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首页> 外文期刊>Chemistry: A European journal >Loss of ammine from platinum(II) complexes: Implications for cisplatin inactivation, storage, and resistance
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Loss of ammine from platinum(II) complexes: Implications for cisplatin inactivation, storage, and resistance

机译：铂（II）配合物的胺损失：对顺铂失活，储存和耐药性的影响。

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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.
机译：通过使用组合的密度泛函理论和连续介电模型方法，已经研究了抗癌药顺铂与细胞中各种生物分子结合的潜在后果。由于氨基配体在形成最常见的DNA加合物时在金属上保持配位，而在药物代谢物形成时却被金属置换，因此我们分析了从铂（ii）配合物中脱除氨的因素。顺铂失活的可能途径。计算系统地显示了1）反式配体，2）配合物的电荷，3）亲核体和4）环境对铂-氨基键的热力学不稳定性和动力学稳定性的影响。在将顺铂水解产物与硫醚或硫醇初始结合后，氨的反式损失会转移至该硫配体，而不是被其他亲核试剂（如鸟嘌呤-N7）取代硫配体本身，这是主要的反应。这项研究的结果有助于理解DNA结合之前顺铂失活的方式，例如，通过提高顺铂耐药性癌细胞中的谷胱甘肽水平。

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