonyl scaffolds<br />
have the greatest potential to act as CO-RMs which has in turn informed a synthetic programme<br />
designed to prepare a library <strong>of</strong> novel complexes with bio-compatible ligands. For example, we have<br />
prepared a range <strong>of</strong> Group 6 compounds which contain both natural and non-natural amino acids<br />
incorporated into the coordination sphere <strong>of</strong> the metal through a range <strong>of</strong> binding modes (Figure 1).<br />
This presentation will detail the key results from the findings <strong>of</strong> our synthetic and mechanistic studies<br />
into the CO-release process, as well as the behaviour <strong>of</strong> the new bio-compatible CO-RMs. For<br />
example, we have demonstrated how the CO-release behaviour <strong>of</strong> the amino ester derivatives 1 may<br />
be simply modulated by the choice <strong>of</strong> the substituent on the organic ligand. A mechanistic study has<br />
demonstrated that this process is controlled by loss <strong>of</strong> the amino ester and therefore supply <strong>of</strong> the<br />
“M(CO)5” (M = Cr, Mo, W) fragment is crucial to CO-release in aqueous systems. For the CO-RMs<br />
with structure 2 the rate <strong>of</strong> CO-release correlates with the electrophilicity <strong>of</strong> the carbene carbon,<br />
consistent with a mechanism in which nucleophilic attack <strong>of</strong> water initiates the CO-release process.<br />
The scope <strong>of</strong> biologically-relevant ligands which can be introduced into the coordination sphere <strong>of</strong> the<br />
metal will also be detailed.<br />
References<br />
1. (a) T. T. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green, R. Motterlini, R. Angew. Chem.<br />
Int. Ed. 2003, 42, 3722-3729. (b) I. J. S. Fairlamb, A.-K. Duhme-Klair, J. M. Lynam, B. E. Moulton,<br />
C. T. O’Brien, P. Sawle, J. Hammad, R. Motterlini, Bioorg. & Med. Chem. Lett. 2006, 16, 995-998.<br />
(c) P. Sawle, J. Hammad, I. J. S. Fairlamb, B. E. Moulton, C. T. O'Brien, J. M. Lynam, A.-K. Duhme-<br />
Klair, R. Foresti, R. Motterlini, J. Pharmacol. Exp. Ther. 2006, 318, 403-410. (d) I. J. S. Fairlamb, J.<br />
M. Lynam, B. E. Moulton, I. E. Taylor, A. K. Duhme-Klair, P. Sawle, R. Motterlini, Dalton Trans.<br />
2007, 3603-3605.<br />
2. W.-Q. Zhang, A. J. Atkin, R. J. Thatcher, A. C. Whitwood, I. J. S. Fairlamb, J. M. Lynam, Dalton<br />
Trans. 2009, 4351-4358.<br />
44
OP-29<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Peptide-carbenes and peptide-phosphines transition metal catalysts for “Green”<br />
solid phase catalysts.<br />
Morten Meldal, *a Kasper Worm-Leonhard, a and Christian A. Christensen a<br />
a Carlsberg Laboratory, SPOCC-Centre, Gamle Carlsberg Vej 10, 2500 Valby, Denmark,<br />
E-mail: mpm@crc.dk<br />
In Nature metalloproteins play a crucial role in complex biochemical transformations while displaying<br />
exquisite regio- and enantio-selectivity. More importantly the protein framework coordinates the<br />
catalytic metal and ensure substrate match and lower activation energy <strong>of</strong> the reaction to provide very<br />
high turnovers, which in turn facilitates the efficient biochemical transformation at low concentration<br />
<strong>of</strong> the catalytic protein.<br />
These properties can advantageously be mimicked in the field peptide and peptide-organic chemistry<br />
to putatively create catalysts for “green” chemistry. By engineering the peptide scaffold with one or<br />
several ideal ligands for a variety <strong>of</strong> transition metals, e. g. Pd, Zn or Cu. artificial enzyme like<br />
compounds, displaying selectivity and turnover for general organic chemistry transformations may be<br />
obtained.<br />
This presentation describes the synthesis and application <strong>of</strong> carbene- and phosphine-precursors for<br />
incorporation into peptide frameworks that folds around a transition metal and forms relatively<br />
compact and stable globular structures with an enzyme like binding cavity for substrate binding and<br />
catalysis. The strategy is modular and well suited for a Split/Mix approach where a large number <strong>of</strong><br />
catalysts may be generated in a single combinatorial synthesis.<br />
Backbone phosphinylated peptides (1) were synthesized on polar PEGA supports and in solution and<br />
the catalytic activity was compared. The solid supported catalysts were very efficient and could be<br />
recycled at least 5 times without loss <strong>of</strong> activity. The palladium coordination <strong>of</strong> the phosphine could<br />
furthermore be combined with folding and complexation with other dedicated functional groups in the<br />
peptide.<br />
Backbone carbenes (2) formed extremely stable palladium-peptido carbene complexes that did not<br />
loose any activity with time or use. These solid phase catalysts could be used in microwave assisted C-<br />
C and C-N couplings in water with good selectivities and quantitative yields.<br />
References<br />
1. (a) C. A. Christensen and M. Meldal. Efficient Solid-Phase Synthesis <strong>of</strong> Peptide Based<br />
Phosphine Ligands: Towards Combinatorial Libraries <strong>of</strong> Selective Transition Metal Catalysts.<br />
Chem. Eur. J. 2004, 11, 4121-4131; (b) C. A. Christensen and M. Meldal. Solid-phase<br />
synthesis <strong>of</strong> a P,S-ligand system designed for generation <strong>of</strong> combinatorial peptide-based<br />
catalyst libraries. J. Comb. Chem. 2007, 9, 79-85.<br />
2. (a) J. F. Jensen, K. Worm-Leonhard, and M. Meldal. Optically active (peptido-carbene)<br />
palladium complexes: towards true combinatorial solid phase libraries <strong>of</strong> transition metal<br />
catalysts. Eur. J. Org. Chem. 2008, 3785-3797 (b) K. Worm-Leonhard and M. Meldal. Green<br />
catalysts: Solid-phase peptide carbene ligands in aqueous transition metal catalysis. Eur. J. Org.<br />
Chem. 2008, 5244-5253.<br />
45
OP-30<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Construction <strong>of</strong> an Immunosensor via Copper-Free ‘Click’ Reaction Between<br />
Azido SAMs and Alkynyl Fischer Carbene Complex. Application to the detection<br />
<strong>of</strong> Staphyloccal Enterotoxin A<br />
Pratima Srivastava, a Amitabha Sarkar, b Sudeshna Sawoo, b Amarnath Chakraborty, b Pinak Dutta, b<br />
Othman Bouloussa, c Claire-Marie Pradier; d Souhir Boujday, d and Michelle Salmain *a<br />
a Ecole Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel (UMR CNRS 7223),<br />
11, rue Pierre et Marie Curie, 75231 Paris cedex 05, France. b Indian Association for the Cultivation<br />
<strong>of</strong> Sciences, Department <strong>of</strong> Organic Chemistry, 700032, Kolkata, India. c Institut Curie, laboratoire<br />
Physico-chimie Curie (UMR CNRS 168), 26 rue d’Ulm, 75248, Paris , cedex 05, France. d Université<br />
Pierre et Marie Curie, Laboratoire de réactivité de surface (UMR CNRS 7197), 4 place Jussieu,<br />
75252, Paris cedex 05, France. E-mail: pratima-srivastava@chimie-paristech.fr<br />
Keywords: Immunosensor, IRRAS, ‘click’ reaction, Fischer carbene, antibody-antigen reaction.<br />
A copper-free « click » reaction between azido-terminated self-assembled monolayers (SAMs) on gold<br />
and an alkynyl Fischer carbene complex yielded functionalized surfaces on which facile and swift<br />
grafting <strong>of</strong> amine-containing molecules was achieved via aminolysis <strong>of</strong> the Fischer carbene moieties<br />
(Figure). 1<br />
S<br />
+<br />
N3 N<br />
N N<br />
MeO<br />
W(CO) 5<br />
Ph<br />
NH2 Au Au S<br />
Au S<br />
OMe<br />
W(CO) 5<br />
46<br />
(OC) 5W<br />
This 3-step process could be conveniently monitored by Infrared Reflection-Absorption Spectroscopy<br />
(IRRAS). An extensive study <strong>of</strong> the different parameters involved in the covalent grafting <strong>of</strong> proteins<br />
on the Fischer carbene modified SAMs was carried out. As an application, an antibody against<br />
Staphylococcal Enterotoxin A (SEA) was immobilized onto gold chips so as to ultimately construct an<br />
optical immunosensor for the detection <strong>of</strong> this toxin in food samples.<br />
References<br />
1. S. Sawoo, P. Dutta, A. Chakraborty, R. Mukhopadhyay, O. Bouloussa, A. Sarkar, Chem. Commun.<br />
2008, 5957-5959.<br />
NH<br />
N<br />
N N<br />
Ph
OP-31<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Polypeptides Induced Self-Association and Emission Properties <strong>of</strong><br />
Platinum(II) and Gold(I) Complexes<br />
Toshiyuki Moriuchi, *a Masahiro Yamada, a Kazuki Yoshii, a and Toshikazu Hirao a<br />
a Department <strong>of</strong> Applied Chemistry, Graduate School <strong>of</strong> Engineering, Osaka University,<br />
Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: moriuchi@chem.eng.osaka-u.ac.jp<br />
Highly-ordered molecular assemblies are constructed in bio-systems to fulfill unique functions as<br />
observed in enzymes, receptors, etc. Introduction <strong>of</strong> functional complexes into highly-ordered<br />
biomolecules is considered to be a convenient approach to novel biomaterials, bio-inspired systems,<br />
etc. Recently, the field <strong>of</strong> bioorganometallic chemistry has drawn great attention and undergone rapid<br />
development. Conjuction <strong>of</strong> organometallic compounds with biomolecules such as peptides and<br />
nucleobases is envisioned to afford such bioconjugates. The non-covalent bond is a powerful tool in<br />
the construction <strong>of</strong> architectural molecular assemblies. We have already demonstrated the chirality<br />
organization <strong>of</strong> ferrocene-peptide bioconjugates to induce highly-ordered molecular assemblies. 1<br />
Poly-L-glutamic acid (P(Glu)) is known to exist in a �-helix form at around pH 4.3. The carboxyl<br />
groups <strong>of</strong> side chains are expected to assemble cationic metal complexes along the exterior <strong>of</strong> poly-Lglutamic<br />
acid through the electrostatic interactions. On the other hand, poly-L-Lysine (P(Lys)) exists<br />
as a random coil conformation at a neutral pH due to repulsion between positively charged side chains,<br />
and an �-helical conformation at above pH 10.6 due to the reduced charge on the side chains at a pH<br />
above the pKa (10.5). P(Lys) bearing multiple positively charged side chains is envisioned to serve as a<br />
polymeric spatially aligned scaffold for the aggregation <strong>of</strong> negatively charged metal complexes. From<br />
these points <strong>of</strong> view, we embarked upon the assembling and self-association <strong>of</strong> luminescent metal<br />
complexes spatially along the cationic or anionic polypeptides to form the luminescent aggregates.<br />
The cationic organoplatinum(II) complexes<br />
[Pt(trpy)C≡CR] + (trpy = 2,2',6',2''-terpyridine; R = Ph<br />
(PtH), PhC12H25 (PtC12)) were introduced into the anionic<br />
poly-L-glutamic acid (P(Glu)) through electrostatic<br />
interactions. An emission based on metal-metal-to-ligand<br />
charge transfer (MMLCT) transition was observed in the<br />
case <strong>of</strong> P(Glu)-PtC12. However, such synergistic effect<br />
was not observed in the case <strong>of</strong> P(Glu)-PtH. Poly-L-<br />
glutamic acid was found to serve as an efficient molecular scaffold, wherein the platinum(II)<br />
complexes might be accommodated.<br />
The assembling and self-association <strong>of</strong> anionic dicyanoaurate(I), [Au(CN)2] � , spatially around the<br />
cationic poly-L-Lysine (P(Lys)) through electrostatic interactions was also demonstrated to form the<br />
luminescent [Au(CN)2] � aggregates.<br />
References<br />
1. (a) Chem. Commun. 1998, 1963. (b) J. Organomet. Chem. 1999, 589, 50. (c) J. Am. Chem. Soc.<br />
2001, 123, 68. (d) Organometallics 2001, 20, 1008. (e) Organometallics 2001, 20, 3101. (f) J.<br />
Organomet. Chem. 2001, 637-639, 75. (g) Org. Lett. 2003, 5, 4285. (h) Org. Lett. 2005, 7, 5265. (i)<br />
Org. Lett. 2006, 8, 31-34. (j) Dalton Trans. 2009, 4286.<br />
47<br />
M M M M M<br />
M M M M M
OP-32<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Homogeneous and Bio-Catalysis in Concert:<br />
Hybrids <strong>of</strong> ECE-pincer Organometallics and Lipases<br />
Gerard van Koten *a<br />
a Organic Chemistry and Catalysis, Faculty <strong>of</strong> Science, Utrecht University, The Netherlands<br />
g.vankoten@uu.nl<br />
Bis-ortho-chelated aryl-metal complexes, the socalled ECE-pincer metal complexes, exist in great<br />
varieties. Several novel strategies for anchoring these ECE-pincer metal complexes to soluble and<br />
insoluble supports have been developed. Novel synthetic routes have been developed for the direct<br />
introduction <strong>of</strong> functional para-substituents onto the pre-formed ECE-pincer metal complexes. 1 This<br />
allows, for example the introduction <strong>of</strong> anionic tethers which can non-covalently bind the ECE-pincer<br />
metal complex to the core <strong>of</strong> multicationic core-shell dendrimers.<br />
Recently, we concentrated on the covalent anchoring <strong>of</strong> ECE-pincer metal complexes to proteins. 2<br />
This approach, involving the inhibitory activity <strong>of</strong> nitrophenyl phosphonate esters to the catalytic triad<br />
(serine, histidine and asparagine) <strong>of</strong> lipases, has great potential for future applications in the fields <strong>of</strong><br />
protein structure elucidation (NMR, X-Ray, mass spectrometry), medicinal chemistry (biomarkers,<br />
MRI contrast agents, radiopharmaceuticals), biomaterials and catalysis (enantioselectivity, catalysis in<br />
aqueous media). Crystal structures <strong>of</strong> these novel ECE-pincer metal-lipase hybrids show in detail how<br />
the ECE-pincer metal unit is covalently attached to the enzyme. 3 The photophysical (biomarker),<br />
coordinative and catalytic (dynamic kinetic resolution) properties <strong>of</strong> these and related rutheniumlipase<br />
hybrid materials will be discussed.<br />
Fig 1. Structure in the solid state <strong>of</strong> the NCN-pincer platinum bromide-cutinase hybrid.<br />
References<br />
1. M.Gagliardo, D.J.M. Snelders et al., Angew. Chem. 2007, 46, 8558.<br />
2. C.A. Kruith<strong>of</strong> et al., Chem. Eur. J. 2005, 11, 6869.<br />
3. B. Wieczorek et al., Chem. Eur. J. 2009, 15, 4270.<br />
48
OP-33<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Chemo-Genetic Optimization <strong>of</strong> DNA Recognition by Metallodrugs using a<br />
Presenter Protein Strategy<br />
Jeremy M. Zimbron, a A. Sardo, a T. Heinisch, a,b T. Wohlschlager, c J. Gradinaru, d C. Massa, b<br />
T. Schirmer, *b Marc Creus, *a and Thomas R. Ward *a<br />
aUniversity <strong>of</strong> Basel, Department <strong>of</strong> Chemistry, Spitalstrasse 51, Basel 4056, Switzerland, b University<br />
<strong>of</strong> Basel, Biozentrum, Klingelbergstrasse 50/70, Basel 4056, Switzerland, c University <strong>of</strong> Neuchâtel,<br />
Institute <strong>of</strong> Chemistry, Avenue de Bellevaux 51, Neuchâtel 2009, Switzerland<br />
DNA is a privileged target <strong>of</strong> anticancer metallodrugs like cisplatin. However, such drugs <strong>of</strong>ten suffer<br />
from high toxicity and drug-resistance due to non-selective binding to other than oncogenic DNA. 1<br />
To increase selectivity <strong>of</strong> small molecule drugs for macromolecular targets, “surface borrowing” can<br />
be used to provide additional surface contacts via a presenter protein, which modulates the specificity<br />
and affinity <strong>of</strong> ligand–macromolecule interaction. 2 The use <strong>of</strong> bifunctional molecules based on biotinstreptavidin<br />
technology has been used for targeting RNA, in which a contribution for protein contacts<br />
to the anti-tobramycin RNA aptamer was suggested. 3 Inspired by these presenter protein strategies and<br />
our previous experience <strong>of</strong> enantioselective artificial metalloenzymes, 4 we synthesized a biotinylated<br />
metallodrug (compound 1, Fig.1) inspired on promising anticancer Ru(II) piano-stool complexes, 4 for<br />
incorporation into streptavidin (Sav).<br />
Here we shown that a supramolecular assembly <strong>of</strong> a drug with a presenter protein can modulate<br />
selectivity through provision <strong>of</strong> additional non-covalent interactions with the target that are not<br />
typically available to small molecule drugs, thus allowing selectivity toward macromolecules such as<br />
DNA telomeres.<br />
Fig.1 Presenter protein strategy for targeting telomeric DNA with ruthenium metallodrugs.<br />
References<br />
1. L. Kelland, Nat. Rev. Cancer 2007, 7, 573.<br />
2. R. Briesewitz, G. T. Ray, T. J. Wandless, G. R. Crabtree, Proc. Natl. Acad. Sci. U. S. A. 1999, 96,<br />
1953.<br />
3. I. Harvey, P. Garneau, J. Pelletier, Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 1882.<br />
4. M. Creus, A. Pordea, T. Rossel, A. Sardo, C. Letondor, A. Ivanova, I. Letrong, R. E. Stenkamp, T.<br />
R. Ward, Angew. Chem. Int. Ed. 2008, 47, 1400.<br />
5. P. C. Bruijnincx, P. J. Sadler, Curr. Opin. Chem. Biol. 2008, 12, 197.<br />
49
OP-34<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
RAPTA-T interacts with �1�1 integrin at the molecular level<br />
Alletta Schmidt-Hederich, a Michael Grössl, c Alessia Masi, b Alberta Bergamo, b Gianni Sava, b Paul J.<br />
Dyson, c and Johannes A. Eble *a<br />
a Goethe University <strong>of</strong> Frankfurt, Faculty <strong>of</strong> Medicine, Center for Molecular Medicine, Vascular<br />
Matrix Biology, Excellence Cluster CardioPulmonary System, Theodor-Stern-Kai 7, 60590<br />
Frankfurt/Main, Germany. b Callerio Foundation, Via Fleming 31, 34127 Trieste, Italy. c Ècole<br />
Polytechnique Fedèrale de Lausanne, Department <strong>of</strong> Chemistry and Chemical Engineering, 1015<br />
Lausanne, Switzerland. E-mail: Eble@med.uni-frankfurt.de<br />
Metal-based compounds, such as cisplatin and ruthenium complexes have been used as cytostatic<br />
drugs in cancer treatment. These compounds are generally thought to target DNA and hence interfere<br />
with the growth <strong>of</strong> highly proliferative tumor cells. However, recent experiments have suggested that<br />
ruthenium compounds, such as RAPTA-T, additionally affect cellular interactions with the<br />
extracellular matrix (ECM). Among cell adhesion molecules, integrins form a numerous and most<br />
versatile family. They bind to ECM proteins in a divalent cation-dependent manner and thus mediate<br />
cell-matrix interactions and regulate tissue-specific cell morphology, migration, cell survival and<br />
proliferation. Therefore, they play key roles in various physiological situations and diseases, such as<br />
tumor progression and metastasis.<br />
To analyse the effects <strong>of</strong> ruthenium-based compounds, in particular RAPTA-T, on integrins at both<br />
cellular and molecular level, we used cell attachment studies as well as cell-free protein interaction<br />
assays with recombinant human integrins. Moreover, a test system to determine the binding <strong>of</strong> metal<br />
organic compounds to integrins was established.<br />
At the cellular level, RAPTA-T affected cell adhesion especially to the basement membrane collagen<br />
IV and to fibronectin, which is mediated via the integrins �1�1 and �5�1, respectively. The isolated<br />
integrins were affected in their binding properties towards their cognate ligands, depending on the<br />
incubation time with RAPTA-T. Bioanalytical studies, such as gel filtration <strong>of</strong> �1�1 integrin with the<br />
ruthenium compound followed by an on-line detection <strong>of</strong> ruthenium by inductively coupled plasma<br />
mass spectrometry (ICP-MS), demonstrated that RAPTA-T binds to �1�1 integrin and alters its ability<br />
to form higher aggregates. In parallel, the binding activity <strong>of</strong> �1�1 integrin is compromised.<br />
Additional studies will be necessary in the future to elucidate the molecular mechanism.<br />
50
OP-35<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Advances in Organometallic Chemistry for the Preparation <strong>of</strong> Molecular Imaging<br />
and Therapy Agents<br />
John F. Valliant*, a,b Anika Louie, a Alla Darwish, a Michael Cooke, a Antonio Toppino, a Karin<br />
Stephenson, b Ryan Simms b<br />
a McMaster University, Faculty <strong>of</strong> Science, Department <strong>of</strong> Chemistry, 1280 Main St. West, L8S 4M1,<br />
Hamilton, Canada. b The Centre for Probe Development and Commercialization, McMaster<br />
University, BSB-B231, 1280 Main St. West, L8S 4K1, Hamilton, Canada. E-mail:<br />
valliant@mcmaster.ca<br />
Medical isotopes that are metallic in nature are playing an increasingly important role in modern<br />
nuclear medicine and basic biological research. 1 Delivering these radioisotopes to specific<br />
biochemical targets while minimizing non-specific binding requires the development <strong>of</strong> new<br />
prosthetic groups that form robust metal complexes in high yield under conditions that do not<br />
degrade or modify sensitive targeting vectors. These prosthetic groups or ligands must also be<br />
versatile with respect to how they are linked to targeting vectors and structurally modified in<br />
order to meet the lipophilicity needs <strong>of</strong> the agent under development. With these requirements in<br />
mind, organometallic complexes <strong>of</strong> Tc and Re are attractive platforms for developing new<br />
imaging and therapy agents in that inert complexes can be formed in high yield using an array <strong>of</strong><br />
unique chelates and organometallic ligands. The work to be presented will include the<br />
development <strong>of</strong> isostructural Re and Tc complexes that can be imaged in vitro and in vivo using<br />
fluorescence microscopy and radioimaging methods respectively. 2 Complexes will include novel<br />
chelates for the [M(CO)3] + core, which can be labeled at room temperature and incorporated into<br />
peptide vectors as if they were natural amino acids. In addition, a new generation <strong>of</strong> isostructural<br />
organometallic probes derived from carboranes will be presented. New labeling strategies for<br />
tagging these molecules that go beyond conventional bulk solution methods will also be<br />
discussed.<br />
References<br />
1. R. Alberto, J. Organomet. Chem. 2004, 692, 1179-1186.<br />
2. K. Stephenson, S.R. Banerjee, T. Besanger, O.O. Sogbein, M.K. Levadala, N. McFarlane, J.<br />
Lemon, D. R. Boreham, K. P. Maresca, J. D. Brennan, J. W. Babich, J. Zubieta, J. F. Valliant, J. Am.<br />
Chem. Soc. 2004, 126, 8598-8599.<br />
51
OP-36<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Syntheses <strong>of</strong> New Isomeric Analogues <strong>of</strong> HYNIC for Evaluation<br />
as a Bifunctional Chelator for Technetium-99m<br />
Anica Dose, a L. K. Meszaros, b S. C. G. Biagini* a and P. J. Blower* b<br />
a University <strong>of</strong> Kent, Functional Materials Group, School <strong>of</strong> Physical Sciences, Canterbury CT2 7NH,<br />
UK. b Kings College London, Division <strong>of</strong> Imaging Sciences, Rayne Institute 4 th Floor Lambeth Wing,<br />
St. Thomas’ Hospital, London SE1 7EH, UK. E-mail: ad308@kent.ac.uk<br />
N<br />
N<br />
Tc<br />
N<br />
N<br />
N<br />
N Tc<br />
1 2<br />
Fig 1: possible monodentate 1<br />
and chelating 2 structures <strong>of</strong> Tc-<br />
HYNIC complex<br />
Introduction: Technetium, as a meta-stable isotope is extensively used in<br />
nuclear medicine. It is a transition metal <strong>of</strong> the 7 th subgroup with all formal<br />
oxidation states between -1 and +7 accessible and therefore possesses a large<br />
range <strong>of</strong> coordination structures. 1 Since the first use <strong>of</strong> radiolabelled<br />
antibodies with the bifunctional chelator 6-hydrazinonicotinamide (6-HYNIC)<br />
3, 2 the use <strong>of</strong> radiopeptides with the metastable isotope <strong>of</strong> technetium 99m Tc as<br />
an imaging agent for cancer cells has increased significantly until today. 3<br />
However, robust structural data for these conjugates is lacking. The HYNIC<br />
and 99m Tc coordinating sphere is still not fully determined and previous studies provide ambiguous<br />
results about the complex. 4 To radiolabel a peptide with HYNIC and 99m Tc also requires one or more<br />
co-ligands to fulfil the coordination sphere around the metal. Different co-ligands can have different<br />
effects on the homogeneity and stability <strong>of</strong> the complex and its biodistribution. Finally they are<br />
responsible for the formation <strong>of</strong> more than one end product. The latest results gives a clear insight that<br />
there is one chelating HYNIC per metal site and the oxidation state <strong>of</strong> Tc is formally +5. 5 The question<br />
as to which mode <strong>of</strong> the HYNIC coordination, monodentate 1 or chelating 2 is operating, remains<br />
uncertain.<br />
Aims: The aim <strong>of</strong> this project is to assess the specific binding <strong>of</strong> the complex between HYNIC and Tc,<br />
Tc and co-ligands and a further investigation <strong>of</strong> potential direct interactions between Tc and the<br />
peptide. 6<br />
Results: Isomeric HYNIC analogues<br />
4-7 were synthesised. These syntheses<br />
are related to the synthesis <strong>of</strong> 6-<br />
HYNIC-Boc. 2 The preparation <strong>of</strong><br />
HYNIC-rhenium crystals, will provide<br />
new data about the binding structure<br />
and this will be followed by the<br />
preparation <strong>of</strong> analogous HYNIC-Tc<br />
HO O<br />
N<br />
HO O<br />
crystals. The novel synthesis <strong>of</strong> Fmoc-Lysine-NHS-2-HYNIC-Boc was also succesfully accomplished.<br />
This will allow for its use in solid phase peptide synthesis (SPPS) to synthesise the “nanogastrin”<br />
peptide [Lys(R)-Glu-Ala-Tyr-Gly-Trp-Met-Asp-PheNH2] where R= HYNIC, which binds to the<br />
CCK-2 receptor overexpressed on certain tumours. 7<br />
Further work will evaluate the new ligands for labelling with Tc-99m and investigate the structural<br />
chemistry <strong>of</strong> the rhenium and technetium-99m complexes.<br />
References<br />
1. U. Abram, R. Alberto, J. Braz. Chem. Soc. 2006, 17, 1486-1500.<br />
2. M. J. Abrams, M. Juweid, C. I. Tenkate, D. A. Schwartz, M. M. Hauser, F. E. Gaul, A. J. Fuccello,<br />
R. H. Rubin, H. W. Strauss, A. J. Fischman, J. Nucl. Med. 1990, 31, 2022-2028.<br />
3. M. L. Bowen, C. Orvig, Chem. Commun. 2008, 41, 5077-5091.<br />
4. L. K. Meszaros, A. Dose, S. C. G. Biagini, P. J. Blower, Inorg. Chim. Acta 2010,<br />
DOI:10.1016/j.ica.2010.01.009<br />
5. R. C. King, M. Surfraz, S. Biagini, P. J. Blower, S. J. Mather, Dalton Trans. 2007, 43, 4998-5007.<br />
6. M. Surfraz, R. King, S. J. Mather, S. Biagini, P. J. Blower, J. Inorg. Biochem. 2009, 107, 971-977.<br />
7. R. King, M. B. U. Surfraz, C. Finucane, S. C. G. Biagini, P. J. Blower, J. Nuc. Med. 2009, 50, 591-<br />
598.<br />
52<br />
N<br />
H<br />
N<br />
NH 2·HCl<br />
HCl·H 2N<br />
H<br />
N<br />
HO O<br />
HO O<br />
HO O<br />
HN<br />
HN<br />
N<br />
HN<br />
NH2·HCl NH2 3 4 5 6 7<br />
Fig 2: HYNIC analogues<br />
N<br />
Cl<br />
N<br />
H<br />
N<br />
NH 2·HCl<br />
NH 2·HCl
OP-37<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Fluorescent Conjugates Between Dinuclear Rhenium(I) Complexes and Peptide<br />
Nucleic Acids (PNA) for Cell imaging and DNA Targeting<br />
Emanuela Licandro, *a S. Maiorana, a C. Baldoli, b G. Prencipe, a E. Ferri, a D. Donghi, c M. Panigati, c<br />
G. D’Alfonso, c and L. D’Alfonso d<br />
a Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Venezian 21,<br />
I-20133, Milano, Italy. b Istituto di Scienze e Tecnologie Molecolari, C.N.R., Via C. Golgi 19, I-20133<br />
Milano, Italy. c Dipartimento di Chimica Inorganica, Metallorganica e Analitica, Università degli<br />
Studi di Milano, Via Venezian 21, I- 20133, Milano, Italy. d Dipartimento di Fisica, Università di<br />
Milano-Bicocca, P.za Scienze 6, I-20126 Milan. Italyo.<br />
E-mail: emanuela.licandro@unimi.it<br />
Peptide nucleic acids (PNA) are structural analogues <strong>of</strong> DNA, with pseudo-peptide backbone based on<br />
N-(2-aminoethyl)glycine, which show high binding affinity and specificity for the complementary<br />
DNA and RNA. 1 The conjugation <strong>of</strong> organometallic complexes to biomolecules finds applications<br />
both in diagnostic and therapeutic fields. The incorporation <strong>of</strong> Re(I) complexes into PNA, can <strong>of</strong>fer a<br />
double advantage, due both to its radiochemical and photo-emitting properties.<br />
In this communication we describe the set up <strong>of</strong> the synthesis <strong>of</strong> new PNA-rhenium organometallic<br />
bioconjugates as luminescent compounds for DNA targeting. In particular, we utilized two novel<br />
rhenium complexes, namely [Re2(CO)6(�-Cl)2(�-4-COOH-pyridazine)] and Re2(CO)6(�-Cl)2(�-4-<br />
(CH2)3COOH-pyridazine)], belonging to a recently developed family <strong>of</strong> dimeric luminescent<br />
rhenium(I) complexes, 2 which were conjugated with the tymine PNA monomer and decamer. The<br />
second complex was prepared in order to check the influence <strong>of</strong> the n-propyl chain spacer on the<br />
lifetime and quantum yields <strong>of</strong> the emission <strong>of</strong> the PNA-rhenium bioconjugate. The most fluorescent<br />
Re-PNA conjugate also showed two photon absorption properties as assessed by “in cell” experiments,<br />
that revealed that it permeates the cell membrane, staining both the cytoplasm and the nucleus.<br />
Although more detailed experiments are needed, in order to establish the kinetics <strong>of</strong> the process and to<br />
set a lower limit to the sample concentration to be used, these preliminary results indicate that the Re-<br />
PNA conjugate is viable as a fluorophore for cell imaging.<br />
References<br />
1. Peptide Nucleic Acids; 2nd Ed.; P. E. Nielsen, Ed.; Horizon Bioscience: Norfolk, UK, 2004.<br />
2. D. Donghi, G. D’Alfonso, M. Mauro, M. Panigati, P. Mercandelli, A. Sironi, P. Mussini, L.<br />
D’Alfonso, Inorg. Chem. 2008, 47, 4243-4255.<br />
53
OP-38<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Design <strong>of</strong> Cyclometalated Iridium(III) Polypyridine Complexes as Luminescent<br />
Biological Labels and Probes<br />
Kenneth Kam-Wing Lo<br />
Department <strong>of</strong> Biology and Chemistry, City University <strong>of</strong> Hong Kong, Tat Chee Avenue, Kowloon,<br />
Hong Kong, P. R. China. E-mail: bhkenlo@cityu.edu.hk<br />
Many cyclometalated iridium(III) polypyridine complexes exhibit intense and long-lived emission that<br />
is very sensitive to the molecular structures and local environments <strong>of</strong> the complexes. These<br />
interesting properties allow the complexes to serve as useful probes for various biological molecules<br />
including oligonucleotides, peptides, and proteins. We have attached amine- and sulfhydryl-specific<br />
reactive functional groups such as isothiocyanate, aldehyde, and iodoacetamide to cyclometalated<br />
iridium(III) polypyridine complexes <strong>of</strong> the type [Ir(N^C)2(N^N)] + to yield new luminescent labels for<br />
biomolecules. Additionally, we have designed related iridium(III) polypyridine complexes appended<br />
with various biological substrates including indole, �-estradiol, biotin, and lipids, and utilized the<br />
complexes as luminescent probes for indole-binding proteins, estrogen receptors, avidin, and lipidbinding<br />
proteins, respectively. Some <strong>of</strong> these complexes show interesting dual-emissive properties<br />
that enable the biological binding event to be reflected by a change <strong>of</strong> emission pr<strong>of</strong>iles <strong>of</strong> the probes.<br />
Furthermore, we have recently developed DNA-metallointercalators, dendrimers, and PEGylation<br />
reagents derived from luminescent iridium(III) polypyridine complexes. We have focused on the<br />
molecular design, photophysical properties, biomolecule-binding behavior, cytotoxicity, and cellularuptake<br />
characteristics <strong>of</strong> these luminescent probes.<br />
R 1<br />
R 1<br />
References<br />
C<br />
C<br />
N<br />
Ir<br />
N<br />
N<br />
N<br />
R2<br />
+<br />
Emission Intensity (A. U.)<br />
500 550 600 650 700 750<br />
Wavelength / nm<br />
1. K. K.-W. Lo, K. Y. Zhang, C.-K. Chung, K. Y. Kwok, Chem. Eur. J. 2007, 13, 7110 – 7130.<br />
2. K. K.-W. Lo, P.-K. Lee, J. S.-Y. Lau, Organometallics 2008, 27, 2998 – 3006.<br />
3. K. K.-W. Lo, K. Y. Zhang, S.-K. Leung, M.-C. Tang, Angew. Chem. Int. Ed. 2008, 47, 2213 –<br />
2216.<br />
4. J. S.-Y. Lau, P.-K. Lee, K. H.-K. Tsang, C. H.-C. Ng, Y.-W. Lam, S.-H. Cheng, K. K.-W. Lo,<br />
Inorg. Chem. 2009, 48, 708 – 719.<br />
5. K. Y. Zhang, S. P.-Y. Li, N. Zhu, I. W.-S. Or, M. S.-H. Cheung, Y.-W. Lam, K. K.-W. Lo, Inorg.<br />
Chem. 2010, 49, 2530 – 2540.<br />
54<br />
+ ER�
OP-39<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Subcellular Imaging <strong>of</strong> a Re(CO)3 Complex by Photothermal Infrared<br />
Spectromicroscopy (PTIR).<br />
Anne Vessières, a Clotilde Policar, b Marie-Aude Plamont, a Sylvain Clède, b Alexandre Dazzi c<br />
a ENSCP, CNRS-UMR 7223, 11 rue P. et M. Curie, F-75231 Paris Cedex 05, France, b Département<br />
Chimie de l’ENS, CNRS-UMR 7203, 24 rue Lhomond, F-75231 Paris Cedex 05, c Laboratoire de<br />
Chimie Physique, CNRS-UMR 8000, Université Paris-Sud 11, F-91405 Orsay Cedex,<br />
E-mail: a-vessieres@chimie-paristech.fr<br />
The most widely developed techniques for bio-imaging are those based on fluorescence<br />
spectroscopy, however vibrational techniques including infra-red (IR) are also valuable. However, in<br />
classical optical microscopy, sub-micrometric resolutions are not attainable in the mid-IR-range, as the<br />
diffraction criterion imposes resolution higher than �/2 (i.e. 2.5 µM at 2000 cm -1 ) which is not well<br />
suited for intracellular mapping. To reach sub-micrometric resolution, near-field techniques are<br />
mandatory. Photothermal induced resonance (PTIR) is a cutting edge technique using a set-up recently<br />
patented by Dazzi et al., 1 coupling atomic force microscopy (AFM) and a tunable infrared laser to<br />
make spatially resolved absorption measurements in the IR-range. It has been successfully used to<br />
map a single air-dried E. coli cell by irradiation in the amide I and II bands. 2 The next challenge is the<br />
identification and localization <strong>of</strong> exogeneous diluted compounds inside single cells. The Re(CO)3 unit<br />
grafted to a hydroxy-tamoxifen-like molecule has been selected for this study as it is stable in<br />
biological environments and displays intense absorption in the 1850 – 2100 cm -1 region where<br />
biological samples are transparent.<br />
Figure : left: AFM-set up. middle: PTIR mapping at 1925 cm -1 <strong>of</strong> a single cell incubated 1h with 10<br />
µM <strong>of</strong> the Re(CO)3 complex (red = high concentration) right : spectromicroscopy at the nucleus<br />
We will present the results <strong>of</strong> the chemical imaging <strong>of</strong> this Re complex, inside a single cell,<br />
using PTIR. Cells are initially located on the surface <strong>of</strong> a ZnSe prism by using the AFM topology.<br />
Then the complex is localized thanks to its two characteristic �CO bands at 1925 and 2017 cm -1 . Cells<br />
showed an uneven distribution <strong>of</strong> the complex with one hot spot (red area on the picture above) and<br />
cold regions (blue zones). Interestingly, this location seems to correspond to cell nucleus located using<br />
irradiation at 1240 cm -1 (phosphate band) and 1650 cm -1 (amide I <strong>of</strong> proteins). In addition, a spectrum<br />
recorded inside the hot spot shows the two characteristic bands <strong>of</strong> the complex at 1925 and 2017 cm -1 ,<br />
thus confirming its presence (right part <strong>of</strong> the figure).<br />
References<br />
1. A. Dazzi, M. Reading, P. Rui, K. Kjoller, Patent 2008, WO/2008/143817 A. B. Lastname, C. D.<br />
2. A. Dazzi, R. Prazeres, F. Glotin, J.-M. Ortega, Infrared Physics Techn. 2006, 49, 113.<br />
55
OP-40<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Dynamical Studies <strong>of</strong> Bioconjugated Luminescent Ruthenium Complexes in<br />
Lipid Vesicles<br />
Edward Rosenberg, a Ayesha Sharmin, a J. B. Alexander Ross a<br />
a Department <strong>of</strong> Chemistry and Biochemistry<br />
University <strong>of</strong> Montana, Missoula, MT 59812, USA Email: edward.rosenberg@mso.umt.edu<br />
A detailed analysis <strong>of</strong> the time-resolved anisotropy decay <strong>of</strong> the emission from luminescent molecules<br />
can provide useful information about molecular dynamics in a given media. To obtain such<br />
information, the excited-state lifetime must match the time scale <strong>of</strong> the process being examined and it<br />
is desirable that the time-zero emission anisotropy be in the range <strong>of</strong> 0.1 or greater. In our prior work,<br />
we designed a series <strong>of</strong> phosphorescent ruthenium complexes that have the longer lifetimes, higher<br />
quantum yields and the lower symmetry required for studying the dynamics <strong>of</strong> these probes in lipid<br />
vesicle bilayers. 1 Starting with the complexes [Ru(H)(trans-PPh3)2(dcbpy)CO][PF6] (1) and [Ru(<br />
dppene) (5-amino- phen)CO(TFA)][PF6] (2) (dcbpy = 4,4’-dicarboxy bipyridine, dppene = 1,2diphenylphosphino<br />
ethene, 5-amino phen = 5-amino phenanthroline, TFA = trifluoroacetic acid) we<br />
have used standard techniques to covalently conjugate these molecules to two and one phosphatidyl<br />
ethanolamine molecules, respectively. Complex 2 has also been conjugated to cholesterol via reaction<br />
with cholesterol chlor<strong>of</strong>ormate. Analyses <strong>of</strong> the anisotropy decay as a function <strong>of</strong> temperature from<br />
the conjugated probes in vesicles—made from both naturally occurring and synthetic lipids—reveal<br />
that the lipid conjugates are located within the lipid bilayer while the cholesterol conjugated complex<br />
is at the bilayer-water interface. The rotational correlation times for the complexes are responsive to<br />
the nature <strong>of</strong> the lipid vesicle used and analyses <strong>of</strong> this parameter allowed a detailed picture <strong>of</strong> the<br />
kinds <strong>of</strong> motions <strong>of</strong> the conjugated complex in the vesicle. The lipid conjugates with 1and 2<br />
incorporated into vesicles via extrusion through a size-selective membrane, showed an unexpected<br />
blue-shift in the emission spectra and a corresponding short excited-state lifetime in the range <strong>of</strong> 10 ns;<br />
the lifetimes in solvents are in the range <strong>of</strong> 0.1-2 �s. This unusual phenomenon will be discussed in<br />
terms <strong>of</strong> the properties <strong>of</strong> the excited states in the lipid vesicle environment in contrast to in bulk<br />
solvents. For comparison with complexes 1and 2, related complexes have been conjugated to lipids<br />
and cholesterol via the phosphine ligands, and their photophysical properties in lipid vesicles will also<br />
be presented<br />
References<br />
1. Ayesha Sharmin , Reuben C. Darlington , Kenneth I. Hardcastle, Mauro Ravera, Edward Rosenberg,<br />
J. B. Alexander Ross “Tuning Photophysical Properties with Ancillary Ligands in Ru(II) Mono-<br />
Diimine Complexes,” J. Organometal. Chem. 2009, 694, 988-1000.<br />
56
OP-41<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Multi-Organometallic-Containing Peptide Nucleic Acids: Preparation and<br />
Biological Applications<br />
Gilles Gasser, *a,b Antonio Pinto, b Sebastian Neuman b and Nils Metzler-Nolte *b<br />
a University <strong>of</strong> Zurich, Institute <strong>of</strong> Inorganic Chemistry, Winterthurerstrasse 190, CH-8057 Zurich,<br />
Switzerland. E-mail: gilles.gasser@aci.uzh.ch; b <strong>Ruhr</strong>-University <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and<br />
Biochemistry, Department <strong>of</strong> Bioinorganic Chemistry, <strong>Universität</strong>strasse 150, D-44780 <strong>Bochum</strong>,<br />
Germany.<br />
Peptide nucleic acids (PNAs) are non-natural nucleic acid analogues. Their neutral pseudopeptide<br />
backbone is made <strong>of</strong> N-(2-aminoethyl)glycine units which are ligated via a methylene carbonyl to the<br />
four nucleobases (Figure 1). 1 In comparison to double-stranded DNA (dsDNA), corresponding<br />
