DNA minor groove binding-directed poisoning of human DNA topoisomerase I by terbenzimidazoles

Zhitao Xu, Tsai Kun Li, Jung Sun Kim, Edmond J. LaVoie, Kenneth J. Breslauer, Leroy-Fong Liu, Daniel S. Pilch

研究成果: 雜誌貢獻文章同行評審

39 引文 斯高帕斯(Scopus)

摘要

We have employed a broad range of spectroscopic, calorimetric, DNA cleavage, and DNA winding/unwinding measurements to characterize the DNA binding and topoisomerase I (TOP1) poisoning properties of three terbenzimidazole analogues, 5-phenylterbenzimidazole (5PTB), terbenzimidazole (TB), and 5-(naphthyl[2,3-d]imidazo-2-yl)bibenzimidazole (5NIBB), which differ with respect to the substitutions at their C5 and/or C6 positions. Our results reveal the following significant features. (i) The overall extent to which the three terbenzimidazole analogues poison human TOP1 follows the hierarchy 5PTB > TB >> 5NIBB. (ii) The impact of the three terbenzimidazole analogues on the superhelical state of plasmid DNA depends on the [total ligand] to [base pair] ratio (r(bp)), having no effect on DNA superhelicity at r(bp) ratios ≤0.1, while weakly unwinding DNA at r(bp) ratios > 0.1. This weak DNA unwinding activity exhibited by the three terbenzimidazoles does not appear to be correlated with the abilities of these compounds to poison TOP1. (iii) Upon complexation with both poly(dA) · poly(dT) and salmon testes DNA, the three terbenzimidazole analogues exhibit flow linear dichroism properties characteristic of a minor groove-directed mode of binding to these host DNA duplexes. (iv) The apparent minor groove binding affinities of the three terbenzimidazole analogues for the d(GA4T4C)2 duplex follow a qualitatively similar hierarchy to that noted above for ligand-induced poisoning of human TOP1-namely, 5PTB > TB > 5NIBB. In the aggregate, our results suggest that DNA minor groove binding, but not DNA unwinding, is important in the poisoning of TOP1 by terbenzimidazoles.

原文英語
頁(從 - 到)3558-3566
頁數9
期刊Biochemistry
37
發行號10
DOIs
出版狀態已發佈 - 三月 10 1998
對外發佈Yes

ASJC Scopus subject areas

  • Biochemistry

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