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首页> 外文期刊>Chemistry: A European journal >Unique properties of DNA interstrand cross-links of antitumor oxaliplatin and the effect of chirality of the carrier ligand
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Unique properties of DNA interstrand cross-links of antitumor oxaliplatin and the effect of chirality of the carrier ligand

机译：抗肿瘤奥沙利铂DNA链间交联的独特性质以及载体配体的手性影响

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摘要

The different antitumor and other biological effects of the third-generation antitumor platinum drug oxaliplatin [(1R,2R-diamminocyclohexane)oxalatoplatinum(II)] in comparison with those of conventional cisplatin [cis-diamminedichloridoplatinum(II)] are often explained by the ability of oxaliplatin to form DNA adducts of different conformation and consequently to exhibit different cytotoxic effects. This work describes, for the first time, the structural and biochemical characteristics of the interstrand cross-links of oxaliplatin. We find that: 1)DNA bending, unwinding, thermal destabilization, and delocalization of the conformational alteration induced by the cross-link of oxaliplatin are greater than those observed with the cross-link of cisplatin; 2) the affinity of high-mobility-group proteins (which are known to mediate the antitumor activity of platinum complexes) for the interstrand cross-links of oxaliplatin is markedly lower than for those of cisplatin; and 3) the chirality at the carrier 1,2-diaminocyclohexane ligand can affect some important structural properties of the interstrand cross-links of cisplatin analogues. Thus, the information contained in the present work is also useful for a better understanding of how the stereochemistry of the carrier amine ligands of cisplatin analogues can modulate their anticancer and mutagenic properties. The significance of this study is also reinforced by the fact that, in general, interstrand cross-links formed by various compounds of biological significance result in greater cytotoxicity than is expected for monofunctional adducts or other intrastrand DNA lesions. Therefore, we suggest that the unique properties of the interstrand cross-links of oxaliplatin are at least partly responsible for this drug's unique antitumor effects.
机译：第三代抗肿瘤铂药物奥沙利铂[（1R，2R-二氨基环己烷）草酰铂（II）]与常规顺铂[顺二氨二氯铂（II）]相比，具有不同的抗肿瘤和其他生物学作用。草酸铂的抗氧化剂形成不同构象的DNA加合物，因此表现出不同的细胞毒性作用。这项工作首次描述了奥沙利铂的链间交联的结构和生化特性。我们发现：1）由奥沙利铂交联引起的DNA弯曲，解旋，热不稳定和构象改变的离域作用大于顺铂交联引起的DNA改变; 2）高迁移率基团蛋白（已知可介导铂络合物的抗肿瘤活性）对奥沙利铂的链间交联的亲和力明显低于顺铂。 3）载体1,2-二氨基环己烷配体的手性会影响顺铂类似物的链间交联的一些重要结构性质。因此，本工作中包含的信息对于更好地理解顺铂类似物的载体胺配体的立体化学如何调节其抗癌和诱变特性也很有用。通常，由具有生物学意义的各种化合物形成的链间交联比单功能加合物或其他链内DNA损伤所预期的具有更大的细胞毒性，这一事实也增强了这项研究的意义。因此，我们建议奥沙利铂的链间交联的独特性质至少部分负责该药物的独特抗肿瘤作用。

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