PNA•DNA hybrids are thermally more stable due to the missing electrostatic repulsion between the<br />
strands. Moreover, PNA is much more mismatch sensitive than DNA enabling sensitive and selective<br />
mismatches discrimination. All these favourable features led to application <strong>of</strong> PNAs in various<br />
research areas such as antisense and antigene therapies or biosensing.<br />
O<br />
HO P O<br />
O<br />
O<br />
Base<br />
O<br />
O<br />
P<br />
O<br />
O<br />
O<br />
Base<br />
O<br />
O<br />
P<br />
O<br />
O<br />
n<br />
O<br />
Base<br />
OH<br />
57<br />
HO<br />
O O<br />
N<br />
Base<br />
N<br />
H<br />
O O<br />
DNA PNA<br />
Figure 1. Structure comparison between DNA and PNA.<br />
N<br />
Base<br />
N<br />
H<br />
Base<br />
O<br />
O<br />
N<br />
NH2 In order to modify the intrinsic properties <strong>of</strong> PNAs or in order to add new functionalities and/or<br />
spectroscopic properties to PNA oligomers, organometallics have been synthetically attached to these<br />
non-natural DNA analogues. During this talk, we will present our recent advances on the preparation<br />
<strong>of</strong> multi-organometallic-containing PNA monomers and oligomers as well as their potential for<br />
biological purposes (see Figure 2 for an example <strong>of</strong> application <strong>of</strong> metal-containing PNAs). 2-6<br />
Figure 2. Re-containing PNA oligomer mediated the silencing <strong>of</strong> enhanced green fluorescent protein<br />
(eGFP) in HeLa-eGFP cells 48 h after cellular delivery by electroporation. (200 x magnification in all<br />
images)<br />
References<br />
1. P.E. Nielsen, P., M. Egholm, R.H. Berg, O. Buchardt, Science 1991, 254, 1497-1500<br />
2. G. Gasser, N. Hüsken, S.D. Köster and N. Metzler-Nolte, Chem. Comm. 2008, 3675-3677.<br />
3. N. Hüsken, G. Gasser, S.D. Köster and N. Metzler-Nolte, Bioconjugate Chem. 2009, 20, 1578–1586.<br />
4. G. Gasser, O. Brosch, A. Ewers, T. Weyhermüller and N. Metzler-Nolte, Dalton Trans. 2009, 4310-<br />
4317.<br />
5. A. Sosniak, G. Gasser and N. Metzler-Nolte, Org. Biomol. Chem. 2009, 7, 4992 – 5000.<br />
6. M. Patra, G. Gasser, D. Bobukhov, K. Merz, A.V. Shtemenko and N. Metzler-Nolte, 2010, submitted.<br />
n
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Poster presentations<br />
58
P-01<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
In Vitro and In Vivo Anti-tumor Activities <strong>of</strong> Five Coordinated Cyclometallated<br />
Organoplatinum(II) Complexes Containing Biphosphine Ligands<br />
Hamidreza Samouei, a Mehdi Rashidi,* a Q. Ping Dou, *b Michael Frezza, b Yan Xiao, b<br />
amd Frank W. Heinemann c<br />
a Chemistry Department, College <strong>of</strong> Sciences, Shiraz University, Shiraz 71454, Iran. b Department <strong>of</strong><br />
Pathology, School <strong>of</strong> Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, Detroit,<br />
USA. c Institut fuer Anorganische Chemie, Universitaet Erlangen-Nuernberg, Egerlandstrasse 1, D-<br />
91058 Erlangen, Germany. E-mail:samouei@gmail.com<br />
Ever since Rosenberg in late 1960s discovered the anti-tumor activity <strong>of</strong> cisdiamminedichloroplatinum(II),<br />
cis-[Pt(NH3)2Cl2] known as cisplatin, 1 many other Pt complexes have<br />
been designed, synthesized and tested in order to circumvent the cisplatin acquired resistance, side<br />
effects, toxicity and low water solubility in order to increase the efficacy <strong>of</strong> the drug. 2 Most platinum<br />
complexes being used as therapeutic agents usually contain amine (with at least one N-H bond)<br />
ligands, 3 but the analogous complexes containing phosphine ligands are not unusual in these kinds <strong>of</strong><br />
applications. 3b,4 Many attempts have been made during the past 3 decades to synthesize new<br />
complexes <strong>of</strong> platinum and other transition metals (such as Ru) to overcome the difficulties associated<br />
with cisplatin. For example some cyclometallated Pt(II) complexes have recently been used as active<br />
cytotoxic anticancer drugs. 4,5 The use <strong>of</strong> phosphine ligands instead <strong>of</strong> amines has recently been<br />
envisaged, in particular because a large number <strong>of</strong> gold complexes containing phosphine ligands have<br />
successfully been used as therapeutic agents. 4,6<br />
In the present study, we report two novel cyclometallated Pt(II) complexes containing biphosphine<br />
ligands with unique structural features that are more potent than cisplatin in relation to their anti-tumor<br />
activity and have also been found to exhibit proteasome-inhibitory activities in vitro and in vivo. We<br />
also have suggested a potential relationship between the structure <strong>of</strong> the complexes and their cytotoxic<br />
effects.<br />
References<br />
1. B. Rosenberg, L. VanCamp, J.E. Trosko and V.H. Mansour, Nature 1969, 222, 385-386.<br />
2. K. S. Lovejoy, S. J. Lippard, Dalton Trans. 2009, 10651-10659.<br />
3. (a) P. J. Miguel, M. Roitzsch, L. Yin, P. M. Lax, L. Holland, O. Krizanovic, M. Lutterbeck, M.<br />
Schurmann, E. C. Fusch, B. Lippert, Dalton Trans. 2009, 10774-10786; (b) J.C. Shi, C.H. Yueng,<br />
D.X. Wu, Q.T. Liu, and B.S. Kang, Organomet. 1999, 18, 3796-3801.<br />
4. R. W.Y. Sun, D. Ma, E. L. M. Wong, C. M. Che, Dalton Trans. 2007, 4884-4892.<br />
5. T.Okada, I.M.El-Mehasseb, M.Kodaka,, T.Tomohiro, K.Okamoto, H.Okuno, J. Med. Chem. 2001,<br />
44, 4661-4667.<br />
6. (a) L. C. Eiter, N. W. Hall, C. S. Day,G. Saluta, G. L. Kucera, U. Bierbach, J. Med. Chem. 2009, 52,<br />
6519-6522; (b) C. P. Bagowski, Y. You, H. Scheffler, D. H. Vlecken, D. J. Schmitz, I. Ott, Dalton<br />
Trans, 2009, 10799-10805.<br />
59
P-02<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Degradation <strong>of</strong> Platinum-Based Anticancer Drugs by Thiosulfate Ions:<br />
an EXAFS Study<br />
Diane Bouvet- Muller, a A. Michalowicz, a S.Crauste-Manciet, b,c and K. Provost a<br />
a Institut de Chimie et des Matériaux Paris Est, ICMPE/SAX, UMR 7182 CNRS-Paris Est, 2 à 8 rue<br />
Henri Dunant, 94320 Thiais, France, b Laboratoire de Pharmacie Galénique, Université Paris V,<br />
75006 Paris, France, c Service de Pharmacie, CHI Poissy Saint Germain en Laye, 78105 Saint<br />
Germain en Laye, France. E-mail: muller@u-pec.fr<br />
Three platinum complexes are currently used worldwide: cisplatin, carboplatin and oxaliplatin. 1<br />
Cisplatin is the most common, and its reactivity has been widely studied. On the contrary, derivatives<br />
<strong>of</strong> carboplatin and oxaliplatin deserve to be structurally characterized in order to understand their<br />
mode <strong>of</strong> action and stability in solution. This study takes place in the work carried out by our group on<br />
the behavior <strong>of</strong> these platinum complexes in presence <strong>of</strong> various halogen and sulfur ligands. 2-4<br />
These drugs react rapidly with nucleophilic species in solution. Their degradation has two<br />
consequences: in vitro, it can compromise the stability <strong>of</strong> the drug in solution before administration; in<br />
vivo, the structural modification <strong>of</strong> these molecules can induce notable changes in their modes <strong>of</strong><br />
action. Sulfur nucleophilic ligands are particularly interesting: 5 they play a major role in the<br />
detoxification <strong>of</strong> the drugs. Particularly, thiosulfate ions are used to prevent nephro- and ototoxicity. 6<br />
This study deals with the reaction <strong>of</strong> carboplatin and oxaliplatin with thiosulfate. For both drugs, the<br />
reaction products remain in solution. Thus we used X-ray absorption spectroscopy in order to<br />
characterize their structures. Spectra have been recorded for different reaction times (from one hour to<br />
one month) and for different drug/thiosulfate ratios (from 1/2 to 1/40). For a 1/2 ratio at one month <strong>of</strong><br />
reaction, we observe the displacement <strong>of</strong> the carboxylate ligand for both drugs,and a strong similarity<br />
<strong>of</strong> the signal between 3 and 4 Å. This EXAFS signal can be used as a signature <strong>of</strong> the Pt-Thiosulfate<br />
binding, in order to model the complete reaction products structures in solution.<br />
On this basis, the spectral and structural evolution as a function <strong>of</strong> the reaction time on one hand and<br />
<strong>of</strong> the drug/thiosulfate ratio on the other hand are discussed.<br />
References<br />
1. L.R. Kelland, Nat. Rev. Cancer 2007, 7, 573-584.<br />
2. D.Bouvet, A. Michalowicz, S. Crauste-Manciet, D. Brossard, K. Provost. Inorg. Chem 2006,<br />
45, 3393-3398.<br />
3. D. Bouvet et al. J. Synchr. Rad. 2006, 13, 477-483.<br />
4. K. Provost et al. Biochimie 2009, 91, 1301-1306.<br />
5. J. Reedjik, Chem. Rev. 1999, 99, 2499-2510.<br />
6. D.J. Leitao, B.W. Blakley. Journal <strong>of</strong> Otolaryngology 2003, 32, 146-150.<br />
60
P-03<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Biological Activity <strong>of</strong> Enantiomeric Complexes [PtCl2L2]<br />
(L2 = Aromatic Bisphosphanes and Aromatic Diamines)<br />
Luca Gaviglio, a Sophie Bombard, b Marzia Bruna Gariboldi, c Elena Monti, c Elisabetta Gabano, a<br />
Mauro Ravera, a amd Domenico Osella a<br />
a University <strong>of</strong> Piemonte Orientale “A. Avogadro”, Department <strong>of</strong> Environmental and Life Sciences,<br />
Viale Michel 11, 15121, Alessandria, Italy. b Université Paris Descartes, Laboratoire de Chimie et<br />
Biochimie Pharmacologiques et Toxicologiques, 45, Rue des Saints-Pères, 75006 Paris, France.<br />
c Department <strong>of</strong> Structural and Functional Biology, University <strong>of</strong> Insubria, Section <strong>of</strong> Pharmacology,<br />
Via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. E-mail: luca.gaviglio@mfn.unipmn.it<br />
Enantiomeric complexes <strong>of</strong> formula [PtCl2L2] (L2 = R-(+)- and S-(-)-BINAP, where BINAP = 2,2’bis(diphenylphosphane)-1,1’-binaphthyl,<br />
and R-(+)- and S-(-)-DABN, where DABN = 1,1'binaphthyl-2,2'-diamine,<br />
were tested for their cytotoxic activity against three cancer cell lines and for<br />
their ability to bind to the human telomeric sequence folded in the G-quadruplex structure. Similar<br />
experiments were carried out on prototypal complexes cisplatin and cis-[PtCl2(PPh3)2] for comparison.<br />
Pt-complexes containing phosphanes proved less cytotoxic against cancer cell lines and less likely to<br />
interact with the nucleobases <strong>of</strong> the G-quadruplex than those containing amines; in both cases the S-(-<br />
)-isomer was more active than the R-(+)-counterpart. More specifically, whereas all the platinum<br />
complexes were able to platinate the G–quadruplex structure from the human telomeric repeat, the<br />
extent and sites <strong>of</strong> platination depended on the nature <strong>of</strong> the ligands. Complexes containing (bulky)<br />
phosphanes interacted only with the adenines <strong>of</strong> the loops, while those containing the less sterically<br />
demanding amines interacted with adenines and some guanines <strong>of</strong> the G-quartet. 1<br />
References<br />
1. S. Bombard, M. B. Gariboldi, E. Monti, E. Gabano, L. Gaviglio, M. Ravera, D. Osella, J. Biol.<br />
Inorg. Chem., 2010, in press, doi: 10.1007/s00775-010-0648-8.<br />
61
P-04<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Organometallic Palladium(II) Complexes Containing Tridentate [C,N,S]<br />
Thiosemicarbazone Ligands: Synthesis, Structure and Antimalarial activity<br />
Prinessa Chellan, a Kelly Chibale, a,b and Gregory S. Smith *a<br />
a University <strong>of</strong> Cape Town, Faculty <strong>of</strong> Science, Department <strong>of</strong> Chemistry, Private Bag, Rondebosch<br />
7701, South Africa, b Institute <strong>of</strong> Infectious Disease and Molecular Medicine, University <strong>of</strong> Cape<br />
Town, Rondebosch 7701, South Africa. E-mail: prinessa.chellan@uct.ac.za<br />
Thiosemicarbazones (TSCs) are Schiff base type compounds that are noted for their pharmacological<br />
properties, particularly as antiparisital, 1 antibacterial 2 and antitumoral agents. 3 The antiplasmodial<br />
activity <strong>of</strong> thiosemicarbazones against Plasmodium falciparum strains has been reported. 4 However,<br />
reports on the use <strong>of</strong> thiosemicarbazone metal complexes as antimalarial agents are sparse.<br />
In this presentation, we report the synthesis, characterisation and antimalarial study <strong>of</strong> mono-, di- and<br />
tetrameric cyclopalladated [C,N,S] Pd(II) complexes prepared from two thiosemicarbazone ligands,<br />
3,4-dichloroacetophenone thiosemicarbazone (1, Scheme 1) and 3,4-dichloropropiophenone<br />
thiosemicarbazone (2), which have previously been screened for biological activity. 5 Attendant<br />
questions to be addressed in this presentation are, whether coordination <strong>of</strong> these compounds to<br />
palladium enhances their inhibitory effects and if the number <strong>of</strong> thiosemicarbazone Pd(II) complex<br />
moieties per molecule would increase antiplasmodial activity.<br />
References<br />
Cl<br />
Cl<br />
4<br />
3<br />
Scheme 1<br />
5<br />
2<br />
1<br />
R<br />
Cl<br />
Cl<br />
N<br />
Pd<br />
Cl<br />
Cl<br />
PPh 3<br />
4<br />
3<br />
PPh 3 / Acetone<br />
5: R = CH 3<br />
6: R = CH 2CH 3<br />
N NH 2<br />
S<br />
5<br />
2<br />
R<br />
R<br />
N<br />
H<br />
N NH 2<br />
6<br />
N<br />
N NH2 3: R = CH3 4: R = CH2CH3 1<br />
Pd S<br />
Cl<br />
R<br />
5<br />
62<br />
S<br />
K 2[PdCl 4] / EtOH-H 2O<br />
4<br />
6<br />
3<br />
N<br />
R.T.<br />
Cl<br />
N<br />
1<br />
2<br />
4<br />
P P / Acetone<br />
Pd<br />
S<br />
NH 2<br />
P<br />
1: R = CH 3<br />
2: R = CH 2CH 3<br />
P<br />
H 2N<br />
S<br />
P P = bis(diphenylphoshino)ferrocene (7 and 8);<br />
trans-bis(diphenylphosphino)ethylene (9 and 10);<br />
bis(diphenylphosphino)benzene (11 and 12)<br />
Pd<br />
N<br />
Cl<br />
N<br />
7, 9, 11: R = CH 3<br />
8, 10, 12: R = CH 2CH 3<br />
1. K. J. Duffy, A. N. Shaw, E. Delorme, S. B. Dillon, C. Erickson-Miller, L. Giampa, Y. Huang, R. M. Keenan,<br />
P. Lamb, N. Liu, S. G. Miller, A. T. Price, J. Rosen, H. Smith, K. J. Wiggall, L. Zhang and J. I. Luengo, J.<br />
Med. Chem. 2002, 45, 3573-3578.<br />
2. X. Du, C. Guo, E. Hansel, P.S. Doyle, C.R. Caffery, T.P. Holler, J. H. McKerrow and F.E. Cohen, J. Med.<br />
Chem. 2002, 45, 2695-2707.<br />
3. D. Kovala-Demertzi, M.A. Demertzis, E. Filou, A.A Pantazaki, P.N. Yadav, J.R. Miller, Y. Zheng and D.A.<br />
Kyriakidis, Biometals 2003, 16, 411-418.<br />
4. For example, A. Walcourt, M. Loyevsky, D. B. Lovejoy, V. R. Gordeuk and D. R. Richardson, Int. J.<br />
Biochem. Cell Biol. 2004, 36, 401-407.<br />
5. For example, N. Fujii, J. P. Mallari, E. J. Hansell, Z. Mackey, P. Doyle, Y. M. Zhou, J. Gut, P. J. Rosenthal,<br />
J. H. McKerrow and R. K. Guy, Bioorg. Med. Chem. Lett. 2005, 15, 121-123.<br />
R<br />
Cl
P-05<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Solid-State Synthesis <strong>of</strong> Peptide-Tethered Pt(IV) Complexes<br />
and Their Cytotoxic Properties<br />
Sergey Abramkin, a Markus Galanski, a and Bernhard Keppler *a<br />
a University <strong>of</strong> Vienna, Faculty <strong>of</strong> Chemistry, Department <strong>of</strong> Inorganic Chemistry, Währingerstrase<br />
42, 1090, Vienna, Austria. E-mail: sergey.abramkin@univie.ac.at<br />
Platinum-based drugs play an essential role in cancer treatment since the discovery <strong>of</strong> the anticancer<br />
drug cisplatin. Subsequent development <strong>of</strong> complexes resulted in three generations <strong>of</strong> drugs, the last<br />
one to be approved by the FDA was oxaliplatin. Side effects remain one <strong>of</strong> the main shortcomings <strong>of</strong><br />
chemotherapy, arising from lack <strong>of</strong> specificity and inefficient cell entry.<br />
Short peptides can be used for targeting and transportation <strong>of</strong> drug molecules. They can change not<br />
only the basic parameters like lipophilicity or water solubility, but even more complex interactions <strong>of</strong><br />
drugs with the microenvironment can be influenced. The axial ligands <strong>of</strong> Pt (IV) are the optimal site<br />
for derivatization: upon reduction they are cleaved from the prodrug, and the Pt(II) complex is<br />
released.<br />
Inefficient cell entry is the reason for higher dosage <strong>of</strong> drugs, however stimulated uptake will increase<br />
the amount <strong>of</strong> the drug, reaching the intracellular target. Cell-penetrating peptides can be used for<br />
intracellular delivery <strong>of</strong> Pt complexes; the TAT peptide is the best studied example <strong>of</strong> this group.<br />
Selectivity can be achieved using the peptides as delivery vectors. High expression <strong>of</strong> the GRP<br />
receptor in many tumors (prostate, lung, breast) makes it an interesting target for platinum conjugates.<br />
The short peptide bombesin was chosen for conjugation to Pt to investigate its influence on cytotoxic<br />
properties.<br />
H 2<br />
N<br />
N<br />
H 2<br />
O<br />
Pt<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
OH<br />
OH<br />
R<br />
R = TAT47-57(YGRKKRRQRRR) or Bombesin(QWAVGHLM)<br />
Solid-phase synthesis is a commonly used method for the preparation <strong>of</strong> peptides and their conjugates.<br />
Oxaliplatin was oxidized and two uncoordinated carboxyl groups were introduced, thereafter the<br />
complex was reacted with polymer-bound TAT and bombesin. Cleavage with TFA and purification<br />
afforded mono- and bisconjugates, characterized with ESI-MS, NMR and analytical HPLC. Synthesis<br />
and cytotoxic properties will be presented.<br />
The support <strong>of</strong> COST, the FWF, the FFG and the Austrian Council for Research and Technology<br />
Development is gratefully acknowledged.<br />
63<br />
H 2<br />
N<br />
N<br />
H 2<br />
O<br />
Pt<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
OH<br />
+<br />
R<br />
H 2<br />
N<br />
N<br />
H 2<br />
O<br />
Pt<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
O<br />
R<br />
R
P-06<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Response Pr<strong>of</strong>ile <strong>of</strong> Cancer Cells to Cisplatin Treatment<br />
Hamed Alborzinia, a Pavlo Holenya a and Stefan Wölfl *a<br />
a Ruprecht-Karls-<strong>Universität</strong> Heidelberg, Institute <strong>of</strong> Pharmacy and Molecular Biotechnology,<br />
Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany<br />
E-mail: hamed.alborzinia@uni-heidelberg.de, wolfl@uni-hd.de<br />
The cell based sensor chip system BIONAS® 2500 <strong>of</strong>fers the ability to measure three important<br />
parameters <strong>of</strong> cellular metabolism on line in living cell cultures: (i) glycolytic flux measured as pH<br />
change; (ii) cellular respiration (mitochondrial activity) measured as oxygen consumption; and (iii)<br />
cellular morphology, adhesion and membrane function measured as cellular impedance. These<br />
parameters are analyzed with metabolic sensor chips (SC1000) that feature the following analytical<br />
tools: (i) ion-sensitive field effect transistors (ISFETs) to record pH changes; (ii) oxygen electrodes to<br />
monitor oxygen consumption; and (iii) interdigitated electrode structures (IDES) to measure<br />
impedance under the cell layer. Cells are grown on the chip surface and all parameters are measured<br />
continuously with the electrodes on the chip surface. To work under stable conditions the medium is<br />
exchanged in short cycles with an automated fluidic system.<br />
We use this system to measure changes in cellular metabolism and morphology in response to<br />
treatment with cisplatin in different cell lines on line. Cisplatin treatment shows a well defined onset<br />
<strong>of</strong> change in acidification and impedance at about 7h and 10h respectively after treatment is started. At<br />
these time points we collected cells for further analysis <strong>of</strong> specific signalling pathways and gene<br />
expression. Protein phosphorylation <strong>of</strong> growth related signalling pathways was analyzed with a<br />
phosphoprotein ELISA micro array. Gene expression was analyzed using whole genome Affymetrix<br />
Gene Expression micro arrays.<br />
This work was in part supported by the BMBF (FKZ 01 EA 0509: “Nutrition.Net”) and the DFG<br />
Forschergruppe FOR630.<br />
64
P-07<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Development <strong>of</strong> Novel [Diarylsalene]- and [Salophene]platinum(II) Complexes<br />
as Cytotoxic Agents<br />
Maria Proetto a amd Ronald Gust *a<br />
a Institute <strong>of</strong> Pharmacy, Freie <strong>Universität</strong> Berlin, Königin-Luise-Str. 2 + 4, 14195 Berlin, Germany<br />
Breast cancer is the most common cancer in women. 1 Platinum-based drugs are widely used against<br />
various solid tumours, but they are inactive against breast cancer.<br />
In this project, new platinum analogues have been synthesized in an attempt to overcome this problem.<br />
The complexes were tested in vitro for growth inhibitory activity on both hormone dependent MCF-7<br />
(ER+) and hormone independent MDA-MB-231 (ER-) breast cancer cells to determine possible<br />
selective effects.<br />
Based on the experience <strong>of</strong> the coordination chemistry <strong>of</strong> Schiff base ligands with different metals,<br />
we chose diarylsalene and salophene as ligands and synthesized two types <strong>of</strong> platinum complexes<br />
(Figure 1). Variations <strong>of</strong> the substituents in the aromatic rings were made to evaluate their significance<br />
for the cytotoxic pr<strong>of</strong>ile. In order to understand the mode <strong>of</strong> action <strong>of</strong> these [diarylsalene]platinum(II)<br />
and [salophene]platinum(II) complexes, they were tested in vitro for DNA-binding and DNAintercalation.<br />
R'<br />
R<br />
References<br />
N N<br />
Pt<br />
O O<br />
R<br />
R'<br />
Figure 1<br />
1. World Health Organization International Agency for Research on Cancer. "World Cancer Report"<br />
2003.<br />
2. R. Gust, I. Ott, D. Posselt, K. Sommer, J. Med. Chem. 2004, 47, 5837-5846.<br />
3. A. Hille, I. Ott, A. Kitanovic, I. Kitanovic, H. Alborzina, E. Lederer, S. Wölfl, N. Metzler-Nolte, S.<br />
Schäfer, W.S. Sheldrick, C. Bisch<strong>of</strong>, U. Schatzschneider, R. Gust, J. Biol. Inorg. Chem. 2009, 14, 711-<br />
725.<br />
65<br />
R''<br />
N N<br />
Pt<br />
O O<br />
[diarylsalene]Pt(II) complexes [salophene]Pt(II) complexes<br />
R'''<br />
R''<br />
2, 3
P-08<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Following Investigations <strong>of</strong> Antiradical and Bioconjugative Properties <strong>of</strong><br />
Cluster Rhenium Compounds<br />
Alexander V. Shtemenko, a Alexander A. Golichenko, a and Nataliia I. Shtemenko b<br />
a Department <strong>of</strong> Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin<br />
Ave. 8, Dnipropetrovs’k 49005, Ukraine., b Department <strong>of</strong> Biophysics and Biochemistry,<br />
Dnipropetrovs’k National University, 72 Gagarin avenue, Dnipropetrovs’k 49010, Ukraine, E-mail:<br />
shtemenko@ukr.net<br />
Antiradical and bioconjugative properties <strong>of</strong> the five structural types <strong>of</strong> cluster dirhenium(III)<br />
compounds with halide, carboxylate and phosphate ligands were described. Antiradical properties <strong>of</strong><br />
these substances occurred by δ-component <strong>of</strong> quadruple Re-Re bond ( �2�� bonds ) and was welldetectable<br />
in electronic absorption spectra (EAS) due to ���* transition (20000 - 14000 cm -1 ). It has<br />
been shown that the binuclear cluster fragment Re2 6+ actively reacts with artificial radicals in vitro,<br />
however the rate <strong>of</strong> such interaction strongly depended from the ligand environment <strong>of</strong> the cluster<br />
Re2 6+ -centre. The reaction rate decreased with an increase <strong>of</strong> induction effects <strong>of</strong> alkyl groups in the<br />
carboxylic ligands. The mechanism <strong>of</strong> antiradical action <strong>of</strong> Re2 6+ -derivatives may be explained by the<br />
transition <strong>of</strong> an unpaired electron <strong>of</strong> a synthetic radical to a δ-orbital <strong>of</strong> the Re2 6+ fragment, thus<br />
decreasing the Re-Re bond order. Cluster rhenium compounds revealed their antiradical properties in<br />
the model <strong>of</strong> tumor growth. We consider that antiradical properties <strong>of</strong> the rhenium compounds may<br />
also play a leading role in their antitumor properties. Recent investigations showed that the antiradical<br />
properties <strong>of</strong> rhenium compounds in vivo depended from the structure <strong>of</strong> the compounds, but this<br />
dependence did not coincide with that obtained from the investigations with artificial radicals shown<br />
herein and was more complex due to multidirectional interactions in living cells. Presented data<br />
showed positive future prospects for Re2 6+ -substances applications as therapeutic agents due to their<br />
low toxicity and antiradical activity.<br />
Very important was the fact that EAS gave information about the quadruple rhenium - rhenium bond<br />
mode <strong>of</strong> substitution that was used in the bioconjugative investigations. Different structural types <strong>of</strong><br />
Re2 6+ -derivatives had the characteristic absorption maxima, which position were dependent from the<br />
quantity <strong>of</strong> hyperconjugated cycles around Re2 6+ -centre. The effect <strong>of</strong> hyperconjugation is realized<br />
due to the interaction <strong>of</strong> the delocalized �-bond <strong>of</strong> �-carboxylic ligands group and the �-component<br />
<strong>of</strong> the Re-Re bond. Bidentate coordinated tetra-�-phosphates [Re2(HPO4)4(H2O)2] 2- and<br />
[Re2(HPO4)2(H2PO4)2(H2O)2] .. 4H2O had the δ→δ* absorption band in the area 15625 см -1 , that<br />
corresponded to the existence <strong>of</strong> two hyperconjugated cycles around Re2 6+ - centre. These facts were<br />
used by us to show what was happened to the quadruple bond during formation <strong>of</strong> liposomes and<br />
interactions with lipids. The mechanism <strong>of</strong> interaction between nucleic bases and rhenium(III)<br />
compounds was studied and another mechanism <strong>of</strong> the interactions in comparison with platinides was<br />
demonstrated. Some experiments with proteins were also discussed. Thus, quadruple Re-Re bond<br />
<strong>of</strong>fers unique opportunities to study processes <strong>of</strong> bioconjugation.<br />
66
P-09<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Lead Structure Development <strong>of</strong> Cytotoxic ([9]aneS3)Rh(III) Compounds<br />
Containing Polypyridyl and Related Ligands<br />
Ruth Bieda, a Andreas Meyer, b Ingo Ott, b and William S. Sheldrick *a<br />
a <strong>Ruhr</strong> <strong>Universität</strong> <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong> Analytical<br />
Chemistry, <strong>Universität</strong>sstraße 150, 44780 <strong>Bochum</strong>, Germany. b Technische <strong>Universität</strong> Braunschweig,<br />
Institute <strong>of</strong> Pharmaceutical Chemistry, Beethovenstraße 55 ,38106 Braunschweig, Germany.<br />
E-mail:ruth.bieda@rub.de<br />
Various compounds <strong>of</strong> the type [RhCl(LL)([9]aneS3)] 2+ (LL = bpy, bpm, phen, tap, dpq, dppz)<br />
containing the tridentate ligand [9]aneS3 were prepared with the goal <strong>of</strong> establishing structure-activity<br />
relationships with regard to their DNA interaction and cytotoxic activity. 1 Polypyridyl ligands <strong>of</strong><br />
different size and length were used as well as diamine and thiaether ligands. Recently published data<br />
have revealed that rhodium(III) complexes containing polypyridyl ligands, which were previously well<br />
known for their intercalating DNA binding properties, also exhibit pronounced cytotoxic activity. 2<br />
For the determination <strong>of</strong> structure-activity relationships, modified ligands similar to 2,2’-bipyridine<br />
were also investigated. For instance, the organometallic compound containing the ligand 2phenylpyridine<br />
reduces the overall charge <strong>of</strong> the compounds to +1, a change that could lead to an<br />
improvement in the cellular uptake. The biological properties <strong>of</strong> this complex were compared with<br />
those <strong>of</strong> the analogous 2,2’-bipyridine and 2,2’- bipyrimidine compounds.<br />
Interactions <strong>of</strong> the cytotoxic ([9]aneS3)Rh(III) complexes with DNA were investigated by CD, UV/Vis<br />
and NMR spectroscopy and by gel electrophoresis. Peptide interaction due to covalent binding<br />
following chloride exchange were also established by ESI-MS. IC50 values toward the cancer cells<br />
MCF-7 and HT-29 as well as toward the human embryonic kidney cells HEK-293 were determined<br />
using the crystal violet assay. Apoptosis induction was ascertained for non-adherent BJAB lymphoma<br />
cells and healthy leukocytes. The studies indicate dramatic differences in cytotoxic activity and cell<br />
selectivity within the ligand series LL = bpm, bpy, 2-phenylpyridine. A very high cell selectivity<br />
towards malign lymphoma cells was established for LL = bpm. The complexes induce apoptosis by<br />
the intrinsic mitrochondrial pathway and cause negligible necrosis.<br />
References<br />
S<br />
S<br />
S<br />
Rh<br />
Cl<br />
N<br />
+ 2+<br />
67<br />
Rh<br />
2-phenylpyridine 2,2’-bipyrimidine<br />
1. R. Bieda, I. Ott, M. Dobroschke, A. Prokop, R. Gust, W. S. Sheldrick, J. Inorg. Biochem. 2009,<br />
103, 698-708.<br />
2. (a) M. Harlos, I. Ott, R. Gust, H. Alborzinia, S. Wölfl, A. Kromm, W. S. Sheldrick, J. Med. Chem.<br />
2008, 51, 3924-3933. (b) R. Bieda, I. Ott, R. Gust, W. S. Sheldrick, Eur. J. Inorg. Chem. 2009, 3821-<br />
3831.<br />
S<br />
S<br />
S<br />
Cl<br />
N<br />
N<br />
N<br />
N
P-10<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Octahedral Ruthenium Complexes as Protein Kinase Inhibitors<br />
Sebastian Blanck a and Erik Meggers* a<br />
a Philipps-<strong>Universität</strong> Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35043 Marburg,<br />
Germany. E-mail: sebastian.blanck@chemie.uni-marburg.de<br />
Protein kinases are an important target in the field <strong>of</strong> medicinal chemistry. Since protein<br />
phosphorylation represents a key step in many crucial cellular processes, the synthesis <strong>of</strong> potent and<br />
selective kinase inhibitors has become more and more important. The ATP competitive<br />
indolocarbazole alkaloid staurosporine is a potent but rather unselective inhibitor. Meggers et al. have<br />
pioneered the design <strong>of</strong> inert and rigid organometallic complexes using staurosporine as a lead<br />
structure (Figure 1). 1<br />
Figure 1: Staurosporine as lead structure for octahedral metal complexes as kinase inhibitors.<br />
By varying the ligands A-D around the metal center the preference for certain kinases can be<br />
changed. 2 Thus it is possible to synthesize a variety <strong>of</strong> different kinase inhibitors using combinatorial<br />
chemistry. The octahedral complex 1 has been found to be a good inhibitor for the protein kinase<br />
GSK-3. GSK-3 has been shown to be a key component <strong>of</strong> the signal transduction in the insulin and<br />
wnt signalling pathways. 3 1 is significantly more potent for the α-is<strong>of</strong>orm (IC50 = 8 nM) over the βis<strong>of</strong>orm<br />
(IC50 = 50 nM), which is astonishing because GSK-3α and GSK-3β show 97% sequence<br />
identity in the ATP-binding pocket. By using molecular modeling and structure based drug design it<br />
was possible to increase the potency against GSK-3α by almost an order <strong>of</strong> magnitude (IC50 = 1 nM),<br />
while the is<strong>of</strong>orm selectivity remained the same. The amino group <strong>of</strong> the complex is very important<br />
for the binding to the kinase since a protection <strong>of</strong> the functional group results in a complete loss <strong>of</strong><br />
inhibition as in metal complex 3 (Figure 2).<br />
References<br />
Figure 2: 2-(Aminomethyl)pyridine complexes as kinase inhibitors.<br />
1. E. Meggers, G. E Atilla-Gokcumen, H. Bregman, Synlett 2007, 8, 1177.<br />
2. H. Bregman, P. J. Carroll, E. Meggers, J. Am. Chem. Soc. 2006, 128, 877.<br />
3. N. Pagano, J. Maksimoska, E. Meggers, Org. Biomol. Chem. 2007, 5, 1218<br />
68
P-11<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis, Characterizatiotion and Biological Evaluation <strong>of</strong> New Organometallic<br />
Rhenium(I) Complex with Ferulic Acid<br />
Dmytro Bobukhov, a Maksym Izumsky, a and Alexander Shtemenko *a<br />
a Ukrainian State Chemical Technological University, Department <strong>of</strong> Inorganic Chemistry, Gagarin<br />
Avenue 8, 49005, Dnipropetrovs’k, Ukraine. E-mail: dbobukhov@googlemail.com<br />
The aqueous chemistry <strong>of</strong> the organometallic cation [Re(CO)3(H2O)3] + has received much attention<br />
over the past decade, due to its relevance to the design <strong>of</strong> 186/188 Re radiopharmaceuticals as well as its<br />
ability to act as a surrogate for the chemistry <strong>of</strong> [ 99m Tc(CO)3] + . In many cases, these investigations<br />
have focused on reactions between biomolecules and [Re(CO)3(H2O)3] + . The attractiveness <strong>of</strong> this<br />
low-valent precursor results from its particularly high thermodynamic stability, that is, high<br />
substitution stability <strong>of</strong> CO ligands and substitution lability <strong>of</strong> water molecules, which can be easily<br />
replaced by a variety <strong>of</strong> mono, bis, and tridentate ligands <strong>of</strong> different size, shape, and donor atom sets. 1<br />
Here we report the synthesis, characterization and biological evaluation <strong>of</strong> new rhenium(I) complex<br />
with ferulic acid (3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid, C10H10O4). Ferulic acid is a<br />
phenolic acid <strong>of</strong> low toxicity, it can be absorbed and easily metabolized in the human body. Ferulic<br />
acid has been reported to have many physiological functions, including antioxidant, antiinflammatory,<br />
antithrombosis, and anticancer activities. 2 Because <strong>of</strong> these properties and its low<br />
toxicity, we decided to study interaction between trans-ferulic acid and [Re(CO)3(H2O)3] + cation, and<br />
possibility <strong>of</strong> using phenolic acid – rhenium(I) complexes in biomedicine. The corresponding complex<br />
was synthesized in a stepwise manner from [Re(CO)3(H2O)3]Br and trans-ferulic acid in methanol.<br />
The compound has been characterized by 1 H NMR, ESI-MS and IR spectroscopy. Crystal structure<br />
and biological activity <strong>of</strong> the corresponding complex will be discussed.<br />
References<br />
1. S. Alves, A. Paulo, J. D. G. Gorreia, L. Gano, C. J. Smith, T. J. H<strong>of</strong>fman, I. Santos, Bioconjugate<br />
Chem. 2005, 16, 438-449.<br />
2. S. Ou, K.-C. Kwok, J. Sci. Food Agric. 2004, 84, 1261-1269.<br />
69
P-12<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis <strong>of</strong> Ferrocene Peptide Conjugates and their Application as Inhibitors <strong>of</strong><br />
Peptide Association<br />
Samaneh Beheshti, a and Heinz-Bernhard Kraatz a<br />
a The University <strong>of</strong> Western Ontario, Faculty <strong>of</strong> Science, Department <strong>of</strong> Chemistry, 1151 Richmond St,<br />
N6A 5B7, London, Ontario, Canada. Email: sbehesh@uwo.ca<br />
The amyloid beta peptide (Aβ) with 40-42 amino acids is the major constituent <strong>of</strong> plaques found in<br />
the brain <strong>of</strong> people affected with Alzheimer’s disease. 1 There is a hypothesis that conformational<br />
switching from α-helical to β-sheet ultimately leads to amyloid fibril formation . On this basis, finding<br />
compounds that are able to destabilize the β-sheet structure and to interfere with the assembly <strong>of</strong><br />
peptide strands is a useful strategy to prevent peptide aggregation and fibril formation. Synthetic<br />
peptides have been reported as β-sheet breakers that preclude amyloid formation. 2 For example, a<br />
novel pentapeptide inhibitor that has a proline in place <strong>of</strong> valine and an aspartic acid in place <strong>of</strong><br />
alanine in the Aβ17-21 (Leu-Val-Phe-Phe-Ala) fragment has been reported with the ability to inhibit the<br />
formation <strong>of</strong> amyloid fibrils. 3 In this work, a series <strong>of</strong> Fc-peptide conjugates is prepared <strong>of</strong> the type<br />
FcCO-Val-Phe-Phe-OR (1:R = Me, 2:R = H), Fc[CO-Val-Phe-Phe-OR]2 (3:R = Me, 4:R = H), Fc[CO-<br />
Val-Phe-OR]2 (5:R = Me, 6:R = H) and Fc[CO-Leu-Val-OR]2 (7:R = Me, 8:R = H) . Conformational<br />
properties <strong>of</strong> these ferrocene peptide conjugates and their interaction with several sequences <strong>of</strong> Aβ<br />
have been studied in solution by circular dichroism and scanning electron microscopy. In addition, the<br />
interaction <strong>of</strong> Aβ attached on the gold surface with these ferrocene peptide conjugates has been<br />
studied by using electrochemical methods.<br />
References<br />
1. L. O. Tjernberg, J. Naslund, F. Lindqvist, J. Johansson, A.R. Karlstrom, J.Thyberg, L. Terenius,C.<br />
Nordstedt, J. Biol. Chem. 1996, 271, 8545-8548.<br />
2. C. Soto, E.M. Sigurdsson, L. Morelli, R.A. Kumar, E.M. Castano, B. Frangione, Nat. Med. 1998, 4,<br />
822-826.<br />
3. C. Adessi, M.J. Frossard, C. Boissard, S. Fraga, S. Bieler, T. Ruckle,F. Vilbois, S.M. Robinson, M.<br />
Mutters, W.A. Banks, C. Soto, J. Biol. Chem. 2003, 278, 13905-13911.<br />
70
P-13<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis, Characterization, and Biological Study <strong>of</strong> Functionalized<br />
Cyclopentadienylmanganese and Rhenium Tricarbonyl Complexes<br />
and Their Peptide Bioconjugates<br />
Wanning Hu, a Katrin Splith, b Ines Neundorf, b and Ulrich Schatzschneider *a<br />
a <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Lehrstuhl für Anorganische Chemie I - Bioanorganische Chemie,<br />
<strong>Universität</strong>sstr. 150, D-44801 <strong>Bochum</strong>, Germany.<br />
b Institut für Biochemie, <strong>Universität</strong> Leipzig, Brüderstr. 34, D-04103 Leipzig, Germany.<br />
wanning.hu@rub.de<br />
rel. cell viability [%]<br />
125<br />
100<br />
75<br />
50<br />
25<br />
0<br />
0 50 100 150 200 250<br />
csubstance [�mol]<br />
Cym1-sC18<br />
Cyr1-sC18<br />
Cyr5-sC18<br />
71<br />
OC<br />
M<br />
CO CO<br />
O<br />
M = Mn, Re<br />
L<br />
COOH<br />
Several functionalized cyclopentadienyl manganese and rhenium tricarbonyl half-sandwich complexes<br />
were prepared and coupled to the sC18 carrier peptide to investigate whether the structural<br />
modification <strong>of</strong> the linker and the change <strong>of</strong> the metal center would influence the biological properties<br />
<strong>of</strong> the metal-peptide-bioconjugates. Two new cymantrene complexes with a 1,3- and 1,4-phenylene<br />
linker were prepared and were fully characterized with 1 H-NMR, 13 C-NMR, IR, ESI-MS, elemental<br />
analysis, and X-ray crystallography. 1 In addition, three novel related CpRe(CO)3 complexes showed<br />
good purity in 1 H-NMR, IR and ESI-MS. Four <strong>of</strong> the compounds were successfully coupled to the<br />
sC18 peptide and the cytotoxicity <strong>of</strong> the conjugates was studied with the resazurin assay on MCF-7<br />
human breast cancer cells. The CpMn(CO)3 conjugates showed IC50 values <strong>of</strong> about 55 µM on MCF-7<br />
human breast cancer cells, which is comparable to other cymantrene-sC18 conjugates already studied. 2<br />
In contrast, the rhenium analogue <strong>of</strong> the cymantrene complex with the 1,2-phenylene linker is inactive<br />
at up to 150 µM. However, a CpRe(CO)3 complex with the 1,4-phenylene linker but a methylene<br />
group between the Cp and phenyl rings gave a bioconjugate with an activity very similar to the<br />
cymantrene- sC18-bioconjugates. The cellular internalization <strong>of</strong> these conjugates was studied with<br />
confocal fluorescence microscopy on MCF-7 cells.<br />
References<br />
1. K. Splith, I. Neundorf, W. Hu, H. W. Peindy N'Dongo, V. Vasylyeva, K. Merz, U. Schatzschneider,<br />
Dalton Trans. 2010, 39, 2536-2545.<br />
2. I. Neundorf, J. Hoyer, K. Splith, R. Rennert, H. W. Peindy N'dongo, U. Schatzschneider, Chem.<br />
Commun. 2008, 5604-5606.
