Loss of ammine from platinum(II) complexes: Implications for cisplatin inactivation, storage, and resistance
Loss of ammine from platinum(II) complexes: Implications for cisplatin inactivation, storage, and resistance
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DOI：
10.1002/chem.200401053
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发表时间：
2005-04-22
影响因子：
4.3
通讯作者：
Deubel, DV
中科院分区：
文献类型：
--
作者：
Lau, JKC;Deubel, DV
用密度泛函理论和连续介质介电模型相结合的方法研究了抗癌药物顺铂与细胞内各种生物分子结合的潜在后果。由于在形成最常见的DNA加合物时，胺配体仍然配位在金属上，而在药物代谢产物形成时，它们被发现从金属上移位，因此我们分析了影响铂(II)络合物中胺损失的因素，作为顺铂失活的可能途径。计算系统地揭示了1)反式配体，2)络合物电荷，3)亲核试剂，4)环境对铂-胺键热力学不稳定性和动力学不稳定性的影响。顺铂的水解物最初与硫醚或硫醇结合后，预计主要的反应将是硫配体上的胺的损失，而不是硫配体本身被其他亲核试剂如鸟嘌呤-N7取代。这项研究的结果有助于理解顺铂在DNA结合之前的失活模式，例如，顺铂耐药癌细胞中谷胱甘肽水平的升高。
Potential consequences of the binding of the anticancer drug cisplatin to various biomolecules in the cell have been investigated by using a combined density functional theory and continuum dielectric model approach. Since the ammine ligands remain coordinated at the metal upon formation of the most frequent DNA adducts, whereas they were found to be displaced from the metal upon formation of drug metabolites, we have analyzed the factors governing ammine loss from platinum(ii) complexes as a possible pathway of cisplatin inactivation. The calculations systematically show the effect of 1) the trans ligand, 2) the charge of complex, 3) the nucleophile, and 4) the environment on the thermodynamic instability and kinetic lability of the platinum-ammine bonds. After initial binding of cisplatin hydrolysis products to thioethers or thiols, loss of the ammine trans to this sulfur ligand rather than replacement of the sulfur ligand itself by other nucleophiles like guanine-N7 is predicted to be the predominant reaction. The results of this study contribute to an understanding of the modes of cisplatin inactivation prior to DNA binding, for example, by elevated glutathione levels in cisplatin -resistant cancer cells.