Book of Abstracts - Ruhr-Universität Bochum
Book of Abstracts - Ruhr-Universität Bochum Book of Abstracts - Ruhr-Universität Bochum
P-81 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Apoptosis induction and cytotoxicity by metalbased drugs: lights and shadows of DNA Gianni Sava a,b and Alberta Bergamo b a University of Trieste, Department of Life Sciences, via L. Giorgieri 7, 34127, Trieste, Italy. b Callerio Foundation Onlus, via A. Fleming 22-31, 34127, Trieste, Italy. E-mail: gsava@units.it Cisplatin is a well known DNA-damaging agent and the current thinking is that DNA platination (DNA-adduct formation) is an essential first step in the cytotoxic activity of the drug. Information about the chemistry of the platinum compounds and correlations of their structures with anticancer activity have provided guidance for the design of novel anticancer drug candidates based on the proposed mechanisms of action. 1 The question is: DNA-adduct formation guided synthesis of metalbased anticancer drugs is a real concept or a misleading interpretation? The mechanism(s) whereby the DNA adducts kill cells is not fully understood. One potentially important way by which cisplatin- DNA adducts may kill cells is by induction of programmed cell death or apoptosis (Figure 1). 2,3 From: to: Figure 1. types of DNA adduct formation of platinum drugs: (a) interstrand cross-link, (b) 1,2intrastrand cross-link, (c) 1,3-intrastrand crosslink, (d) protein-DNA cross-link (adapted from Lit. 2) However, these concepts are not sufficient to account for the particular effectiveness of the most important platinum drugs in cancer therapy where cisplatin and carboplatin (two drugs with a rather different chemistry) are active on the same tumours, oxaliplatin is active on colorectal tumours and satraplatin (the emerging oral platinum drug) is active on prostate cancer. None of these tumours were selected a priori as the targets for these drugs. Then, how focusing on the ligands that allow DNA binding or to get insensitivity to acquired resistance, may help researchers to understand what to take into consideration to design the expected more potent, more selective and less toxic new metal-based antitumour drugs? Apoptosis and cell death is not simply related to DNA binding properties as shown by the many biological and targeted drugs emerged in the last years which killed cells by apoptoptic mechanisms following interactions with protein components of important cellular pathways. Given that cisplatin and also many platinum drugs have a poor capacity to enter the nucleus compartment (in the case of cisplatin almost 99% of the cellular drug is in the cytoplasm) the focus should be directed on what are the final destinations of all these platinum molecules in this protein-rich compartment. As an example, interesting data are emerging on HSP90 block by cisplatin, a phenomenon that could account for many apoptotic cytotoxicities observed. This work was done in the framework of COST D39 – WG3. References 1. K.S. Lovejoy, S.J. Lippard, Dalton Trans. 2009, 48, 10651-10659. 2. A. Eastman: The mechanism of action of cisplatin: From adducts to apoptosis in: Cisplatin. Chemistry and Biochemistry of a Leading Anticancer Drug; B. Lippert, Ed.; Wiley-VCH: Basel, Switzerland, 1999, pp. 111–134. 3. R.C. Todd, S.J. Lippard, Metallomics 2010, 4, 280-291. 139
P-82 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Selective Recognition of Actinides by Protein-Based Reagents Salih Özçubukçu, a Seraphine V. Wegner, a Kalyaneswar Mandal, b Stephen B. H. Kent, b Mark P. Jensen, c and Chuan He *a a The University of Chicago, Department of Chemistry, 60637, Chicago, IL, USA. b The University of Chicago, Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, 60637, Chicago, IL, USA. c Argonne National Laboratory, Chemical Sciences and Engineering Division, 60439, IL, USA,. e-mail: chuanhe@uchicago.edu It is generally accepted that trivalent actinides prefer softer chelating atoms such as sulfur rather than oxygen; hence selective separation of trivalent actinides from trivalent lanthanides can be obtained by soft-donor ligands. Barbara Imperiali and her coworkers have developed a series of peptides, called lanthanide binding tag (LBT) which selectively binds lanthanide ions with high affinities 1 . This pre-organized ligand template provides an ideal system to study these long standing questions regarding separate trivalent actinides from trivalent lanthanides. Pre-organization of the ligands by the peptide scaffold provides high binding affinity. We can redesign these small peptides with nitrogen- and sulfur- based ligands to provide selectivity. We plan to systematically screen ligand types and geometries to achieve selective binding of actinides over lanthanides (Figure 1). References 1. M. Nitz, M. Sherawat, K. J. Franz, E. Peisach, K. N. Allen, B. Imperiali, Angew. Chem. Int. Ed. 2004, 43, 3682-3685. 140
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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
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