P-14<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Coordination <strong>of</strong> a Peptide �-Turn Mimetic to Tungsten:<br />
Possible Applications for the Study <strong>of</strong> �-Sheets<br />
Adam N. Boynton a and Timothy P. Curran *a<br />
a Department <strong>of</strong> Chemistry, Trinity College, Hartford, CT 06106 USA<br />
Email: timothy.curran@trincoll.edu<br />
In 1995 Kemp and Li described the synthesis <strong>of</strong> 2-amino-2'-carboxyphenylacetylene (1) and its use as<br />
a peptide turn mimetic. 1,2 Their work showed that 1 does function as a �-turn mimetic, and that<br />
1<br />
peptide derivatives incorporating 1 adopted �-sheet structures. A key structural element in 1 is the<br />
alkyne group that links both phenyl rings. Because <strong>of</strong> our ongoing interest in the use <strong>of</strong> tungstenalkyne<br />
coordination for generating constrained peptides, 3,4,5 we have begun investigations into whether<br />
peptide derivatives <strong>of</strong> 1 can be reacted with W(CO)3(dmtc)2 to yield tungsten-bis(alkyne) complexes<br />
(like 2), and whether the peptides maintain a �-sheet structure after coordination to tungsten. If the<br />
peptides do maintain their sheet structure, then it would be <strong>of</strong> interest to know whether the two �sheets<br />
interact with each other via stacking arrangements. Owing to solubility and oligomerization<br />
issues, there are very few model systems for investigating �-sheet stacking interactions.<br />
2<br />
N<br />
H<br />
O<br />
O<br />
N<br />
H<br />
H<br />
N<br />
O<br />
O<br />
H<br />
N<br />
S<br />
S S<br />
W<br />
S<br />
O<br />
H<br />
N<br />
H<br />
N<br />
O<br />
72<br />
O<br />
N<br />
H<br />
O<br />
NH 2<br />
N<br />
H<br />
O<br />
OH<br />
S S<br />
=<br />
H3C S<br />
N<br />
H3C S<br />
This presentation will detail the status <strong>of</strong> our efforts to prepare and study these novel<br />
bioorganometallic species.<br />
References<br />
1. D. S. Kemp, Z. Q. Li, Tetrahedron Lett., 1995, 36, 4175-4178.<br />
2. D. S. Kemp, Z. Q. Li, Tetrahedron Lett., 1995, 36, 4179-4180.<br />
3. T. P. Curran, A. L. Grant, R. L. Lucht, J. C. Carter, J. Affonso, Org. Lett., 2002, 4, 2917-2920.<br />
4. T. P. Curran, R. S. H. Yoon, B. R. Volk, J. Organometallic Chem., 2004, 689, 4837-4847.<br />
5. T. P. Curran, A. B. Lesser, R. S. H. Yoon, J. Organometallic Chem., 2007, 692, 1243-1254.
P-15<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis and Characterisation <strong>of</strong> Palladium Bioconjugates<br />
Jan Dittrich a and Nils Metzler-Nolte* a<br />
a <strong>Ruhr</strong>-University <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong><br />
Inorganic Chemistry I, <strong>Universität</strong>sstr. 150, 44801 <strong>Bochum</strong>, Germany<br />
E-mail: Jan.Dittrich@rub.de<br />
Some transition metals like gold and platinum play a major role in anti-tumor research. 1,2 Palladium is<br />
a homologue element <strong>of</strong> platinum with related chemical behaviour, but is not in focus <strong>of</strong> cancer<br />
research until now. The ligand exchange rate <strong>of</strong> palladium is much higher than the one <strong>of</strong> platinum,<br />
consequently cispalladium would not work as an anticancer drug. The goal we are striving for are<br />
palladium bioconjugates like 1. A suitable metal complex is formed from a cyclometallated palladiumazide<br />
3 and methyl 2-isocyanoacetate, which undergo a [3+2] cycloaddition reaction to yield after<br />
rearrangement an ester functionalised palladium-tetrazole. After saponification this compound can be<br />
linked to an amino acid or peptide, both in solution and on solid phase. The compounds were<br />
characterized by multidimensional and multinuclear NMR techniques, mass spectrometry and IR<br />
spectroscopy.<br />
References<br />
N<br />
Pd<br />
N<br />
N<br />
N<br />
N N<br />
1<br />
O<br />
H<br />
N<br />
1. I. Ott, Coord. Chem. Rev. 2009, 52, 763-770.<br />
2. Z. Guo, P.J. Sadler, Angew. Chem. Int. Ed. Engl. 1999, 38, 1512-1531.<br />
3. Y.J. Kim, X. Chang, J.T. Han, M.S. Lim, S.W. Lee, Dalten Trans. 2004, 3699-3708.<br />
O<br />
N<br />
H<br />
73<br />
O<br />
OH<br />
H<br />
N<br />
O<br />
N<br />
H<br />
O<br />
H<br />
N<br />
O<br />
OH
P-16<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Conjugation <strong>of</strong> Rheniumtricarbonyl Bisimine Complexes to Polylactides -<br />
Fluorescent Polymers for in vivo Tumour Diagnostics<br />
Nadine E. Brückmann a and Peter C. Kunz* a<br />
a Heinrich-Heine-University <strong>of</strong> Düsseldorf, Department <strong>of</strong> Inorganic Chemistry I,<br />
<strong>Universität</strong>sstr. 1, 40225, Düsseldorf, Germany. E-mail: peter.kunz@uni-duesseldorf.de<br />
In order to improve current cancer pharmaceuticals, new polymer-based transport systems are being<br />
developed that deliver the drug directly to the tumour, where it can subsequently be released.<br />
Macromolecules can accumulate in tumours due to the EPR-effect. 1 Although polymers are now<br />
widely used in therapeutic approaches, only a few examples <strong>of</strong> diagnostically applied polymerconjugates<br />
exist. 2 Rheniumtricarbonyl bisimines e.g. are useful as dyes for fluorescence microscopy.<br />
Their fluorescence emission lies in the visible light spectrum, resulting from a metal-to-ligand-chargetransfer<br />
(MLCT). These transitions typically have large Stokes shifts, which makes the fluorescence<br />
easily destinguishable from tissue aut<strong>of</strong>luorescence. 3 Attachment <strong>of</strong> these rhenium cores to ligandfunctionalised<br />
polylactides leads to biodegradable fluorescent polymers.<br />
In particular, rheniumtricarbonyl complexes <strong>of</strong> 2,2’bipyridine (bipy), 1,10-phenanthroline (phen) as<br />
well as dipyrido[3,2-a:2’,3’-c]phenazine (dppz) were prepared. Absorption and emission data were<br />
ascertained, cytotoxicity was determined on A2780 ovarian cancer cell lines and the in vivo<br />
localisation was examined by confocal microscopy. Investigations into their degradation kinetics are<br />
currently ongoing.<br />
References<br />
1. H. Maeda, J. Wu, T. Sawa, Y. Matsamura, K. Hori, J. Cont. Rel. 2000, 65, 271-284.<br />
2. A. Mitra, A. Nan, H. Ghandehari et al., Pharm. Res. 2004, 21(7), 1153-1159.<br />
3. A. Amoroso, M. Coogan, J.E. Dunne et al., Chem. Commun. 2007, 29, 3066-3068.<br />
74
P-17<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Organometallic Complexes Coupled to Cell-Penetrating Peptides: Generation <strong>of</strong><br />
Promising New Cytostatic Compounds<br />
K. Splith, a Jan Hoyer, a Wanning Hu, b Ulrich Schatzschneider, b Yvonne Geldmacher, c<br />
Malte Kokoschka, c William S. Sheldrick, c and Ines Neundorf *a<br />
a Leipzig University, Faculty <strong>of</strong> Biosciences, Pharmacy and Psychology, Department <strong>of</strong> Biochemistry,<br />
Brüderstr. 34, 04103, Leipzig, Germany. b <strong>Ruhr</strong>-University <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and<br />
Biochemistry, Department <strong>of</strong> Inorganic Chemistry I, <strong>Universität</strong>sstr.150, 44801, <strong>Bochum</strong>, Germany.<br />
c <strong>Ruhr</strong>-University <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong> Analytical<br />
Chemistry, <strong>Universität</strong>sstr.150 ,44801, <strong>Bochum</strong>, Germany. E-mail: splith@uni-leipzig.de<br />
Bioorganometallic chemistry has become more and more important in several fields, especially in the<br />
development <strong>of</strong> new drugs for cancer treatment. A number <strong>of</strong> metal-based building blocks have<br />
promising features for applications in therapy and diagnosis. Introduction <strong>of</strong> a metal centre could add<br />
new features which might help to overcome some problems in cancer treatment. However the low<br />
water solubility and bioavailability <strong>of</strong> these organometallic compounds inhibits their therapeutic use in<br />
medicine. Recently, so called cell-penetrating peptides (CPP) have emerged as potent tools to<br />
introduce substances into cells. CPP are an inhomogenic group <strong>of</strong> peptides that share the ability to<br />
translocate in a large number <strong>of</strong> different cell-lines without the need <strong>of</strong> a receptor or transporter<br />
molecule. Thereby they are capable to transport various cargos inside cells, like proteins,<br />
oligonucleotides, nanoparticles or small organic drugs. 1,2<br />
This work describes the coupling <strong>of</strong> metal-based building blocks to cell-penetrating peptides based on<br />
an antimicrobial peptide cathelicidin CAP18. 3 Synthesis was achieved by solid phase peptide synthesis<br />
using standard Fmoc chemistry and activation by HOBt/DIC. Several different metal complexes have<br />
been investigated, e.g. half-sandwich-complexes <strong>of</strong> different metals. Cellular uptake <strong>of</strong> the new<br />
bioconjugates was investigated with different methods and high accumulation in different tumour cells<br />
could be observed. Furthermore, cell viability assays showed that those organometallic peptide<br />
conjugates are very potent and possess promising cytotoxic properties. 4,5,6<br />
References<br />
1. K. M. Stewart, K. L. Horton, S. O. Kelley, Org. Biomol. Chem. 2008, 6, 2242-2255.<br />
2. I. Neundorf, R. Rennert, J. Franke, I. Közle, R. Bergmann, Bioconjugate Chem. 2008, 8, 1596-603.<br />
3. I. Neundorf, R. Rennert, J. Hoyer, F. Schramm, K. Löbner, I. Kitanovic, S. Wölfl, Pharmaceuticals 2009, 2,<br />
49-65.<br />
4. I. Neundorf, J. Hoyer, K. Splith, R. Rennert, H.W. Peindy N’dongo, U. Schatzschneider, Chem. Commun.<br />
2008, 43, 5604-5606.<br />
5. K. Splith, I. Neundorf, W. Hu, H.W. Peindy N'dongo, V. Vasylyeva, K. Merz, U. Schatzschneider, Dalton<br />
Trans. 2010, 39, 2536-2545.<br />
6. K. Splith, W. Hu, U. Schatzschneider, R. Gust, I. Ott, I. Neundorf, manuscript submitted.<br />
75
P-18<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Interaction between [Ru(� 6 -p-cym)(H2O)3] 2+ and (O,O) Donor Ligands <strong>of</strong><br />
Biological Importance in Aqueous Solution<br />
Péter Buglyó, *a Linda Bíró, a and Etelka Farkas a<br />
a University <strong>of</strong> Debrecen, Faculty <strong>of</strong> Science and Technology, Department <strong>of</strong> Inorganic and Analytical<br />
Chemistry, P. O. Box 21, H- 4032 Debrecen, Hungary. E-mail: buglyo@delfin.unideb.hu<br />
Numerous Ru(III) and Ru(II) complexes have been synthesized, characterized in the solid state and<br />
tested for antitumor activity. The most promising candidates are shown to act differently both in vitro<br />
and in vivo from the antitumor platinum complexes currently used in the therapy. Beside Ru(III)<br />
complexes with octahedral geometry half-sandwich organometallic Ru(II) complexes with typical<br />
“piano stool” geometry are also investigated intensively. 1<br />
Recently we have shown that one class <strong>of</strong> important biomolecules, monohydroxamates (being also<br />
(O,O) chelators), are capable to form stable complexes with the [Ru(� 6 -p-cym)(H2O)3] 2+ core both in<br />
the solid state and in aqueous solution. 2 We have also explored in detail the hydrolysis <strong>of</strong> the metal ion<br />
using different (pH-potentiometry, NMR, UV-VIS and ESI-MS) techniques and estimated the stability<br />
constants <strong>of</strong> the hydroxo complexes formed in the H + –[Ru(� 6 -p-cym)(H2O)3] 2+ system. Taking into<br />
consideration the hydrolysis we were able to obtain the pH dependent speciation <strong>of</strong> the H + –[Ru(� 6 -pcym)(H2O)3]<br />
2+ –meaha system (meaha = N-methyl-acetohydroxamate) and to determine the<br />
composition and stability constants <strong>of</strong> the complexes formed with the monohydroxamate.<br />
In order to compare the [Ru(� 6 -p-cym)(H2O)3] 2+ binding strength <strong>of</strong> meaha with that <strong>of</strong> other (O,O)<br />
donors partly used as building blocks in ruthenium complexes with potential anticancer activity or<br />
present in bi<strong>of</strong>luids a systematic study has been carried out. Ligands capable to form five membered<br />
(oxalic acid, lactic acid, kojic acid, maltol, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one, 1,2dihydroxybenzene-3,5-disulfonate)<br />
and six-membered (cyclobutane-1,1-dicarboxylic acid,<br />
acetylacetone, salicylic acid) chelates in which the donor atoms exhibit different basicity were choosen<br />
and the interaction <strong>of</strong> these chelators with [Ru(� 6 -p-cym)(H2O)3] 2+ was investigated. This contribution<br />
summarises the results <strong>of</strong> a detailed solution equilibrium work. During this study our goal was to<br />
estimate the speciation and to compare the composition and stabiliy constants <strong>of</strong> Ru-(O,O) type<br />
complexes formed applying different (pH-potentiometry, 1 H-NMR, ESI-MS) experimental techniques.<br />
References<br />
1. (a) P. C. A. Bruijnincx, P. J. Sadler, Adv. Inorg. Chem., 2009, 61, 1-62. (b) W. Kandioller, C. G.<br />
Hartinger, A. A. Nazarov, M. L. Kuznetsov, R. O. John, C. Bartel, M. A. Jakupec, V. B. Arion, B. K.<br />
Keppler, Organometallics, 2009, 28, 4249-4251.<br />
2. P. Buglyó, E. Farkas, Dalton Trans., 2009, 8063-8070.<br />
Acknowledgement: We thank the members <strong>of</strong> the EU COST Action D39 for motivating discussions.<br />
This work was supported by the Hungarian Scientific Research Fund (OTKA K76142).<br />
76
P-19<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Organometallic Osmium Arene Complexes with Potent Cancer Cell Cytotoxicity<br />
Ying Fu, a Abraha Habtemariam, a Ana M. Pizarro, a Sabine H. van Rijt, a Guy J. Clarkson, a<br />
and Peter J. Sadler *a<br />
University <strong>of</strong> Warwick, Department <strong>of</strong> Chemistry, Gibbet Hill Road, Coventry, CV4 7AL,<br />
U.K, E-mail: fuyingpku@gmail.com<br />
Arene complexes <strong>of</strong> the heavier congener osmium(II) display similar<br />
structures in the solid state to those <strong>of</strong> Ru II but are subtly different<br />
with regard to their chemical reactivity. For example, Os II arene<br />
ethylenediamine chlorido complexes hydrolyze ca. 40x more slowly<br />
and the related aqua adducts have pKa values for Os�OH2/OH which<br />
are ca. 1.5 pKa units lower (more acidic) than those <strong>of</strong> the analogous<br />
Ru II complexes. 1,2 Faster ligand exchange in Os II complexes can be<br />
achieved by incorporating oxygen-containing chelating ligands, e.g.<br />
picolinates. 3,4 In general they show a different cytotoxicity pr<strong>of</strong>ile and<br />
have a larger reactivity window compared to Ru arene complexes.<br />
The synthesis <strong>of</strong> a range <strong>of</strong> osmium complexes <strong>of</strong> the general<br />
structure shown will be discussed including the X-ray crystal<br />
structures <strong>of</strong> five complexes. Surprisingly, several <strong>of</strong> these Os II<br />
Arene<br />
X<br />
Os<br />
N<br />
N<br />
complexes with iodide as the X ligand are an order <strong>of</strong> magnitude [Os(Arene)(NN)X]<br />
more potent than the clinically-used drug cisplatin towards a range <strong>of</strong> human cancer cell lines.<br />
We thank Dr. Michael Khan (Biological Sciences) for provision <strong>of</strong> facilities for cell culture, and the<br />
MRC, EPSRC (Knowledge Transfer Network), ERC and EU EDRF/AWM (APOC) for funding, and<br />
members <strong>of</strong> COST Action D39 for discussion.<br />
+<br />
References<br />
1. Peacock, A. F. A.; Habtemariam, A.; Fernandez, R.; Walland, V.; Fabbiani, F. P. A.; Parsons, S.;<br />
Aird, R. E.; Jodrell, D. I.; Sadler, P. J. J. Am. Chem. Soc. 2006, 128, 1739-1748.<br />
2. Wang, F.; Habtemariam, A.; van der Geer, E. P.; Fernandez, R.; Melchart, M.; Deeth, R. J.; Aird,<br />
R.; Guichard, S.; Fabbiani, F. P.; Lozano-Casal, P.; Oswald, I. D.; Jodrell, D. I.; Parsons, S.; Sadler, P.<br />
J. Proc Natl Acad. Sci.U.S.A. 2005, 102, 18269-18274.<br />
3. Peacock, A. F. A.; Sadler, P. J. Chem.--Asian J. 2008, 3, 1890-1899.<br />
4. van Rijt, S. H.; Peacock, A. F. A.; Johnstone, R. D. L.; Parsons, S.; Sadler, P. J. Inorg. Chem. 2009,<br />
48, 1753-1762.<br />
77
P-20<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Cytotoxic Apoptosis-Inducing Organometallic Rhodium Complexes with<br />
Substituted Polypyridyl Ligands<br />
Yvonne Geldmacher, a Riccardo Rubbiani, b Ingo Ott, b and William S. Sheldrick a*<br />
a <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>,Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong> Analytical<br />
chemistry, <strong>Universität</strong>sstr. 150, 44780 <strong>Bochum</strong>, Germany, b Technical University <strong>of</strong> Braunschweig,<br />
Department <strong>of</strong> Pharmaceutical Chemistry, Beethovenstr. 55, 38106 Braunschweig, Germany<br />
E-mail: yvonne.geldmacher@rub.de<br />
The complexes <strong>of</strong> the type [(η 5 -C5Me5)RhCl(pp)]CF3SO3 (with pp= dpq, dppz, dppn) represent a new<br />
class <strong>of</strong> cytotoxic substances. Cytotoxicity and cellular uptake studies on the HEK-293, MCF-7 and<br />
HT-29 cell lines have been employed to establish relationships between the structure and the activity<br />
<strong>of</strong> the complexes. UV/Vis kinetic, thermal denaturation and CD studies have shown, that the prefered<br />
binding mode <strong>of</strong> the complexes to DNA is intercalation. [(η 5 -C5Me5)RhCl(dppz)]CF3SO3 invokes the<br />
largest increase in Tm with a value 12 °C being recorded for a 1:10 complex/DNA mixture in the<br />
denaturation experiment. In contrast, complexes containing the smaller chelate ligands with pp = en,<br />
bpy and phen exhibit negative ΔTm values, which indicates the presence <strong>of</strong> a covalent binding mode.<br />
CD spectra for the complex/DNA mixtures with pp = dpq and dppz contain a negative ICD-signal in<br />
the range 280-300 nm, which also indicates intercalation. Viscosity measurements also confirm the<br />
conclusions from UV/Vis and CD studies. 1<br />
100<br />
Figure 1: crystal structure <strong>of</strong> Figure 2: DNA-fragmentation after a 72 h treatment <strong>of</strong><br />
[(η 5 -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 BJAB cells with [(η 5 -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 at different<br />
concentrations<br />
The biological activity also correlates with the lipophilicity and thereby with the size <strong>of</strong> the<br />
polypyridyl ligand. The IC50 values decrease in the series en, bpy>> phen,dpq > dppz > dppn. One<br />
goal <strong>of</strong> our ongoing studies is to improve the cell selectivity and identify lead substances by varying<br />
the ligands L and pp in complexes [(η 5 -C5Me5)RhL(pp)](CF3SO3)n. It has previously been shown that<br />
there are significant differences between the cytotoxicities <strong>of</strong> Pt(II) complexes with methylated 1,10phenanthroline<br />
ligands. 2 We now report studies <strong>of</strong> the biological activity <strong>of</strong> [(η 5 -<br />
C5Me5)RhCl(pp)]CF3SO3 complexes containing methylated phenanthroline ligands and other<br />
substituted polypyridyl ligands. Measurements <strong>of</strong> the LDH release for lymphoma (BJAB) cells after<br />
1h incubation with phen, 5,6-Me2phen and dppz complexes demonstrated that unspecific necrosis is<br />
negligible. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72<br />
h (Figure 2).<br />
References<br />
apoptotic cells [%]<br />
75<br />
50<br />
25<br />
0<br />
1. M.A. Scharwitz, I. Ott, Y. Geldmacher, R. Gust, W.S. Sheldrick, J. Organomet. Chem. 2008, 693,<br />
2299-2309.<br />
2. C.R. Brodie, J.G. Jollins, J.R. Aldrich-Wright, Dalton Trans. 2004, 1145.<br />
78<br />
Co DMSO0.1 1 5 10 25 50 75 100<br />
concentration [µM]
P-21<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Antiproliferative Activity <strong>of</strong> Cationic and Neutral Heterobimetallic<br />
Ferrocene-(Vinyl)Ru(CO)Cl(P i Pr3)2 Complexes<br />
Konrad Kowalski, *a Ingo Ott, *b Rainer. F. Winter, c and Ronald Gust d<br />
a University <strong>of</strong> Łódź, Faculty <strong>of</strong> Chemistry, Department <strong>of</strong> Organic Chemistry, Tamka 12, 91-403<br />
Łódź, Poland. b Technische <strong>Universität</strong> Braunschweig, Institute <strong>of</strong> Pharmaceutical Chemistry,<br />
Beethovenstraße 55, 38106 Braunschweig, Germany. c <strong>Universität</strong> der Regensburg, Institut für<br />
Anorganische Chemie, <strong>Universität</strong>sstraße 31, D-93040 Regensburg, Germany. d Freie <strong>Universität</strong><br />
Berlin, Institute <strong>of</strong> Pharmacy, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.<br />
E-mail: kondor15@wp.pl<br />
Recently, some <strong>of</strong> us reported 1 on the mixed ferrocene ruthenium organometallic species 1 and 2 with<br />
the main focus on measuring the degree <strong>of</strong> electron delocalization in mixed-valent 2 and its medium<br />
dependence. In the bioorganometallic chemistry field the cytotoxic activity <strong>of</strong> some ferrocenium salts<br />
and the lack <strong>of</strong> activity <strong>of</strong> the corresponding ferrocenes is well known 2 . On the other hand the<br />
anticancer activity <strong>of</strong> mixed ferrocene/ruthenium complexes has been recently reported 3 . Considering<br />
these data, complexes 1 and 2 along with their monometallic counterparts 3-8 have been subjected<br />
toward biological studies 4 . Antiproliferative activity <strong>of</strong> 1-8 was carried out in HT-29 colon carcinoma<br />
and MCF-7 breast cancer cells. Both bimetallic derivatives 1 and 2 exhibited IC50 values between 4.8<br />
μM and 16.8 μM. These values are within the range <strong>of</strong> common cytostatics such as cisplatin and 5fluorouracil<br />
investigated as control in the same assay. In addition our tests show higher<br />
antiproliferative activity <strong>of</strong> cationic 2 than <strong>of</strong> neutral 1. In order to rationalize this observation the<br />
cellular uptake <strong>of</strong> 1, 2 and 4 was determined by measurement <strong>of</strong> the ruthenium content <strong>of</strong> cells<br />
exposed to the complexes by atomic absorption spectroscopy. Unexpectedly, the cellular uptake <strong>of</strong><br />
cationic 2 exceeded those <strong>of</strong> neutral 1 and were comparable to those exhibited by 4. This results<br />
suggest that 2 might be effectively transported across cellular lipid membranes by an active transporter<br />
system. Such a transporter systems are known to be crucial factors for cellular metal biodistribution.<br />
However, they haven’t been identified for any cationic ferrocenes yet.<br />
Fe<br />
P i Pr 3<br />
Ru<br />
P i Pr 3<br />
Cl<br />
CO<br />
Fe<br />
PiPr +<br />
3<br />
Ru<br />
P i Pr 3<br />
Cl<br />
CO<br />
PF 6 -<br />
1 2 3<br />
79<br />
Fe<br />
R<br />
R = -OCH 3<br />
-F<br />
-CF 3<br />
-N(CH 3) 2<br />
-CHO<br />
Acknowledgements: KK is grateful to the Alexander von Humboldt-Stiftung for a research<br />
fellowship at the group <strong>of</strong> Pr<strong>of</strong>. Dr. R. F. Winter, University <strong>of</strong> Regensburg<br />
References<br />
1. K. Kowalski, M. Linseis, R. F. Winter, M. Zabel, S. Záliš, H. Kelm,; H-J. Krüger, B. Sarkar, W.<br />
Kaim, Organometallics 2009, 28, 4196.<br />
2. G. Tabbi, G. Cassino, G. Cavigiolio, D. Colangelo, A. Ghiglia, I Viano, D. Osella, J. Med. Chem.<br />
2002, 45, 5786.<br />
3. M. Auzias, B. Therrien, G. Süss-Fink, P. Stepnicka, W.H. Ang, P. J. Dyson, Inorg. Chem. 2008, 47,<br />
578.<br />
4. I. Ott, K. Kowalski, R. Gust, J. Maurer, P. Mücke, R.F. Winter, Bioorg. Med. Chem. Lett. 2010, 20,<br />
866-869.<br />
P i Pr 3<br />
Ru<br />
P i Pr 3<br />
4<br />
5<br />
6<br />
7<br />
8<br />
Cl<br />
CO
P-22<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Green Chemistry in the Production <strong>of</strong> Ferrocene Derivatives Using Recyclable<br />
Solid Heteropolyacids as Catalysis<br />
Jorge Jios, a Gustavo Romanelli, b and Nils Metzler-Nolte *c<br />
a Laseisic (CIC-CONICET-UNLP), Departamento de Química, Facultad de Ciencias Exactas, UNLP.<br />
Camino Centenario e/505 y 508, CP1897, Gonnet, Argentina. b Centro de Investigación y Desarrollo<br />
en Ciencias Aplicadas “Dr. J. J. Ronco” (CINDECA), Departamento de Química, Facultad de<br />
Ciencias Exactas, UNLP-CONICET. Calle 47 Nº 257, B1900AJK La Plata, Argentina. c Lehrstuhl für<br />
Anorganische Chemie I, Bioanorganische Chemie, Fakultät für Chemie und Biochemie, <strong>Ruhr</strong>-<br />
<strong>Universität</strong> <strong>Bochum</strong>, <strong>Universität</strong>sstrasse150, D-44801 <strong>Bochum</strong>, Germany. E-mail:<br />
jljios@quimica.unlp.edu.ar<br />
Dihydropyrimidinone are known to exhibit a wide range <strong>of</strong> biological activities such as antiviral,<br />
antitumour, antibacterial, and anti-inflammatory properties. 1 Several reagents/methods have been<br />
reported for their preparation under milder and more efficient procedures such as Amberlyst-15,<br />
Nafion-H, KSF clay with dry acetic acid under microwave irradiation, ionic liquids, cerric ammonium<br />
nitrate under ultrasonication, Lewis acids with transition metals, lanthanides, and indium chloride. 2 In<br />
this work we present an improved procedure for the obtention <strong>of</strong> dihydropyrimidinones bearing<br />
ferrocene in a three component one-pot condensation reaction using heteropolyacid catalysts (Figure<br />
1).<br />
R<br />
Fe +2<br />
+<br />
O O<br />
C<br />
O<br />
H<br />
R´<br />
NH 2CONH 2<br />
Superacid Catalyst<br />
The results are discussed in terms <strong>of</strong> the catalyst used, their selectivity and the reaction conversion<br />
degree. The aim <strong>of</strong> this work is investigate a convenient synthesis for the production <strong>of</strong> new<br />
metallocene carrying heterocyclic compounds with biological activities. The spectral data are<br />
discussed in detail.<br />
References<br />
1. C. O. Kappe, Tetrahedron 1993, 49, 6937-6963, and references cited therein.<br />
2. (a) F. Bigi, S. Carloni, B. Frullanti, R. Maggi, G. Sartori, Tetrahedron Lett. 1999, 40, 3465-3468.<br />
(b) J. Peng, Y. Deng, Tetrahedron Lett. 2001, 42, 5917-5919. (c) J. S. Yadav, B. V. S. Reddy, K. B.<br />
Reddy, K. S. Raj, A. R. J. Prasad, Chem. Soc. Perkin Trans. 1 2001, 1939-1941. (d) E. H. Hu, D. R.<br />
Sidler, U. H. Dolling, J. Org. Chem. 1998, 63, 3454-3457. (e) Y. Ma, C. Qian, L. Wang, M. Yang, J.<br />
Org. Chem. 2000, 65, 3864-3868. (f) J. Lu, Y. Bai, Z. Wang, B. Yang, H. Ma, Tetrahedron Lett. 2000,<br />
41, 9075-9078. (g) B. C. Rannu, A. Hajra, U. Jana, J. Org. Chem. 2000, 65, 6270-6272. (h) H. N.<br />
Karade, M. Sathe, M. P. Kaushik. Molecules 2007, 12, 1341-1351.<br />
80<br />
R'<br />
O<br />
R<br />
Fe +2<br />
N<br />
H<br />
NH<br />
O
P-23<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Antiproliferative Activity <strong>of</strong> Diphenylmethylidenyl-[3]ferrocenophanes on Breast<br />
and Prostate Hormone-independent Cancer Cell Lines<br />
Meral Gormen, a Pascal Pigeon, a Siden Top,* a Elizabeth A. Hillard, a Marie-Aude Plamont, a<br />
Anne Vessières, a amd Gérard Jaouen a<br />
a ENSCP, Laboratoire Charles Friedel, UMR 7223, 11, Rue Pierre et Marie Curie, 75231, Paris,<br />
Cedex 05, France. E-mail: meral-gormen@chimie-paristech.fr<br />
Breast cancer is the leading cause <strong>of</strong> cancer death among women in the Western world and accounts for<br />
23% <strong>of</strong> all female cancer cases worldwide. 1 In terms <strong>of</strong> incidence rate, breast cancer touches one woman in<br />
eight in Western countries.<br />
Tamoxifen, whose active metabolite is hydroxytamoxifen (1), is currently the most widely used antiestrogen<br />
in the adjuvant therapy <strong>of</strong> hormone-dependent breast cancers. 2 However, it is known that one-third <strong>of</strong> these<br />
cases are hormone-independent cancers, and don’t respond to tamoxifen therapy. We found that<br />
hydroxyferrocifen (2) and ferrocifenol (3) exhibit strong antiproliferative activities against both hormonedependent<br />
MCF-7 cancer cells and hormone-independent MDA-MB-231cancer cells. 3<br />
OH<br />
OH<br />
Fe<br />
Fe<br />
Fe<br />
O(CH2) 2N(CH3) 2<br />
OR<br />
1 2. R = (CH2) 3N(CH3) 2<br />
3. R = H<br />
4 5<br />
R1,R2= H,OH,NH2,NHAc It has recently been shown that dihydroxy [3]ferrocenophane 4 is 7 times more potent than ferrocifenol 3 on<br />
MDA-MB-231 cells. 4 We now extend our work on this new and interesting series by synthesizing other<br />
compounds by varying the nature <strong>of</strong> the substituents R1 and R2 (5). 5 These new compounds show high<br />
activity compared to that <strong>of</strong> classical ferrocene analogues. The inhibitory concentrations (IC50) <strong>of</strong> 5 on<br />
MDA-MB-231 cells range from 50 to 90 nM.<br />
Our work was extended to prostate cancer which is one <strong>of</strong> the most frequently diagnosed cancers and is the<br />
second leading cause <strong>of</strong> cancer death in men after lung. We found that [3]ferrocenophane derivatives are also<br />
active against PC3 hormone-independent prostate cancer cells with IC50 ranging from 20 to 140 nM.<br />
Synthesis and antitumor activities <strong>of</strong> [3]ferrocenophane derivatives will be presented.<br />
References<br />
1. (a) J. Ferley, F. Bray, P. Pisani, D. M. Parkin. GLOBOCAN 2002: Cancer Incidence, Mortality and<br />
Prevalence Worldwide. IARC CancerBase No. 5 version 20. IARCPress, Lyon, France, 2004. (b) A.<br />
Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, M. J. Thun, CA Cancer J Clin 2007, 57, 43-66. (c) R. Y.<br />
Wood, N.R. Della-Monica. Int. J. Older People Nursing, 2006, 1 (2), 75-84.<br />
2. (a) V. C. Jordan, J. Med. Chem., 2003, 46 (6), 883-908 (b) V. C. Jordan, J. Med. Chem., 2003, 46 (7),<br />
1081-1111.<br />
3. S. Top, A. Vessières, G. Leclercq, J. Quivy, J. Tang, J. Vaissermann, M. Huche, G. Jaouen.<br />
Chem. Eur. J., 2003, 9, 5223-5236. (b) A. Vessières, S. Top, P. Pigeon, E. Hillard, L. Boubeker,<br />
D. Spera, G. Jaouen J. Med. Chem., 2005, 48, 3937-3940<br />
4. D. Plazuk, A. Vessieres, E.A. Hillard, et al. J. Med. Chem., 2009, 52, 4964-4967.<br />
5. M. Gormen, P. Pigeon, E.A. Hillard, et al. Tetrahedron Lett., 2010, 51, 118-120.<br />
81<br />
HO<br />
OH<br />
R 1<br />
R 2
P-24<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Cell Uptake and Cytotoxicity <strong>of</strong> Metal-Peptide-Bioconjugates<br />
Annika Groß a and Nils Metzler-Nolte* a<br />
a <strong>Ruhr</strong>-University <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong><br />
Inorganic Chemistry I, <strong>Universität</strong>sstr. 150, 44801 <strong>Bochum</strong>, Germany<br />
E-mail: Annika.Gross@rub.de<br />
Organometallic conjugates <strong>of</strong> cell-invasive peptides are proposed as interesting candidates for a future<br />
generation <strong>of</strong> novel cancer therapies since they are structurally unique compared to other classes <strong>of</strong><br />
routinely used cytotoxic drugs. We therefore aimed to synthesise various metal compounds linked to<br />
peptides.<br />
Solid and solution phase methods were used to generate peptides and their fluorescent and metal<br />
containing analogs. Cell uptake, and the effect <strong>of</strong> the metal was investigated by comparison <strong>of</strong><br />
metallocene-peptide conjugates to acetylated peptides using fluorescence microscopy. Intracellular fate<br />
was examined in co-localisation studies using compartment-specific dyes.<br />
Cytotoxicity studies <strong>of</strong> functionalised peptides were performed using the Resazurin and Crystal Violet<br />
proliferation assays on different cell lines.<br />
Peptides containing acetyl, ferrocene, ruthenocene, cobaltocene and cobalt carbonyl moieties were<br />
successfully synthesised, purified and characterised. All bioconjugates were cell permeable and colocalised<br />
with a lysosome-specific dye. Metallocene and reference compounds were not toxic in the range<br />
100-1000 µM. However, depending on the cell line, the cobalt carbonyl gave IC50 values down to 10 µM<br />
in these assays. Ferrocene, ruthenocene and cobaltocenium show no cytotoxicity, but cobalt carbonyl<br />
renders the conjugate cytotoxic.<br />
82
P-25<br />
R<br />
OH<br />
O<br />
N<br />
R = Ph : hydroxytamoxifen<br />
R = Fc : hydroxyferrocifen<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
On the Mechanism <strong>of</strong> Hydroxyferrocifen Cytotoxicity<br />
Didier Hamels, a Patrick M. Dansette, b Elizabeth A. Hillard, a Siden Top, a Anne Vessières, a Gérard<br />
Jaouen, a and Daniel Mansuy. b<br />
a Chimie ParisTech, Laboratoire Charles Friedel, UMR 7223; 11, rue Pierre et Marie Curie<br />
75231 Paris Cedex 05, France. b Université Paris Descartes, Laboratoire de Chimie et Biochimie<br />
Pharmacologiques et Toxicologiques, UMR 8601; 45, rue des Saints Pères 75006 Paris, France.<br />
E-mail : didier-hamels@chimie-paristech.fr<br />
Breast cancer is one <strong>of</strong> the most common cancers <strong>of</strong> women in the Western World. When the estrogen<br />
receptor (ER) is expressed in tumor cells, the breast cancer is categorized as hormone-dependent<br />
(ER+). ER+ breast cancer is the most commonly diagnosed (2 out <strong>of</strong> 3 cases), and can be treated with<br />
the help <strong>of</strong> selective estrogen receptor modulators (SERMs). Some SERMs act as ER antagonists in<br />
the cancer cell, thus preventing cell division. Unfortunately, SERMs are not active against ER� breast<br />
cancer cells, and alternative molecules have to be found.<br />
Fe<br />
Me<br />
O<br />
Me<br />
A hydroxyferrocifen<br />
derivative QM (QM-1)<br />
In 1996, Jaouen et al. designed and synthesized “hydroxyferrocifen”,<br />
a compound in which one <strong>of</strong> the phenyl groups <strong>of</strong><br />
hydroxytamoxifen had been replaced by a ferrocene moiety. 1<br />
The original idea was to combine the antiestrogenic effect <strong>of</strong><br />
hydroxytamoxifen with the potentially cytotoxic effect <strong>of</strong><br />
ferrocene. Our expectations were rewarded by the discovery<br />
that hydroxyferrocifen is indeed active against ER+ (MCF-7)<br />
and ER� (MDA-MB-231) breast cancer cells. 2 When the side<br />
chain was extended to three carbon atoms, the resulting Fc-OHTam[3] molecule was found to be even<br />
more cytotoxic.<br />
We thus decided to investigate the mechanism <strong>of</strong> action <strong>of</strong> the<br />
hydroxyferrocifens and related molecules. We hypothesized that<br />
their cytotoxicity is due to the in situ formation <strong>of</strong> highly<br />
cytotoxic quinone methide (QM) species. This interpretation was<br />
supported by electrochemical experiments 3 but neither<br />
hydroxytamoxifen 4 nor hydroxyferrocifen QMs had ever been<br />
isolated this far. Metabolic and chemical oxidation <strong>of</strong> Fc-<br />
OHTam[3] and three related conjugated ferrocene phenols<br />
allowed us to isolate and characterize the QMs by 1 H and 13 C<br />
NMR spectroscopy, and by X-ray crystallography in one case.<br />
The obtained QMs were then tested against ER� breast cancer<br />
cells (MDA-MB231) and were found to be cytotoxic. 5 This strongly supports the hypothesis that QMs<br />
are indeed relevant intermediates in the cytotoxicity <strong>of</strong> hydroxyferrocifens and related molecules<br />
against breast cancer cells. We are currently investigating the reactivity <strong>of</strong> such QMs in order to identify<br />
potential biological targets.<br />
References<br />
1. Top et al., Chem. Com. 1996, 955-956.<br />
2. Top et al., Chem. Eur. J. 2003, 9, 5223-5236.<br />
3. Hillard et al., Angew. Chem. Int. Ed. 2006, 45, 285-290.<br />
4. Fan et al., Chem. Res. Toxicol. 2000, 13 (1), 45-52.<br />
5. Hamels et al., Angew. Chem. Int. Ed. 2009, 48, 9124-9126.<br />
83<br />
QM-1 X-ray crystal structure
P-26<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Influence <strong>of</strong> Cisplatin and Other (Bio-)organometalic Compounds on Changes in<br />
Cellular Signaling Using Novel Phosphoprotein Microarray Elisa Assays<br />
Pavlo Holenya, a Igor Kitanovic, a and Stefan Wölfl *a<br />
Institute <strong>of</strong> Pharmacy and Molecular Biotechnology, University Heidelberg, Germany<br />
Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany<br />
E-mail: wolfl@uni-hd.de<br />
Understanding aspects <strong>of</strong> the regulatory network <strong>of</strong> signaling pathways and their role in the<br />
development <strong>of</strong> the diseases is one <strong>of</strong> the crucial starting points in drug research. Signal transduction<br />
in cells is regulated, among other things, by phosphorylation and dephosphorylation <strong>of</strong> numerous<br />
signaling proteins. In many cases, phosphorylation reflects the activation state <strong>of</strong> those proteins within<br />
pathways that control various biological responses. In order to understand how drugs influence cells<br />
by modulating different pathways, it is highly desirable to simultaneously measure the<br />
phosphorylation states <strong>of</strong> diverse signaling proteins and temporarily monitore their levels in cells.<br />
For this we used a novel technology based on protein microarray platforms ArrayTube TM and<br />
ArrayStrip TM developed by CLONDIAG Chip Technologies, Jena. Both platforms represent less<br />
expensive and easy to handle systems for the development <strong>of</strong> protein arrays. The heart <strong>of</strong> the device is<br />
a chemically modified glass surface assembled to form the bottom <strong>of</strong> a 1.5 ml plastic polystyrol<br />
microtube or a standard well <strong>of</strong> a 96-well plate. Capture antibodies are deposited onto agarose-film<br />
coated glass surface by contact spotting. Handling <strong>of</strong> the protein chip is easy and rapid and involves<br />
the simple steps <strong>of</strong> an ELISA in a sandwich format. Specific interactions <strong>of</strong> antibody and antigen are<br />
simply revealed by colorimetric detection. Acquisition and analysis <strong>of</strong> processed chip images are<br />
performed by optical transmission microscopy in combination with image analysis s<strong>of</strong>tware.<br />
Using the ArrayTube TM and ArrayStrip TM platforms and commercially available capture and detection<br />
antibodies, we established a protocol to quantitatively analyze changes in protein phosphorylation<br />
upon treatment with diverse organometallic compounds. We demonstrate high sensitivity and<br />
specificity <strong>of</strong> the microarrays and show quantitative analysis <strong>of</strong> several phosphorylated proteins,<br />
among them phospho GSK-3β, phospho RSK1, phospho Akt1, phospho p38α, phospho Erk1, phospho<br />
Erk2, phospho CREB, phospho TOR, phospho Src, phospho JNK, phospho p53, phospho STAT3,<br />
phospho ATM.<br />
Our results show that these newly developed arrays enable reliable evaluation <strong>of</strong> multiple target<br />
protein phosphorylation in a single sample. The method requires minimal sample volumes (~10 μl)<br />
and minimal amount <strong>of</strong> total protein (~1 μg) to obtain quantitative data, and it enables rapid evaluation<br />
<strong>of</strong> multiple analytes.<br />
We thank Clondiag GmbH, Jena, Germany for providing the microarray technology and the<br />
colleagues from the DFG-Forschergruppe FOR630 for bioorganometallic substances.<br />
84
P-27<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Variable Binding <strong>of</strong> Heterodinuclear (Cu, Fe) Organometallics to N and O Donor<br />
Functions <strong>of</strong> Guanine, Pterin, Lumazine and Alloxazine Heterocycles<br />
Rajkumar Jana, a Biprajit Sarkar, a Jan Fiedler, b and Wolfgang Kaim *a<br />
a Institut für Anorganische Chemie, <strong>Universität</strong> Stuttgart, Pfaffenwaldring 55, D-70550, Stuttgart,<br />
Germany; b J. Heyrovský Institute <strong>of</strong> Physical Chemistry, v.v.i., Academy <strong>of</strong> Sciences <strong>of</strong> the Czech<br />
Republic, Dolejškova 3, 182 23 Prague 8, Czech Republic. E-mail: jana@iac.uni-stuttgart.de<br />
Co-ordination compounds <strong>of</strong> the first row transition elements with small biorelevant heterocycles such<br />
as coenzymes, vitamins, and also nucleobases are frequently labile, precluding the isolation and<br />
structural identification <strong>of</strong> species present in solution equilibria. In contrast, complexes <strong>of</strong> the heavier<br />
