Inhibition of Topoisomerase I Function by Coralyne and 5,6-Dihydrocoralyne

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• 作者：Li-Kai Wang ; Brian D. Rogers ; and Sidney M. Hecht
• 刊名：Chemical Research in Toxicology
• 出版年：1996
• 出版时间：January 1996
• 年：1996
• 卷：9
• 期：1
• 页码：75 - 83
• 全文大小：433K
• 年卷期：v.9,no.1(January 1996)
• ISSN：1520-5010

文摘

The antitumor agent coralyne and a number of structural analogueswere found to beinhibitors of DNA topoisomerase I and were characterized biochemically.Several of theseanalogues stabilized the covalent binary complex formed between calfthymus topoisomeraseI and pSP64 plasmid DNA; coralyne and 5,6-dihydrocoralyne had thegreatest potency asinhibitors in this assay. In common with camptothecin, the effectsof coralyne and 5,6-dihydrocoralyne were reversed in the presence of increasing saltconcentration or temperature,consistent with the interpretation that both functioned mechanisticallyin a fashion analogousto camptothecin. The sequence specificity of DNA cleavage bycoralyne and 5,6-dihydrocoralynewas also studied in comparison with camptothecin using a 471-bp DNAduplex as a substratefor topoisomerase I. Seven sites of cleavage were apparent, fourof which were shared incommon by coralyne, 5,6-dihydrocoralyne and camptothecin. Coralyneand 5,6-dihydrocoralyneproduced cleavage at one sequence, 5'-TCTCGTAA-3',that was not apparent in the presenceof camptothecin; correspondingly, two cleavage bands appeared only whencamptothecin waspresent. Coralyne and 5,6-dihydrocoralyne also inhibitedtopoisomerase I-mediated relaxationof supercoiled plasmid DNA. Coralyne was the most potent inhibitorof DNA relaxation; theeffects of camptothecin and 5,6-dihydrocoralyne were roughly equal.At high concentrations,coralyne completely suppressed the formation of the topoisomeraseI-DNA covalent binarycomplex.