Department of Chemistry, Syracuse University, 111 College Place, CST, Rm 1-014, Syracuse, New York 13244-4100, USA.
J Inorg Biochem. 2012 Feb;107(1):6-14. doi: 10.1016/j.jinorgbio.2011.10.012. Epub 2011 Nov 3.
The antitumor effects of platinum(IV) complexes, considered prodrugs for cisplatin, are believed to be due to biological reduction of Pt(IV) to Pt(II), with the reduction products binding to DNA and other cellular targets. In this work we used pBR322 DNA to capture the products of reduction of oxoplatin, c,t,c-[PtCl(2)(OH)(2)(NH(3))(2)], 3, and a carboxylate-modified analog, c,t,c-[PtCl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)(NH(3))(2)], 4, by ascorbic acid (AsA) or glutathione (GSH). Since carbonate plays a significant role in the speciation of platinum complexes in solution, we also investigated the effects of carbonate on the reduction/DNA-binding process. In pH 7.4 buffer in the absence of carbonate, both 3 and 4 are reduced by AsA to cisplatin (confirmed using ((195))Pt NMR), which binds to and unwinds closed circular DNA in a manner consistent with the formation of the well-known 1, 2 intrastrand DNA crosslink. However, when GSH is used as the reducing agent for 3 and 4, ((195))Pt NMR shows that cisplatin is not produced in the reaction medium. Although the Pt(II) products bind to closed circular DNA, their effect on the mobility of Form I DNA is different from that produced by cisplatin. When physiological carbonate is present in the reduction medium, ((13))C NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-à-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed.
铂（IV）配合物的抗肿瘤作用被认为是顺铂前药，其作用机制被认为是生物还原 Pt(IV)为 Pt(II)，还原产物与 DNA 和其他细胞靶标结合。在这项工作中，我们使用 pBR322 DNA 来捕获 oxoplatin（c,t,c-[PtCl(2)(OH)(2)(NH(3))(2)]）、3 和羧酸酯修饰类似物 c,t,c-[PtCl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)(NH(3))(2)]、4 被抗坏血酸（AsA）或谷胱甘肽（GSH）还原的产物。由于碳酸盐在铂配合物在溶液中的形态中起着重要作用，我们还研究了碳酸盐对还原/DNA 结合过程的影响。在无碳酸盐的 pH 7.4 缓冲液中，3 和 4 均被 AsA 还原为顺铂（使用 ((195))Pt NMR 证实），顺铂与闭合环形 DNA 结合并使其解旋，其方式与形成众所周知的 1,2 内链 DNA 交联一致。然而，当 GSH 用作 3 和 4 的还原剂时，((195))Pt NMR 表明反应介质中未生成顺铂。尽管 Pt(II)产物与闭合环形 DNA 结合，但它们对 I 型 DNA 迁移率的影响与顺铂不同。当生理碳酸盐存在于还原介质中时，((13))C NMR 表明形成了 Pt(II)碳酸酯配合物，这些配合物阻止或阻碍铂与 DNA 的结合。讨论了这些研究结果与铂（IV）配合物作为顺铂前药的能力。