d block elements are <strong>of</strong>ten inert as exemplified by the platinum and platinum metal coordination<br />
chemistry <strong>of</strong> nucleobases 1 and coenzymes 2 . Herein we wish to report a number <strong>of</strong> first row transition<br />
metal compounds which owe their stability to the use <strong>of</strong> a particular kind <strong>of</strong> organometallic complex<br />
fragments, viz., [(dopf)Cu] + , dopf = 1,1`-bis(diorganylphosphino)ferrocene.<br />
Bu t OC<br />
H<br />
N<br />
H<br />
The dopf ligands are being extensively used as scaffolding chelate ligands in catalysis 3, 4 , sometimes<br />
using their propensity for reversible one-electron oxidation at the ferrocene iron site. Our experience<br />
especially with the dppf ligand (dppf = 1,1`-bis(diphenylphosphino)ferrocene) in heterobimetallic<br />
[(dppf)Cu] + to stabilize complexes with unreduced strong acceptors such as α-azoimines 5 or oquinones<br />
6 has prompted us to explore the coordination <strong>of</strong> [(dppf)Cu] + and [(dippf)Cu] + , dippf = 1,1`bis(diisopropylphosphino)ferrocene,<br />
with other small biorelevant unsaturated molecules containing the<br />
lumazine, isoalloxazine, pterin and guanine heterocyclic structures. Synthesis and structural<br />
characterization will be reported as will be electrochemical studies on oxidation (ferrocene) and<br />
reduction (heterocycles).<br />
References<br />
N<br />
O<br />
N<br />
Fe<br />
R2P + PR2 Cu<br />
N<br />
N<br />
Me<br />
Bu t OC<br />
H<br />
N<br />
H<br />
N<br />
Fe<br />
R2P + PR2 Cu<br />
O<br />
N<br />
N<br />
N<br />
1. (a) D. Montagner, E. Zangrando, B. Longato, Inorg. Chem. 2008, 47, 2688-2695. (b)<br />
Cisplatin: Chemistry and Biochemistry <strong>of</strong> a Leading Anticancer Drug; B. Lippert, Ed.; Wiley-VCH,<br />
Weinheim, 1999.<br />
2. Bioorganometallics: Biomolecules, Labelling, Medicine; G. Jaouen, Ed.; Wiley-VCH, Weinheim,<br />
2006.<br />
3. L. M. Alcazar-Roman, J. F. Hartwig, A. L. Rheingold, L. M. Liable-Sands, I. A. Guzei, J. Am.<br />
Chem. Soc. 2000, 122, 4618-4630.<br />
4. M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 8232-8245.<br />
5. S. Roy, M. Sieger, B. Sarkar, B. Schwederski, F. Lissner, T. Schleid, J. Fiedler, W. Kaim, Angew.<br />
Chem. Int. Ed. 2008, 47, 6192-6194.<br />
6. S. Roy, B. Sarkar, D. Bubrin, M. Niemeyer, S. Zalis, G. K. Lahiri, W. Kaim, J. Am. Chem. Soc.<br />
2008, 130, 15230-15231.<br />
85<br />
Me<br />
N<br />
O<br />
Fe<br />
R2P + PR2 O<br />
Cu<br />
N<br />
N N<br />
Me<br />
Me<br />
N<br />
O<br />
Fe<br />
R2P + PR<br />
O<br />
Cu 2<br />
N<br />
N N<br />
Me<br />
Me<br />
Me
P-28<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis, Structure and Anticancer Activity <strong>of</strong> new Complexes <strong>of</strong> Copper<br />
with Pyridoxal-semicarbazone<br />
Violeta Jevtovic, *a Dragoslav Vidovic, b Radmila Kovacecic, c and Sonja Kaisarevic c<br />
a University <strong>of</strong> Novi Sad, Faculty <strong>of</strong> Sciences, Department <strong>of</strong> Chemistry, D. Obradovica 3, 38121,<br />
Novi Sad, Serbia<br />
b University <strong>of</strong> Oxford, Chemical Research Laboratory,Masfield Road ,OX1 3TA, City, UK.<br />
c University <strong>of</strong> Novi Sad, Faculty <strong>of</strong> Sciences, Department <strong>of</strong> Biology, D. Obradovica 3, 38121, Novi<br />
Sad, Serbia. E mail: violeta.jevtovic@dh.uns.ac.rs<br />
With reaction <strong>of</strong> ligand pyridoxal-semicarbazone PLSC . 2H2O 1 and appropriate chloride, sulphate<br />
and thiocyanate salts Cu(II) in alcohol and water mixtures which were given in three new copper(II)<br />
complexes: [Cu(PLSC)Cl2](1),[Cu(PLSC)(H2O)(SO4)]2 . 3H2O(2), [Cu(PLSC)2(NCS)2](NCS)2 (3)<br />
(see Fig.1). Cytototoxic activity was evaluated by colorimetric sulforhodamine B (SRB) assay, after<br />
exposure <strong>of</strong> cells to tested compounds for 24 h and 72 h. (see Fig 2.) shows effect <strong>of</strong> different<br />
concentrations <strong>of</strong> tested compounds on two cell lines after 24 h and 72 h incubation times. The results<br />
suggest that compound (A) exibit no antiproliferative effect. Compound (B) exibit cytotoxic effects<br />
on both cell lines only after 72h treatment by the highest tested concentrations. Similar cytotoxicity<br />
patern was observed for compound (C) with aditional cytotoxic effect on MDA-MB-231 after 24 h<br />
treatment with the highest concentration.<br />
(1) (2) (3)<br />
Figure 1. The molecular structure <strong>of</strong> complexes<br />
Figure 2. Effects <strong>of</strong> compounds (1), (2) and (3) on cell proliferation <strong>of</strong> MCF7 and MDA-MB-231<br />
References<br />
1. V. Leovac, V.S. Jevtovic, Lj. Jovanovic, G.A. Bogdanovic, J. Serb. Chem. Soc. 2005, 70, 393-422.<br />
86
P-29<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Transcriptional Pr<strong>of</strong>ile <strong>of</strong> HT-29 Cells upon Treatment with Different<br />
Organometallic Compounds<br />
Igor Kitanovic, a Ana Kitanovic, a Hamed Alborzinia, a Suzan Can, a Pavlo Holenya, a Elke Lederer, a<br />
Hans-Günther Schmalz, b Annegret Hille, c Ronald Gust, c Ingo Ott, d Aram Prokop, e Melanie Oleszak, f<br />
Yvonne Geldmacher, f William S. Sheldrick, f Gilles Gasser, g Nils Metzler-Nolte, h and Stefan Wölfl* a<br />
a Institute <strong>of</strong> Pharmacy and Molecular Biotechnology, University Heidelberg, Germany, b Institute <strong>of</strong><br />
Inorganic Chemistry, University <strong>of</strong> Cologne, Germany, c Institute <strong>of</strong> Pharmacy, Department <strong>of</strong><br />
Pharmaceutical Chemistry, Freie <strong>Universität</strong> Berlin, Germany, d Institute <strong>of</strong> Pharmaceutical<br />
Chemistry, Technische <strong>Universität</strong> Braunschweig, Germany, e Cologne City Hospital, Department <strong>of</strong><br />
Oncology, Cologne, Germany, f Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong> Analytical<br />
Chemistry, University <strong>Bochum</strong>, g Institute <strong>of</strong> Inorganic Chemistry, University <strong>of</strong> Zurich, h Faculty <strong>of</strong><br />
Chemistry and Biochemistry, Department <strong>of</strong> Bioinorganic Chemistry, University <strong>of</strong> <strong>Bochum</strong><br />
email: Igor.Kitanovic@urz.uni-heidelberg.de, wolfl@uni-hd.de<br />
In the past several decades metal compounds containing platinum became an essential part <strong>of</strong> many<br />
clinical protocols for anti-cancer therapy. Considered to be relatively unspecific compounds that block<br />
DNA-replication and cell cycle progression, metal-containing compounds were not in the research<br />
focus <strong>of</strong> medicinal chemistry. New developments in the chemistry <strong>of</strong> (bio-)organometallic compounds<br />
however lead to the discovery <strong>of</strong> several unexpected highly specific activities <strong>of</strong> new organometallic<br />
compounds and opened new important perspectives in this field.<br />
For cancer therapy cancer cell specific toxicity and apoptosis induction are highly desirable features <strong>of</strong><br />
new potential drugs. Within our collaborative network a wide range <strong>of</strong> new (bio-)orgamometallic<br />
compounds were developed that show very distinct cytotoxic properties suggesting that rather than<br />
acting through a common mechanism different cellular targets are responsible for cytotoxicity and cell<br />
death induction.<br />
We will present a comprehensive analysis <strong>of</strong> the cellular response <strong>of</strong> human colorectal<br />
adenocarcinoma cells HT29 with very diverse organometallic compounds: ranging from FeIIsalophenes,<br />
through more classical bioorganometallic compounds to bioorganometallic compounds<br />
derived from established (non-metal containing) drugs. To elucidate their specific activity pr<strong>of</strong>ile,<br />
standard cell based assays were combined with genome wide gene expression pr<strong>of</strong>iling using<br />
affymetrix gene expression arrays. Although the substances represent a wide range <strong>of</strong> different<br />
structures and metal cores, they all are highly cytotoxic and clearly induce apoptosis in HT-29 cells.<br />
For gene expression pr<strong>of</strong>iling concentrations just below the IC50 (cytotoxicity) were chosen to obtain<br />
more compound specific alterations in gene expression rather then common cytotoxicity pr<strong>of</strong>iles, in<br />
addition mRNAs were collected at different time points critical in the cellular response upon<br />
treatment.<br />
The results obtained show similar response characteristics, but also very compound specific changes.<br />
This clearly indicates very distinct biological properties and suggests common response mechanisms<br />
as well as high selectivity and target specificity.<br />
List <strong>of</strong> compounds: Hi41, CoASS (AG Gust), MH1 (AG Scheldrick), MeN69 (AG Schmaltz),<br />
FcOHTAM3, ReGG1 (AG Metzler-Nolte)<br />
This work is supported by the DFG as part <strong>of</strong> the Forschergruppe FOR630.<br />
87
P-30<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Organoiridium(III) and -rhodium(III) Bis-Intercalators: Influence <strong>of</strong> the<br />
Bridging Ligand on Cytotoxicity<br />
Malte Kokoschka, a Andreas Meyer, b Ingo Ott, b and William S. Sheldrick *a<br />
a <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and Biochemistry , Department <strong>of</strong> Analytical<br />
Chemistry, <strong>Universität</strong>sstraße 150, 44801, <strong>Bochum</strong>, Germany. b Technische <strong>Universität</strong><br />
Braunschweig, Institute <strong>of</strong> Pharmaceutical Chemistry, Beethovenstraße 55, 38106, Braunschweig,<br />
Germany. E-mail: malte.kokoschka@rub.de<br />
As we have recently shown, dinuclear iridium(III) polypyridyl complexes bridged by flexible ligands<br />
are capable <strong>of</strong> sequence selective intercalation into a synthetic DNA oligomer. 1 Induced structural<br />
changes in DNA – which have been proposed to account for the cytotoxicity <strong>of</strong> cisdiamminedichloroplatinum(II)<br />
– should be closely related to the molecular shape <strong>of</strong> the employed<br />
bridging ligand. Taking advantage <strong>of</strong> our findings from NMR assisted structure calculations on a<br />
double-stranded decanucleotide bis-intercalator adduct, we have started a systematic investigation <strong>of</strong><br />
bis-intercalative compounds incorporating bridging ligands such as 1,3-benzenedithiol, 1,3- and 1,4benzenedimethanethiol<br />
with the ability to induce stronger distorsions into DNA. The resulting<br />
compounds have being studied with respect to their cytotoxicity and DNA interaction, respectively.<br />
[{(η 5 -C5Me5)Ir(dppz)}2(µ-2,9-dithiadecane)] 4+ bis-intercalated into the double-stranded decanucleotide<br />
d(5’-GCGCATCGGC-3’) as determined by NOESY NMR spectroscopy<br />
References<br />
1. M. Kokoschka, J.-A. Bangert, R. Stoll, W. S. Sheldrick, Eur. J. Inorg. Chem. 2010, 1507-1515.<br />
88
P-31<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis, Structures, Characterization and Biological Activities <strong>of</strong> Some<br />
Diorganotin(IV) Complexes<br />
See Mun Lee, *a H. Mohd. Ali, a and K. M. Lo a<br />
a University <strong>of</strong> Malaya, Faculty <strong>of</strong> Science, Department <strong>of</strong> Chemistry, 50603 Kuala Lumpur,Malaysia.<br />
E-mail: smlee@um.edu.my<br />
Metal complexes are widely prepared and have been successfully used in the treatment <strong>of</strong> numerous<br />
human diseases including cancer. Organotin(IV) complexes have been widely studied for their<br />
biological activities such as anticancer, antihistamine, antifungal and many others. Schiff base derived<br />
from substituted salicylaldehyde has been widely used as polydentate ligands in the preparation <strong>of</strong><br />
metal complexes. In our present studies, a series <strong>of</strong> Schiff base ligands were prepared by reacting 3hydroxy-2-naphthoic<br />
hydrazide with substituted 2-hydroxyacetophenone. The diorganotin complexes<br />
were subsequently prepared by adding the ligands with diorganotin dichloride or oxide in 1:1 molar<br />
ratio and were characterized by various spectroscopic methods including IR, NMR spectroscopies.<br />
The X-ray structures <strong>of</strong> some <strong>of</strong> the diorganotin complexes namely<br />
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV)<br />
{[1-(5-Bromo-2 oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dibutyltin(IV)<br />
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dimethyltin(IV) and<br />
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dimethyltin(IV)<br />
have been determined using single crystal X-ray diffractometry. The in vitro cytotoxic activity <strong>of</strong> the<br />
Schiff base ligands and diorganotin complexes has been evaluated against several cancer cell-lines<br />
such as HT-29, SKOV-3 and MCF7.<br />
References<br />
1. M. Gielen, Coord. Chem. Rev. 1996, 151, 41-51.<br />
2. A. J. Crowe, P. J. Smith, C. J. Cardin, H. E. Parge, F. E. Smith. Cancer Lett. 1984, 24 45-48.<br />
89
P-32<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Organometallic Iridium Anticancer Complexes<br />
Zhe Liu, Abraha Habtemariam, Ana Pizarri, Sally Fletcher, Guy Clarkson and Peter J. Sadler<br />
Department <strong>of</strong> Chemistry, University <strong>of</strong> Warwick, Coventry CV4 7AL, U.K.<br />
E-mail: Z.Liu.2@warwick.ac.uk<br />
Cisplatin has been used to treat various types <strong>of</strong> cancers for over 30 years, however, a number <strong>of</strong><br />
serious side-effects <strong>of</strong> cisplatin have stimulated the long quest for other metal-based anticancer agents,<br />
especially drugs which possess a wider range <strong>of</strong> anticancer activity and with fewer side effects than<br />
cisplatin. There is much current interest in the design <strong>of</strong> ruthenium 1 and osmium 2 complexes as<br />
anticancer agents, but only a small amount <strong>of</strong> work has been done to investigate the antitumour<br />
activity <strong>of</strong> iridium complexes. 3<br />
Here we report the synthesis and characterization <strong>of</strong> a wide range <strong>of</strong> Ir(III) cyclopentadienyl<br />
complexes. We have studied their solid state structures, hydrolysis rates, reactivity towards<br />
nucleobases and acidity <strong>of</strong> aqua complexes. Their cell uptake and distribution and toxicity towards<br />
cancer cells have been studied and correlated with their chemical properties. Both the chemical and<br />
biological activity <strong>of</strong> these complexes show a strong dependence on the nature <strong>of</strong> the substituents on<br />
the cyclopentadienyl and the other ligands in the complexes.<br />
Acknowledgements: We thank WPRS (scholarship for Z.L), ERC (award for P.J.S.), EDRF and<br />
AWM for Science City funding, and members <strong>of</strong> COST Action D39 for stimulating discussions.<br />
References<br />
1. (a) A. Habtemariam, M. Melchart, R. Fernndez, S. Parsons, I. D. H. Oswald, A. Parkin, F. P. A.<br />
Fabbiani, J. E. Davidson, A. Dawson, R. E. Aird, D. I. Jodrell, P. J. Sadler, J. Med. Chem., 2006, 49,<br />
6858-6868. (b) J. M. Redemaker-Lakhai, D. van den. Bongard, D. Pluim, J. H. Beijnen, J. H. M.<br />
Schellens, Clin. Cancer Res. 2004, 10, 3717–3727. (c) I. Bratsos, S. Jedner, T. Gianferrara, E. Alessio,<br />
Chimia 2007, 61, 692-697.<br />
2. (a) A. F. A. Peacock, S. Parsons, P. J. Sadler, J. Am. Chem. Soc. 2007, 129, 3348-3357. (b) P.C. A.<br />
Bruijnincx and P. J. Sadler, Adv. Inorg. Chem. 2009, 61, 1-62.<br />
3. S. Schäfer, I. Ott, R. Gust, W. S. Sheldrick, Eur. J. Inorg. Chem. 2007, 3034-3046.<br />
90
P-33<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
The Research <strong>of</strong> the Interaction between Quercetin and Zirconium (IV) in<br />
Water-Ethanol Medium<br />
Olessya Loiko, a A.Khalitova, a B.Tuleuov, b A.Mashentseva *c<br />
a Karaganda State University, Faculty <strong>of</strong> Chemistry, Department <strong>of</strong> Chemistry, Universitetskaya 28,<br />
100000, Karaganda, Kazakhstan. b ISPH “Phytochemistry”,Gasalieva str.4 , 100000, Karaganda,<br />
Kazakhstan. c L.N.Gumilev Eurasian national university, Faculty <strong>of</strong> Chemistry, Department <strong>of</strong><br />
Chemistry, Munajtpasova 5, 010008, Astana, Kazakhstan.<br />
E-mail: olessya0905@gmail.com<br />
It’s known, that the search <strong>of</strong> new compounds with radioprotective, antioxidant and hepatoprotective<br />
activities is carried out among flavonoids; 1 because <strong>of</strong> their structural molecule uniqueness they can<br />
hamper not only oxidising processes, but also make transfer <strong>of</strong> energy and migration <strong>of</strong> elementary<br />
particles at the irradiation. At the same time, examples <strong>of</strong> individual flavonoids (rutin and quercetin)<br />
and their derivatives’ usage in the medical practice are single, despite their wide variety, accessibility<br />
<strong>of</strong> their production sources and relative availability.<br />
It is suggested that the biological activity <strong>of</strong> an organic ligand can be increased when co-coordinated<br />
or mixed with suitable metal ion, because <strong>of</strong> its ability to act as a free radical acceptor. 2 From the<br />
pharmacology point <strong>of</strong> view zirconium (IV) complexes are noted for their significant biological<br />
properties, namely antibacterial and antifungal activities. Information about mechanism <strong>of</strong> interaction<br />
between zirconium (IV) and quercetin will help to explain and predict biochemical activity <strong>of</strong> these<br />
components’ mixture in the medical product.<br />
The ability to form complex between quercetin and zirconium (IV) was studied in this work using<br />
spectrophotometer method. Quercetin zirconium (IV) complex is characterized by 3 absorption bands:<br />
in UV and visible parts <strong>of</strong> spectrum at 360 nm, 395 nm and 475 nm; the extension coefficients (ε)<br />
were calculated for these bands: 1042, 1045 and 2966 correspondingly. In the presence <strong>of</strong> metal ions,<br />
a bathochromic shift on 55 nm is observed in the absorption spectra <strong>of</strong> complex. Such bathochromic<br />
shift can be explained by the interaction <strong>of</strong> cobalt chloride with the free C3-oxo group <strong>of</strong> quercetin.<br />
Investigated complex was synthesized in the solid state. IR spectra <strong>of</strong> ligand and complex present<br />
evidence <strong>of</strong> the coordination between zirconium ions and oxo-group <strong>of</strong> quercetin. It can be noted that<br />
Zr-O frequencies appear at 559.78, 538.53 and 472.02cm -1 .<br />
As the result <strong>of</strong> made researches <strong>of</strong> complex formation between zirconium (IV) and quercetin, the<br />
influence <strong>of</strong> time, solvent and organic reagent concentration were studied. Studying the complex<br />
solubility, it was determined that the compound sufficiently dissolves in water-ethanol mixture. It has<br />
been shown, that if the content <strong>of</strong> ethanol is under 15%, the complex will fall in a precipitation. Using<br />
Jobs method it was established, that made compound has content, which formula is C30H18O15Zr. The<br />
stability constant <strong>of</strong> complex is (9,56 ± 0,01)·10 9 , this number shows that the complex is averagely<br />
stable. Complex forms at the room temperature.<br />
According to the PASS biocsreening calculation follow activities for the synthesized complex are<br />
antiparkinsonian, nootropic, cardioprotectant and creatine kinase inhibitor.<br />
References<br />
1. I.S. Vasil’eva, V.A. Paseshnichenko, The achievements <strong>of</strong> Biological Chemistry, 2000, 3, 153-156.<br />
2. M.Y. Morandi, J. Pourahmad, Free Radic. Biol. Med. 2003, 34, 243‐250.<br />
91
P-34<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Photocytotoxicity and DNA Cleavage Activity <strong>of</strong> 2-Ferrocenyl Adducts having<br />
Imidazophenanthroline and Imidazophenanthrene Moieties<br />
Basudev Maity, a Mithun Roy, a Sounik Saha, a Ritankar Majumdar, b Rajan R. Dighe, b and Akhil R.<br />
Chakravarty* a<br />
a Indian Institute <strong>of</strong> Science, Department <strong>of</strong> Inorganic and Physical Chemistry, b Department <strong>of</strong><br />
Molecular Reproduction, Development and Genetics, Sir C V Raman avenue, 560012, Bangalore,<br />
India. E-mail: basudev@ipc.iisc.ernet.in<br />
Ferrocene is an important constituent in the field <strong>of</strong> bioorganometallic chemistry related to nucleic<br />
acids in spite <strong>of</strong> having any effective anticancer activity. 1 It is the ferrocenium cation, the oxidized<br />
form <strong>of</strong> ferrocene, which is responsible for the anticancer activity. 2 The designing <strong>of</strong> new ferrocenebased<br />
molecules showing photo-induced DNA cleavage and/or photocytotoxic activities are <strong>of</strong><br />
interests for their potential applications in the field <strong>of</strong> molecular biology, biotechnology and<br />
particularly in medicine. This presentation includes the synthesis, characterization, interactions with<br />
DNA, photo-induced DNA cleavage activity and photocytotoxicity <strong>of</strong> 2-ferrocenylimidazophenanthroline<br />
(1) 3 and 2-ferrocenyl-imidazophenanthrene (2). To understand the role <strong>of</strong> the<br />
ferrocenyl moiety, 2-phenyl-imidazophenanthroline (3) 4 has been studied as a control species.<br />
Compound 2 has been characterized by X-ray crystallography. The interaction <strong>of</strong> the compounds with<br />
DNA has been studied by UV-visible absorption titration and thermal denaturation methods. All the<br />
compounds show good binding affinity to calf thymus DNA with intrinsic binding constant values <strong>of</strong><br />
~10 5 M -1 . The thermal denaturation data suggest DNA groove binding nature <strong>of</strong> the compounds. They<br />
show poor chemical nuclease activity in the presence <strong>of</strong> H2O2 as an oxidizing agent and are inactive in<br />
the presence <strong>of</strong> cellular reducing agent glutathione. Compound 1 shows significant photo-induced<br />
DNA cleavage activity in UV-A light <strong>of</strong> 365 nm and visible light <strong>of</strong> 488 (blue light) and 530 nm<br />
(green light). The mechanistic investigations <strong>of</strong> the DNA cleavage activity reveal the involvement <strong>of</strong><br />
reactive oxygen species. The photocytotoxicity <strong>of</strong> the compounds in human cervical HeLa cancer cell<br />
line has been studied in UV-A light <strong>of</strong> 365 nm.<br />
References<br />
1. D. R. van Staveren, N. Metzler-Nolte, Chem. Rev. 2004, 104, 5931-5985.<br />
2. G. Tabbì, C. Cassino, G. Cavigiolio, D. Colangelo, A. Ghiglia, I.Viano, D. Osella, J. Med. Chem.<br />
2002, 45, 5786-5796.<br />
3. F. Zapata, A. Caballero, A. Espinosa, A. Tárraga, P. Molina, J. Org. Chem. 2008, 73, 4034–4044.<br />
4. N. M. Shavaleev, H. Adams, J. A. Weinstein, Inorg. Chim. Acta 2007, 360, 700–704.<br />
92
P-35<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Carbon Monoxide Release and Biological Properties <strong>of</strong> Manganese Tricarbonyl<br />
Trispyrazolyl Complexes<br />
Johanna Niesel, a Hendrik Pfeiffer, a and Ulrich Schatzschneider *a<br />
a <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Lehrstuhl für Anorganische Chemie I, <strong>Universität</strong>sstrasse 150, D-44801<br />
<strong>Bochum</strong>, Germany. E-mail: johanna.niesel@rub.de<br />
Carbon monoxide is an important small molecule messenger in the human body. 1 For its controlled<br />
release to biological systems, transition metal carbonyl complexes can be utilized to exploit the<br />
beneficial physiological effects <strong>of</strong> CO like vasodilatation and protection against oxidative stress. In<br />
addition, cytotoxic activity <strong>of</strong> carbon monoxide against cancer cells and pathogenic microorganisms<br />
has been established. In contrast to hydrolytic liberation <strong>of</strong> CO from metal carbonyl complexes,<br />
photoactivated CO release will allow for a precise spatial and temporal control <strong>of</strong> its biological<br />
activity. 2 Recently, we have identified [Mn(CO)3(tpm)] + with tpm = tris(1-pyrazolyl)methane as a<br />
stable in aqueous solution and inactive against cancer cells in the dark. However, upon light activation<br />
it efficiently kills HT29 human colon cancer cells. 3,4 To study the influence <strong>of</strong> the ligand system on the<br />
CO release and the biological properties, manganese trispyrazolylcomplexes with variations on the<br />
pyrazol rings 6 or the alpha carbon 7 were synthesized and their CO release efficiency as well as<br />
biological activity against human breast cancer cells MCF7 and colon cancer cells HT-29 was<br />
investigated.<br />
References<br />
1. S.W. Ryter, J. Alam, A.M.K. Choi, Physiol. Rev. 2006, 583-650.<br />
2. U. Schatzschneider, Eur. J. Inorg. Chem. 2010, 10, 1451-1467.<br />
3. J. Niesel, A. Pinto, H. W. Peindy N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem.<br />
Commun. 2008, 1798-1800.<br />
4. H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider, Dalton Trans. 2009, 4292-4298.<br />
5. K. Meister, J. Niesel, U. Schatzschneider, N. Metzler-Nolte, D.A. Schmidt, M. Havenith, Angew.<br />
Chem. 2010, 122, 3382-3384; Angew. Chem. Int. Ed. 2010, 49, 3310-3312.<br />
6. D.L. Reger, R.D. Sommer, J. Organomet. Chem. 2000, 607, 120-128.<br />
7. B.J. Liddle, J.R. Gardinier, J. Org. Chem. 2007, 72, 9794-9797.<br />
93<br />
c(MbCO) in µM<br />
30<br />
20<br />
10<br />
0<br />
0 50 100<br />
t(min)
P-36<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Novel Polypyrrole Substituted Carbon Monoxide Releasing Molecules<br />
(CO-RMs); New Delivery System for Carbon Monoxide<br />
Niall B. McGuinness, a Carmel B. Breslin, a and A. Denise Rooney a<br />
a Environmental Technologies and Biomaterials Research Group, Department <strong>of</strong> Chemistry,<br />
National University <strong>of</strong> Ireland, Maynooth, Co. Kildare, Ireland. Email: niall.b.mcguinness@nuim.ie<br />
Research has shown that minute quantities <strong>of</strong> carbon monoxide (CO) molecules produced in the<br />
human body are a fundamental component for life processes, but in larger doses the inherent toxic<br />
nature <strong>of</strong> CO cannot be ignored. However, CO liberated from CO-RMs can be accurately controlled<br />
and delivered at precise concentrations. Beneficial actions <strong>of</strong> CO include cardioprotection against<br />
blood flow restriction, heart attack and cardiac graft rejection; prevention against the increase <strong>of</strong><br />
strength in muscle contraction <strong>of</strong> the heart; and suppression <strong>of</strong> the inflammatory response 1 . A problem<br />
associated with several <strong>of</strong> the CO-RMs is the transition metal (T.M.) employed, which can be toxic<br />
due to accumulation in the human body.<br />
N<br />
N<br />
O<br />
O<br />
N<br />
H<br />
N<br />
H<br />
N N<br />
4,4'-Bis-(N -propyl-3-pyrrole-carbamoyl)-2,2'-bipyridine<br />
1<br />
Figure 1: Novel substituted pyrrole monomer and metal complex synthesised.<br />
OC<br />
OC<br />
94<br />
CO<br />
Mo<br />
CO<br />
N<br />
N<br />
O<br />
O<br />
N<br />
H<br />
N<br />
H<br />
N N<br />
Tetracarbonyl (4,4'-bis-(N-propyl-3-pyrrole-carbamoyl)-2,2'-bipyridine)<br />
molybdenum (0)<br />
We have set out to bind T.M. carbonyl complexes to polypyrrole, a biocompatible conducting<br />
polymer. The carbonyl complex is trapped in the polymer so that after CO is released into the tissue<br />
the complex can then be removed. The monomer unit 1 has been synthesised and successfully<br />
undergoes electrochemical polymerization. Mo(CO)4 has been complexed to this monomer at high<br />
yield using a microwave-assisted method. Before investigating the electrochemical response <strong>of</strong> the<br />
polymer formed from complex 2, studies were carried out on 2 in solution. Electrochemical studies<br />
indicate that upon 1-electron oxidation, Mo(CO)4(bipy-pyr) undergoes CO subsitution in a<br />
coordinating solvent (Figure 2). Direct evidence that the oxidation results in CO release was provided<br />
by studies performed using an Optically Transparent Thin-Layer Electrochemical (OTTLE) cell with<br />
IR detection. Our results indicate that this is a promising approach for the controlled release <strong>of</strong> CO<br />
from a polymer.<br />
0.0002<br />
0.0001<br />
I (Amps/cm 2 )<br />
0<br />
Black: redox couple <strong>of</strong> Mo(CO) 4(bpy‐pyr)<br />
in DCM<br />
Grey: redox couple <strong>of</strong> Mo(CO) 4(bpy‐pyr)<br />
in DCM with 3 eq. <strong>of</strong> MeCN present<br />
*1‐electron oxidation and reduction<br />
<strong>of</strong> Mo(CO) 4(bpy‐pyr)<br />
Loss <strong>of</strong> reduction peak<br />
caused by rapid CO<br />
substitution due to<br />
-0.0001<br />
* presence <strong>of</strong> MeCN<br />
0 0.25 0.50 0.75 1.00 1.25<br />
Figure 2: Cyclic voltammograms <strong>of</strong> Mo(CO)4(bipy-pyr) in DCM and MeCN.<br />
References<br />
E (Volts)<br />
1. R. Foresti, M. G. Bani-Hani, R. Motterlini Intensive Care Med. 2008, 34, 649-658.<br />
*<br />
2
P-37<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Cytotoxicity Studies on Rhenium(I) Tricarbonyl Complexes<br />
Teck-Tian Wong, Li-Peng Wong, Peng-Foo Peter Lee and Yaw-Kai Yan*<br />
Nanyang Technological University, National Institute <strong>of</strong> Education, Natural Sciences & Science<br />
Education Department, 1 Nanyang Walk, Singapore 637616. E-mail: yawkai.yan@nie.edu.sg<br />
Since the late 1980’s, there has been a steady growth <strong>of</strong> interest in ruthenium anti-cancer drugs as<br />
reflected in the accelerating growth <strong>of</strong> publications in this area. 1 In particular, a series <strong>of</strong> water soluble<br />
and stable ruthenium(II) arene ethylenediamine complexes (1) was shown to exhibit promising anticancer<br />
activity in vitro and in vivo. 2 Anti-cancer activity has also been observed in rhenium(I)<br />
tricarbonyl complexes. 3 Since both rhenium(I) and ruthenium(II) are d 6 configuration metal ions, it<br />
would be interesting to investigate the anti-cancer activity <strong>of</strong> rhenium(I) tricarbonyl complexes with<br />
N,N- and P,P- chelating agents. The three CO ligands <strong>of</strong> the Re(I) complexes correspond to the arene<br />
ligand <strong>of</strong> the Ru(II) complexes in that both donate six electrons. The chelating N,N- and P,P- ligands<br />
<strong>of</strong> the Re(I) complexes correspond to the ethylenediamine ligand <strong>of</strong> the Ru(II) complexes and both<br />
types <strong>of</strong> complexes have a single ligand exchange site occupied by a monoanionic ligand.<br />
In this study, we are concerned with the synthesis and bio-physicochemical characterization <strong>of</strong> a series<br />
<strong>of</strong> mononuclear rhenium(I) tricarbonyl complexes [Re(X)(CO)3L2] (2) [where X = Br, Cl, Cl2HCCO2;<br />
L2 = ethylenediammine (en), N,N,N ′ ,N ′ -tetramethylethylenediamine (tmen), 2,2 ′ -bipyridine (bpy),<br />
N,N ′ -dimethylethylenediamine (dmen), 2,2 ′ -bipyridine-4,4 ′ -dicarboxylic acid (H2bpdc),<br />
1,3-bis(diphenylphosphino)propane (dppp) and 1,1′-bis(diphenylphosphino)ferrocene (dppf)]. All the<br />
complexes were characterized by IR and 1 H NMR spectroscopy and elemental analysis. The rhenium<br />
complexes and their respective ligands were screened using the human leukaemia (MOLT-4) cell line<br />
via the MTT assay. The results will be presented in the poster.<br />
References<br />
Cl<br />
Ru<br />
N<br />
N<br />
R<br />
+<br />
95<br />
OC<br />
OC<br />
Re<br />
1 2<br />
1. A. Levina, A. Mitra, P. L. Lay, Metallomics 2009, 1, 458-470.<br />
2. Y. K. Yan, M. Melchart, A. Habtemariam, P. J. Sadler, Chem. Commun. 2005, 4764-4776.<br />
3. (a) J. Zhang, J. J. Vittal, W. Henderson, J. Wheaton, I. H. Hall, T. S. A. Hor, Y. K. Yan, J.<br />
Organomet. Chem. 2002, 650, 123-132. (b) Y. K. Yan, S. E. Cho, K. A. Shaffer, J. E. Rowell, B. J.<br />
Barnes, I. H. Hall, Pharmazie 2000, 55, 307-313. (c) W. Wang, Y. K. Yan, T. S. A. Hor, J. J. Vittal, J.<br />
R. Wheaton, I. H. Hall, Polyhedron 2002, 21, 1991-1999.<br />
X<br />
L<br />
CO<br />
L
P-38<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Bioorthogonal Coupling Strategies in the Synthesis <strong>of</strong> CORM-peptide Conjugates<br />
a<br />
Hendrik Pfeiffer, a Johanna Niesel, b and Ulrich Schatzschneider* a<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Department <strong>of</strong> Chemistry and Biochemistry,<br />
<strong>Universität</strong>sstrasse 150, 44801 <strong>Bochum</strong>, Germany, hendrik.pfeiffer@rub.de<br />
In the human body carbon monoxide possesses versatile properties as a signalling mediator and<br />
participates in important biological processes. Beside being a potent vasodilator, CO can exert antiinflammatory,<br />
anti-apoptotic, and anti-proliferative effects. 1,2 Since it is a toxic gas and difficult to<br />
handle, there is considerable interest in the development <strong>of</strong> CO releasing molecules (CORMs) as<br />
"solid storage forms" for carbon monoxide. Therefore, transition metal carbonyl complexes are highly<br />
interesting target structures. 3 Compared to thermally induced liberation <strong>of</strong> CO, photoactivated CO<br />
release will allow for a precise spatial and temporal control <strong>of</strong> its biological action. 4 We have recently<br />
synthesized several tungsten, molybdenum, and manganese complexes with bidentate as well as<br />
tridentate nitrogen donor ligands as promising new photoCORMs, which are inert in the dark in<br />
aqueous solution, but release CO upon irradiation. 5<br />
Carrier peptides are important vehicles to achieve accumulation <strong>of</strong> bioactive cargos in specific<br />
biological target sites. Thus, we have explored the functionalization <strong>of</strong> the parent photoCORMs with<br />
model peptides using bioorthogonal coupling strategies, such as oxime ligation, Sonogashira crosscoupling,<br />
or the alkyne-azide 1,3-dipolar cycloaddition (click reaction). 6<br />
References<br />
1. S. W. Ryter, J. Alam, A. M. K. Choi, Physiol. Rev. 2006, 86, 583-650.<br />
2. T. R. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green, R. Motterlini, Angew. Chem. Int. Ed.<br />
2003, 42, 3722-3729.<br />
3. J. Boczkowski, J. J. Poderoso, R. Motterlini, Trends Biochem. Sci 2006, 31, 614-621.<br />
4. U. Schatzschneider, Eur. J. Inorg. Chem. 2010, 1451-1467.<br />
5. J. Niesel, A. Pinto, H. W. Peindy N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem.<br />
Commun. 2008, 1798-1800.<br />
6. H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider, Dalton Trans. 2009, 4292-4298.<br />
96
P-39<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Metallocarbonyl Complexes <strong>of</strong> Bromo- and Dibromomaleimide. Synthesis and<br />
Reactions with Cysteine Derivatives<br />
Bogna Rudolf, a* Marcin Palusiak, b and Emilia Fornal c<br />
a Department <strong>of</strong> Organic Chemistry, University <strong>of</strong> Łódź, Tamka 12, Łódź 91-403, Poland,<br />
b Department <strong>of</strong> Crystalography and Crystal Chemistry, University <strong>of</strong> Lodz, Tamka 12,<br />
Łódź 91-403, Poland<br />
c Chemistry Department, Faculty <strong>of</strong> Mathematics and Life Sciencies, The John Paul II Catholic<br />
University <strong>of</strong> Lublin, al. Krasnicka 102, 20-718 Lublin, E-mail:brudolf@chemia.uni.lodz.pl<br />
The maleimide motif is widely used for the selective reactions with thiols and there are numerous N–<br />
functionalized maleimide reagents applied for cysteine modification. Among them the (η 5 -<br />
C5H5)M(CO)x(η 1 -N-maleimidato) (M = Fe, x = 2; M = W, Mo, x = 3) markers were reacted<br />
with cysteine containing peptides and proteins. These metallocarbonyl complexes display<br />
characteristic strong absorption bands in their IR spectra, �C≡O, appearing in the 1950-2060<br />
cm -1 spectral region, which is usually free <strong>of</strong> any absorption <strong>of</strong> biomolecules or biological<br />
matrices. 1,2<br />
Recently it was reported that the bromomaleimide and its derivatives are <strong>of</strong> interest for<br />
bioconjugation and reversible cysteine modification. 3,4<br />
Fe<br />
OC<br />
OC<br />
cysteine derivatives<br />
In this communication, synthesis <strong>of</strong> metallocarbonyl derivatives <strong>of</strong> bromo- and dibromomaleimide<br />
(e.g. 1) along with reactions <strong>of</strong> these complexes with cysteine derivatives will be presented.<br />
References<br />
O<br />
1<br />
N<br />
O<br />
Br<br />
HS<br />
1. B. Rudolf, J. Zakrzewski, Tetrahedron Lett. 1994, 35, 9611-9612.<br />
2. B. Rudolf, M. Palusiak, J. Zakrzewski, M. Salmain, G. Jaouen, Bioconjugate Chem. 2005, 16, 1218-<br />
1224.<br />
3. L. M. Tedaldi, M. E. B. Smith, R. I. Nathani, J. R Baker, Chem. Com. 2009, 43, 6583-6585.<br />
4. M. E. B. Smith, F. F. Schumacher, C. P. Ryan, L. M. Tedaldi, D. Papaioannou, G. Waksman,<br />
S. Caddick, J. R. Baker J. Am. Chem. Soc. 2010, 132, 1960-1965.<br />
97<br />
OC OC<br />
Fe<br />
O<br />
N<br />
O<br />
S
P-40<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Molybdenum Carbonyl Complexes as CO Releasing Molecules<br />
Lukas Kromer a and Carlos Romão* a,b<br />
a ITQB-UNL, Av. da República, Estação Agronómica Nacional, 2780-157 Oeiras, Portugal.<br />
b ALFAMA Lda., Taguspark, Núcleo Central 267, 2740-122 Porto Salvo, Portugal.<br />
E-mail: kromer@itqb.unl.pt<br />
Carbon Monoxide (CO) is an essential signalling molecule produced in the body. Endogenous<br />
overproduction <strong>of</strong> CO in pathological situations strongly suggests medicinal applications for CO.<br />
Rather than using CO gas; drug research is focused on the development <strong>of</strong> CO-releasing Molecules<br />
(CO-RMs). 1 Although there are a large number <strong>of</strong> CO-RMs known, few if any fulfil the essential<br />
criteria for use as drugs, such as solubility in aqueous solutions <strong>of</strong> physiological pH, stability during<br />
storage and controlled release <strong>of</strong> CO in vivo, and efficacy at non-toxic doses. Furthermore, targeting <strong>of</strong><br />
specific tissue is desirable. To obtain water-soluble organometallic complexes, they either have to be<br />
charged or contain ligands that can be ionised in aqueous solutions through protonation or<br />
deprotonation.<br />
Charged complexes were synthesised with two types <strong>of</strong> ligands: 1,3-diketone and 2-hydroxyketone<br />
ligands. Both types <strong>of</strong> ligand can be deprotonated and form anionic complexes with the general<br />
structure (Et4N)[Mo(O-O)(CO)4]. 2 A second series <strong>of</strong> neutral complexes bearing functional groups<br />
were synthesised with several mono- and bidentate amine ligands in a conventional microwave. 3<br />
OC<br />
CO<br />
Mo<br />
O<br />
OC<br />
CO<br />
O<br />
R<br />
R<br />
0, 1<br />
-<br />
OC<br />
OC<br />
Mo<br />
CO<br />
CO<br />
R 2<br />
N<br />
N<br />
R 2<br />
OC<br />
CO<br />
Mo<br />
NHR<br />
OC<br />
CO<br />
NHR<br />
98<br />
4.00<br />
3.50<br />
3.00<br />
2.50<br />
O<br />
.<br />
C 2.00<br />
e<br />
q<br />
1.50<br />
1.00<br />
0.50<br />
0.00<br />
CO‐Hb formation in blood<br />
0 20 40 60 80<br />
time [min]<br />
The synthesised complexes were fully characterised and investigated in terms <strong>of</strong> solubility,<br />
stability in aqueous solution and the CO release rate was determined both in vitro by GC-TCD as in ex<br />
vivo assays in sheep blood with an Oxymeter. The direct measurement <strong>of</strong> CO-Hb levels in sheep blood<br />
gives you an immediate answer about CO release under biological conditions. The water soluble,<br />
neutral amine complexes exhibited a ligand-dependant CO release rate decreasing from primary,<br />
secondary to tertiary amine ligands with half life times between 15 and 60 minutes. In contrary, the<br />
results from the non water soluble amine and the less stable anionic complexes showed the limitation<br />
<strong>of</strong> the setup, in which the solubility and stability under physiological conditions is crucial. In<br />
conclusion, complexes with tuneable CO release rates are accessible and led to further improvements<br />
