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首页> 外文期刊>Biochemistry >DNA binding mode of the cis and trans geometries of new antitumor nonclassical platinum complexes containing piperidine, piperazine, or 4-picoline ligand in cell-free media. Relations to their activity in cancer cell lines.
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DNA binding mode of the cis and trans geometries of new antitumor nonclassical platinum complexes containing piperidine, piperazine, or 4-picoline ligand in cell-free media. Relations to their activity in cancer cell lines.

机译：在无细胞培养基中含有哌啶，哌嗪或4-甲基吡啶配体的新型抗肿瘤非经典铂络合物的顺式和反式几何结构的DNA结合模式。与它们在癌细胞系中活性的关系。

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摘要

The global modification of mammalian and plasmid DNAs by novel platinum compounds, cis- or trans-[PtCl(2)(NH(3))(Am)], where Am = NH(3), nonplanar heterocycle piperidine, piperazine, or aromatic planar heterocycle 4-picoline, was investigated in cell-free media using various biochemical and biophysical methods. These modifications have been compared with the activity of these new compounds in several tumor cell lines including those resistant to antitumor cis-diamminedichloroplatinum(II) (cisplatin). The results show that the replacement of the NH(3) group in cisplatin by the heterocyclic ligands does not considerably affect the DNA binding mode of this drug. Cytotoxicity studies have revealed that the replacement lowers the activity of the platinum compound in both sensitive and resistant cell lines. It has been suggested that the reduced activity of these analogues of cisplatin is associated with some features of the damaged DNA and/or its cellular processing. Alternatively, the reduced activity of the analogues of cisplatin might also be due to the factors that do not operate directly at the level of the target DNA, such as intracellular platinum uptake. In contrast to the analogues of cisplatin, the replacement of one ammine group by the heterocyclic ligand in its clinically ineffective trans isomer (transplatin) results in a radical enhancement of its activity in tumor cell lines. Importantly, this replacement also markedly alters the DNA binding mode of transplatin. The results support the view that one strategy of how to activate the trans geometry in bifunctional platinum(II) compounds including circumvention of resistance to cisplatin may consist of a chemical modification of the ineffective transplatin that results in an increased stability of its intrastrand cross-links in double-helical DNA and/or in an increased efficiency to form interstrand cross-links.
机译：全球修饰的哺乳动物和质粒DNA的新型铂化合物，顺式或反式[PtCl（2）（NH（3））（Am）]，其中Am = NH（3），非平面杂环哌啶，哌嗪或芳香族使用各种生化和生物物理方法在无细胞培养基中研究了平面杂环4-甲基吡啶。这些修饰已与这些新化合物在几种肿瘤细胞系中的活性进行了比较，其中包括对抗肿瘤顺二氨二氯铂（II）（顺铂）具有抗性的细胞。结果表明，由杂环配体取代顺铂中的NH（3）基团不会显着影响该药物的DNA结合模式。细胞毒性研究表明，在敏感和耐药细胞系中，这种替代都会降低铂化合物的活性。已经提出，这些顺铂类似物的活性降低与受损DNA和/或其细胞加工的某些特征有关。或者，顺铂类似物活性降低也可能归因于不能直接在靶DNA水平上起作用的因素，例如细胞内铂的吸收。与顺铂类似物相反，临床上无效的反式异构体（transplatin）中的杂环基取代了一个氨基，导致其在肿瘤细胞系中的活性得到了根本性的增强。重要的是，这种替代也显着改变了反铂的DNA结合方式。结果支持以下观点：一种如何激活双功能铂（II）化合物中反式几何结构的策略（包括规避对顺铂的耐药性）可能包括无效的反铂的化学修饰，从而导致其链内交联的稳定性提高在双螺旋DNA中和/或以增加的效率形成链间交联。

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