Book of Abstracts - Ruhr-Universität Bochum
Book of Abstracts - Ruhr-Universität Bochum Book of Abstracts - Ruhr-Universität Bochum
P-51 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum The Synthesis and Characterization of Aqueous and Organic Soluble, Acid Selective Cytotoxic Ruthenium Anticancer Compounds Paul J. Dyson, a Olivier Zava, a David J. Kavanagh, b and Andrew D. Phillips* b a Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Sciences et Ingénierie Chimiques, CH-1015, Lausanne, Switzerland. b University College Dublin, School of Chemistry and Chemical Biology, Belfield, Dublin 4 , Ireland.E-mail: andrew.phillips@ucd.ie From the serendipitous discovery of cisplatin as an anticancer agent by Rosenberg in 1965, 1 there has been considerable interest in the field of metallopharmaceuticals. Currently only two further platinum complexes have received worldwide application in cancer treatment, Oxaliplatin and Carboplatin. Recently, organometallic ruthenium complexes have attracted greater attention as potential antitumour reagents 2-4 and systems featuring oxidation states of +2 and +3 have entered clinical trials. 5 These Ru compounds (i and ii) are relatively non-toxic in comparison to platinum compounds and the mode of inducing apoptosis differs significantly from cisplatin. Therefore, Ru-based pharmaceuticals offer valuable alternatives that may overcome Pt resistant tumours and alleviate problematic sideeffects observed with other chemotherapeutic drugs. This project focuses on the synthesis of water soluble, selective and adaptable ruthenium(II) complexes (iii) employing a mixed ligand set that convey a number of useful properties important for metallo-pharmaceuticals. The oxygen-stable phosphine, PTA (1,3,5-triaza-7-phosphaadamantane) confers water solubility, while the � 5 -coordinated anionic C5H5 group provides the necessary lipophilicity for passive cell transport. Uniquely, the bidentate triazapentadienyl ligand allows for the ‘fine-tuning’ of hydrolysis behaviour by alternating the α-R groups and has proven more stable than the related Ru complexes (ii). Moreover, the triazapentadienyl ligand in compound iii imparts additional cytotoxicity as observed in previous work on similar � 6 -C6H6 Ru chloro β-diketiminates (iv). Finally, we will present our latest research which discusses the further adaption of complexes of type iv towards long term biological stability and increased cytotoxicity. References (i) (ii) (iii) (iv) 1. B. Rosenberg, L. Van Camp, T. Krigas. Nature. 1965, 205, 698. 2. P. J. Dyson, A. D. Phillips. Organometallics. 2009, 28, 5061. 3. B K. Keppler, K. Jakupec. Organometallics. 2008, 27, 2405. 4. G. Sava, P. J. Dyson,. Int. J. Oncology. 2008, 33, 1281. 5. (a) C. G. Hartinger, B. K. Keppler, J. Inorg. Biochem. 2006, 100, 891. (b) H. M. Schellens, J. M. Rademaker-Lakhai. Clin Cancer Res. 2004, 10, 3717. 6. A. D. Phillips, O. Zava, R. Scopelitti, A. A. Nazarov, P. J. Dyson. Organometallics. 2010, 29, 417. 109
P-52 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Encapsulation of Pyrenyl-Containing Dendrimers in Arene-Ruthenium Metalla-Prisms A. Pitto-Barry, a N. Barry, a R. Deschenaux, a* and B. Therrien a * a Université de Neuchâtel, Institut de chimie, 51 Ave de Bellevaux, 2000, Neuchâtel, Switzerland. E-mail: bruno.therrien@unine.ch Extravasation of macromolecules is considerably enhanced in tumor tissues. This phenomenon called “enhanced permeability and retention” (EPR) effect is believed to play a major role in selective delivery of nanomedicines. 1 Nanomedicines lead up to 100 times greater intratumor drug delivery efficacy to cancer cells as compared to healthy cells. 2 Nanomedicines include antibodies and polymeric drug but also large drug delivery vectors like micelles, nanoparticles and dendrimers. Among new large drug carriers, we recently proposed to use metalla-prisms built from areneruthenium units. 3 These water-soluble and cytotoxic metalla-assemblies offer many possibilities. On the other hand, we have been working on dendritic system incorporating lipophilic functionalized pyrenes. Encapsulation of the pyrenyl moiety in the hydrophobic cavity of the arene-ruthenium metalla-prism, with the dendritic part hanging out of the cage, generates a potential target seeking missile for cancer cells. The synthesis and characterization as well as the preliminary cytotoxicity studies are presented. References 1. Y. Matsumura, H. Maeda, Cancer Res. 1986, 46, 6387-6392. 2. H. Maeda, Adv Drug Deliv Rev. 2001, 46, 169-185. 3. B. Therrien, G. Süss-Fink, P. Govindaswamy, A. K. Renfrew, P. J. Dyson, Angew. Chem. Int. Ed. 2008, 47, 3773-3776. 110
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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
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