in terms <strong>of</strong> stability and solubility <strong>of</strong> CO-RM’s.<br />
References<br />
1. R. Motterlini, B. E. Mann, R. Foresti, Expert Opin. Invest. Drugs 2005, 14, 1305-1318. (b) S. W.<br />
Ryter, L. E. Otterbein, Bioessays 2004, 26, 270-280. (c) R. Motterlini, J. E. Clark, R. Foresti, P.<br />
Sarathchandra, B. E. Mann and C. J. Green, Circ. Res. 2002, 90, E17-E24.<br />
2. G. Doyle, J. Organomet. Chem 1973, 61, 235-245.<br />
3. M. Ardon, G. Hogarth, D.T.W. Oscr<strong>of</strong>t, J. Organomet. Chem. 2004, 689, 2429-2435.<br />
a)<br />
b)<br />
c)
P-41<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Constrained Peptides Constructed by Coordination<br />
<strong>of</strong> Propargylcysteines with Tungsten<br />
Thomas A. McTeague, Zephyr D. Dworsky, and Timothy P. Curran*<br />
Department <strong>of</strong> Chemistry, Trinity College, 06106, Hartford, CT, USA.<br />
E-mail: timothy.curran@trincoll.edu<br />
In prior work we have demonstrated that alkynes can be appended to peptide carboxylic acids (via<br />
acylation with propargylamine) and amines (via acylation with propargylchlor<strong>of</strong>ormate), that peptides<br />
bearing two alkynes can be prepared, and that reaction <strong>of</strong> these dialkynylpeptides with W(CO)3(dmtc)2<br />
yields a cyclic peptide that incorporates the tungsten atom (which is called a metallacyclicpeptide). 1,2<br />
We have sought to use the tungsten-alkyne coordination to constrain peptides to specific threedimensional<br />
conformations; in one case peptide turns were constrained by the tungsten-alkyne<br />
coordination. 2 In an effort to create helical peptides we have appended alkynes to the side chain<br />
amines <strong>of</strong> lysines, and have constructed peptides having two <strong>of</strong> these alkynyllysines. Coordination <strong>of</strong><br />
these dialkynylpeptides to tungsten has produced metallacyclicpeptides. Investigations using NMR<br />
spectroscopy has shown that these metallacyclicpeptides are too flexible to constrain the peptide to a<br />
specific conformation. In particular, in these metallacycles we have found that the two alkyne groups<br />
can rotate around the tungsten center, generating a number <strong>of</strong> conformational isomers in solution.<br />
We have hypothesized that appending the alkyne group to the side chain amine <strong>of</strong> lysine locates the �ligand<br />
too far from the peptide backbone for coordination to tungsten to constrain the peptide.<br />
Accordingly, we have begun investigations to see whether locating the alkyne group closer to the<br />
peptide backbone will make the complexes more rigid. Towards this end we have been investigating<br />
the use <strong>of</strong> propargylcysteine as our alkynylamino acid. Attractive features <strong>of</strong> propargylcysteine are<br />
that it can readily be prepared in multigram quantities from cysteine, and derivatives <strong>of</strong><br />
propargylcysteine are easy to work with in peptide synthesis.<br />
This presentation will discuss the preparation <strong>of</strong> peptides possessing two propargylcysteines, the<br />
coordination <strong>of</strong> both alkynes in these peptides to tungsten, and the conformational analysis <strong>of</strong> the<br />
resulting metallacyclicpeptides. Particular emphasis will be on the study <strong>of</strong> compounds 1 and 2.<br />
References<br />
O<br />
H<br />
N<br />
H<br />
N<br />
O<br />
O<br />
NH<br />
S<br />
S<br />
1<br />
W(dmtc) 2<br />
99<br />
ButO N<br />
O<br />
N<br />
H<br />
N<br />
O<br />
H<br />
N<br />
O<br />
H<br />
H<br />
O<br />
CONHR<br />
S<br />
S<br />
2<br />
W(dmtc) 2<br />
1. T. P. Curran, R. S. H. Yoon, B. R. Volk, J. Organometallic Chem., 2004, 689, 4837-4847.<br />
2. T. P. Curran, A. B. Lesser, R. S. H. Yoon, J. Organometallic Chem., 2007, 692, 1243-1254.
P-42<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Characterisation <strong>of</strong> Zeise´s Salt - Analogues Regarding Cytotoxicity and Stability<br />
Sandra Meieranz a amdRonald Gust *a<br />
a Freie <strong>Universität</strong> Berlin, Institute <strong>of</strong> Pharmacy, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.<br />
Platinum complexes are widely used in antitumor therapy. DNA is their main target in cells forming a<br />
covalent bond to the N7 position <strong>of</strong> guanine. The intolerable side effects and the acquired resistance<br />
during the therapy encouraged the synthesis <strong>of</strong> new platinum compounds to afford drugs with<br />
improved pharmacological properties and broaden antitumor activity. 1 Therefore, we synthesized<br />
Zeise´s Salts analogues and examined their cytotoxicity in comparison to cisplatin. The complexes<br />
were prepared according to literature procedures. 2 Zeise´s Salt is known as a water stable platinum<br />
complex.<br />
We tested the synthesized compounds on hormone dependent MCF-7 and hormone independent<br />
MDA-MB-231 breast cancer cell lines. The cytotoxicity was very low. Therefore, we determine the<br />
stability in aqueous solution using HPLC and LC-MS. Interestingly, the ester in our compounds is<br />
rapidly cleaved resulting in inactive degradation products. Further investigations on the stability are <strong>of</strong><br />
interest to get stabile Zeise´s Salt analogue platinum complexes.<br />
References<br />
1. Wong, E.; Giandomenico, C. M. Chem. Rev. 1999, 99, 2451.<br />
2. Chock, P. B.; Halpern, J.; Paulik, F. E. Inorg. Syn. 1973, 14, 90.<br />
100
P-43<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Bengin Reactions with Acetylferrocene for the Synthesis <strong>of</strong> some<br />
Ferrocenylhydrazones <strong>of</strong> Expected Biological Activity<br />
Mohamed A. Metwally *a<br />
a Chemistry Department, Faculty <strong>of</strong> Science, University <strong>of</strong> Mansoura, P.O. Box 23, Mansoura, Egypt.<br />
Email: mamegs@mans.edu.eg<br />
Waste-free environmentally benign solid-state reactions means 100% yield <strong>of</strong> one product without any<br />
necessity for purifying workup by recrystallization, chromatography, etc. Continuing our earlier<br />
studies on ferrocenes, 1,2 the solid state reaction <strong>of</strong> acetylferrocene using the ball-milling technique<br />
with several hydrazines and hydrazides resulted in the formation <strong>of</strong> the hydrazones 1 in quantitative<br />
yields (95-98%). The products were screened for their antibacterial and antifungal activities and gave<br />
promising results.<br />
References<br />
Fe<br />
1. M.A. Metwally, E.E.M. Kandel, F.A. Amer, J. Indian Chem. Soc. 1987, 64, 517-518.<br />
2. M.A. Metwally, F.A. Amer, J. Indian Chem. Soc. 1988, 65, 51-53.<br />
CH 3<br />
C<br />
101<br />
N.NH.R<br />
1, a, R= -C 6H 5NO 2-p,<br />
b, R= -C 6H 3(NO 2) 2-2,4-,<br />
c, R= -SO 2C 6H 5,<br />
d, R= -CSNH 2,<br />
e, R= -COCH 2CN
P-44<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Ferrocenyl Flavonoids: A Novel Class <strong>of</strong> Cytotoxics<br />
Jean-Philippe Monserrat, a Elizabeth A. Hillard, a and Gérard Jaouen *a<br />
a Organometallic Medicinal Chemistry Team, UMR 7223, Laboratoire Charles Friedel<br />
11, rue Pierre et Marie Curie<br />
75231 Paris Cedex 05<br />
Occupying the second step <strong>of</strong> the mortality podium in the western countries, cancer has become one <strong>of</strong><br />
the most widely studied diseases in the world, and one <strong>of</strong> the most challenging targets for scientists. In<br />
order to combat the common problem <strong>of</strong> drug resistance, we have decided to approach the problem via<br />
the redox machinery <strong>of</strong> the cell. It is now accepted that elevated levels <strong>of</strong> cellular oxidative stress and<br />
dependence on ROS-signaling for mitosis and apoptosis represent a specific vulnerability <strong>of</strong> cancer<br />
cells that can be targeted by redox modulators. 1<br />
Ferrocene is an organometallic complex that possesses a stable and reversible redox couple, and<br />
possesses many attractive qualities for use in medicinal chemistry. Ferrocene-tamoxifen derivatives, in<br />
particular, are known to be highly toxic against cancer cells via a redox mechanism. 2<br />
Fe<br />
O<br />
OH<br />
hydroxyferrocifen<br />
N<br />
102<br />
O<br />
OH O<br />
quercetin<br />
Flavonoids are a large class <strong>of</strong> natural products, some <strong>of</strong> which are active against cancer and are<br />
thought to act, at least partially, via a redox mechanism. For instance, quercetin, in the process <strong>of</strong><br />
scavenging free radicals, can be converted to four quinone forms (QQ), which can form adducts with<br />
glutathione, thus disturbing the redox balance <strong>of</strong> the cell. 3 Other polyphenols specifically act as<br />
prooxidants in oxidizing environments. 4 Because some cancer cells are under oxidative stress, these<br />
properties could be useful in the design <strong>of</strong> selective cancer agents. 5,6 By the introduction <strong>of</strong> ferrocene,<br />
we hope to modulate the flavonoids’ redox properties and enhance their antiproliferative effects.<br />
We have recently discovered a novel reaction which gives easy access to the first reported ferrocenyl<br />
flavones. Preliminary results show that the antiproliferative effects <strong>of</strong> ferrocene flavones against the<br />
highly aggressive B16 mouse melanoma cell line are considerably stronger than those <strong>of</strong> organic<br />
flavones, with IC50 values in the low micromolar range. The synthesis and biological results <strong>of</strong> this<br />
original class <strong>of</strong> molecules will be presented.<br />
References<br />
1. G. T. Wondrak, Antiox. Redox. Sign. 2009, 11, 3013-3069.<br />
2. E. A. Hillard, A. Vessières, L. Thouin, G. Jaouen and C. Amatore, Angew. Chem. Int. Ed. 2006,<br />
45, 285-290.<br />
3. W. Boots, H. Li, R. P. F. Schins, R. Duffin, J. W. M. Heemskerk, A. Bast and G. R. M. M.<br />
Haenen, Toxicol. App.Pharmacol. 2007, 222, 89-96.<br />
4. Simić, D. Manojlović, D. Šegan and M. Todorović, Molecules, 2007, 12, 2327.<br />
5. H. Pelicano, D. Carney and P. Huang, Drug Resist. Update 2004, 7, 97-110.<br />
6. H<strong>of</strong>fman, L. M. Spetner and M. Burke, J. Theor. Biol. 2001, 211, 403-407.<br />
HO<br />
OH<br />
OH<br />
OH
P-45<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Octahedral Ruthenium Complexes as Phosphatidyl-inositol-3-kinase Inhibitors<br />
Stefan Mollin, a Jie Qin, b Ronen Marmorstein b and Eric Meggers *a<br />
a Philipps-<strong>Universität</strong> Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35032, Marburg,<br />
Germany. b The Wistar Institute, 3601 Spruce Street, 19104, Philadelphia, PA, USA.<br />
E-mail: stefan.mollin@chemie.uni-marburg.de<br />
The design <strong>of</strong> bioactive compounds for applications in medicinal chemistry and chemical biology is<br />
focused predominantly on organic molecules, whereas inorganic compounds are mainly known for<br />
their reactivity (e.g. cisplatin) or imaging properties (e.g. gadolinum complexes in MRI). 1 However, in<br />
recent years, MEGGERS et al. developed a novel strategy, wherein inert ruthenium(II) complexes were<br />
designed as protein kinase inhibitors. 2 Here, the ability <strong>of</strong> metal complexes is used to organize organic<br />
ligands in three-dimensional space to form structures with unique and defined shapes. Based on the<br />
natural product staurosporine 1, a potent but unselective kinase inhibitor, MEGGERS et al. designed<br />
half-sandwich complexes initially and achieved a number <strong>of</strong> potent and selective inhibitors.<br />
Phosphatidyl-inositol-3-kinases (PI3Ks) are a family <strong>of</strong> lipid kinases which act as signal transducers.<br />
They serve phosphatidylinositol-3,4,5-triphosphate (PIP3), an important second messenger which<br />
recruits AKT/PKB. Disruption <strong>of</strong> the PI3K signaling pathway leads to uncontrolled cell proliferation,<br />
survival, and cell growth. Thus, PI3K is a highly attractive target for the development <strong>of</strong> therapeutic<br />
agents to treat cancer and other related diseases.<br />
MARMORSTEIN and MEGGERS et al. found that a methylation <strong>of</strong> the pyridocarbazole-imide leads to a<br />
selectivity switch between protein and lipid kinases. Whereas half-sandwich complexes with free<br />
imides were found as nanomolar GSK-3 and Pim-1 inhibitors, complex 2 shows good selectivity for<br />
PI3Ks. 3 To further increase the potency and selectivity our focus has shifted now to octahedral<br />
compounds 3 with even more defined and rigid shapes. Following this strategy more potent inhibitors<br />
have been synthesized with up to tenfold selectivity between the different is<strong>of</strong>orms PI3Kα and PI3Kγ.<br />
References<br />
1. C. Orvig, M. J. Abrams, Chem. Rev. 1999, 99, 2201-2204.<br />
2. (a) H. Bregman, P. J. Carroll, E. Meggers, J. Am. Soc. 2006, 128, 877-884. (b) E. Meggers, G. E.<br />
Atilla-Gokcumen, H. Bregman, J. Maksimoska, S. P. Mulcahy, N. Pagano, D. S. Williams, Synlett<br />
2007, 8, 1177-1189.<br />
3. X. Peng, D. S. Williams, G. E. Atilla-Gokcumen, L. Milk, X. Min, K. S. M. Smalley, M. Herlyn, E.<br />
Meggers, R. Marmorstein, ACS Chem. Biol. 2008, 3, 305-316.<br />
103
P-46<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
New Topoisomerase II Poisons<br />
Matthew P. Akerman, a Mark T. Muller, b and Orde Q. Munro* a<br />
a University <strong>of</strong> KwaZulu-Natal, School <strong>of</strong> Chemistry, AuTEK Biomed, Private Bag X01, Scottsville,<br />
Pietermaritzburg, South Africa. b University <strong>of</strong> Central Florida, College <strong>of</strong> Medicine, Biomolecular<br />
Research Annex, 12722 Research Parkway, 32826-3227, Orlando, FL, USA.<br />
E-mail: munroo@ukzn.ac.za<br />
DNA topoisomerase II (topo II) is a well-established anticancer drug target. We have identified novel<br />
metallo-drugs that act specifically on topo IIA. Topo II enzymes are essential for life and are primarily<br />
responsible for decatenation <strong>of</strong> daughter chromatids during mitosis. 1 To function as a decatenase, topo<br />
II makes a transient double strand DNA break, providing an enzyme/DNA gate through which a distal<br />
duplex strand may pass. 1 The DNA cleavage intermediate is unique since a covalent DNA-topo II<br />
complex exists during the trans-esterification at the site <strong>of</strong> the break. Compounds that react with this<br />
transient intermediate, forming a ternary DNA-enzyme-drug complex, can arrest or poison the<br />
cleavage/religation cycle, inducing permanent DNA breaks, thereby damaging the genome <strong>of</strong> the<br />
target cell. Acute cytotoxicity results as the cell accumulates double strand DNA breaks. Drugs that<br />
induce breaks are topo II poisons and are generally excellent anti-cancer agents.<br />
We have synthesized and fully characterized a series <strong>of</strong> crystalline d 8 coordination compounds with<br />
tetradentate ligands. The compounds were screened by the National Cancer Institute (NCI, USA)<br />
against their panel <strong>of</strong> 60 human cancer cell lines. The most active compound is chiral, has a mean IC50<br />
<strong>of</strong> 14(2) �M, and is more cytotoxic than cisplatin (mean IC50 = 27 �M). Some cancer cell lines were<br />
substantially more susceptible to the new compounds than to cisplatin (ca. 12–30% <strong>of</strong> the cell lines<br />
tested, depending on the compound used). Statistical comparison <strong>of</strong> the ex vivo data for the most active<br />
compounds with drugs having known modes <strong>of</strong> action in the NCI database indicated that the cellular<br />
target is most likely topo II. This prediction was confirmed by in vitro DNA cleavage experiments<br />
using purified topo I and II and supercoiled DNA substrate. The data indicate that the compounds act<br />
as poisons at low concentrations (best current EC50 ∼ 1 �M) and as catalytic inhibitors at higher<br />
concentrations (typical EC50 ∼ 20–30 �M). The compounds are specific for topo II and do not target<br />
topo I, even at high concentrations. In vivo experiments are currently underway to assess whether the<br />
compound can target topo II in a chromatin setting. Preliminary data demonstrate that topo I is not<br />
being targeted in the cancer cell lines tested.<br />
Some <strong>of</strong> the compounds hydrolyze in aqueous buffer to generate metal-hydroxo derivatives. All<br />
hydrolysis-inert compounds bind calf thymus DNA (pH 7 phosphate buffer, 37 �C) with association<br />
constants ranging from 1.43(3) × 10 5 to 1.01(4) × 10 6 M –1 . The compounds with a high affinity for calf<br />
thymus DNA were all active cytotoxic agents in the NCI-60 screen. Reduction <strong>of</strong> the compounds by<br />
cellular levels <strong>of</strong> glutathione (pH 7 phosphate buffer, 37 �C) was followed by visible spectroscopy.<br />
Loss <strong>of</strong> the metal-to-ligand charge transfer (MLCT) band and appearance <strong>of</strong> the �–�* band <strong>of</strong> the free<br />
ligand confirmed reductive demetallation <strong>of</strong> the chelate in each case. The kinetics had second-order<br />
rate constants ranging from 0.0463(2) to 0.301(7) M –1 s –1 . Importantly, the most active compounds in<br />
the NCI-60 screen had the slowest reduction kinetics. Several structure–activity relationships for this<br />
new class <strong>of</strong> topoisomerase II poison have thus been delineated. A provisional patent has been filed<br />
and toxicology screens on the most active compounds have been scheduled.<br />
Acknowledgements: We thank AuTEK Biomed (Mintek and Harmony) for permission to publish selected data<br />
and financial support, the Department <strong>of</strong> Science and Technology (SA-COST EU Reciprocal Agreement) for a<br />
travel grant, and the Developmental Therapeutics Program (NCI, USA) cytotoxicity screens.<br />
References<br />
1. K. C. Dong, J. M. Berger, Nature 2007, 450, 1201-1205.<br />
104
P-47<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Organometallic Ruthenium and Osmium Complexes with Carbohydrate-Based<br />
Ligands as Anticancer Agents<br />
Alexey A. Nazarov, a * Muhammad Hanif, b Lucienne Juillerat-Jeanneret, a Christian G.<br />
Hartinger, b Olivier Zava, a Michael A. Jakupec, b Bernhard K. Keppler, b Paul J. Dyson a<br />
a Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL),<br />
CH-1015 Lausanne, Switzerland.<br />
b University <strong>of</strong> Vienna, Institute <strong>of</strong> Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna,<br />
Austria.E-mail: alexey.nazarov@epfl.ch<br />
Half-sandwich organometallic compounds have attracted increasing interest due to their potential as<br />
anticancer drugs. 1 Different approaches have been explored, including mono- and bifunctional<br />
compounds such as RAPTA compounds, targeted approaches, kinase inhibitors, ruthenium-arene<br />
clusters and polynuclear ruthenium arene compounds. Increase <strong>of</strong> glucose uptake in malignant cells<br />
due to upregulation <strong>of</strong> glycolysis and glucose transporters in comparison to healthy cells is almost<br />
universal for cancer cells. Attaching a carbohydrate moiety to a Ru or Os center provides new metalbased<br />
compounds that exploit the biochemical and metabolic functions used for sugars in living<br />
organisms for transport and accumulation. 2,3<br />
This presentation will focus on synthesis <strong>of</strong> new sugar containing ruthenium(II) and osmium(II)–arene<br />
complexes and their characterization in terms <strong>of</strong> stability and cytotoxicity. The structural modification<br />
with regard to the arene ligand, the leaving group, and the nature the metal centers is discussed.<br />
The authors are indebted to the EU for a Marie Curie Intra European Fellowship within the<br />
7th European Community Framework Programme project 220890-SuRuCo (A.A.N.) and the<br />
Higher Education Commission <strong>of</strong> Pakistan (M.H.).<br />
References<br />
1. C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391-401.<br />
2. C. G. Hartinger, A. A. Nazarov, S. M. Ashraf,; P. J. Dyson, B. K. Keppler, Curr. Med. Chem.,<br />
2008, 15, 2574-2591.<br />
3. I. Berger, M. Hanif, A. A. Nazarov, C. G. Hartinger, R. O. John, M. L. Kuznetsov, M. Groessl, F.<br />
Schmitt, O. Zava, F. Biba, V. B. Arion, M. Galanski, M. A. Jakupec, L. Juillerat-Jeanneret, P. J.<br />
Dyson, B. K. Keppler, Chem. Eur. J. 2008, 14, 9046 – 9057.<br />
105
P-48<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Cytotoxic Organoiridium(III) mono- and bis-intercalators with rigid bridging<br />
ligands <strong>of</strong> different lengths<br />
Ali M. Nazif a and William S. Sheldrick *a<br />
a Lehrstuhl für Analytische Chemie, <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, D-44780 <strong>Bochum</strong><br />
We have recently reported significant in vitro activity for members <strong>of</strong> the organometallic halfsandwich<br />
series [(η 5 -C5Me5)IrCl(pp)] + containing a single polypyridyl ligand (pp = dpq, dppz, dppn).<br />
Their IC50 values towards human MCF-7 (breast carcinoma) and HT-29 cells (colon-carcinoma) lie in<br />
the range 30.3 - 0.12�M and correlate with the size <strong>of</strong> the polypyridyl ligand, i.e. the IC50 values<br />
decrease significantly in the order dpq > dppz> dppn.<br />
An attractive design strategy to enhance both the affinity and specificity <strong>of</strong> DNA interactions is to<br />
combine an intercalator with other functionalities such as a second intercalator or a metal fragment<br />
capable <strong>of</strong> coordinative binding to nucleobases. Bis-intercalators might be expected to exhibit a<br />
greatly increased binding affinity for DNA, which could also lead to improved cytotoxicity owing to<br />
both the increased number <strong>of</strong> DNA adducts formed and decreased effectiveness <strong>of</strong> DNA repair<br />
proteins.<br />
These considerations prompted us to investigate the suitability <strong>of</strong> rigid bridging ligands <strong>of</strong> different<br />
lengths including pyrazine, 4,4'-bipyridine, trans-1,2-bis(4-pyridyl)ethylene and 1,2-bis(4pyridyl)ethyne<br />
for enabling bis-intercalation <strong>of</strong> the polypyridyl ligands belonging to the dinuclear<br />
complexes [{(η 5 -C5Me5)Ir(pp)}2(B)](CF3SO3)4 (pp = dpq, dppz, dppn). The interaction <strong>of</strong> the<br />
complexes with DNA was studied using UV/VIS spectroscopy, circular dichroism, viscosity titrations<br />
and gel electrophoresis. The studies confirm dppz as representing an optimum surface area for<br />
intercalation. In contrast, the dppn-containing complexes prefer surface binding with π-stacking.<br />
Based on these results, our research has focused on dppz-containing complexes which exhibit high<br />
cytotoxicities towards the human cell lines MCF-7 (breast cancer) and HT-29 (colon cancer), with<br />
IC50 values <strong>of</strong> respectively 3.1 �M and 3.7 �M being observed for the cell lines for B =4,4´-bipyridyl.<br />
Bis-intercalation <strong>of</strong> the 4,4´-bipyridyl complex was indicated by CD measurements and confirmed by<br />
viscosity titration, where the degree <strong>of</strong> DNA lengthening was doubled in comparison to an analogous<br />
monointercalator. 1<br />
Conclusive evidence for the bis-intercalative binding mode <strong>of</strong> [{(η 5 -C5Me5)Ir(dppz)}2(4,4´bpy)](CF3SO3)4<br />
was also obtained from an NMR-NOESY study <strong>of</strong> its interaction with the<br />
decanucleotide d(5´-CGCGTAGGCC-3´). The observed interruptions <strong>of</strong> intramolecular NOE cross<br />
peaks between nucleobase H6/H8 protons and sugar H2´/H2´´ protons <strong>of</strong> the preceding nucleobase are<br />
in accordance with a bis-intercalation mode sandwiching the G4/C17 and T5/A16 base pairs. A range<br />
<strong>of</strong> intermolecular NOE cross peaks are also observed between the dppz complex and decanucleotide<br />
protons. These include contacts between the H3 and H4 protons <strong>of</strong> one dppz ligand to T5-H2´ and<br />
between the H3´ and H4´ protons <strong>of</strong> the other dppz ligand to C17-H2´. The presence <strong>of</strong> these and other<br />
NOE cross peaks underlines the degree <strong>of</strong> detailed information that can be obtained from the NOESY<br />
spectrum, and allows a satisfactory refinement <strong>of</strong> the NMR structure <strong>of</strong> the complex-DNA adduct.<br />
References<br />
1. M.A. Nazif, J.-A. Bangert, I. Ott, R. Gust, R. Stoll, W. S. Sheldrick, J. Inorg. Biochem. 2009, 103, 1405-<br />
1414.<br />
106
P-49<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Bioinspired Catalysts With Bifunctional P,N - Ligands in Alkyne – Hydration<br />
Anna Louisa N<strong>of</strong>fke a and Peter C. Kunz *a<br />
a Department <strong>of</strong> Inorganic Chemistry I, Heinrich-Heine-University <strong>of</strong> Düsseldorf<br />
<strong>Universität</strong>sstr. 1, D-40225 Düsseldorf, Email: anna-louisa.n<strong>of</strong>fke@uni-duesseldorf.de<br />
Addition <strong>of</strong> water to terminal alkynes is a common path to carbonyl compounds. However, most<br />
synthetic strategies suffer from rather intense conditions or low selectivity. In nature, the<br />
tungstenoenzyme acetylene hydratase catalyzes the formation <strong>of</strong> ethanal from acetylene, for example<br />
in pelobacter acetylenicus. 1 For higher alkynes, the hydration-reaction can be equally accelerated<br />
using transition-metal catalysts with bifuntional ligands. 2 Systems similar to 1 (Fig. 1) perform with<br />
high yields and splendit selectivity. 2<br />
Fig. 1 Preparation <strong>of</strong> a Ru(II)-vinylidene complex and P,N-Ligands used.<br />
With ruthenium(II)-complexes <strong>of</strong> the general formula [(Cp)Ru(L)2Cl] (Cp = cyclopentadienyl) bearing<br />
our water-soluble, hemilabile P,N-ligands 3 (Fig. 1), catalytic activity in alkyne-hydration is observed<br />
under certain conditions. The first mechanistic steps <strong>of</strong> this reaction involve formation <strong>of</strong> vinylidene<br />
species which are subsequently aquated. In particular, the special role that is played by H-bonddonating<br />
and/or accepting ligand-functionalities within this catalytic process is explored in further<br />
detail.<br />
References<br />
1. S. Antony and C. A. Bayse, Organometallics 2009, 28, 4938–4944. (b) M. A. Vincent, I. H. Hillier,<br />
G. Periyasamy and N. A. Burton, Dalton Trans. 2010, 39, 3816–3822.<br />
3. (a) D. B. Grotjahn, D.A. Lev; J. Am. Chem. Soc. 2004, 126, 12232. (b) D.B. Grotjahn, Dalton<br />
Trans. 2008, 6497.<br />
2. (a) P. C. Kunz, M. U. Kassack, A. Hamacher, B. Spingler, Dalton Trans. 2009, 7741-7747. (b) P. C.<br />
Kunz, G. J. Reiß, W. Frank, W. Kläui, Eur. J. Inorg. Chem. 2003, 3945-3951.<br />
107
P-50<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
A Tri-organometallic Derivative Containing a PNA Backbone: Synthesis and<br />
Antibacterial Activity<br />
Malay Patra, a Gilles Gasser, a# Dmytro Bobukhov, b Klaus Merz, a Alexander V. Shtemenko b<br />
Julia E. Bandow c and Nils Metzler-Nolte* a<br />
a Lehrstuhl für Anorganische Chemie I, Fakultät für Chemie und Biochemie, <strong>Ruhr</strong>-<strong>Universität</strong><br />
<strong>Bochum</strong>, Gebäude NC 3 Nord, <strong>Universität</strong>sstr. 150, 44801 <strong>Bochum</strong>, Germany; b Department <strong>of</strong><br />
Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin Avenue 8,<br />
Dnipropetrovs'k, 49005 Ukraine; c Lehrstuhl für Biologie der Mikroorganismen, Fakultät für Biologie<br />
und Biotechnologie, <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, <strong>Universität</strong>sstr. 150, 44801 <strong>Bochum</strong>, Germany. # new<br />
address: Institute <strong>of</strong> Inorganic Chemistry, University <strong>of</strong> Zurich, Winterthurerstrasse 190, CH-8057<br />
Zurich, Switzerland.<br />
Novel synthetic routes for the incorporation <strong>of</strong> different organometallic entities into the same<br />
biomolecule are highly demanded. With the strive <strong>of</strong> developing a reaction sequence for the controlled<br />
and sequential insertion <strong>of</strong> distinct organometallics into a PNA oligomer, we have chosen, as a model<br />
compound, namely, 2-(N-(2-(2-(9H-fluoren-9-yloxy)acetamido)ethyl)pent-4-ynamido)acetic acid<br />
containing both a PNA backbone and an alkyne side-chain and three different organometallics,<br />
azidomethyl ferrocene, β-cymantrenoyl-propionic acid and [{N, N-bis((pyridin-2-yl)methyl)prop-2yn-1-amine}Re(CO)3]PF6<br />
– were inserted using click chemistry, amide bond formation and<br />
Sonogashira coupling as orthogonal derivatisation methods respectively. Moreover, we discovered, the<br />
triorganometallic compound (1) has excellent antibacterial activity against a number <strong>of</strong> multidrug<br />
resistant gram-positive bacterial strains.<br />
References<br />
1. M. Patra, G. Gasser, D. Bobukhov, K. Merz, A.V. Shtemenko, N. Metzler-Nolte, Dalton Trans.<br />
2010, DOI: 10.1039/c003598j.<br />
108
P-51<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
The Synthesis and Characterization <strong>of</strong> Aqueous and Organic Soluble, Acid<br />
Selective Cytotoxic Ruthenium Anticancer Compounds<br />
Paul J. Dyson, a Olivier Zava, a David J. Kavanagh, b and Andrew D. Phillips* b<br />
a Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Sciences et Ingénierie Chimiques,<br />
CH-1015, Lausanne, Switzerland. b University College Dublin, School <strong>of</strong> Chemistry and Chemical<br />
Biology, Belfield, Dublin 4 , Ireland.E-mail: andrew.phillips@ucd.ie<br />
From the serendipitous discovery <strong>of</strong> cisplatin as an anticancer agent by Rosenberg in 1965, 1 there has<br />
been considerable interest in the field <strong>of</strong> metallopharmaceuticals. Currently only two further platinum<br />
complexes have received worldwide application in cancer treatment, Oxaliplatin and Carboplatin.<br />
Recently, organometallic ruthenium complexes have attracted greater attention as potential antitumour<br />
reagents 2-4 and systems featuring oxidation states <strong>of</strong> +2 and +3 have entered clinical trials. 5<br />
These Ru compounds (i and ii) are relatively non-toxic in comparison to platinum compounds and the<br />
mode <strong>of</strong> inducing apoptosis differs significantly from cisplatin. Therefore, Ru-based pharmaceuticals<br />
<strong>of</strong>fer valuable alternatives that may overcome Pt resistant tumours and alleviate problematic sideeffects<br />
observed with other chemotherapeutic drugs.<br />
This project focuses on the synthesis <strong>of</strong> water soluble, selective and adaptable ruthenium(II)<br />
complexes (iii) employing a mixed ligand set that convey a number <strong>of</strong> useful properties important for<br />
metallo-pharmaceuticals. The oxygen-stable phosphine, PTA (1,3,5-triaza-7-phosphaadamantane)<br />
confers water solubility, while the � 5 -coordinated anionic C5H5 group provides the necessary<br />
lipophilicity for passive cell transport. Uniquely, the bidentate triazapentadienyl ligand allows for the<br />
‘fine-tuning’ <strong>of</strong> hydrolysis behaviour by alternating the α-R groups and has proven more stable than<br />
the related Ru complexes (ii). Moreover, the triazapentadienyl ligand in compound iii imparts<br />
additional cytotoxicity as observed in previous work on similar � 6 -C6H6 Ru chloro β-diketiminates<br />
(iv). Finally, we will present our latest research which discusses the further adaption <strong>of</strong> complexes <strong>of</strong><br />
type iv towards long term biological stability and increased cytotoxicity.<br />
References<br />
(i) (ii) (iii) (iv)<br />
1. B. Rosenberg, L. Van Camp, T. Krigas. Nature. 1965, 205, 698.<br />
2. P. J. Dyson, A. D. Phillips. Organometallics. 2009, 28, 5061.<br />
3. B K. Keppler, K. Jakupec. Organometallics. 2008, 27, 2405.<br />
4. G. Sava, P. J. Dyson,. Int. J. Oncology. 2008, 33, 1281.<br />
5. (a) C. G. Hartinger, B. K. Keppler, J. Inorg. Biochem. 2006, 100, 891. (b) H. M. Schellens, J. M.<br />
Rademaker-Lakhai. Clin Cancer Res. 2004, 10, 3717.<br />
6. A. D. Phillips, O. Zava, R. Scopelitti, A. A. Nazarov, P. J. Dyson. Organometallics. 2010, 29, 417.<br />
109
P-52<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Encapsulation <strong>of</strong> Pyrenyl-Containing Dendrimers in<br />
Arene-Ruthenium Metalla-Prisms<br />
A. Pitto-Barry, a N. Barry, a R. Deschenaux, a* and B. Therrien a *<br />
a Université de Neuchâtel, Institut de chimie, 51 Ave de Bellevaux, 2000, Neuchâtel, Switzerland.<br />
E-mail: bruno.therrien@unine.ch<br />
Extravasation <strong>of</strong> macromolecules is considerably enhanced in tumor tissues. This phenomenon called<br />
“enhanced permeability and retention” (EPR) effect is believed to play a major role in selective<br />
delivery <strong>of</strong> nanomedicines. 1 Nanomedicines lead up to 100 times greater intratumor drug delivery<br />
efficacy to cancer cells as compared to healthy cells. 2 Nanomedicines include antibodies and<br />
polymeric drug but also large drug delivery vectors like micelles, nanoparticles and dendrimers.<br />
Among new large drug carriers, we recently proposed to use metalla-prisms built from areneruthenium<br />
units. 3 These water-soluble and cytotoxic metalla-assemblies <strong>of</strong>fer many possibilities.<br />
On the other hand, we have been working on dendritic system incorporating lipophilic functionalized<br />
pyrenes. Encapsulation <strong>of</strong> the pyrenyl moiety in the hydrophobic cavity <strong>of</strong> the arene-ruthenium<br />
metalla-prism, with the dendritic part hanging out <strong>of</strong> the cage, generates a potential target seeking<br />
missile for cancer cells. The synthesis and characterization as well as the preliminary cytotoxicity<br />
studies are presented.<br />
References<br />
1. Y. Matsumura, H. Maeda, Cancer Res. 1986, 46, 6387-6392.<br />
2. H. Maeda, Adv Drug Deliv Rev. 2001, 46, 169-185.<br />
3. B. Therrien, G. Süss-Fink, P. Govindaswamy, A. K. Renfrew, P. J. Dyson, Angew. Chem. Int. Ed.<br />
2008, 47, 3773-3776.<br />
110
P-53<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Silicium dioxide nanoparticles as carriers<br />
for bio-active organometal complexes<br />
Gregor Dördelmann a and Ulrich Schatzschneider a *<br />
a Lehrstuhl für Anorganische Chemie I – Bioanorganische Chemie, <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>,<br />
<strong>Universität</strong>sstr. 150, D-44801 <strong>Bochum</strong>, Germany, E-Mail: gregor.doerdelmann@rub.de.<br />
.<br />
CO-releasing molecules (CORMs) find steadily increasing use as a stable storage form <strong>of</strong> carbon<br />
monoxide for potential therapeutic applications. Several compounds reported, such as<br />
[Mn(CO)3(tpm-L1)]PF6, show significant cytotoxicity after photoactivation, comparable to that <strong>of</strong> the<br />
established anticancer agent 5-fluorouracil (5-FU). [1,2]<br />
Most solid tumors possess unique pathophysiological characteristics that are not observed in normal<br />
tissue, like leaky vasculature and impaired lymphatic drainage, leading to an enhanced permeability<br />
and retention (EPR) <strong>of</strong> macromolecules in the malignant tissue. [3] Thus, we wanted to explore whether<br />
silicium dioxide nanoparticles can be utilized as delivery agents for CORMs in solid tumors.<br />
SiO 2<br />
N 3<br />
CuSO 4 5H 2O<br />
Na-ascorbate<br />
SiO 2<br />
+<br />
O<br />
tButOH, H 2O<br />
N<br />
N<br />
N<br />
O<br />
N N<br />
N N<br />
N N<br />
N N<br />
N N<br />
N N<br />
Mn CO<br />
CO<br />
CO<br />
Mn CO<br />
CO<br />
CO<br />
Silicium dioxide nanoparticles containing the azidopropyl group were prepared by emulsion<br />
copolymerization <strong>of</strong> tetraethylorthosilicate and (3-azidopropyl)triethoxysilane. [4] This procedure<br />
provides a reproducible synthesis <strong>of</strong> particles in the ~90 nm size regime as determined by transmission<br />
electron microscopy (TEM) and dynamic light scattering (DLS). The presence <strong>of</strong> the azido groups and<br />
the manganese CORM on the surface <strong>of</strong> the particles was analysed by spectroscopic methods like<br />
UV/VIS, IR and NMR spectroscopy as well as energy dispersive X-ray spectroscopy (EDX).<br />
Reference<br />
1. J. Niesel, A. Pinto, H.W. Peindy N’Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem.<br />
Commun. 2008, 1798-1800.<br />
2. H. Pfeiffer, A. Rojas, J. Niesel and U. Schatzschneider, Dalton Tran . 2009, 4292-4298.<br />
3. I. Brigger, C. Dubernet, P. Couvreur, Adv. Drug Delivery Rev. 2002, 54, 631-651.<br />
4. C. A. Bradley, B. D. Yuhas, M. J. McMurdo, T. D. Tilley, Chem. Matter. 2009, 21, 174-185.<br />
111
P-54<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis and Biological evaluation <strong>of</strong> [99mTc]-N-[4-nitro-3-trifluoromethylphenyl]<br />
Cyclopentadienyltricarbonyltechnetium Carboxamide, a Nonsteroidal<br />
Antiandrogen Flutamide Derivative<br />
Tensim Dallagi, a S. Top, b S. Masi, b G. Jaouen, b and M. Saidi a<br />
a Unité d'utilisation Médicale et Agricole des Techniques Nucléaires Laboratoire des<br />
Radiopharmaceutiques, Centre National des Sciences et Technologies Nucléaires,<br />
Technopôle de Sidi Thabet, 2020 Sidi Thabet,Tunisie. E-mail : t.dallegi@laposte.net. b Ecole<br />
Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel, UMR 7223, 11, rue Pierre et<br />
Marie Curie, F-75231 Paris Cedex 05, France. E-mail : siden-top@chimie-paristech.fr<br />
Prostate cancer is one <strong>of</strong> the most frequently diagnosed cancers and is the second leading cause <strong>of</strong><br />
cancer death in American men, after lung cancer. 1 In 2009, prostate cancer is predicted to kill 27,360<br />
American men. A similar statistic holds for French men. It is important to note that when the cancer is<br />
detected it has already had a long time to develop. Therefore, it is crucial to detect the cancer at its<br />
earliest stages. Few compounds have been labelled with 99m Tc for use as androgen receptor-based<br />
prostatic imaging agents. 2,3 Rapid metabolic cleavage, low receptor binding affinity or inadequate<br />
specific activity is a common feature <strong>of</strong> most <strong>of</strong> PET and SPECT radioimaging agents. We have<br />
recently developed ferrocenyl derivatives <strong>of</strong> nonsteroidal antiandrogens and have found that<br />
ferrocenyl nilutamide derivatives show a significant cytotoxicity on hormone-independent prostate<br />
cancer cells PC-3. 4<br />
O2N O<br />
O2N O<br />
F3C N<br />
H<br />
F3C N<br />
Fe<br />
H<br />
NFFe<br />
112<br />
NF 99m Tc<br />
NFRe<br />
99m Tc(CO)3<br />
(M = 99m Tc)<br />
(M = Re)<br />
In our efforts to develop a novel class <strong>of</strong> SPECT imaging agents based on nonsteroidal androgen<br />
receptor (AR) antagonists, we have synthesized N-cyclopentadienyltricarbonyltechnetium-N-[4-nitro-<br />
3-trifluoromethyl-phenyl] carboxamide (NF 99m Tc), an analog <strong>of</strong> the AR antagonist ligand flutamide.<br />
NF 99m Tc was obtained in 82% yield from the reaction <strong>of</strong> N-[4-nitro-3-trifluoromethyl-phenyl]ferrocenecarboxamide<br />
(NFFe) with fac-[ 99m Tc(H2O)3(CO)3] + in DMF/water at pH 1 and at 150 °C for<br />
1 h. We also prepared N-[4-nitro-3-trifluoromethyl-phenyl]-rheniumcyclopentadienyltricarbonylcarboxamide<br />
(NFRe) which is useful for the identification <strong>of</strong> the technetium compound. In vitro<br />
assays demonstrated high stability <strong>of</strong> NF 99m Tc under physiological conditions, buffer and blood. The<br />
tissue biodistribution in mature male Wistar rats showed a significant selective uptake by prostate but<br />
this uptake was not blocked by an excess <strong>of</strong> testosterone acetate.<br />
References<br />
1. A. Jemal, R. Siegl, E. Ward, Y. Hao, J. Xu, M. J. Thun, CA Cancer J. Clin. 2009, 59, 225-249.<br />
2. T. Das, S. Banerjee, G. Samuel, K. Bapat, S. Subramanian, M. R. A. Pillai, M. Venkatesh, Bioorg.<br />
Med. Chem. Lett., 2006, 16, 5788-5792.<br />
3 H. He, J. E. Morely, E. Silva-Lopez, B. Bottenus, M. Montajano, G. A. Fugate, B. Twamley, P. D.<br />
Benny, Bioconjugate Chem. 2009, 20, 78-86.<br />
4. O. Payen, S. Top, A. Vessières, E. Brulé, M.-A. Plamont, M. J. McGlinchey, H. Müller-Bunz, G.<br />
Jaouen, J. Med. Chem. 2008, 51, 1791-1799.
