拓扑异构酶
喜树碱
DNA超螺旋
DNA
劈理(地质)
酶
立体化学
化学
生物化学
作用机理
结合位点
生物
体外
DNA复制
断裂(地质)
古生物学
作者
Christine Jaxel,Kurt W. Kohn,Mansukh C. Wani,Monroe E. Wall,Yves Pommier
出处
期刊:PubMed
日期:1989-03-15
卷期号:49 (6): 1465-9
被引量:444
摘要
Twenty-two compounds related to camptothecin, a known inhibitor of eukaryotic topoisomerase I, were studied. The following effects on the actions of topoisomerase I were observed and were well correlated among most of the compounds studied: (a) inhibition of the first-order rate of relaxation of supercoiled DNA; (b) conversion of supercoiled DNA to nicked circles; and (c) single-strand cleavage of linear DNA at specific sites. The locations of the stimulated cleavage sites were the same for all of the active derivatives. Stereochemistry and the positions of substituents were found to be crucial for the presence or absence of effects on topoisomerase I, indicating that the compounds interact with an asymmetrical receptor site on the enzyme or enzyme-DNA complex. From the structure-activity relations, the regions of interaction between the camptothecin ring system and the receptor site were inferred. Striking correlations were observed between activity against topoisomerase I and reported activity against murine leukemias, indicating that an action on topoisomerase I is responsible for the antitumor activity of the camptothecins.
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