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

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Eurobic9, 2-6 September, 2008, Wrocław, Poland P105. Structural Studies of Copper(II) Binding to the Novel Peptidyl Derivative of Quinoxaline: N-(3-(2, 3-di(pyridin-2-yl)quinoxalin-6yl)alanyl)glycine M. Kucharczyk a , W. Szczepanik a , P. Młynarz b , N. D’Amelio c , A. Staszewska a , P. Stefanowicz a , Z. Szewczuk a , A. Olbert-Majkut a and M. Jeżowska-Bojczuk a a Faculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland e-mail: marzenak@eto.wchuwr.pl b Faculty of Chemistry, Wrocław University of Technology, Wyspiańskiego 27, 50-373 Wrocław, Poland c Department of Chemistry, University of Siena, Via Aldo Moro, 53100 Siena, Italy Studies of interactions between organic compounds and DNA, especially the characteristics of structural aspects of DNA interaction with small molecules, are of particular interest as they can result in effective in highly targeted therapeutic applications. It may be expected that peptides conjugated with quinoxaline analogs may deliver novel probes of DNA structure and may help to design new DNA targeting agents. Attachment of the peptidic chain to the substance of potential biological activity may enable its cellular recognition and subsequent transport. Transition metal complexes capable of cleaving DNA are of importance for their potential use as new structural probes in nucleic acids chemistry and as therapeutic agents. They also can be used to studies of the polymorphic nature of nucleic acid conformation. In this context, several metal ions were tested for their ability to form stable complexes with 2, 3-di(pyridin-2-yl)quinoxaline. Cupric complexes appeared efficient to generate oxidative nicks within DNA [1], while the species that contained platinum [2], palladium [3] and ruthenium ions [4] focused attention as highly effective metal chelators that may show significant chemotherapeutic activity. Our previous study on the DNA cleavage in the presence of the copper(II) and iron(II) complexes of N-(3-(2, 3di(pyridin-2-yl)quinoxalin-6-yl)alanyl)glycine (DPQa-Gly) showed that this ligand may greatly enhance the yield of DNA degradation by metal ions, especially copper(II) [5]. N H 2 _____________________________________________________________________ 224 O N NH Herein we report the coordination characteristics of the Cu(II)-DPQa-Gly system. By means of potentiometric titrations, NMR, EPR, CD and UV-Vis spectroscopic methods, mass spectrometry as well as molecular modeling it was resolved, which residue in the studied substance possesses stronger chelating properties: 2, 3di(pyridin-2-yl)quinoxaline or Ala-Gly dipeptides. Acknowledgement: This work is financially supported by the Polish State Committee for Scientific Research (KBN), grant no. N N204 1616 33. N N N COOH References: [1] B.K. Santra, P.A.N. Reddy, G. Neelakanta, S. Mahadevan, M. Nethaji, A.R.J. Chakravarty, J. Inorg. Biochem. 89, 191 (2002) [2] J. Granifo, M.E. Vargas, M.T. Garland, R. Baggio, Inorg. Chim. Acta 305, 143 (2000) [3] J. Granifo, M.T. Garland, R. Baggio, Inorg. Chim. Acta 348, 263 (2003) [4] R.L. Williams, H.N. Toft, B. Winkel, K.J. Brewer, Inorg. Chem. 42, 4394 (2003) [5] W. Szczepanik, M. Kucharczyk, A. Staszewska, P. Stefanowicz, Z. Szewczuk, J. Skała, A. Mysiak, M. Jeżowska-Bojczuk, submitted
Eurobic9, 2-6 September, 2008, Wrocław, Poland P106. In Silico Approaching to Cisplatin Toxicity Quantum Chemical Studies on Platinum(II) – Cysteine Systems J. Kuduk-Jaworska a , I. Jaroszewicz a , J. Jański a , H. Chojnacki b a Faculty of Chemistry Wroclaw University, F. Joliot-Curie 14, 50-383 Wroclaw, Poland b Institute of Physical and Theoretical Chemistry, Wrocław University of Technology, Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland The differences in therapeutic ability of antitumor drug cisplatin (cis- diamminedichloroplatinum(II)) and its trans-isomer, are still intriguing for investigators who would like to learn in more detail about the molecular bases of such behavior [1]. It is well documented that cisplatin has high antitumor activity and strong toxicity, especially towards kidneys, whereas the trans isomer is therapeutically inefficient and non nephrotoxic. However, the studies on mechanisms of biological activity of both isomers, performed so far, were focused on interaction of platinum(II) complexes with DNA as critical target molecule. The problems of cisplatin and its congeners toxicity, though clinically very important, were far less studied [1]. Similar preferences can be observed in theoretical approaches [2]. Contrary to this tendency, our interest has been concentrated on the toxicity of cisplatin in comparison with nontoxicity of its trans isomer. Therefore we evaluated the reactions responsible for harmful biological effects, and consequently, the impact of platinum(II) complexes on molecules containing sulphur donors became the object of the presented study. Our approach relied on applying quantum chemical in silico methodology for the evaluation of "platinum(II) - cysteine" and its model systems. There were investigated the following systems: (1) a/cisplatin (b/transplatin) with CH3SH; (2) a/cisplatin (b/transplatin) with cysteine. The electronic structure for molecular systems has been studied at non-empirical all-electron level by using density functional (DFT) or Moeller-Plesset (MP2) methods within the correlation consistent cc-pVTZ [3] basis set. In the case of platinum the widest Huzinaga basis set with polarization functions has been used. In order to avoid the long optimization process, at the first stage, the optimization was performed at the all-valence MOPAC-PM6 method [4] following the B3LYP density functional or MP2 formalism [5] in the next step. The B3LYP [6] density functional was applied using GAUSSIAN-03 program package [7]. Acknowledgements: The numerical calculations have been performed in part at Wrocław Networking and Supercomputing Center. Wrocław University of Technology support is also acknowledged. References: [1] Reedijk, J.; Tauben, J. M. in: Cisplatin. Chemistry and Biochemistry of a Leading Anticancer Drug, Lippert, B. (Ed.), Wiley-WCH, 1999, 339-362. [2] Kozelka, J.; ibid, 537-556. [3] Huzinaga, S.; (Ed.), Gaussian Basis Sets for Molecular Calculations, Elsevier, Amsterdam 1984. [4] . [5] Szabó, A.; Ostlund, N.S. Modern Quantum Chemistry, Dover, Mineola 1996. [6] Becke, A.D.; J Chem Phys, 1993, 98, 5648- 5653. [7] GAUSSIAN-03, Rev. D-01, Pople, J.A. Gaussian Inc., Pittsburgh, PA, 2004. _____________________________________________________________________ 225
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ISBN: 978-83-60043-10-3 - eurobic9

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