Pt(IV) complexes as prodrugs for cisplatin
Pt(IV) complexes as prodrugs for cisplatin
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DOI：
10.1016/j.jinorgbio.2011.10.012
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发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Dabrowiak, James C.
中科院分区：
文献类型：
--
作者：
Shi, Yi;Liu, Shu-An;Dabrowiak, James C.
铂（IV）络合物（被认为是顺铂的前药）的抗肿瘤作用被认为是由于Pt（IV）生物还原为Pt（II），还原产物与DNA和其他细胞靶点结合。在这项工作中，我们使用pBR 322 DNA捕获抗坏血酸（阿萨）或谷胱甘肽（GSH）还原氧代铂的产物c，t，c-[PtCl 2（OH）（2）（NH 3）（2）]，3和羧酸修饰的类似物c，t，c-[PtCl 2（OH）（O2 CCH 2CH 2CO 2 H）（NH 3）（2）]，4。由于碳酸盐在溶液中铂络合物的形态中起着重要的作用，我们还研究了碳酸盐对还原/DNA结合过程的影响。在不存在碳酸盐的pH 7.4缓冲液中，3和4都被阿萨还原为顺铂（使用Pt-195 NMR证实），其以与形成公知的1，2链内DNA交联一致的方式结合并解旋闭合的环状DNA。然而，当GSH用作3和4的还原剂时，Pt-195 NMR显示在反应介质中不产生顺铂。虽然Pt（II）的产品结合到封闭的环状DNA，其对I型DNA的流动性的影响是不同的顺铂所产生的。当生理碳酸盐存在于还原介质中时，C-13 NMR显示形成了阻止或阻碍铂与DNA结合的Pt（II）碳酸根络合物。的研究结果，相对于一个，相对于Pt（IV）配合物作为顺铂的前药的能力进行了讨论。(C)2011 Elsevier Inc. All rights reserved.
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-[PtCl2(OH)(2)(NH3)(2)], 3, and a carboxylate-modified analog, c,t,c-[PtCl2(OH)(O2CCH2CH2CO2H)(NH3)(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 Pt-195 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, Pt-195 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, C-13 NMR shows that Pt(II) carbonato complexes form which block or impede platinum binding to DNA. The results of the study vis-a-vis the ability of the Pt(IV) complexes to act as prodrugs for cisplatin are discussed. (C) 2011 Elsevier Inc. All rights reserved.