ISBN: 978-83-60043-10-3 - eurobic9

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Eurobic9, 2-6 September, 2008, Wrocław, Poland P209. Cytotoxicity, Cellular Uptake and DNA Binding Mode of a New Dinuclear Platinum(II) Complex L. Zerzankova a , J. Kasparkova a , N.P. Farrell b , V. Brabec a a Institute of Biophysics ASCR, v.v.i., Kralovopolska 135, CZ-612 65, Brno, Czech Republic e-mail: zerzankova@ibp.cz b Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Virginia-232 84, Richmond, United States One concept of designing new platinum drugs is based on the observation that carrier amine ligands of cisplatin can modulate its anticancer properties. This concept has resulted in a new structural analog of cisplatin - oxaliplatin that is currently used in the clinic. Another series of antitumor platinum compounds is based on polynuclear geometry. From this large family, the sub-class [{PtCl(NH3)2}2µ-(H2N-Y-NH2)] n+ , where the bridging linker contains a diamine, polyamine or a third coordination sphere, was chosen for clinical development. We examined the biological properties of novel dinuclear Pt II complex BBR3610-DACH (figure 1). In this compound, the structural features of two classes of the platinum compounds with proven antitumor activity are combined, namely DACH carrier ligands and polynuclear platinum geometry with a polyamine linker. DNA binding mode of this new complex was analyzed by biophysical and biochemical methods. These modifications have been compared with the cytotoxicity and mutagenicity of this new complex in several tumor cell lines, cellular uptake and inhibition of DNA synthesis. The results show that the new complex coordinates DNA in a unique way, different from that of mononuclear analog as well as from that of dinuclear spermine complex. These results are also consistent with the observation that the new dinuclear complex shows different biological properties in human tumor cell lines. _____________________________________________________________________ 328
Eurobic9, 2-6 September, 2008, Wrocław, Poland P210. Interaction of Cap43 Protein Fragment with Ni(II) and Cu(II) Ions M.A. Zoroddu a , M. Peana a , and S. Medici a , T. Kowalik-Jankowska b , H. Kozłowski b a Department of Chemistry, University of Sassari, Via Vienna 2, 07100, Sassari, Italy e-mail: zoroddu@uniss.it b Faculty of Chemistry, University of Wrocław, 14 Joliot-Curie, 50-383 Wrocław, Poland One of the research topics in our group is protein Cap 43, which seems directly related to the cellular response after nickel exposure, [1, 2] as well as to a number of cancers.[1, 3] The studies we carried out for several years started from a small peptide model of Cap 43 and were successively expanded to include a two- (TRSRSHTSEG-TRSRSHTSEG) and a three-repeated (TRSRSHTSEG-TRSRSHTSEG-TRSRSHTSEG) monohistidinic decapeptide fragment in its C-terminus.[4-6] Such 20- and 30-amino acid sequences were tested for Ni(II)- and Cu(II)- coordination at different pH values, by both potentiometry and spectroscopic techniques (NMR, EPR, UV-Vis, CD). The two metals showed a slightly different behaviour towards coordination, and the interaction of Cu(II) ions with the two peptides started at pH values lower than those for Ni(II). What appeared clear was that in both cases each 10-amino acid fragment TRSRSHTSEG was able to coordinate a single metal ion to form a square planar 4N {4N} chromophore. The coordination mode involved an imidazole nitrogen from the His residue, and the amidic nitrogens from His, Ser, and Arg. At high pH values, further deprotonations were observed for the Cu(II) species. References: [1] D. Zhou, K. Salnikow, M. Costa; Cancer Res., 58, 2182 (1998) [2] K. Salnikow, D. Zhou, T. Kluz, C. Wang, M. Costa, in: Metal and Genetics, (Sarkar Bed), New York, 131 (1999) [3] K. Salnikow, T. Kluz, M. Costa, Toxicol. Appl. Pharmacol., 160, 127 (1999) [4] M.A. Zoroddu, T. Kowalik-Jankowska, H. Kozlowski, K. Salnikow, M. Costa, J. Inorg. Biochem., 84, 47 (2001) [5] M.A. Zoroddu, M. Peana, T. Kowalik-Jankowska, H. Kozlowski, M. Costa, J. Chem. Soc. Dalton Trans., 458 (2002) [6] M.A. Zoroddu, M. Peana, T. Kowalik-Jankowska, H. Kozlowski, M. Costa, J. Inorg Biochem., 98, 931 (2004) _____________________________________________________________________ 329
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ISBN: 978-83-60043-10-3 - eurobic9

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