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首页> 外文期刊>Molecular pharmacology. >A three-dimensional quantitative structure-activity relationship study of the inhibition of the ATPase activity and the strand passing catalytic activity of topoisomerase IIalpha by substituted purine analogs.
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A three-dimensional quantitative structure-activity relationship study of the inhibition of the ATPase activity and the strand passing catalytic activity of topoisomerase IIalpha by substituted purine analogs.

机译：三维三维定量构效关系研究取代的嘌呤类似物对ATP酶活性的抑制和拓扑异构酶IIα的链传递催化活性。

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摘要

Based on the topoisomerase IIalpha catalytic inhibitory activity of a previous hit compound, NSC35866, we screened 40 substituted purines or purine-like compounds from the National Cancer Institute repository for their ability to inhibit the ATPase activity of human topoisomerase IIalpha. Several compounds, including NSC348400, NSC348401 and NSC348402, were inhibitory at submicromolar concentrations. Three-dimensional quantitative structure-activity relationship models using comparative molecular field and comparative molecular similarity indices analyses were constructed using 24 of these compounds. The ability of 10 selected compounds to inhibit the complete DNA strand passage reaction of topoisomerase IIalpha correlated well with their potency as ATPase inhibitors. None of the 40 compounds significantly increased levels of the topoisomerase IIalpha-DNA covalent complex, suggesting that they functioned as catalytic topoisomerase II inhibitors and not as topoisomerase II poisons. Although some of these compounds could antagonize the effect of etoposide on the level of topoisomerase IIalpha-DNA covalent complex formation in vitro, in contrast to NSC35866, they were not capable of antagonizing etoposide-induced cytotoxicity and DNA strand breaks in cells. Two independently selected human SCLC cell lines with reduced topoisomerase IIalpha expression displayed cross-resistance to NSC348400, NBSC348401, and NSC348402, whereas an MDR1 line was fully sensitive. These results suggest that topoisomerase IIalpha is a functional cellular target for most of these substituted purine compounds and that these compounds do not display MDR1 liability.
机译：基于先前的热门化合物NSC35866的拓扑异构酶IIalpha催化抑制活性，我们从美国国家癌症研究所库中筛选了40种取代的嘌呤或嘌呤样化合物抑制人拓扑异构酶IIalpha ATPase活性的能力。包括NSC348400，NSC348401和NSC348402在内的几种化合物在亚微摩尔浓度下均具有抑制作用。使用这些化合物中的24种，建立了使用比较分子场和比较分子相似性指数分析的三维定量构效关系模型。 10种选定化合物抑制拓扑异构酶IIalpha的完整DNA链通过反应的能力与其作为ATPase抑制剂的能力密切相关。 40种化合物中没有一种能显着增加拓扑异构酶IIalpha-DNA共价复合物的水平，表明它们起催化拓扑异构酶II抑制剂的作用，而不作为拓扑异构酶II的毒物。尽管这些化合物中的某些可以在体外拮抗依托泊苷对拓扑异构酶IIα-DNA共价复合物形成水平的影响，但与NSC35866相比，它们无法拮抗依托泊苷诱导的细胞毒性和细胞DNA链断裂。拓扑异构酶IIalpha表达降低的两个独立选择的人SCLC细胞系显示出对NSC348400，NBSC348401和NSC348402的交叉耐药性，而MDR1系完全敏感。这些结果表明拓扑异构酶IIalpha是大多数这些取代的嘌呤化合物的功能性细胞靶标，并且这些化合物不显示MDR1责任。

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