P-55<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis and 99m Tc-Labeling <strong>of</strong> a PNA Oligomer Containing a New Ligand<br />
Derivative <strong>of</strong> 2,2´-Dipicolylamine<br />
Katrin Jäger, a Gilles Gasser, b Martin Zenker, a Ralf Bergmann, a Jörg Steinbach, a Holger Stephan, a<br />
and Nils Metzler-Nolte b<br />
a Forschungszentrum Dresden-Rossendorf, Institute <strong>of</strong> Radiopharmacy, Bautzner Landstrasse 128,<br />
01314 Dresden, Germany. b <strong>Ruhr</strong>-University <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and Biochemistry,<br />
Department <strong>of</strong> Inorganic Chemistry I, <strong>Universität</strong>sstrasse 150, 44801 <strong>Bochum</strong>, Germany.<br />
E-mail: k.jaeger@fzd.de<br />
The search for chelating ligands which can be efficiently labeled with radiometals, and which also<br />
contain a functional group allowing a facile conjugation to biomolecules is currently a hot topic in<br />
radiopharmacy. The 2,2’-dipicolylamine (Dpa) has already been found to be a good candidate for<br />
labeling with 186 Re, 188 Re and 99m Tc 1 while the Cu(I)-catalyzed [2+3] azide/alkyne cycloaddition, <strong>of</strong>ten<br />
referred to as Click Chemistry, 2 has been shown to be an effective coupling method. With this in mind,<br />
we recently developed the facile synthesis <strong>of</strong> an azido derivative <strong>of</strong> Dpa (Dpa-N3, Figure 1). 3<br />
Furthermore, as a pro<strong>of</strong> <strong>of</strong> principle <strong>of</strong> the possible functionalization <strong>of</strong> our ligand to a biomolecule,<br />
Dpa-N3 was successfully coupled, on the solid phase, to a ethinyl-substituted Peptide Nucleic Acid<br />
(PNA) oligomer employing the Click Chemistry methodology to give the expected Dpa-ethyl-triazol-<br />
PNA. Both Dpa-N3 and Dpa-ethyl-triazol-PNA could be efficiently labeled with 99m Tc using the<br />
precursor [ 99m Tc(H2O)3(CO)3] + to afford [ 99m Tc(CO)3(Dpa-ethyl-triazol-N3)] + and [ 99m Tc(CO)3(Dpaethyl-triazol-PNA],<br />
respectively. The radionuclide 99m Tc was tightly bound by the Dpa-chelator<br />
avoiding the formation <strong>of</strong> pertechnetate for at least 24h. Partitioning experiments in a 1-octanol/water<br />
system confirmed that both [ 99m Tc(CO)3(Dpa-N3)] + and [ 99m Tc(CO)3(Dpa-ethyl-triazol-PNA] are<br />
rather hydrophilic. Biodistribution studies <strong>of</strong> [ 99m Tc(CO)3(Dpa-ethyl-triazol-PNA] in Wistar rats<br />
showed a fast blood clearance and only a modest accumulation in the kidneys. Similar results were<br />
found when a mouse model (NMRI nu/nu) was used.<br />
N<br />
N<br />
N<br />
N 3<br />
N<br />
(CO) 99m<br />
3 Tc<br />
N<br />
Figure 1. Structures <strong>of</strong> Dpa-N3(left) and [ 99m Tc(CO)3(Dpa-N3)] + (right).<br />
References<br />
1. T. Storr, C. L. Fisher, Y.Mikata, S. Yano, M. J. Adam, C. Orvig, Dalton Trans., 2005, 654-655.<br />
2. M. V. Gil, M. J. Arévalo, Ó. López Synthesis, 2007, 11, 1589-1620.<br />
3. G. Gasser, K. Jäger, M. Zenker, R.Bergmann, J. Steinbach, H. Stephan, N. Metzler-Nolte, 2010,<br />
submitted.<br />
113<br />
N<br />
N 3<br />
+
P-56<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Novel MRI Contrast Agents based on a Silsesquioxane Core<br />
Jörg Henig, a,b* É. Jakab-Tóth, c J. Engelmann, d S. Gottschalk, d H.A. Mayer a<br />
a <strong>Universität</strong> Tübingen, Institut für Anorganische Chemie, Auf der Morgenstelle 18, 72076 Tübingen,<br />
Germany. b <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Zentrum für Elektrochemie, <strong>Universität</strong>sstraße 150, 44801<br />
<strong>Bochum</strong>, Germany. c CNRS Orléans, Le Centre de Biophysique Moléculaire, 45071 Orléans, France.<br />
d Max-Planck-Institut für biologische Kybernetik, Hochfeld-Magnetresonanz-Zentrum, 72076<br />
Tübingen, Germany. E-mail: joerg.henig@rub.de<br />
Large macromolecular MRI contrast agents (CAs) bearing several paramagnetic gadolinium(III)<br />
centres show usually significantly higher relaxivities than small size CAs and are particularly useful<br />
for target specific imaging. However, the large size slows down the excretion rate <strong>of</strong> the CA, which is<br />
a major limitation for clinical use. Furthermore, the Solomon-Bloembergen-Morgan theory predicts<br />
that at the high magnetic fields <strong>of</strong> modern clinical and especially research MRI scanners, medium-size<br />
CAs rather than very large systems are the most favored in order to achieve high relaxivities. Here we<br />
present two novel medium-size CAs (Gadoxane G (GG) and Gadoxane B (GB), Figure 1), based on a<br />
symmetric T8-silsesquioxane core. The use <strong>of</strong> the T8-silsesquioxane cube allows the grafting <strong>of</strong> eight<br />
monohydrated lanthanide (Ln = Gd 3+ , Y 3+ ) complexes in a confined space.<br />
Both Gadoxanes can be synthesised with an intact silsesquioxane core. Diffusion 1 H NMR<br />
measurements showed rotational correlation times <strong>of</strong> about 3.35 ns for both compounds. Even though<br />
both CAs have almost identical water exchange rates, due to the lower internal flexibility, the<br />
longitudinal relaxivities <strong>of</strong> GB are significantly higher than those <strong>of</strong> GG over almost the whole range<br />
<strong>of</strong> magnetic fields. Although both systems still possess a high internal flexibility, the strong effect <strong>of</strong><br />
the altered spacer on the relaxivity and the comparatively high relaxivity <strong>of</strong> both systems at proton<br />
Larmor frequencies above 100 MHz points out the potential <strong>of</strong> moderate-size silsesquioxane-based<br />
CAs. Furthermore, with hydrodynamic radii <strong>of</strong> about 1.44 nm both, GG and GB are still significantly<br />
smaller than the small pores <strong>of</strong> the glomerular filtration system and hence should be excreted<br />
relatively fast via the kidneys. A key feature is also the lability <strong>of</strong> the silsesquioxane cage under<br />
physiological conditions (37°C, pH 7.4). No change in relaxivity is observed within the first three<br />
hours, since the hydrolysis <strong>of</strong> the initial Si-O-Si moieties has no influence on rotational correlation<br />
time. However, then the hydrolysis <strong>of</strong> the silsesquioxane core leads to smaller fragments and therefore<br />
to a decrease in relaxivity. If needed, this degradation might allow the development <strong>of</strong> larger CAs,<br />
whose fragments are then readily excreted via the kidneys.<br />
R =<br />
N<br />
H<br />
O<br />
O<br />
O<br />
N N<br />
N<br />
O O<br />
Ln 3+<br />
Gadoxane G (GG)<br />
N<br />
R<br />
R<br />
R<br />
Si<br />
Si O<br />
O O<br />
OO Si R<br />
Si<br />
O<br />
O R<br />
O<br />
Si O O<br />
O<br />
Si<br />
R<br />
R<br />
Si O Si<br />
R<br />
O<br />
O<br />
O<br />
O<br />
114<br />
R =<br />
N<br />
H<br />
8-<br />
O<br />
O<br />
O<br />
N N<br />
N<br />
O O<br />
Ln 3+<br />
Gadoxane B (GB)<br />
Figure 1. Gadoxane G (GG) and Gadoxane B (GB)<br />
N<br />
O<br />
O<br />
O<br />
O
P-57<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
New Hyperpolazied probes for 13 C-MRI<br />
S. Aime, a E. Cerutti, a S. Ellena, a R. Gobetto, a F. Reineri, a D. Santelia, a A. Viale a<br />
a Department <strong>of</strong> Chemistry I.F.M., University <strong>of</strong> Torino, Via P. Giuria n° 7,<br />
10125 Torino, Italy, E-mail: roberto.gobetto@unito.it<br />
The extraordinary NMR signal enhancement obtained from Para-Hydrogen Induced Polarization<br />
(PHIP) has been exploited in the investigation hydrogenation mechanisms and, more recently, in the<br />
development <strong>of</strong> hyperpolarized contrast agents for MRI applications. In particular the high<br />
signal/noise ratio that can be achieved on heteronuclei such as 13 C or 15 N allows to obtain molecules<br />
that can be traced in vivo. In fact the complete absence <strong>of</strong> those signals in biological tissues leads to<br />
images in which the background signal derives uniquely from instrumental noise. Furthermore, due to<br />
long T1 values that can be reached on these nuclei, hyperpolarization can be maintained for enough<br />
time to allow the acquirement <strong>of</strong> images in in vivo conditions.<br />
In order to produce a 13 C hyperpolarized contrast agent using this approach, an unsaturated substrate is<br />
necessary (usually a triple bond containing molecule, that is efficiently para-hydrogenated in the<br />
presence <strong>of</strong> a suitable catalyst), with an adjacent carbonyl group to which hyperpolarization is<br />
transferred due to its coupling with parahydrogen protons. This group is also characterized by a long<br />
T1 value (which limits the polarization loss due to relaxation). 2 Then, in order to use heteronuclear-<br />
PHIP for MRI application, longitudinal hyperpolarization must be obtained from spin order which<br />
derives directly from parahydrogenation. This task can be achieved by means <strong>of</strong> both field cycling<br />
procedure or an appropriate pulse sequence.<br />
We present the synthesis and parahydrogenation experiments <strong>of</strong> a series <strong>of</strong> novel substrates with the<br />
aim <strong>of</strong> obtaining an in-depth understanding <strong>of</strong> the potential <strong>of</strong> these species as 13 C hyperpolarized<br />
contrast agents. Particular attention is focused on bio-compatible and water soluble parahydrogenated<br />
products. Problems concerning catalyst and organic solvent elimination have been also tackled.<br />
References<br />
1) K. Golman, O. Axelsson, H. Johannesson, S. Mansson, C. Ol<strong>of</strong>sson, J.S. Petersson, Magn. Res.<br />
Med. 2001, 46, 1.<br />
2) F. Reineri, A. Viale, G. Giovenzana, D. Santelia, W. Dastrù, R. Gobetto, S. Aime, J. Am. Chem.<br />
Soc. 2008, 130, 15047.<br />
115
P-58<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Affinity Binding for Controlled Orientation and Electrochemistry in Self<br />
Assembled Monolayers <strong>of</strong> Reductases.<br />
Nicolas Plumeré, a Ellen R. Campbell, b Bill H. Campbell b<br />
a <strong>Ruhr</strong> <strong>Universität</strong> <strong>Bochum</strong>, Center for Electrochemical Science, <strong>Universität</strong>sstrasse 150, 44780,<br />
<strong>Bochum</strong>, Germany. b NECi, 334 Hecla Street, Lake Linden, USA. E-mail: nicolas.plumere@rub.de<br />
Metal-chelating ligands have been designed in the field <strong>of</strong> immobilized metal ion affinity<br />
chromatography 1 (IMAC) for the purification <strong>of</strong> polyhistidine-tagged (His-tagged) proteins. Dense<br />
monolayers <strong>of</strong> similar metal-chelating ligands on electrode surfaces have recently been applied for the<br />
immobilization and controlled orientation <strong>of</strong> His-tagged proteins via affinity binding. 2–4 In particular,<br />
nitrilotriacetic (NTA) and imminodiacetic (IDA) acid terminated gold and carbon electrodes were used<br />
for the immobilization <strong>of</strong> laccase, 4 glucose oxidase, 5 horseradisch peroxidase 2 and hemoprotein. 3 In<br />
these cases, the attachment <strong>of</strong> the enzyme via His-tag yields fully active protein films in the presence<br />
<strong>of</strong> electron mediators. In some cases, direct electron transfer was observed as well. 5 Cu 2+ and Ni 2+<br />
were used as the metal cations.<br />
However, the use <strong>of</strong> affinity binding involving Ni 2+ or Cu 2+ is limited to applications that require redox<br />
potentials less negative than the reduction potential <strong>of</strong> the metal cation complexes. 2 Therefore, most<br />
reductases cannot be used in such systems.<br />
In order to overcome this limitation, we used Zn 2+ as the metal cation for the coordination <strong>of</strong> a Histagged<br />
reductase. Nitrate reductase (NaR) as the enzyme and methyl viologen as the electron mediator<br />
were chosen to test the affinity binding via Zn 2+ cations on NTA modified glassy carbon electrodes.<br />
The electrochemical investigations <strong>of</strong> the NaR monolayer on NTA-Zn 2+ films demonstrate the activity<br />
for the catalytic reduction <strong>of</strong> nitrate to nitrite in presence <strong>of</strong> methyl viologen. The catalytic current<br />
density corresponds to the one expected for a fully active enzyme monolayer. Moreover, the reduction<br />
<strong>of</strong> the Zn 2+ is not observed at the potential necessary for the reduction <strong>of</strong> methyl viologen. Therefore,<br />
affinity binding based on Zn 2+ may be used for the immobilization <strong>of</strong> Nitrate reductases in their active<br />
form.<br />
References<br />
1. G. S. Chaga J. Biochem. Biophys. Methods 2001, 49, 313-334.<br />
2. R. Blankespoor, B. Limoges, B. Schöllhorn, J.-L. Syssa-Magalé, D. Yazidi Langmuir 2005, 21,<br />
3362-3375.<br />
3. V. Balland, S. Lecomte, B. Limoges Langmuir 2009, 25, 6532-6542.<br />
4. V. Balland, C. Hureau, A. M. Cusano, Y. Liu, T. Tron, B. Limoges Chem. Eur. J. 2008, 14, 7186-<br />
7192.<br />
5. S. Demin, E. A. H. Hall, Bioelectrochemistry 2009, 76, 19-27.<br />
116
P-59<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis, Characterization and Properties <strong>of</strong> the Cluster Rhenium(ІІІ)<br />
Compound with β-Alanine Ligands<br />
Mariia S. Randarevych, a Kateryna A. Zablotska, a Konstantin V. Domasevitch, b Alexander V.<br />
Shtemenko a<br />
a Department <strong>of</strong> Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin<br />
Ave. 8, Dnipropetrovs’k 49005, Ukraine. E-mail: shtemenko@ukr.net. b Department <strong>of</strong> Inorganic<br />
Chemistry, Kiev University, Volodimirska Street 64, Kiev 01033, Ukraine. E-mail: dk@univ.kiev.ua.<br />
The theoretical interest in binuclear complex compounds <strong>of</strong> dirhenium(ІІІ) is caused by the fact that<br />
rhenium is one <strong>of</strong> the few elements that are able to form a multiplet metal-metal bond. From the<br />
practical point <strong>of</strong> view, these compounds can be used in medical practice since they have<br />
anticancerogenic, antihemolytic, and antiradical properties and lower toxicity in comparison with<br />
other well-known compounds <strong>of</strong> transition metals.<br />
One <strong>of</strong> the received cluster compounds <strong>of</strong> dirhenium(ІІІ) with γ-aminobutyric acid’s ligands has<br />
already shown excellent antitumor properties. 1 Owing to this, our purpose is to expand the range <strong>of</strong><br />
similar compounds by using other amino acids as ligands which possess own biological activity.<br />
Therefore, the synthesis <strong>of</strong> new cluster aminocarboxylates <strong>of</strong> dirhenium(III) and the study <strong>of</strong> their<br />
physicochemical and biological properties are <strong>of</strong> great interest for us. A synthetic procedure <strong>of</strong><br />
dirhenium(ІІІ) complex compound with β-alanine was developed. The properties <strong>of</strong> this compound are<br />
investigated by spectral method. The compound cis-Re2Cl6{�-AlaH}2 ·1.5H2O is shown to consist <strong>of</strong><br />
coordinating centre Re2 6 + with quadruple bond rhenium-rhenium. In equatorial positions there are<br />
bridge groups containing β-alanine residues being in cys-position relative to Re-Re. The structure <strong>of</strong><br />
the given compound is presented on fig. 1.<br />
Fig.1 cis-Re2Cl6{�-AlaH}2 ·1.5H2O<br />
The structure <strong>of</strong> this compound is confirmed by direct X-ray structure, thermal and spectral analyses.<br />
We have also investigated the biological activity <strong>of</strong> the complex that revealed itself perspective as a<br />
cytostatic and anticancer agent.<br />
References<br />
1. A. Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, E. Zabitskaya, A. Golichenko Dalton<br />
Trans. 2009, 26, 5132 - 5136.<br />
117
P-60<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Exploring Histidines as Biomolecular Anchors to Re(CO)3 +<br />
Richard S. Herrick, a Christopher J. Ziegler, b Roger Rowlett, Americo Gambella a<br />
a College <strong>of</strong> the Holy Cross, Department <strong>of</strong> Chemistry, 1 College St., Worcester, MA 01610, USA.<br />
b University <strong>of</strong> Akron, Department <strong>of</strong> Chemistry, KNCL 402, Akron, OH 444325, USA. c Department<br />
<strong>of</strong> Chemistry, Colgate University, 13 Oak Drive, Hamilton, NY 13346 (USA).<br />
E-mail: rherrick@holycross.edu<br />
In recent years we have explored the potential <strong>of</strong> using amino acids and amino acid conjugates to bind<br />
Re(CO)3 + . We are currently exploring the use <strong>of</strong> histidine-containing peptide conjugates as models <strong>of</strong><br />
His-tags in order to test their ability to bind the Re(CO)3 + . His-OMe, Ac-His-OH and His-His-OH<br />
were each exposed to aqueous solution <strong>of</strong> Re(CO)3 + . Reaction with His-OMe lead to ester cleavage<br />
and formation <strong>of</strong> the previously observed Re(CO)3(� 3 -N�,N�,O - -His). Reactions with Ac-His-OH and<br />
His-His-OH each led to novel compounds containing a carboxamido N-donor group. The<br />
characterization, including X-ray crystallography, <strong>of</strong> each compound, and testing <strong>of</strong> each compounds<br />
ability to withstand challenge experiments will be discussed.<br />
We have also been interested in using proteins to bind Re(CO)3 + . Little work has been carried out on<br />
reactions between rhenium prodrug or drug model complexes and proteins. Such interactions can be<br />
crucial to the biological processing <strong>of</strong> Tc/Re based imaging agents, since proteins, rather than<br />
nucleotides or single amino acids, would be encountered in plasma. Alternatively, protein-Tc/Re<br />
adducts could be novel targets for use as imaging or therapeutic agents. In order to probe this<br />
chemistry, we are examining the interactions between Re(CO)3(H2O)3 + and the readily crystallizable<br />
protein lysozyme. A crystal structure has been obtained <strong>of</strong> a lysozyme-Re(CO)3(H2O)2 adduct.<br />
Experimental details, including the new crystal structure, will be discussed.<br />
From these studies highlighting the binding <strong>of</strong> histidines in peptides and proteins to Re(CO)3(H2O)3 + ,<br />
several conclusions can be drawn. These will be discussed along with future directions <strong>of</strong> this<br />
research.<br />
118
P-61<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Fluorescent Rhenium(I)tricarbonyl Complexes Based on a Novel<br />
Bisphenanthridinyl Chelate<br />
Lukasz Raszeja, a and Nils Metzler-Nolte *a<br />
a <strong>Ruhr</strong>-University <strong>Bochum</strong>, Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong><br />
Inorganic Chemistry I, <strong>Universität</strong>sstr. 150, 44801 <strong>Bochum</strong>, Germany<br />
E-mail: LukaszRaszeja@aol.com<br />
Fluorescence microscopy is a powerful technique for the imaging <strong>of</strong> biological systems. Beside<br />
making endogenous cell organelles visible by specific staining methods, it is also possible to monitor<br />
the intracellular distribution <strong>of</strong> fluorescently labelled compounds such as peptides, oligonucleotides or<br />
drugs in general. Right now most <strong>of</strong> the fluorescent dyes used for labelling are organic compounds<br />
based on an aromatic heterocycle like in the case <strong>of</strong> fluorescein, acridine or cyanine. By now, the<br />
number <strong>of</strong> applications <strong>of</strong> d 6 metal complexes for cellular imaging experiments is modest. Published<br />
systems use the typical luminescent Ir(III), Ru(II) and Re(I) metal complexes. 1<br />
We have developed a novel chelating ligand system based on phenanthridine. This ligand is<br />
fluorescent itself, but by complexing a fac-Rhenium(I)tricarbonyl core the molecule exhibits an<br />
enhanced absorption and a stronger and red shifted fluorescence. With a typical broad absorption<br />
maximum between 310 nm and 380 nm the complex shows strong emission at 540 nm by excitation at<br />
350 nm. The large Stokes shift is a big advantage in comparison to the typical organic dyes due to<br />
prevent self-quenching processes. Beside the application in fluorescence microscopy our ligand could<br />
act as a potential radio marker in the case <strong>of</strong> complexing the isostructural { 99m Tc(CO)3} core.<br />
Several compounds based on the Bisphenanthridine moiety were synthesized (example in Fig. 1), fully<br />
characterized and finally used for cellular imaging and uptake experiments (Fig. 2). The synthesis <strong>of</strong><br />
bioconjugates <strong>of</strong> peptides and PNA was also successful and cellular uptake studies show interesting<br />
and promising results.<br />
References<br />
O<br />
O<br />
N<br />
N<br />
N<br />
I<br />
Re<br />
CO<br />
CO<br />
CO<br />
Br<br />
Fig. 1 Structure <strong>of</strong> the fluorescent Re I complex 1. Fig. 2 Fluorescence image <strong>of</strong> IMIM-PC2 cells after<br />
incubation with 1 (5 µM, 24 h).<br />
1. V. Fernández-Moreira, F. L. Thorp-Greenwood, M. P. Coogan, Chem. Commun. 2010, 46, 186-202.<br />
119
P-62<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Electrochemical Detection <strong>of</strong> Protein Kinases and Inhibitor Screening by Using<br />
Ferrocene-ATP Bioconjugate<br />
Sanela Martić, Mahmoud Labib and Heinz-Bernhard Kraatz*<br />
The University <strong>of</strong> Western Ontario, Faculty <strong>of</strong> Science, Department <strong>of</strong> Chemistry, 1151 Richmond<br />
Street, N6A 5B7, London, Canada.<br />
E-mail: smartic@uwo.ca<br />
Protein kinase plays a critical role in the cellular growth, signalling and function and its malfunction<br />
has been linked to a number <strong>of</strong> diseases, such as cancer. 1 For diagnostic and drug screening purposes<br />
detecting, monitoring and quantifying kinase activity is critical. Recently, an electrochemical<br />
biosensor was developed and was used in our laboratory for measuring casein kinase 2 (CK2) and<br />
protein kinase C (PKC) activity on a Au surface by means <strong>of</strong> the electroactive adenosine-5’-[γferrocene]<br />
triphosphate conjugate (Fc-C6-ATP), as a co-substrate for the protein kinase. 2 As an<br />
extension <strong>of</strong> this work, we have investigated following kinases: sarcoma-related kinase (Src), cyclindependent<br />
kinase (CDK2) and extracellular signal–regulated kinase (Erk1), all <strong>of</strong> which are directly<br />
involved in the cell cycle. The electrochemical detection <strong>of</strong> kinase activity and drug target screening<br />
was performed in addition to the surface characterization <strong>of</strong> phosphorylated assays by MALDI-TOF<br />
MS, XPS and TOF-SIMS techniques. A pro<strong>of</strong>-<strong>of</strong>-concept study was performed using the newly<br />
developed multiplex chip technology which allows for monitoring and quantifying multiple kinase<br />
activities for the first time. The optimized electrochemical multiplex assay was also used for<br />
identification <strong>of</strong> novel protein kinase inhibitors.<br />
References<br />
Erk1<br />
CDK2<br />
control<br />
Src<br />
120<br />
Fe<br />
O<br />
N<br />
H<br />
PO 3 Fc<br />
6<br />
N<br />
H<br />
ATP<br />
No electrochemical signal !<br />
Electrochemical signal<br />
after phosphorylation!<br />
1. (a) G. Manning, D. B. Whyte, R. Martinez, T. Hunter, S. Sudarsanam, Science, 2002, 298, 1912-<br />
1934. (b) J. S. Sebolt-Leopold, J. M. English, Nature, 2006, 441, 457-462.<br />
2. (a) H. Song, K. Kerman, H. B. Kraatz, Chem. Commun. 2008, 502-504. (b) K. Kerman, H. Song, J.<br />
