DNA damage by Pt(IV) and Pt(III) complexes

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The collaboration on this study of DNA damage by Pt(III) and Pt(IV) complexes is based on the complementary expertise of two groups: preparation of Pt complexes (B. Lippert, Dortmund) and mechanism of guanine oxidation (B. Meunier, Toulouse). Despite its success, the antitumoral drug, cisplatin, cis-[PtCl2(NH3)2], has several disadvantages that include severe toxicity, intravenous administration and tumor resistance. The lack of cross-resistance of some Pt(IV) compounds with cisplatin and the fact that JM216, cis,trans,cis[Pt(IV)(NH3)(C6H11NH2)(OCOCH3)2Cl2], for example, is an orally active drug have recently reinitiated the interest in Pt(IV) compounds as anticancer agents. There have been a number of studies in recent years dealing with the question of how metal binding to model nucleobases, nucleosides, nucleotides or even DNA might lead to oxidative transformations of nucleobases. Among them, guanine is the most oxidizable. In this project, several redox active diplatinum(III) or Pt(IV) complexes will be prepared and will be tested onto oligonucleotide DNA models to characterize the Pt-DNA adducts as well as the nature of the oxidized guanines bases if any. The main topic of this proposal is a better understanding of how Pt(IV) and Pt(III) coordination compounds react with DNA. This represents a major challenge of medicinal and bioinorganic chemistry these days. The expected result is the determination of the mechanism of DNA damage by Pt(IV) or Pt(III) complexes that should facilitate the rational design of new antitumoral compounds.