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首页> 外文OA文献 >Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme.
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Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme.

机译：具有对拓扑异构酶II活性的新型1-8桥联手性喹诺酮类药物：真核酶的立体特异性。

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摘要

A series of novel C-7 quinolyl-substituted enantiomers of ofloxacin were used to determine the stereospecificity of topoisomerase II for the C-11 methyl group in tricyclic quinolones. In all cases, the S isomer was the most active compound against the eukaryotic enzyme. It was approximately 2.2-fold more potent than the R isomer at inhibiting the overall catalytic activity of topoisomerase II (as monitored by DNA relaxation assays). A markedly greater difference in quinolone activity was observed in enzyme-mediated DNA cleavage reactions. While the S enantiomer stimulated nucleic acid breakage approximately 3.5-fold, the R compound did not enhance and, in fact, decreased initial DNA cleavage levels by approximately 50%. The activity of the racemic mixture more closely resembled that of the R enantiomer. In competition experiments, the DNA cleavage-enhancing effects of the S isomer were attenuated by the R compound. Taken together, these latter results indicate that the R enantiomer is an antagonist of S isomer-promoted topoisomerase II-mediated DNA cleavage. Finally, the cytotoxic potential of quinolyl-substituted ofloxacin analogs correlated with the ability to stimulate enzyme-mediated DNA cleavage. Thus, stereochemistry appears to be a governing factor for the potential development of tricyclic quinolones as topoisomerase II-targeted drugs with antineoplastic activity.
机译：氧氟沙星的一系列新颖的C-7喹啉基取代的对映体用于确定拓扑异构酶II对三环喹诺酮中C-11甲基的立体特异性。在所有情况下，S异构体都是针对真核酶活性最高的化合物。在抑制拓扑异构酶II的总体催化活性方面（通过DNA弛豫分析监测），其效力比R异构体高约2.2倍。在酶介导的DNA切割反应中观察到喹诺酮活性的显着更大差异。尽管S对映异构体刺激的核酸断裂约为3.5倍，但R化合物并未增强，实际上使初始DNA裂解水平降低了约50％。外消旋混合物的活性与R对映异构体的活性更相似。在竞争实验中，R化合物减弱了S异构体的DNA切割增强作用。两者合计，这些后面的结果表明，R对映异构体是S异构体促进的拓扑异构酶II介导的DNA切割的拮抗剂。最后，喹啉基取代的氧氟沙星类似物的细胞毒性潜力与刺激酶介导的DNA切割的能力有关。因此，立体化学似乎是三环喹诺酮类药物作为具有抗肿瘤活性的拓扑异构酶II靶向药物潜在发展的主导因素。

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