D. Duncan, D. W. Litchfield, H. B. Kraatz, Anal. Chem. 2008, 80, 9395-9401.
P-63<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Electrochemical Evaluation <strong>of</strong> the Interaction between Ru(II) mono-diimine<br />
Complexes and Biomolecules<br />
Mauro Ravera, a Ayesha Sharmin, b Edward Rosenberg, b Domenico Osella, a<br />
a University <strong>of</strong> Piemonte Orientale “A. Avogadro”, Department <strong>of</strong> Environmental and Life Sciences,<br />
Viale Michel 11, 15121, Alessandria, Italy. b Department <strong>of</strong> Chemistry and Bio-Chemistry, University<br />
<strong>of</strong> Montana, Missoula, MT 59812, USA. E-mail: mauro.ravera@mfn.unipmn.it<br />
Transition metal luminescent complexes containing one or more diimine ligands typically have<br />
excited-state lifetimes ranging from about 100 ns to 10 �s. Because the lifetimes <strong>of</strong> these<br />
luminophores are long compared to fluorescent dyes that are used as biological probes, time-gated<br />
detection can be used to suppress interfering auto-fluorescence from the biological sample. In<br />
addition, highly polarized emission from some <strong>of</strong> these complexes has stimulated interest in using<br />
them as biophysical probes for studying the dynamics <strong>of</strong> macromolecular assemblies and interactions<br />
on membranes.<br />
The series <strong>of</strong> complexes [XRu(CO)(L–L)(L’)2][PF6] (X = H, TFA, Cl; L–L = 2,2’-bipyridyl, 1,10phenanthroline,<br />
5-amino-1,1’-phenanthroline and 4,4’-dicarboxylic-2,2’-bipyridyl; L’2 = 2PPh3,<br />
Ph2PC2H4PPh2, Ph2PCH=CHPPh2) have been synthesized from the starting complex<br />
K[Ru(CO)3(TFA)3] (TFA = CF3CO2). The purpose <strong>of</strong> the project was to synthesize a series <strong>of</strong><br />
complexes that exhibit a range <strong>of</strong> excited-state lifetimes and that have large Stokes shifts, high<br />
quantum yields and high intrinsic polarizations associated with their metal-to-ligand charge-transfer<br />
(MLCT) emissions. To a large degree these goals have been realized in that excited-state lifetimes in<br />
the range <strong>of</strong> 100 ns to over 1 �s are observed. 1<br />
The measured quantum yields and intrinsic anisotropies<br />
are higher than for previously reported Ru(II) complexes. Interestingly, the neutral complex with one<br />
phosphine ligand shows no MLCT emission. The compounds show multiple reduction potentials<br />
which are chemically and electrochemically reversible in a few cases as examined by cyclic<br />
voltammetry. The same technique has been use to evaluate the interaction between some <strong>of</strong> the<br />
synthesized complexes and biomolecules (DNA and bovine serum albumin, BSA).<br />
SWV <strong>of</strong> a solution <strong>of</strong> 1 with successive additions <strong>of</strong> BSA. Electrochemical conditions: 0.5 mM <strong>of</strong><br />
complex in 0.05 M phosphate buffer (pH 7.4) + 5% DMSO; glassy carbon electrode<br />
References<br />
1. A. Sharmin, R. C. Darlington, K. I. Hardcastle, M. Ravera, E. Rosenberg, J. B. A. Ross, J.<br />
Organomet. Chem., 2009, 694, 988-1000.<br />
121
P-64<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Electrochemical Studies <strong>of</strong> Fc-PNA(•DNA) Surface Dynamics<br />
Nina Hüsken, a Magdalena Gębala, b Wolfgang Schuhmann b and Nils Metzler-Nolte *a<br />
a <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Fakultät für Chemie und Biochemie, Lehrstuhl für Bioanorganische<br />
Chemie, <strong>Universität</strong>sstrasse 150, 44801 <strong>Bochum</strong>, Germany. b <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Fakultät für<br />
Chemie und Biochemie, Analytische Chemie, <strong>Universität</strong>sstrasse 150, 44801 <strong>Bochum</strong>, Germany. Email:<br />
nina.huesken@rub.de<br />
The application <strong>of</strong> peptide nucleic acids (PNA) as receptor molecules in DNA biosensors promises an<br />
enhanced specificity and selectivity for the analysis <strong>of</strong> DNA, due to the favourable hybridization<br />
properties <strong>of</strong> PNA. N-terminal ferrocene (Fc) labelled and C-terminal gold surface confined PNA<br />
oligomers present unique tools for electrochemical DNA biosensing, since structural and<br />
conformational changes <strong>of</strong> the nucleic acid strand directly affect the Fc-electrode redox process. 1<br />
By means <strong>of</strong> fast scan cyclic voltammetry (FSCV), the kinetic <strong>of</strong> the Fc-electrode redox process was<br />
studied at Fc-PNA(•DNA) modified gold electrodes. The gold surfaces were loosely packed (< 8%)<br />
with Fc-PNA(•DNA) single or double strands, to exclude any lateral interactions between the probe<br />
molecules and to facilitate with this an unrestricted thermal strand motion <strong>of</strong> the Fc tethered strands.<br />
These studies primary revealed, that the large elasticity <strong>of</strong> the PNA single strand evokes a diffusion<br />
like motion <strong>of</strong> the Fc head group (“Fc-on-rope”), whereas the Fc label attached to the rather rigid<br />
PNA(•DNA) duplex exhibits a significantly less diffusional behaviour (“Fc-on-rod”). Based on the<br />
FSCV studies, a clear correlation between the determined electron transfer (ET) rate constants k 0 and<br />
the inherent strand elasticity was developed. Thereby a large strand elasticity leads at high scan rates<br />
to a ‘kinetic freeze’ <strong>of</strong> the tethered Fc head groups, to result in a large spectrum <strong>of</strong> Fc-electrode<br />
distances and a large average Fc-electrode distance, being correlated to a rather low ET rate constant.<br />
Vice versa, an increase in the strand rigidity leads to a smaller spectrum <strong>of</strong> possible Fc-electrode<br />
distances and an average Fc-electrode distance, which is located closer to the gold surface due to an<br />
attractive effect exerted by the electric field and hence correlates a larger ET rate constant. 2<br />
Concluding, the established correlation between the Fc-electrode ET rate constants, determined by<br />
FSCV, and the inherent PNA(•DNA) strand elasticity renders the ET rate constants a new means to<br />
study Fc-PNA(•DNA) surface dynamics. This correlation furthermore presents the basis for an<br />
electrokinetic analysis <strong>of</strong> DNA with Fc-PNA biosensors.<br />
References<br />
1. N. Hüsken, M. Gębala, W. Schuhmann, N. Metzler-Nolte, ChemBioChem 2010, DOI:<br />
10.1002/cbic.200900748<br />
2. N. Hüsken, M. Gębala, W. Schuhmann, N. Metzler-Nolte, manuscript submitted.<br />
122
P-65<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Study <strong>of</strong> Heavy Metals Biosorption from Aqueous Solutions<br />
by Using Biological Wastes<br />
Mohammad Ali Zazouli, *a and Mayram Bagheri a<br />
a Department <strong>of</strong> Environmental Health Engineering, Faculty <strong>of</strong> Health, Mazandaran University <strong>of</strong><br />
Medical Sciences, Sari, Iran, E-mail: Zazoli49@yahoo.com<br />
Heavy metal pollution is posing significant threats to the environment and public health because <strong>of</strong> its<br />
toxicity, non-biodegradability and bioaccumulation. 1 The increasing environmental concern for these<br />
contaminants, there has been serious interest in removal <strong>of</strong> heavy metals from contaminated<br />
wastewater & water. A number <strong>of</strong> technologies such as precipitations, ion exchange, membrane<br />
processes and adsorption on activated carbon, have been used over the years to remove toxic metals<br />
from water but these techniques are <strong>of</strong>ten ineffective and/or very expensive in the reduction <strong>of</strong> heavy<br />
metals from water at very low concentration. 2 The search for alternative and innovate treatment<br />
techniques has focused attention on the use <strong>of</strong> biological materials for heavy metal removal. The<br />
objective <strong>of</strong> this study is to investigate <strong>of</strong> heavy metals (Cadmium, Chromium and lead) biosorption<br />
from aqueous solutions by using orange mesocarp and rice husk.<br />
The selected biomass were first cut into small size, washed with water to remove impurity and soluble<br />
components and oven-dried at 100 o C for 24h until constant weight was reached. The washed and<br />
dried materials were crushed and sieved using 1.00 mm mesh size sieve. Then pretreated separately<br />
with soaking in NaOH(0.4N) and HNO3(0.4N) for 24h. After that washed with distilled water until it<br />
had no color in the filtrate. Biosorption studies were carried out batch method. After the desired<br />
contact time, the biosorbent was removed by filtration. The metal concentrations were measured by<br />
using atomic absorption spectrophotometer. All experiments were conducted in duplicate. Finally,<br />
Adsorption isotherms <strong>of</strong> metal on adsorbents were determined.<br />
Results show that metal sorption initially increases with increasing in metal concentration in the<br />
solution, and then becoming saturated after a certain concentration <strong>of</strong> metal. The maximum sorption<br />
capacities with orange waste were for Cr and with rice husk was Pb. The results showed that the<br />
percentage removal <strong>of</strong> metals as a function <strong>of</strong> equilibrium pH. The effect <strong>of</strong> pH on metals sorption was<br />
very different for all metals and for two biosorbents. Biosorption was very fast for the first 30 min but<br />
slowed markedly after 1 h. Biosorption continued to increase after which it became constant reaching<br />
equilibrium. The adsorption data fit well with the Langmuir and Freundlich isotherm model for orange<br />
waste and rice husk, respectively.<br />
This study indicates that both biomass residues have the capacity to remove metal ions from aqueous<br />
solution, and the amount <strong>of</strong> the heavy metal ions bound by cellulosic substrate depends on the metal<br />
ion type, biosorbent type and dosage, pH and contact time. Thus, orange waste and rice husk could be<br />
potentially used for the removal <strong>of</strong> heavy metals from aqueous solution as erials stand out as very<br />
good and lowest biosorbents.<br />
Keywords: Biosorption, Heavy metals, Orange wastes, Rice husk, Biological wastes<br />
References<br />
1. E.-S. Z. El-Ashtoukhy, N.K. Amin, O. Abdelwahab, Desalination. 2008, 223, 162-173.<br />
2. A.B. Pérez-Marín, A. Ballester, F. González, M.L. Blázquez, J.A. Muñoz, J. Sáez, V. Meseguer<br />
Zapata, Bioresour. Technol. 2008, 99, 8101-8106.<br />
123
P-66<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthetic Analogs for Evaluating Organometallic and Nickel(0) Involvement in<br />
Acetyl Coenzyme A Synthase<br />
Molly J. O’Hagan, Nathan A. Eckert, and Charles G. Riordan *a<br />
a University <strong>of</strong> Delaware, Department <strong>of</strong> Chemistry and Biochemistry, 19716, Newark, USA.<br />
E-mail: riordan@udel.edu<br />
Acetyl coenzyme A synthase (ACS) is a NiFeS protein found in archaea and anaerobic organisms that<br />
can grow on CO2 as their sole carbon source. 1 Some <strong>of</strong> these, including methane, acetate and sulfateproducing<br />
organisms are found in the intestinal tracts <strong>of</strong> higher mammals including humans. ACS<br />
catalyzes the dis/assembly <strong>of</strong> a methylcorrinoid, CO and CoA to acetyl CoA. The mechanism <strong>of</strong> the<br />
reaction undoubtedly involves bioorganometallic intermediates, although none have yet to be directly<br />
identified. Using small molecule synthetic chemistry, we seek to establish chemical precedents for<br />
relevant, elementary steps in ACS catalysis. 2 Central among these is the transalkylation <strong>of</strong><br />
methylcorrinoid to a reduced site <strong>of</strong> the ACS cluster. One proposal for this site is a zero-valent nickel<br />
ion. 3 Studies detailed in this presentation establish the feasibility and mechanistic boundaries for alkyl<br />
group transfer to nickel(0) and nickel(I) acceptors with emphasis on our recent results in deducing the<br />
mechanism <strong>of</strong> a model in which SN2 transfer to nickel(0) is suggested. 4<br />
References<br />
1. S.W. Ragsdale, E. Pierce, Biochim. Biophys. Acta 2008, 1784, 1873-1898.<br />
2. (a) R. Krishnan, J.K. Voo, C.G. Riordan, L. Zakharov, A.L. Rheingold, J. Am. Chem. Soc. 2003,<br />
125, 4422-4423; (b) R. Krishnan, C.G. Riordan, J. Am. Chem. Soc. 2004, 126, 4484-4485.<br />
3. P.A. Lindahl, J. Biol. Inorg. Chem. 2004, 9, 516-524.<br />
4. N.A. Eckert, W.G. Dougherty, G.P.A. Yap, C.G. Riordan, J. Am. Chem. Soc. 2007, 129, 9286-<br />
9287.<br />
124
P-67<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis <strong>of</strong> Mixed Gold(I)-Phosphine-Ferrocene-Phenylalanine<br />
and Peptide Conjugates<br />
Christine D<strong>of</strong>fek, a S. David Köster, a and Nils Metzler-Nolte *a<br />
a <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Lehrstuhl für Anorganische Chemie I, <strong>Universität</strong>sstraße 150,<br />
D-44801 <strong>Bochum</strong>, Germany. E-mail: christine.d<strong>of</strong>fek@rub.de<br />
The combination <strong>of</strong> gold(I)-phosphine and ferrocene derivatives enlarges the number <strong>of</strong> interesting<br />
bioconjugates. The gold(I)-phosphine-ferrocene-phenylalanine conjugate 1 was prepared by Cu(I)catalyzed<br />
[3+2]-cycloaddition <strong>of</strong> azido-modified phenylalaninemethylester with the internal alkyne <strong>of</strong><br />
a gold(I)-phosphine-ferrocene-acetylide in good yields. 1,2 The corresponding peptide conjugate was<br />
synthesized using solid phase peptide synthesis (SPPS) in combination with Cu(I)-catalyzed [3+2]cycloaddition<br />
<strong>of</strong> the azido-modified peptide with the gold(I)-phosphine-ferrocene-acetylide, also<br />
showing good yields. During the final cleavage the peptide conjugate decomposed. The gold(I)phosphine-ferrocene-phenylalanine<br />
conjugate 1 was comprehensively characterized by multinuclear<br />
and multidimensional NMR spectroscopy, mass spectrometry and cyclic voltammetry (CV). The<br />
electrochemical studies showed reversible processes <strong>of</strong> the redox couple Fc 0 /Fc + (Fc = ferrocenyl) and<br />
an irreversible reduction <strong>of</strong> Au + to Au 0 .<br />
References<br />
O<br />
O<br />
O<br />
125<br />
1<br />
Au<br />
N<br />
N<br />
N<br />
1. D. A. Gray, L. Gao, T. S. Teets, J. B. Updegraff III, N. Deligonul, T. G. Gray, Organometallics<br />
2009, 28, 6171-6182.<br />
2. S. Back, R. A.. Gossage, H. Lang, G. van Koten, Eur. J. Inorg. Chem. 2000, 1457-1464.<br />
Fe
P-68<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Study <strong>of</strong> Interaction <strong>of</strong> Gold Drugs with Thiols<br />
Using Various Analytical Techniques<br />
Gohar T. Kazimi a* and Mohammad S Iqbal b<br />
a Department <strong>of</strong> Chemistry, University <strong>of</strong> Sargodha, Sargodha 40100, Pakistan. E-mail:<br />
gohartaqi@hotmail.com<br />
b Department <strong>of</strong> Chemistry, GC University, Lahore 54000, Pakistan. E-mail: saeediq50@hotmail.com<br />
Since ancient times, gold has occupied a special place in medicine to cure diseases. Now a days gold<br />
based drugs are being used in the treatment <strong>of</strong> an autoimmune inflammatory disease known as<br />
rheumatoid arthritis (RA). 1 Solganal TM (gold thioglucose), Myochrisine TM (gold sodium thiomalate)<br />
and Ridaura TM (auran<strong>of</strong>in, 2,3,4,6-tetraacetyl-β-1-D-thiogluco-pyranosato-S-(triethyl phosphine)gold(I),<br />
Et3PAuStagl) are used for the treatment <strong>of</strong> this disease but their mode <strong>of</strong> action is still<br />
uncertain. Furthermore, several studies have demonstrated that several gold (I) and gold (III) salts also<br />
exhibit anti-tumour activities. 2-4 The pharmacokinetic and pharmacological properties <strong>of</strong> these drugs<br />
mainly depend upon ligands present on them and various studies have shown that these ligands are<br />
replaced in the body by some endogenous molecules. 1<br />
In this work some <strong>of</strong> the ligand exchange reactions <strong>of</strong> gold drugs with various thiols including<br />
cysteine, glutathione, N-acetylcysteine and O-methylcysteine were studied in both solution and in<br />
solid state. Various analytical techniques like ESI-MS, DESI-MS, pXRD and FT-IR used in this study<br />
confirmed the ligand exchange mechanism. ESI-MS was successfully employed for characterization <strong>of</strong><br />
the ligand-exchange products. When cysteine reacts with auran<strong>of</strong>in in solution, the formation <strong>of</strong><br />
[Et3PAuSCy] – (m/z = 434), [taglSAuCyS] – (m/z = 680) and [Au(Stagl)2] – (m/z = 923) were observed<br />
along with [Au(PEt3)2] + (m/z =433) in the positive-ion spectrum. Similarly with O-methylcysteine the<br />
formation <strong>of</strong> [TaglSSOMeCy] – (m/z = 497), [taglSAuSOMeCyS] – (m/z = 694), [Au(Stagl)2] – (m/z =<br />
923) and [Et3PAuSOMeCy] + (m/z =450) indicated the ligand exchange during reaction. DESI-MS,<br />
pXRD and FT-IR were found to be helpful in characterization the products <strong>of</strong> the reactions performed<br />
in the solid state.<br />
This study provides very useful information in understanding the in vivo biochemistry <strong>of</strong> the gold<br />
drugs used for rheumatoid arthritis.<br />
References<br />
1. C.F. Shaw, III, Chem. Rev. 1999, 99, 2589-2600.<br />
2. E.R.T. Tiekink, P.D. Cookson, B.M. Linahan, L.K. Webster, Metal-Based Drugs 1994, 1,299.<br />
3. L.K.Webster, S. Rainone, E. Horn, E.R.T. Tiekink, Metal-Based Drugs 1996, 3, 63.<br />
4. D. Crump, G. Siasios, E.R.T. Tiekink, Metal-Based Drugs 1999, 6, 361.<br />
126
P-69<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Glutathione Reductase/Thioredoxin Reductase Systems as Molecular Target for<br />
Antiproliferative Gold(I) Carbene Complexes<br />
R. Rubbiani a and I. Ott *a<br />
a Institute <strong>of</strong> Pharmaceutical Chemistry, Technische <strong>Universität</strong> Braunschweig, Beethovenstr. 55,<br />
38106 Braunschweig, Germany, r.rubbiani@tu-bs.de<br />
Human Thioredoxin-Reductase (TrxR) and Glutathione-Reductase (GR) are two NADPH-dependent<br />
flavoenzymes belonging to the main responsibles <strong>of</strong> the antioxidant cellular network. They consist <strong>of</strong> a<br />
FAD domain, a NADPH domain but they differ for the active site, which is characterized by a<br />
cysteine-cysteine (Cyscys) bridge in the case <strong>of</strong> GR and by a cysteine-selenocysteine (Secys) bridge in<br />
the case <strong>of</strong> TrxR. The main substrate <strong>of</strong> GR is glutathione (Glu), a tripeptide formed by γ-L-Glutamyl-<br />
L-cysteinylglycine that has the role to act directly against reactive oxygen species (ROS). The<br />
substrate <strong>of</strong> TrxR is thioredoxin (Trx), a protein <strong>of</strong> 12 kDa with an active disulfide motif. 1 With the<br />
development <strong>of</strong> Auronafin, it has been demonstrated that certain metal complexes (especially gold<br />
complexes) have a strong affinity for TrxR, based on the formation <strong>of</strong> a covalent bond. 2 Because <strong>of</strong> the<br />
overexpression <strong>of</strong> these enzymes in the tumoral cells, as well as their substrates, they become a<br />
possible target for the developing <strong>of</strong> new active molecules. Based on a computational study, our<br />
research focuses on gold(I) carbene complexes, a new stable class <strong>of</strong> compounds that show activity on<br />
these enzymatic systems. We synthesized a series <strong>of</strong> di-substituted benzimidazole carbenes (see<br />
figure) and evaluated their interactions with the mentioned substrates and enzymes. We also<br />
investigated the proliferation inhibition in two tumoral cell lines. Our results indicate a selective<br />
inhibition <strong>of</strong> TrxR in the nanomolar range, most probably due to the stronger affinity <strong>of</strong> gold(I) for<br />
Secys compared to Cys. The proliferation studies showed a cytotoxic activity in the range <strong>of</strong> 7-16 µM.<br />
References<br />
1. S. Gromer et al., Med. Res. Rev. 2004, 24, 40-89.<br />
2. I. Ott.,Coord. Chem. Rev. 2009, 52, 763-770.<br />
127
P-70<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis, Characterization and Antitumor Screening <strong>of</strong> some<br />
Di- and Triorganotin(IV) Complexes <strong>of</strong> 2,9-Dimethyl-1,10-phenanthrolin<br />
Mojdeh Safari,* a Mohammad Yousefi, a Maryam Bikh<strong>of</strong>, a Amir Amanzadeh, b<br />
Mohammad Ali Shokrgozar, b and Fatemeh Tavakolinia a<br />
a Azad University, Shahre-rey branch, Tehran, Iran<br />
b Pasteur Institute, Tehran, Iran. E-mail: msafari96@yahoo.com<br />
Malignancy is the result from a multiple process by accumulation <strong>of</strong> mutations and other genetic<br />
alteration. 1 Searches for non-platin metal-based antitumor drugs have attracted considerate interest.<br />
Diorganotin(IV) complexes are potential antitumor agents mainly active against P388 lymphocytic<br />
leukemia and other tumors. 2-4 Recent studies have shown very promising in vitro antitumor properties<br />
<strong>of</strong> organotin compounds against a wide panel <strong>of</strong> tumor cell lines <strong>of</strong> human origin. 5-11 In some cases,<br />
organotin(IV) derivatives have also shown acceptable antiproliferative in vivo activity as new<br />
chemotherapy agents. 12-17 In this context ,we decided to study the cytotoxic activity <strong>of</strong> 2,9-Dimethyl-<br />
1,10phenanthrolin tin(IV) derivatives, in order to observe the influence <strong>of</strong> the substituents attached to<br />
the central Sn atom on the final anticancer activity <strong>of</strong> the organotin(IV) complexes. In the present<br />
research the new complexes <strong>of</strong> organotin were obtained by reacting R2SnCl2 and Ŕ3SnCl (where R=<br />
Methyl, Butyl, Benzyl and Ŕ= Phenyl) with 2,9-Dimethyl-1,10phenanthrolin. These complexes have<br />
been characterized by FT-IR and 1 H, 13 C, 119 Sn NMR and Mass spectroscopy. The cytotoxic activity <strong>of</strong><br />
the studied compounds has been investigated against K562 cell line and the IC50 values have been<br />
determined.<br />
References<br />
1. P. Blume-Jensen, T. Hunter, Nature, 2001, 411, 355–357.<br />
2. A.J. Crowe: Antitumor activity <strong>of</strong> tin compounds in Metal Compounds in Cancer Therapy; S.P.<br />
Fricker, Ed., Chapman & Hall: London, GB, 1994, pp. 147–179.<br />
3. A.J. Crowe, P.J. Smith, C.J. Cardin, H.E. Parge, F.E. Smith, Cancer Lett., 1984, 24, 45–48.<br />
4. (a) A.K. Saxena, F. Huber, Coord. Chem. Rev., 1989, 95, 109–123. (b) M. Gielen (Ed.), Tin-Based<br />
Anti-Tumor Drugs, Springer-Verlag, Berlin, 1990.<br />
5. M. Gielen (Ed.), Tin-Based Anti-Tumor Drugs, Springer-Verlag, Berlin, 1990.<br />
6. M. Gielen, Coord. Chem. Rev., 1996, 151, 41-51.<br />
7. P. Yang, M. Guo, Coord. Chem. Rev., 1999, 189, 185–186.<br />
8. M. Gielen, M. Biesemans, D. De Vos, R. Willem, J. Inorg. Biochem., 2000, 79, 139-145.<br />
9. M. Gielen, Appl. Organomet. Chem., 2002, 16, 481-494.<br />
10. S.K. Hadjikakou, N. Hadjiliadis, Coord. Chem. Rev., 2009, 253, 235-249.<br />
11. in Tin Chemistry: Fundamentals,Frontiers, and Applications; M. Gielen, A.G. Davies, K. Pannell,<br />
E. Tiekink, Ed.: John Wiley and Sons, Wiltshire, 2008.<br />
12. L. Nagy, A. Szorcsik, K. Kovacs, Pharm. Hungarica, 2000, 70, 53-71.<br />
13. M. Nath, S. Pokharia, R. Yadav, Coord. Chem. Rev., 2001, 215, 99-149.<br />
14. M. Gielen, in: NATO ASI Ser. 2, vol. 26, 1997, p. 445.<br />
15. D. De Vos, R. Willem, M. Gielen, K.E. Van Wingerden, K. Nooter, Met. Based Drugs, 1998, 5,<br />
179-188.<br />
16. C. Pettinari, Main Group Met. Chem., 1999, 22, 661-692.<br />
17. S.P. Fricker, Ed., Metal Compounds in Cancer Therapy, Chapman & Hall, London, UK, 1994, pp.<br />
147–179.<br />
128
P-71<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis <strong>of</strong> Chromium-Containing Diterpene Analogs<br />
for the Modulation <strong>of</strong> NOD Proteins<br />
Aroonchai Saiai a , Janna Velder a , Harald Bielig b , Tomas A. Kufer b , Hans-Günther Schmalz* a<br />
a Institute for Organic Chemistry, University <strong>of</strong> Cologne, Greinstr.4, 50939, Cologne, Germany.<br />
b Institute for Medical Microbiology, Immunology and Hygiene, University <strong>of</strong> Cologne, Joseph-<br />
Stelzmann-Str.9, Geb.37, 50931, Cologne, Germany. E-mail: asaiai@smail.uni-koeln.de<br />
Polymorphisms in NOD1 and NOD2 are linked to chronic inflammatory barrier diseases such as<br />
asthma, Blau syndrome, early onset sarcodoisis and Crohn’s disease. 1 Many synthetic compounds in<br />
our group are structurally related pseudoterosins which exhibit pronounced analgesic and antiinflammatory<br />
properties were screened. In continuative research, we found that AKS-01 can inhibit<br />
NOD2-mediated NF-KB activation.<br />
To investigate the structure-activity relationships, Cr(CO)3-complexed compounds which structurally<br />
related to AKS-01were synthesized. 2,3<br />
Synthesis and biological evaluation will be presented in details.<br />
References<br />
OMe<br />
H<br />
OMe<br />
Cr(CO) 3<br />
H<br />
N<br />
AKS-01<br />
OMe<br />
Cr(CO) 3<br />
1.(a) P. Hysi, M. Kabesch, M. F. M<strong>of</strong>fatt, M. Schedel, D. Carr, N. Klopp, A.W. Musk, A. James, G.<br />
Nunez, N. Inohara and W.O. Cookson, Hum mol genet. 2005, 14, 935-941; (b) P. Rosenstiel, A. Till<br />
and S. Schreiber, Microbes and infection. 2007, 9, 648-657.<br />
2. H.-G. Schmalz, S. Siegel and J.W. Bats, Angew. Chem. Int. Ed. 1995, 34, 2383-2385.<br />
3. O. H<strong>of</strong>fmann and H.-G. Schmalz, Synlett. 1998, 12, 1426-1428.<br />
129<br />
H<br />
O<br />
OMe<br />
Cr(CO) 3<br />
1 R 1 = H R 2 = H<br />
2 R 1 = F R 2 = H<br />
3 R 1 = Me R 2 = H<br />
4 R 1 = OMe R 2 = H<br />
5 R 1 = CF 3 R 2 =H<br />
6 R 1 = H R 2 = F<br />
7 R 1 = H R 2 = Me<br />
8 R 1 = H R 2 = CF 3<br />
R 1<br />
R 2
P-72<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Analyzing Drug Action on Mitochondrial Targets using Functional Assays with<br />
Isolated Biological Active Mitochondria<br />
Suzan Can, a Ana Kitanovic, a Igor Kitanovic, a Annegret Hille, b Ronald Gust, b Melanie Oleszak, c<br />
Yvonne Geldmacher, c William S. Sheldrick, c Andreas Meyer, d Riccardo Rubbiani, d Ingo Ott d and<br />
Stefan Wölfl *a<br />
a Institute <strong>of</strong> Pharmacy and Molecular Biotechnology, University Heidelberg, Im Neuenheimer Feld<br />
364, 69120 Heidelberg, Germany. b Institute <strong>of</strong> Pharmacy, Department <strong>of</strong> Pharmaceutical Chemistry,<br />
Free university <strong>of</strong> Berlin, Germany. c Faculty <strong>of</strong> Chemistry and Biochemistry, Department <strong>of</strong><br />
Analytical Chemistry, University <strong>Bochum</strong>. d Institute <strong>of</strong> Pharmaceutical Chemistry, Technische<br />
<strong>Universität</strong> Braunschweig, Germany. email: wolfl@uni-hd.de<br />
Mitochondria play crucial roles in living cells. They are not only the source <strong>of</strong> energy via oxidative<br />
phosphorylation and ATP synthesis, but are also an important regulators <strong>of</strong> cellular survival and in the<br />
control <strong>of</strong> programmed cell death. Mitochondrial damage and inhibition <strong>of</strong> the electron transfer in the<br />
respiratory chain can trigger the production <strong>of</strong> reactive oxygen species (ROS) and the release <strong>of</strong><br />
cytochrome c. The latter initiates mitochondrial induction <strong>of</strong> apoptosis. Previous studies in intact cells<br />
showed that several bioorganometallic compounds significantly induced ROS formation and triggered<br />
cell death inducing pro-apoptotic pathways.<br />
To further elucidate their specific activity we wanted to investigate if mitochondria and mitochondrial<br />
activity are direct targets <strong>of</strong> some <strong>of</strong> these compounds. With the central role <strong>of</strong> mitochondria in the<br />
regulation <strong>of</strong> cell death such compounds could play an important role for anti-cancer therapy to trigger<br />
cell death in proliferating cancer cells.<br />
We isolated mitochondria from mouse liver and established a series <strong>of</strong> tests that show mitochondrial<br />
functionality. With these functional assays for several complexes <strong>of</strong> the respiratory chain and by<br />
measuring oxygen consumption we analysed the capability <strong>of</strong> various substances to influence<br />
respiration and selectively inhibit respiratory chain components in isolated mitochondria. Results<br />
revealed that some salophene iron complexes (AG Gust) and rhodium (III) polypyridyl complexes<br />
(AG Sheldrick) directly inhibit mitochondrial respiration. Furthermore it could be shown that<br />
treatment with several bioorganometallic substances lead to a release <strong>of</strong> cytochrome c and to changes<br />
<strong>of</strong> mitochondrial membrane potential which indicates a strong influence on the integrity <strong>of</strong> the<br />
mitochondrial membrane.<br />
This work is supported by the DFG as part <strong>of</strong> the Forschergruppe FOR630.<br />
130
P-73<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Asborin Meets Titanium<br />
Matthias Scholz a and Evamarie Hey-Hawkins* a<br />
a <strong>Universität</strong> Leipzig, Institute <strong>of</strong> Inorganic Chemistry, Johannisallee 29, D-04103 Leipzig, Germany,<br />
E-mail: mscholz@chemie.uni-leipzig.de<br />
Asborin, the carbaborane analogue <strong>of</strong> aspirin ® , is one <strong>of</strong> the few examples in which carbaboranes are<br />
used as phenyl-mimetic pharmacophores. Asborin was synthesised in a high-yield procedure starting<br />
from ortho-carbaborane. The compound proved to inhibit both cyclooxygenase (COX) isozymes, the<br />
target enzymes <strong>of</strong> aspirin. 1 The COX inhibition potential, however, was lower compared to aspirin and<br />
the general pharmacological pr<strong>of</strong>ile was also different to that <strong>of</strong> aspirin. Integration <strong>of</strong> the cluster in<br />
place <strong>of</strong> the phenyl ring turned aspirin into a more toxic compound, which triggers apoptosis<br />
pathways. Asborin was cytotoxic toward several cancer cell lines and exhibited the lowest potency<br />
toward healthy fibroblasts. This behaviour made the carbaborane compound interesting for anticancer<br />
drug development. As the IC50 values obtained from the cytotoxicity assays were higher than those <strong>of</strong><br />
commercial chemotherapeutic agents, the compound requires further fine-tuning <strong>of</strong> its cytotoxic<br />
pr<strong>of</strong>ile.<br />
A promising approach to increase the antitumour activity <strong>of</strong> asborin is combination with another<br />
cytotoxic moiety. Therefore, we decided to modify asborin with titanium complexes, as some<br />
derivatives were found to be active toward several tumour cells. The most prominent anticancer<br />
titanium derivatives are the organometallic compound titanocene dichloride and the bioinorganic<br />
complex budotitane. 2 The carboxyl group and carbaborane moiety <strong>of</strong> asborin allow it to form both<br />
bioinorganic and organometallic titanium compounds. Coordination <strong>of</strong> asborin as carboxylate could<br />
displace the chloride ions in titanocene dichloride. Alternatively, instead <strong>of</strong> a cyclopentadienyl ring the<br />
nido carbaborane cluster can act as ligand for titanium. Thus, carbaboranes can easily be deboronated<br />
to give anionic nido clusters, which feature an open pentagonal plane. These anions can then form<br />
different metallocene analogues.<br />
References<br />
1. M. Scholz, K. Bensdorf, R. Gust, E. Hey-Hawkins, ChemMedChem. 2009, 4, 746-748.<br />
2. J. C. Dabrowiak: Titanium compounds for treating cancer in Metals in Medicine; 1. Ed.; Wiley:<br />
New York, USA, 2009; pp. 167-177.<br />
131
P-74<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Coordination Behavior and Spectroscopic Studies <strong>of</strong> Biologically Active<br />
Organotin(IV) Complexes <strong>of</strong> 2-(N-naphthylamido)benzoic Acid<br />
Khadija Shahid a�<br />
a Riphah Institute <strong>of</strong> Pharmaceutical, Sciences 7 th Avenue, G-7/4, Riphah International<br />
University, Islamabad-45320 Pakistan<br />
New organotin(IV)complexes <strong>of</strong> 2-(N-naphthylamido)benzoic acid were synthesized in<br />
stoichiometric ratio in anhydrous toluene under the reflux yield the organotin(IV) carboxylates with<br />
general formula R 4-nSnLn(R= Me, n-Bu, Ph, n-Oct, Bz and n= 2, 3). All the complexes have been<br />
characterized by various spectroscopic methods (IR, 1 H, 13 C, 119 Sn NMR) and mass spectrometry. 1<br />
Cytotoxicity <strong>of</strong> the synthesized compounds was checked against Brine-shrimp larvae.<br />
In vitro activities against some Gram-positive and Gram-negative bacteria and fungi were also<br />
determined. 2 Antimicrobial activities show that species with tetrahedral geometry in solution are<br />
more toxic. 3<br />
References<br />
Scheme: Synthesis <strong>of</strong> Di/Tri organotin Complexes.<br />
1. (a) K. Shahid, S. Ali, S. Shahzadi, J. Coord. Chem. 2009, 62(17), 2919–2926. (b) K. Shahid, S.<br />
Shahzadi, J. Serb Chem. Soc. 2009, 74(2), 141-154.<br />
2. A. Rahman, M.I. Choudhary, W.J. Thomsen, Bioassay Techniques for Drug Development;<br />
Hardward Academic Press, Amsterdam 2001.<br />
132
P-75<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Raman Microscopic Cell Uptake Studies <strong>of</strong><br />
Bioactive Organometal Peptide Conjugates<br />
Thomas Sowik a , Eugen Edengeiser b , Martina Havenith-Newen, b and Ulrich Schatzschneider a *<br />
a Lehrstuhl für Anorganische Chemie I – Bioanorganische Chemie, <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>,<br />
<strong>Universität</strong>sstr. 150, D-44801 <strong>Bochum</strong>, Germany, E-Mail: thomas.sowik@rub.de.<br />
b Lehrstuhl für Physikalische Chemie II, <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, <strong>Universität</strong>sstr. 150, D-44801<br />
<strong>Bochum</strong>, Germany.<br />
A major problem is the lack <strong>of</strong> molecular markers which do not influence the intracellular distribution<br />
and biological activity and show signals where constitutions <strong>of</strong> the cell normal do not. Raman<br />
microscopy, however, is a potent technique for cell imaging and drug uptake studies. 1 The C-D<br />
stretching vibration <strong>of</strong> deuterated compounds appears in a spectroscopic window between 2100 and<br />
2350 cm -1 where bio (macro) molecules do not show vibrational signals. Thus, it is possible to<br />
investigate the cell uptake and metabolism <strong>of</strong> these compounds. 2 Peptide bioconjugates with<br />
cyclopentadienylrhenium- or cyclopentadienylmangenese tricarbonyl are known for their biological<br />
activity depending on the peptide sequence. 3 Their analogues with deuterated metal complexes are<br />
promising candidates for Raman microscopy (Fig. 1). An example is sC18 with the sequence<br />
GLRKRLRKFRNKIKEK-NH2 which delivers metal complex bioconjugates to cancer cells.<br />
Rayleigh signal<br />
1650<br />
1907<br />
1942<br />
2020<br />
2352<br />
0 1000 2000 3000 4000<br />
Wavenumber cm -1<br />
3119<br />
Figure 1: Raman spectrum (left) <strong>of</strong> deuterated cyclopentadienylrhenium(I) tricarbonyl carbocylic acid (right). The C-D<br />
stretching vibrations appear at 2352 cm -1 .<br />
Within this work we have prepared deuterated cyclopentadienyl carboxylic acid, which was reacted<br />
with dirhenium decacarbonyl to deuterated cyclopentadienylrhenium(I) tricarbonyl carboxylic acid.<br />
Subsequently, bioconjugates were prepared and their biodistribution and cell-uptake was studied using<br />
Raman spectroscopy and microscopy.<br />
Reference<br />
1. C. Matthäus, T. Chernenkoa, L. Quinteroc, L. Milanb, A. Kaleb, M. Amijib, V. Torchilinb, M.<br />
Diema, Proc. SPIE 2008, 6991.<br />
2. H.-J. v. Manen, A. Lenferink, C. Otto, Anal. Chem. 2008, 80, 9576–9582.<br />
3. K. Meister, J. Niesel, U. Schatzschneider, N. Metzler-Nolte, D. A. Schmidt, M. Havenith, Angew.<br />
Chem. 2010, accepted for publication.<br />
133<br />
D<br />
D<br />
D<br />
COOH<br />
D<br />
Re<br />
CO<br />
OC CO
P-76<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesise <strong>of</strong> New Butyl Tin(IV) Compounds and Investigation About Their<br />
Toxicity and Anti-inflammatory Studies<br />
Fatemeh Tavakolinia, a Mohammad Yousefi, a Saeed Amanpour, b Samad Mohammadnejad, b<br />
and Mojdeh Safari *b<br />
a Azad University, Shahre-rey Branch, Tehran, Iran<br />
b Experimental Lab, Cancer Research center, Tehran university <strong>of</strong> medicinal sciences, Tahran, Iran.<br />
E-mail: ftavakolinia@yahoo.com<br />
Chemistry <strong>of</strong> organotin(IV) complexes has developed considerably during the last 30 years,<br />
highlighting the synthesis <strong>of</strong> a number <strong>of</strong> complexes with interesting properties. 1-3 One <strong>of</strong> the most<br />
important bioinorganic chemistry research areas as regards organotin compound is the investigation<br />
<strong>of</strong> their cytotoxic/antitumor activities. In addition many organotin(IV) compounds have been tested for<br />
their in vitro activity against a large variety <strong>of</strong> tumor lines and have been found to be as effective or<br />
better than traditional heavy metal anticancer drugs such as Cis-platin. 4,5 In general, toxicity <strong>of</strong><br />
organotin(IV) compounds seems to increase with the chain length <strong>of</strong> the organic alkyl group, which<br />
are <strong>of</strong>ten more active than aryl ones, and follow the order R3Sn> R2Sn> RSn. 6 In this research three<br />
new organotin(IV) complexes <strong>of</strong> the general formula R3SnŔ and R2SnŔ2 (where R=Ph, Bu, and Ŕ=1-<br />
Butane, 2-Butane, Ph) have been synthesized by the Grignard reaction <strong>of</strong> triphenyltin chloride with 1iodo<br />
butane and 2-chloro butane in 1:1 molar ratio and the reaction <strong>of</strong> dibutyltin dichloride with chloro<br />
benzene in 1:2 molar ratio. The resulted complexes are Ph3Sn1-Bu (1), Ph3Sn2-Bu (2), Ph2SnBu2 (3).<br />
The sample <strong>of</strong> synthesise <strong>of</strong> one <strong>of</strong> the complexes comes below. These new derivatives have been<br />
characterized by FT-TR, 1 H, 13 C, 119 Sn NMR and Mass spectroscopy. The toxicity study and antiinflammatory<br />
effect are going to carry out and the LD50 value is going to determine.<br />
ICH2CH2CH2CH3 + Mg � IMgCH2CH2CH2CH3<br />
IMgCH2CH2CH2CH3 + Ph3SnCl � Ph3SnCH2CH2CH2CH3 (1) + MgClI<br />
References<br />
1. M.J.Clarke, F. Zhu, D. R.Frasca, Chem. Rev. 1999, 99, 2511.<br />
2. J.Beckmann, K. Jurkschat, Coord. Chem. Rev. 2001, 215, 267.<br />
3. L.Pellerito, L.Nagy, Chem. Rev. 2002, 224, 111.<br />
4. M. Gielen, App. Organomet. Chem.2002, 16, 481.<br />
5. M. Gielen, Coord. Chem. Rev. 1996, 26, 1.<br />
6. D. Dc Vos, R.Willem, M. Gielen, K. E. Van Wingerden, K. K. Nooter, Net. Based drugs 1998, 5.<br />
134
P-77<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Water Enables Direct Palladium-Catalyzed C-allylation <strong>of</strong> Cyclic 1,3-Diones with<br />
Allylic Alcohols without Activators<br />
Shyh-Chyun Yang *a and Yi-Jen Shue a<br />
a Kaohsiung Medical University, School <strong>of</strong> Pharmacy, 100 Shih-Chuan 1st Road, 807, Kaohsiung,<br />
Taiwan. E-mail: scyang@kmu.edu.tw<br />
The palladium-catalyzed allylation is a powerful tool for C–C, C–N, and C–O bond formation, which<br />
has been widely applied to organic chemistry. We have recently disclosed a new catalytic system for<br />
palladium/carboxylic acid–catalyzed allylation with allylic alcohols in water as a suspension medium. 1<br />
Organic reactions in water have recently attracted much attention, because water is a safe and<br />
economical substitute for conventional organic solvent. Herein, we report that palladium-catalyzed<br />
ally-OH bond cleavage in the absence <strong>of</strong> activating agents. Allylation <strong>of</strong> cyclic 1,3-diones worked well<br />
with aromatic allylic alcohols in water and gave generally good to high yields. This is a simple and<br />
efficient route for C–C bond formation.<br />
References<br />
O O<br />
R<br />
Pd /P-ligand, H 2O<br />
OH<br />
R<br />
135<br />
R R<br />
O O + O O<br />
1. (a) S.-C. Yang, Y.-C. Hsu, K.-H. Gan. Tetrahedron 2006, 62, 3949-3958. (b) K.-H. Gan, C.-J.<br />
Jhong, S.-C. Yang, Tetrahedron 2008, 64, 1204-1212.
