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

Pt(IV) 和 Pt(III) 复合物造成的 DNA 损伤

• 批准号: 5380585
• 负责人: Professor Dr. Bernhard Lippert
• 金额: --
• 依托单位: Forschungsgebiet Anorganische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2007-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5380585?language=en
• 关键词: DNA; damage; Pt; IV; III

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.

PT（III）和PT（IV）复合物在这项DNA损伤研究上的合作是基于两组的互补专业知识：PT复合物的制备（B. Lippert，Dortmund）和鸟嘌呤氧化机制（B. Meunier，Toulouse）。尽管取得了成功，但抗肿瘤药物，顺铂，顺铂[PTCL2（NH3）2]，有几种缺点，包括严重毒性，静脉内给药和肿瘤耐药性。某些PT（IV）化合物缺乏与顺铂的交叉耐药性以及JM216，顺式，Trans，顺式，顺式[Pt（iv）（NH3）（C6H11NH2）（OCOCH3）2Cl2]（例如，最近对PT（IV）组合（IV）组合（IV）组合（IV）组合。近年来，已经进行了许多研究，该研究涉及金属与模型核苷酸酶，核苷，核苷酸甚至DNA的结合可能导致核碱基的氧化转化。其中，鸟嘌呤是最容易氧化的。在该项目中，将准备几种氧化还原活性外交（III）或PT（IV）复合物，并将测试在寡核苷酸DNA模型上，以表征PT-DNA加合物以及氧化鸟嘌呤碱基的性质。该提案的主要主题是更好地理解PT（IV）和PT​​（III）配位化合物与DNA的反应。如今，这代表了药用和生物无机化学的重大挑战。预期的结果是确定PT（IV）或PT（III）复合物的DNA损伤机理，这些机理应促进新抗肿瘤化合物的合理设计。