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

Pt（III）和Pt（IV）络合物对DNA损伤的这项研究的合作是基于两个小组的互补专业知识：Pt络合物的制备（B. Lippert，多特蒙德）和鸟嘌呤氧化机制（B. Meunier，图卢兹）。尽管它的成功，抗肿瘤药物顺铂，顺-[PtCl 2（NH3）2]，有几个缺点，包括严重的毒性，静脉给药和肿瘤抗性。一些Pt（IV）化合物与顺铂缺乏交叉耐药性，以及例如JM 216，cis，trans，cis[Pt（IV）（NH3）（C6 H11 NH 2）（OCOCH 3）2Cl 2]是口服活性药物的事实，最近重新引发了对Pt（IV）化合物作为抗癌剂的兴趣。近年来有许多研究涉及金属与模型核碱基、核苷、核苷酸甚至DNA结合如何导致核碱基的氧化转化的问题。其中鸟嘌呤是最易氧化的。在本项目中，将制备几种氧化还原活性双铂（III）或铂（IV）络合物，并将在寡核苷酸DNA模型上进行测试，以表征Pt-DNA加合物以及氧化鸟嘌呤碱基（如有）的性质。该提案的主要主题是更好地理解Pt（IV）和Pt（III）配位化合物如何与DNA反应。这是当今医学和生物无机化学的一个重大挑战。预期的结果是确定Pt（IV）或Pt（III）配合物的DNA损伤机制，这将有助于新的抗肿瘤化合物的合理设计。

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.