P-78<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
In Vitro Interactions <strong>of</strong> Rhenium(III) Compounds with Phospholipids and<br />
Nucleic Bases Derivatives<br />
a Dina Y. Yegorova, b Nataliia I. Shtemenko, a Alexander V. Shtemenko<br />
a Department <strong>of</strong> Inorganic Chemistry, Ukrainian State Chemical Technological University,<br />
Gagarin Ave. 8, Dnipropetrovs’k 49005, Ukraine. E-mail: shtemenko@ukr.net, b Department<br />
<strong>of</strong> Biophysics and Biochemistry, Dnipropetrovs’k National University, 72 Gagarin avenue,<br />
Dnipropetrovs’k 49010, Ukraine<br />
In our previous investigations it was shown that rhenium(III) complexes had antitumor, antihemolytic<br />
and red blood cells stabilizing properties. 1 The important component <strong>of</strong> the integral biological activity<br />
<strong>of</strong> any substance is its ability to cross the cell membrane and to react with nuclear bases. Investigations<br />
<strong>of</strong> the interaction between rhenium(III) cluster complexes and phospholipids as one <strong>of</strong> the main<br />
components <strong>of</strong> a cell membrane and nuclear bases is <strong>of</strong> great importance as may help to understand<br />
the mechanism <strong>of</strong> their action and to find further synthetic directions.<br />
In this work the experiments were accomplished with cluster rhenium(III) compounds with common<br />
formulas: [Bu4N]2×[Re2Cl8], cis-[Re2(CH3COO)2Cl4]×2H2O, trans-Re2(C2H5COO)2Cl4 ,<br />
Re2(RCOO)3Cl3, Re2(RCOO)4Cl2, where R - CH3, C2H5, i-C3H7, C10H15; with phospholipids:<br />
phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine and nuclear bases derivatives: 9methyladenin<br />
and 9-methylguanin. The electronic absorbtion spectra <strong>of</strong> mixtures <strong>of</strong> the substances<br />
were studied.<br />
According to the obtained spectra the strongest interaction was found with phosphatidylholine among<br />
other main phospholipids <strong>of</strong> cells membrane. It was shown that the mechanism <strong>of</strong> interaction<br />
depended on the structural type <strong>of</strong> cluster rhenium(III) complexes. In the case <strong>of</strong> tetra-μ-carboxylates<br />
bridged equatorial carboxylic groups were replaced by phosphate groups <strong>of</strong> phosphatidylholine with<br />
following formation <strong>of</strong> monodentate derivatives. During interaction <strong>of</strong> phosphatidylholine with cistetrachlorodi-μ-carboxylates<br />
<strong>of</strong> dirhenium(III) replacement <strong>of</strong> terminal chlorides by<br />
phosphatidylholine ligands with formation <strong>of</strong> monodentate derivatives with the change <strong>of</strong> the<br />
previous structural type was shown. The same interactions were shown to be realized during formation<br />
<strong>of</strong> nanoliposomes <strong>of</strong> cluster rhenium(III) compounds and phosphatidylholine.<br />
Hydrolytic process <strong>of</strong> the complex rhenium(III) compounds was shown to take place in water<br />
solutions, that’s why nanoliposomal forms <strong>of</strong> rhenium(III) complex compounds were obtained from<br />
phosphatidylholine to prolong their therapeutic effect. It was shown that the coordination <strong>of</strong> phosphate<br />
groups <strong>of</strong> phosphatidylholine to the cluster centre (unit) <strong>of</strong> Re2 6+ provided prevention <strong>of</strong> hydrolytic<br />
process and increased the stability <strong>of</strong> these compounds.<br />
Bidentate coordination <strong>of</strong> the 9 MeA to equatorial position <strong>of</strong> the cluster Re2 6+ centre through N1/N6<br />
atoms <strong>of</strong> the nucleic base heterocidic ring was shown. Another type <strong>of</strong> coordination was shown for<br />
Guanine derivative: 9MeG coordinated by monodentate mode to axial position <strong>of</strong> the Re2 6+ centre only<br />
through N1 atom <strong>of</strong> the heterocidic ring. The mechanism <strong>of</strong> interaction between nucleic bases and<br />
rhenium(III) compounds was different in comparison with the same for platinides that explained the<br />
effectiveness <strong>of</strong> the Rhenium – Platinum antitumor system in the earlier experiments in vivo.<br />
References<br />
1. (a) N. Shtemenko, P. Collery, A. Shtemenko, Anticancer Res. 2007, 27, 2487-2492. (b) A.<br />
Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, E. Zabitskaya, A. Golichenko, Dalton Trans.<br />
2009, 5132-5136.<br />
136
P-79<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Tris(pyrazolyl)borates as Versatile Ligands in the Synthesis <strong>of</strong> Bioorganometallic<br />
Compounds<br />
Johannes Zagermann, a Matthew C. Kuchta, a Klaus Merz, a Nils Metzler-Nolte a*<br />
a Fakultät für Chemie und Biochemie, <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, <strong>Universität</strong>sstraße 150,<br />
44801 <strong>Bochum</strong>, Germany, Johannes.Zagermann@rub.de<br />
While cyclopentadienyl (Cp) containing compounds such as ferrocene have found various applications<br />
in bioorganometallic chemistry, little work is found concerning analogue compounds containing Cp<br />
surrogates. As such, we have been interested in exploiting the rich coordination chemistry <strong>of</strong><br />
tris(pyrazolyl)borate (Tp) ligands for the synthesis <strong>of</strong> bioconjugates with possible applications in<br />
biomedical, electrochemical or spectroscopical studies.<br />
We describe the synthesis and characterization <strong>of</strong> mixed ligand (Cp/Tp) and (Tp/Tp') ruthenium<br />
sandwich compounds, 1 both incorporating a “third-generation” p-BrC6H4Tp (Tp') ligand, 2 and their<br />
application in the formation <strong>of</strong> peptide bioconjugates. More recently, we utilized iodocarbonyltungsten<br />
complexes containing a regular Tp* ligand to label peptides via η 2 -coordinated alkyne ligands<br />
including the unusual amino acid propargylglycine. 3<br />
References<br />
1. (a) J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, J. Organomet. Chem. 2009, 694, 862-<br />
867.<br />
(b) J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, manuscript in preparation.<br />
2. J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, Eur. J. Inorg. Chem. 2009, 5407-5412.<br />
3. J. Zagermann, K. Merz, N. Metzler-Nolte, Organometallics 2009, 28, 5090-5095.<br />
137
P-80<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Synthesis <strong>of</strong> Some Metal Dye-complexes as Antimicrobial Agents<br />
Ibrahim F. Zeid *a and Husein A. Agwa a<br />
a Department <strong>of</strong> Chemistry, Faculty <strong>of</strong> Science, Monoufia University Shibin El-Koam, Egypt<br />
E-mail: ifzeid@hotmail.co.uk<br />
An enormous number <strong>of</strong> 4-arylazo-2-pyrazolin-5-ones has been reported in the literature as dyes <strong>of</strong><br />
commercial value. The reaction <strong>of</strong> 4-arylazo-l-phenyl-3 -(methyl or phenyl)-2-pyrazolin-5-ones with<br />
copper and cobalt salts resulted in the formation <strong>of</strong> some new metal dye complexes. 1,2 The importance<br />
<strong>of</strong> the newly synthesized complexes as antimicrobial agents has been discussed.<br />
References<br />
R<br />
N<br />
N<br />
Ph<br />
1<br />
N=NAr<br />
O<br />
R<br />
N<br />
N<br />
Ph<br />
N=NAr<br />
O<br />
1. F. A. Amer, A. H. Harhash, M. A. Metwally, Z .Natuforsch. 1977, 32b, 943.<br />
2. A. A. Fadda, M. A. Metwally. A.M. Khalil, Indian J. Text. 1983, 8, 82.<br />
3. M. A. Metwally, A. A. Fadda, H. M. Hassan, E. Afsah, Org. Prep. Proc. Int. 1985, 17, 198.<br />
4. I. F. Zeid, M.T. Omar, A. A. Makhlouf, M. M. Kamel, N. M. Khalifa, Egypt. J. Pharm. Sci. 1996,<br />
37, 251.<br />
138<br />
M<br />
2<br />
O<br />
ArN=N<br />
Ph<br />
N<br />
N<br />
R
P-81<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Apoptosis induction and cytotoxicity by metalbased drugs:<br />
lights and shadows <strong>of</strong> DNA<br />
Gianni Sava a,b and Alberta Bergamo b<br />
a University <strong>of</strong> Trieste, Department <strong>of</strong> Life Sciences, via L. Giorgieri 7, 34127, Trieste, Italy. b Callerio<br />
Foundation Onlus, via A. Fleming 22-31, 34127, Trieste, Italy. E-mail: gsava@units.it<br />
Cisplatin is a well known DNA-damaging agent and the current thinking is that DNA platination<br />
(DNA-adduct formation) is an essential first step in the cytotoxic activity <strong>of</strong> the drug. Information<br />
about the chemistry <strong>of</strong> the platinum compounds and correlations <strong>of</strong> their structures with anticancer<br />
activity have provided guidance for the design <strong>of</strong> novel anticancer drug candidates based on the<br />
proposed mechanisms <strong>of</strong> action. 1 The question is: DNA-adduct formation guided synthesis <strong>of</strong> metalbased<br />
anticancer drugs is a real concept or a misleading interpretation? The mechanism(s) whereby the<br />
DNA adducts kill cells is not fully understood. One potentially important way by which cisplatin-<br />
DNA adducts may kill cells is by induction <strong>of</strong> programmed cell death or apoptosis (Figure 1). 2,3<br />
From: to:<br />
Figure 1. types <strong>of</strong> DNA adduct formation <strong>of</strong> platinum drugs: (a) interstrand cross-link, (b) 1,2intrastrand<br />
cross-link, (c) 1,3-intrastrand crosslink, (d) protein-DNA cross-link (adapted from Lit. 2)<br />
However, these concepts are not sufficient to account for the particular effectiveness <strong>of</strong> the most<br />
important platinum drugs in cancer therapy where cisplatin and carboplatin (two drugs with a rather<br />
different chemistry) are active on the same tumours, oxaliplatin is active on colorectal tumours and<br />
satraplatin (the emerging oral platinum drug) is active on prostate cancer. None <strong>of</strong> these tumours were<br />
selected a priori as the targets for these drugs. Then, how focusing on the ligands that allow DNA<br />
binding or to get insensitivity to acquired resistance, may help researchers to understand what to take<br />
into consideration to design the expected more potent, more selective and less toxic new metal-based<br />
antitumour drugs? Apoptosis and cell death is not simply related to DNA binding properties as shown<br />
by the many biological and targeted drugs emerged in the last years which killed cells by apoptoptic<br />
mechanisms following interactions with protein components <strong>of</strong> important cellular pathways. Given<br />
that cisplatin and also many platinum drugs have a poor capacity to enter the nucleus compartment (in<br />
the case <strong>of</strong> cisplatin almost 99% <strong>of</strong> the cellular drug is in the cytoplasm) the focus should be directed<br />
on what are the final destinations <strong>of</strong> all these platinum molecules in this protein-rich compartment. As<br />
an example, interesting data are emerging on HSP90 block by cisplatin, a phenomenon that could<br />
account for many apoptotic cytotoxicities observed. This work was done in the framework <strong>of</strong> COST<br />
D39 – WG3.<br />
References<br />
1. K.S. Lovejoy, S.J. Lippard, Dalton Trans. 2009, 48, 10651-10659.<br />
2. A. Eastman: The mechanism <strong>of</strong> action <strong>of</strong> cisplatin: From adducts to apoptosis in: Cisplatin.<br />
Chemistry and Biochemistry <strong>of</strong> a Leading Anticancer Drug; B. Lippert, Ed.; Wiley-VCH: Basel,<br />
Switzerland, 1999, pp. 111–134.<br />
3. R.C. Todd, S.J. Lippard, Metallomics 2010, 4, 280-291.<br />
139
P-82<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Selective Recognition <strong>of</strong> Actinides by Protein-Based Reagents<br />
Salih Özçubukçu, a Seraphine V. Wegner, a Kalyaneswar Mandal, b Stephen B. H. Kent, b<br />
Mark P. Jensen, c and Chuan He *a<br />
a The University <strong>of</strong> Chicago, Department <strong>of</strong> Chemistry, 60637, Chicago, IL, USA. b The University <strong>of</strong><br />
Chicago, Department <strong>of</strong> Chemistry, Department <strong>of</strong> Biochemistry and Molecular Biology, Institute for<br />
Biophysical Dynamics, 60637, Chicago, IL, USA. c Argonne National Laboratory, Chemical Sciences<br />
and Engineering Division, 60439, IL, USA,.<br />
e-mail: chuanhe@uchicago.edu<br />
It is generally accepted that trivalent actinides prefer s<strong>of</strong>ter chelating atoms such as sulfur rather than<br />
oxygen; hence selective separation <strong>of</strong> trivalent actinides from trivalent lanthanides can be obtained by<br />
s<strong>of</strong>t-donor ligands.<br />
Barbara Imperiali and her coworkers have developed a series <strong>of</strong> peptides, called lanthanide binding tag<br />
(LBT) which selectively binds lanthanide ions with high affinities 1 . This pre-organized ligand template<br />
provides an ideal system to study these long standing questions regarding separate trivalent actinides<br />
from trivalent lanthanides. Pre-organization <strong>of</strong> the ligands by the peptide scaffold provides high<br />
binding affinity. We can redesign these small peptides with nitrogen- and sulfur- based ligands to<br />
provide selectivity. We plan to systematically screen ligand types and geometries to achieve selective<br />
binding <strong>of</strong> actinides over lanthanides (Figure 1).<br />
References<br />
1. M. Nitz, M. Sherawat, K. J. Franz, E. Peisach, K. N. Allen, B. Imperiali, Angew. Chem. Int. Ed.<br />
2004, 43, 3682-3685.<br />
140
P-83<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Iridium Complex with Antiangiogenic Properties<br />
Alexander Wilbuer, a D. H. Vlecken, b D. J. Schmitz, b C. P. Bagowski, b and Erik Meggers* a<br />
a Philipps <strong>Universität</strong> Marburg, Fachbereich Chemie, Hans-Meerwein Str., 35032 Marburg,<br />
Germany. b Leiden University, Institute <strong>of</strong> Biology, Wassenaarseweg 64,<br />
2333 AL Leiden, The Netherlands. Wilbuer@chemie.uni-marburg.de<br />
Substitutionally inert metal complexes are promising emerging scaffolds for targeting enzyme active<br />
sites. 1 Our group has demonstrated over the last five years that inert ruthenium(II) complexes can<br />
serve as highly selective nanomolar and even picomolar inhibitors <strong>of</strong> protein kinases. 2 Octahedral<br />
metal coordination geometries in particular <strong>of</strong>fer new gateways to design rigid, globular molecules<br />
with defined shapes that can fill protein pockets such as enzyme active sites in a unique fashion. 3<br />
Although most <strong>of</strong> our previous efforts were focused on ruthenium(II) complexes, we envisioned that<br />
octahedral iridium(III) complexes might be interesting scaffolds for two reasons: First, coordinative<br />
bonds with Ir(III) tend to be very inert 4 and therefore Ir(III) complexes should be able to serve as<br />
stable scaffolds for the design <strong>of</strong> enzyme inhibitors. 5 Second, octahedral Ir(III) complexes can be<br />
accessed from square planar Ir(I) complexes by stereospecific oxidative addition reactions. 6 Here we<br />
present the discovery <strong>of</strong> an octahedral iridium(III) complex, synthesized through oxidative addition as<br />
the key synthetic step. The organometallic compound functions as a low nanomolar and highly<br />
selective inhibitor <strong>of</strong> the protein kinase Flt4, also known as VEGFR-3 (vascular endothelial growth<br />
factor receptor 3). Flt4 is involved in angiogenesis and lymphangiogenesis and we were able to<br />
demonstrate that this iridium complex can indeed interfere with the development <strong>of</strong> blood vessels in<br />
vivo in two different zebrafish angiogenesis models.<br />
References<br />
1. E. Meggers, Curr. Opin. Chem. Biol. 2007, 11, 287-292.<br />
2. E. Meggers, G. E. Atilla-Gokcumen, H. Bregman, Synlett 2007, 8, 1177-1189.<br />
3. J. Maksimoska, L. Feng, K. Harms, J. Am. Chem. Soc. 2008, 130, 15764-15765.<br />
4. J. Burgess, Inorg. React. Mechanism 1972, 2, 140-195.<br />
5. T.-H. Kwon, J. Kwon, J.-I. Hong, J. Am. Chem. Soc. 2008, 130, 3726-3727.<br />
6. J. U. Mondal, D. M. Blake, Coord. Chem. Rev. 1982, 47, 205-238.<br />
141
P-84<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
New Oxorhenium(V) Complex with Aminothiazole Ligand, and Radiochemical<br />
Behavior <strong>of</strong> its Oxotechnetium(V) Complex Analog<br />
Norah S. Al-Hokbany, a* R.M. Mahfouz, a and I.J. Al-Jammaz b<br />
a King Saud University, Department <strong>of</strong> Chemistry, College <strong>of</strong> Science, P.O.Box 2455, Riyadh, 11451<br />
Kingdom <strong>of</strong> Saudi Arabia. b Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist<br />
Hospital and Research Center. P.O. Box 3354, Riyadh 11211, Kingdom <strong>of</strong> Saudi Arabia.<br />
Tel:+966 1 4772245; Fax: +966 1 4772245. e-mail: nhokbany@ksu.edu.sa<br />
A [ReO(amino)2OH] complex was successfully synthesized by ligand exchange method <strong>of</strong><br />
oxorhenuim gluconate with aminothiazole ligand. Geometry optimization <strong>of</strong> complex has been carried<br />
out using DFT at the B3LYP/LANL2DZ functional in singlet state. B3LYP predicted infrared<br />
spectrum <strong>of</strong> geometrical optimized structure using the same level <strong>of</strong> the theory and the same basis set<br />
showed good agreement with experimentally observed values. The complex has been characterized<br />
using elemental analysis and different spectroscopic techniques (IR, UV-Vis, NMR and MS).<br />
At the technetium tracer level, the 99m TcO-complex has been synthesized by two methods ( 99m Tcgluconate<br />
as precursor; direct reduction). The radiochemical purity <strong>of</strong> the complex was over 95% as<br />
measured by thin layer chromatography. In vitro studies showed that the complex possessed good<br />
stability under physiological conditions. Its partition coefficient indicated that it was a hydrophilic<br />
complex. The electrophoresis results showed the complex was neutral. Normal biodistribution <strong>of</strong> 99m<br />
Tc complex, exhibit high lung, liver and spleen uptake (27%, 11%, and 12%, respectively). Blood and<br />
lung clearance was quite fast (% injection dose in blood and lungs 0.36% and 0.18%, respectively at 1<br />
hr post-injection), while liver activity remained high for a longer period (% injection dose 12% at 1 hr<br />
post-injection). The radioactivity from the novel technetium complex was excreted mainly through the<br />
hepatobiliary system (35% at 1 h post-injection) and partially kidney.<br />
References<br />
pH=9<br />
r.t<br />
45min<br />
99m TcO4 -<br />
NaBH 4<br />
Na-gluconate<br />
SnCl2. 2H2O 99m TcO(gluc)2 -<br />
+<br />
NH<br />
O<br />
M<br />
N S<br />
OH<br />
N<br />
S NH2 S<br />
HN<br />
were M = Re, 99m Tc<br />
142<br />
N<br />
ReO 4 -<br />
Na-gluconate<br />
SnCl 2. 2H 2O<br />
ReO(gluconate) 2 -<br />
1. P. Bouziotis, D. Papagiannopoulou, I. Pirmettis, M. Pelecanou, C.P. Raptopoulou, C.I.<br />
Stassinopoulou, A. Terzis, M. Friebe, H. Spies, M. Papadopoulos, E. Chiotellis, Inorg. Chim. Acta<br />
2001, 320, 174-177.<br />
2. H. Zhang, M. Dai, C. Qi, X. Guo, Appl. Radiat. Isot. 2004, 60, 643-651.<br />
3. B. Dhara, P. Chattopadhyay, Appl. Radiat. Isot. 2005, 62, 729-735.<br />
4. K. Schwochau, Technetium Chemistry and Radiopharmaceutical Applications, Wiley-VCH,<br />
Weinheim, 2000.
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Participants<br />
143
Sergey Abramkin<br />
<strong>Universität</strong> Wien, Austria<br />
sergey.abramkin@univie.ac.at<br />
Oladipo Ademola<br />
Lautech, Nigeria<br />
suspyo@yahoo.com<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Ebenezer Aidoo<br />
University <strong>of</strong> South Africa, South Africa<br />
lincollnn@yahoo.com<br />
Pr<strong>of</strong>. Dr. Roger Alberto<br />
Univerität Zürich, Switzerland<br />
ariel@aci.uzh.ch<br />
Hamed Alborzinia<br />
<strong>Universität</strong> Heidelberg, Germany<br />
hamed.alborzinia@uni-heidelberg.de<br />
Dr. Noura Al-Hokbany<br />
King Saud University, Saudi Arabia<br />
nhokbany@ksu.edu.sa<br />
Dr. Wee Han Ang<br />
National University <strong>of</strong> Singapore, Singapore<br />
chmawh@nus.edu.sg<br />
Anusch Arezki<br />
ENSCP, France<br />
anusch-arezki@chimie-paristech.fr<br />
Dr. Braja Gopal Bag<br />
Vidyasagar University, India<br />
bgopalbag@yahoo.co.in<br />
Nicolas Barry<br />
University <strong>of</strong> Neuchatel, Switzerland<br />
nicolas.barry@unine.ch<br />
Pr<strong>of</strong>. Dr. Wolfgang Beck<br />
Ludwig-Maximilians-University München, Germany<br />
wbe@cup.uni-muenchen.de<br />
Samaneh Beheshti<br />
University <strong>of</strong> Western Ontario, Canada<br />
sbehesh@uwo.ca<br />
Dr. Alberta Bergamo<br />
Callerio Foundation, Italy<br />
a.bergamo@callerio.org<br />
144
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Ruth Bieda<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
ruth.bieda@rub.de<br />
Sebastian Blanck<br />
<strong>Universität</strong> Marburg, Germany<br />
sebastian.blanck@chemie.uni-marburg.de<br />
Dmytro Bobukhov<br />
Ukrainian State Chemical Technology University, Ukraine<br />
dbobukhov@googlemail.com<br />
Dr. Diane Bouvet-Muller<br />
ICMPE Paris 12, France<br />
muller@u-pec.fr<br />
Adam Boynton<br />
Trinity College, USA<br />
timothy.curran@trincoll.edu<br />
Nadine Brückmann<br />
<strong>Universität</strong> Düsseldorf, Germany<br />
brueckmn@uni-duesseldorf.de<br />
Pr<strong>of</strong>. Dr. Peter Buglyo<br />
University <strong>of</strong> Debrecen, Hungary<br />
buglyo@delfin.unideb.hu<br />
Daniel Can<br />
<strong>Universität</strong> Zürich, Switzerland<br />
daniel.can@aci.uzh.ch<br />
Suzan Can<br />
<strong>Universität</strong> Heidelberg, Germany<br />
suz.c@gmx.de<br />
Dr. Angela Casini<br />
EPFL, Switzerland<br />
angela.casini@epfl.ch<br />
Prinessa Chellan<br />
University <strong>of</strong> Cape Town, South Africa<br />
prinessa.chellan@uct.ac.za<br />
Dr. Joao Correia<br />
ITN, Portugal<br />
jgalamba@itn.pt<br />
Pr<strong>of</strong>. Dr. Timothy Curran<br />
Trinity College, USA<br />
timothy.curran@trincoll.edu<br />
145
Tensim Dallagi<br />
ENSCP, France<br />
t.dallegi@laposte.net<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Pr<strong>of</strong>. Dr. Marcetta Darensbourg<br />
Texas A&M University, USA<br />
marcetta@mail.chem.tamu.edu<br />
Pr<strong>of</strong>. Dr. Roman Dembinski<br />
Oakland University, USA<br />
dembinsk@oakland.edu<br />
Jan Dittrich<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
jan.dittrich@rub.de<br />
Pr<strong>of</strong>. Dr. Holger Dobbek<br />
Humboldt-<strong>Universität</strong> zu Berlin, Germany<br />
holger.dobbek@biologie.hu-berlin.de<br />
Christine D<strong>of</strong>fek<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
christine.d<strong>of</strong>fek@rub.de<br />
Gregor Dördelmann<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
gregor.doerdelmann@rub.de<br />
Anica Dose<br />
University <strong>of</strong> Kent, Great Britain<br />
ad308@kent.ac.uk<br />
Pr<strong>of</strong>. Dr. Paul Dyson<br />
EPFL, Switzerland<br />
paul.dyson@epfl.ch<br />
Dr. Johannes Eble<br />
<strong>Universität</strong> Frankfurt, Germany<br />
eble@med.uni-frankfurt.de<br />
Pr<strong>of</strong>. Dr. Richard Fish<br />
Lawrence Berkeley National Laboratory, USA<br />
rhf@lbl.gov<br />
Ying Fu<br />
University <strong>of</strong> Warwick, Great Britain<br />
fuyingpku@gmail.com<br />
Dr. Christian Gaiddon<br />
University <strong>of</strong> Strasbourg, France<br />
gaiddon@unistra.fr<br />
146
Dr. Gilles Gasser<br />
Univerität Zürich, Switzerland<br />
gilles.gasser@aci.uzh.ch<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Luca Gaviglio<br />
University <strong>of</strong> Piemonte Orientale, Italy<br />
luca.gaviglio@mfn.unipmn.it<br />
Yvonne Geldmacher<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
yvonne.geldmacher@rub.de<br />
Pr<strong>of</strong>. Dr. Roberto Gobetto<br />
University <strong>of</strong> Torino, Italy<br />
roberto.gobetto@unito.it<br />
Meral Gormen<br />
ENSCP, France<br />
meral-gormen@chimie-paristech.fr<br />
Annika Groß<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
annika.gross@rub.de<br />
Pr<strong>of</strong>. Dr. Ronald Gust<br />
Freie <strong>Universität</strong> Berlin, Germany<br />
rgust@zedat.fu-berlin.de<br />
Frauke Hackenberg<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
frauke.hackenberg@rub.de<br />
Didier Hamels<br />
ENSCP, France<br />
didier.hamels@hotmail.fr<br />
PD Dr. Christian Hartinger<br />
<strong>Universität</strong> Wien, Austria<br />
christian.hartinger@univie.ac.at<br />
Masoumeh Hazratilivari<br />
Iran<br />
zazoli49@yahoo.com<br />
Dr. Jörg Henig<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
joerg.henig@rub.de<br />
Pr<strong>of</strong>. Dr. Richard Herrick<br />
College <strong>of</strong> the Holy Cross, USA<br />
rherrick@holycross.edu<br />
147
Pr<strong>of</strong>. Dr. Toshikazu Hirao<br />
Osaka University, Japan<br />
hirao@chem.eng.osaka-u.ac.jp<br />
Dr. Elizabeth Hillard<br />
ENSCP, France<br />
elizabethhillary@yahoo.com<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Pavlo Holenya<br />
<strong>Universität</strong> Heidelberg, Germany<br />
Wanning Hu<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
wanning.hu@rub.de<br />
Dr. Jamie Humphrey<br />
Royal Society <strong>of</strong> Chemistry, Great Britain<br />
humphreyj@rsc.org<br />
Nina Hüsken<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
nina.huesken@rub.de<br />
Maxim Izumsky<br />
Ukrainian State Chemical Technology University, Ukraine<br />
maksimizumsky@gmail.com<br />
Kartin Jäger<br />
Forschungszentrum Rossendorf, Germany<br />
k.jaeger@fzd.de<br />
Rajkumar Jana<br />
<strong>Universität</strong> Stuttgart, Germany<br />
jana@iac.uni-stuttgart.de<br />
Pr<strong>of</strong>. Dr. Gerard Jaouen<br />
ENSCP, France<br />
gerard-jaouen@chimie-paristech.fr<br />
Pr<strong>of</strong>. Dr. Andres Jäschke<br />
<strong>Universität</strong> Heidelberg, Germany<br />
jaeschke@uni-hd.de<br />
Dr. Violeta Jevtovic<br />
University <strong>of</strong> Novi Sad, Serbia<br />
violeta.jevtovic@dh.uns.ac.rs<br />
Pr<strong>of</strong>. Dr. Jorge Jios<br />
Universidad Nacional de La Plata<br />
Argentina<br />
jijios@quimica.unip.edu.ar<br />
148
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Pr<strong>of</strong>. Dr. Kenneth Kam-Wing Lo<br />
City University <strong>of</strong> Hong Kong, Hong Kong<br />
bhkenlo@cityu.edu.hk<br />
Christine Kasper<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
christine.kasper@rub.de<br />
Syed Gohar Taqi Kazimi<br />
University <strong>of</strong> Sargodha, Pakistan<br />
gohartaqi@hotmail.com<br />
Dr. Srecko Kirin<br />
Institut Ruđer Bošković, Croatia<br />
srecko.kirin@irb.hr<br />
Dr. Igor Kitanovic<br />
<strong>Universität</strong> Heidelberg, Germany<br />
igor.kitanovic@urz.uni-heidelberg.de<br />
Malte Kokoschka<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
malte.kokoschka@rub.de<br />
Dr. Konrad Kowalski<br />
University <strong>of</strong> Lodz, Poland<br />
kondor15@wp.pl<br />
Pr<strong>of</strong>. Dr. Heinz-Bernhard Kraatz<br />
University <strong>of</strong> Western Ontario, Canada<br />
hkraatz@uwo.ca<br />
Dr. Erik Kriel<br />
Mintek , South Africa<br />
erikk@mintek.co.za<br />
Dr. Lukas Kromer<br />
ITQB-UNL, Portugal<br />
kromer@itqb.unl.pt<br />
Dr. Peter Kunz<br />
<strong>Universität</strong> Düsseldorf, Germany<br />
peter.kunz@uni-duesseldorf.de<br />
See Mun Lee<br />
University <strong>of</strong> Malaya, Malaysia<br />
annieleesm@gmail.com<br />
Pr<strong>of</strong>. Dr. Emanuela Licandro<br />
University <strong>of</strong> Milano, Italy<br />
emanuela.licandro@unimi.it<br />
149
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Zhe Liu<br />
University <strong>of</strong> Warwick, Great Britain<br />
z.liu.2@warwick.ac.uk<br />
Olessya Loiko<br />
Karaganda State University, Kazakhstan<br />
olessya0905@gmail.com<br />
Dr. Jason Lynam<br />
University <strong>of</strong> York, Great Britain<br />
jml12@york.ac.uk<br />
Pr<strong>of</strong>. Dr. Stefano Maiorana<br />
University <strong>of</strong> Milano, Italy<br />
stefano.maiorana@unimi.it<br />
Basudev Maity<br />
Indian Institute <strong>of</strong> Science Bangalore, India<br />
ipcbasudev@gmail.com<br />
Sergey Malinkin<br />
Kiev National Taras Shevchenko University, Ukraine<br />
malinachem@mail.ru<br />
Dr. Sanela Martic<br />
University <strong>of</strong> Western Ontario, Canada<br />
smartic@uwo.ca<br />
Niall McGuinness<br />
National University <strong>of</strong> Ireland, Irland<br />
nmguinness@hotmail.com<br />
Thomas McTeague<br />
Trinity College, USA<br />
Pr<strong>of</strong>. Dr. Eric Meggers<br />
<strong>Universität</strong> Marburg, Germany<br />
meggers@chemie.uni-marburg.de<br />
Sandra Mieranz<br />
Freie <strong>Universität</strong> Berlin<br />
Germany<br />
Pr<strong>of</strong>. Dr. Morten Meldal<br />
Carlsberg Laboratory, Denmark<br />
mpm@crc.dk<br />
Pr<strong>of</strong>. Dr. Mohamed Metwally<br />
University <strong>of</strong> Mansoura, Egypt<br />
mamegs@mans.edu.eg<br />
150
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Pr<strong>of</strong>. Dr. Nils Metzler-Nolte<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
nils.metzler-nolte@rub.de<br />
Andreas Meyer<br />
TU Braunschweig, Germany<br />
andreas.meyer@tu-bs.de<br />
Stefan Mollin<br />
<strong>Universität</strong> Marburg, Germany<br />
stefan-mollin@web.de<br />
Jean-Philippe Monserrat<br />
ENSCP, France<br />
jean-philippe-monserrat@chimie-paristech.fr<br />
Pr<strong>of</strong>. Dr. Toshiyuki Moriuchi<br />
Osaka University, Japan<br />
moriuchi@chem.eng.osaka-u.ac.jp<br />
Pr<strong>of</strong>. Dr. Orde Munro<br />
University <strong>of</strong> KwaZulu-Natal, South Africa<br />
munroo@ukzn.ac.za<br />
Ali Nazif<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
alinazif@hotmail.com<br />
Dr. Alexey Nazarov<br />
EPFL, Switzerland<br />
alexey.nazarov@epfl.ch<br />
Johanna Niesel<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
johanna.niesel@rub.de<br />
Dr. Stephan Niland<br />
<strong>Universität</strong> Frankfurt, Germany<br />
niland@med.uni-frankfurt.de<br />
Anna-Luisa N<strong>of</strong>fke<br />
<strong>Universität</strong> Düsseldorf, Germany<br />
anna-louisa.n<strong>of</strong>fke@uni-duesseldorf.de<br />
Luciano Oehninger<br />
TU Braunschweig, Germany<br />
oehninger@gmail.com<br />
Dr. Melanie Oleszak<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
m.oleszak@gmx.de<br />
151
Obiora Augustine Orakwue<br />
Hyqid Nigeria Ltd., Nigeria<br />
hyqidenergy@gmail.com<br />
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Pr<strong>of</strong>. Dr. Chris Orvig<br />
University <strong>of</strong> British Columbia, Canada<br />
orvig@chem.ubc.ca<br />
Pr<strong>of</strong>. Dr. Domenico Osella<br />
University <strong>of</strong> Alessandria, Italy<br />
domenico.osella@mfn.unipmn.it<br />
Pr<strong>of</strong>. Dr. Ingo Ott<br />
TU Braunschweig, Germany<br />
ingo.ott@tu-bs.de<br />
Dr. Salih Özçubukçu<br />
University <strong>of</strong> Chicago, USA<br />
salih@uchicago.edu<br />
Pr<strong>of</strong>. Dr. Mallayan Palaniandavar<br />
Bharathidasan University, India<br />
palanim51@yahoo.com<br />
Malay Patra<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
malay.piu@gmail.com<br />
Dr. Andrew Phillips<br />
University College Dublin, Ireland<br />
andrew.phillips@ucd.ie<br />
Hendrik Pfeiffer<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
hendrik.pfeiffer@rub.de<br />
Anais Pitto-Barry<br />
<strong>Universität</strong> Neuchatel, Switzerland<br />
anais.pitto-barry@unine.ch<br />
Dr. Nicolas Plumere<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
nicolas.plumere@rub.de<br />
Maria Proetto<br />
Freie <strong>Universität</strong> Berlin, Germany<br />
Lukasz Raszeja<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Gmany<br />
lukaszraszeja@aol.com<br />
152
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Mariia Randarevych<br />
Ukrainian State Chemical Technology University, Ukraine<br />
m_randarevich@mail.ru<br />
Pr<strong>of</strong>. Dr. Mauro Ravera<br />
Universtiy <strong>of</strong> Piemonte Orientale, Italy<br />
mauro.ravera@mfn.unipmn.it<br />
Pr<strong>of</strong>. Dr. Charles Riordan<br />
University <strong>of</strong> Delaware, USA<br />
riordan@udel.edu<br />
Steffen Romanski<br />
<strong>Universität</strong> zu Köln, Germany<br />
romansks@uni-koeln.de<br />
Pr<strong>of</strong>. Dr. Edward Rosenberg<br />
University <strong>of</strong> Montana Missoula, USA<br />
edward.rosenberg@mso.umt.edu<br />
Riccardo Rubbiani<br />
TU Braunschweig, Germany<br />
r.rubbiani@tu-bs.fr<br />
Dr. Bogna Rudolf<br />
University <strong>of</strong> Lodz, Poland<br />
brudolf@chemia.uni.lodz.pl<br />
Mojdeh Safari<br />
Azad University, Iran<br />
msafari96@yahoo.com<br />
Hamid Samouei<br />
Shiraz University, Iran<br />
samouei@gmai.com<br />
Pr<strong>of</strong>. Dr. Gianni Sava<br />
Callerio Foundation, Italy<br />
g.sava@callerio.org<br />
Aroonchai Saiai<br />
<strong>Universität</strong> zu Köln, Germany<br />
asaiai@smail.uni-koeln.de<br />
Dr. Ulrich Schatzschneider<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
ulrich.schatzschneider@rub.de<br />
Pr<strong>of</strong>. Dr. Hans-Günther Schmalz<br />
<strong>Universität</strong> zu Köln, Germany<br />
schmalz@uni-koeln.de<br />
153
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Matthias Scholz<br />
<strong>Universität</strong> Leipzig, Germany<br />
mscholz@chemie.uni-leipzig.de<br />
Julia Schur<br />
TU Braunschweig, Germany<br />
j.schur@tu-bs.de<br />
Dr. Brigitte Schwederski<br />
Uni Stuttgart, Germany<br />
schwederski@iac.uni-stuttgart.de<br />
Dr. Khadija Shahid<br />
Riphah International University, Pakistan<br />
khadijajee@yahoo.com<br />
Marjan Shahmir<br />
Amirkabir University, Iran<br />
marjanshahmir@yahoo.com<br />
Pr<strong>of</strong>. Dr. William Sheldrick<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
william.sheldrick@ruhr-uni-bochum.de<br />
Pr<strong>of</strong>. Dr. Alexander Shtemenko<br />
Ukrainian State Chemical Technology University, Ukraine<br />
shtemenko@ukr.net<br />
Pr<strong>of</strong>. Dr. Nataliia Shtemenko<br />
Ukrainian State Chemical Technology University, Ukraine<br />
n.shtemenko@i.ua<br />
Dr. Gregory Smith<br />
University <strong>of</strong> Cape Town, South Africa<br />
gregory.smith@uct.ac.za<br />
Thomas Sowik<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
thomas.sowik@rub.de<br />
Katrin Splith<br />
<strong>Universität</strong> Leipzig, Germany<br />
splith@uni-leipzig.de<br />
Robert Ssekanyonyi<br />
Kiriibwa AIDS Caring Center, Uganda<br />
rebeccanawanji@yahoo.com<br />
Marilena Stefanopoulou<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
stef_point@hotmail.com<br />
154
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Dr. Pratima Srivastava<br />
ENSCP, France<br />
pratima-srivastava@chimie-paristech.fr<br />
Dr. Svetlana Strashnova<br />
People's Friendship University <strong>of</strong> Russia, Russia<br />
sstrashnova@mail.ru<br />
Pr<strong>of</strong>. Dr. Georg Süss-Fink<br />
<strong>Universität</strong> Neuchatel, Switzerland<br />
georg.suess-fink@unine.ch<br />
Pr<strong>of</strong>. Dr. Matthias Tacke<br />
University College Dublin, Ireland<br />
matthias.tacke@ucd.ie<br />
Fatemeh Tavakolinia<br />
Azad University, Iran<br />
ftavakolinia@yahoo.com<br />
Dr. Siden Top<br />
ENSCP, France<br />
siden-top@chimie-paristech.fr<br />
Pr<strong>of</strong>. Dr. John Valliant<br />
McMaster University, Canada<br />
valliant@mcmaster.ca<br />
Pr<strong>of</strong>. Dr. Gerard van Koten<br />
Utrecht University, The Netherlands<br />
g.vankoten@uu.nl<br />
Dr. Anne Vessieres<br />
ENSCP, France<br />
a-vessieres@chimie-paristech.fr<br />
Pr<strong>of</strong>. Dr. Yoshihito Watanabe<br />
Nagoya University, Japan<br />
yoshi@nucc.cc.nagoya-u.ac.jp<br />
Pr<strong>of</strong>. Dr. Wolfgang Weigand<br />
<strong>Universität</strong> Jena, Germany<br />
wolfgang.weigand@uni-jena.de<br />
Alexander Wilbuer<br />
<strong>Universität</strong> Marburg, Germany<br />
wilbuer@chemie.uni-marburg.de<br />
Dr. Dirk Wolters<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
dirk.wolters@rub.de<br />
155
ISBOMC `10 5.7 – 9.7. 2010 <strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong><br />
Pr<strong>of</strong>. Dr. Stefan Wölfl<br />
<strong>Universität</strong> Heidelberg, Germany<br />
wolfl@uni-hd.de<br />
Dr. Teck Tian Wong<br />
Nanyang Techological University, Singapore<br />
nhswtt@nus.edu.sg<br />
Dr. Yaw-Kai Yan<br />
Nanyang Techological University, Singapore<br />
yawkai.yan@nie.edu.sg<br />
Pr<strong>of</strong>. Dr. Shyh-Chyun Yang<br />
Kaohsiung Medical University, Taiwan<br />
scyang@kmu.edu.tw<br />
Dina Yegorova<br />
Ukrainian State Chemical Technology University, Ukraine<br />
dino4ka_ego@ukr.net<br />
Kateryna Zablotska<br />
Ukrainian State Chemical Technology University, Ukraine<br />
pragma8@i.ua<br />
Johannes Zagermann<br />
<strong>Ruhr</strong>-<strong>Universität</strong> <strong>Bochum</strong>, Germany<br />
johannes.zagermann@rub.de<br />
Dr. Mohammad Ali Zazouli<br />
Iran<br />
zazoli49@yahoo.com<br />
Pr<strong>of</strong>. Dr. Ibrahim Zeid<br />
Monoufia University, Egypt<br />
ifzeid@hotmail.co.uk<br />
Macolm Zimbron<br />
<strong>Universität</strong> Basel, Switzerland<br />
malcolm.zimbron@unibas.ch<br />
Dr. Fabio Zobi<br />
Univerität Zürich, Switzerland<br />
fzobi@aci.uzh.ch<br />
156