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首页> 外文期刊>Biochemistry >DNA minor groove binding-directed poisoning of human DNA topoisomerase I by terbenzimidazoles
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DNA minor groove binding-directed poisoning of human DNA topoisomerase I by terbenzimidazoles

机译：苯并咪唑类化合物对人DNA拓扑异构酶I的DNA小沟结合定向中毒

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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 much greater than 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 less than or equal to 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(GA(4)T(4)C)(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. [References: 44]
机译：我们已经使用了广泛的光谱，量热，DNA裂解和DNA缠绕/展开测量来表征3种苯并咪唑类似物，5-苯并苯并咪唑（5PTB），苯并咪唑（TB），和5-（萘[2，3-d]咪唑-2-基）联苯并咪唑（5NIBB），其在C5和/或C6位的取代不同。我们的结果揭示了以下重要特征。 （i）三种苯并咪唑类似物对人TOP1的中毒总体程度遵循5PTB> TB，远大于5NIBB。 （ii）三种苯并咪唑类似物对质粒DNA超螺旋状态的影响取决于[总配体]与[碱基对]之比（r（bp）），而对r（bp）之比的DNA超螺旋性影响较小大于或等于0.1，而以r（bp）比率> 0.1弱解散DNA。三种苯并咪唑显示出的这种弱的DNA解旋活性似乎与这些化合物毒性TOP1的能力无关。 （iii）与聚（dA），聚（dT）和鲑鱼睾丸DNA复合后，三种特苯并咪唑类似物表现出流动线性二色性，其特征是与这些宿主DNA双链体结合的小沟定向模式。 （iv）d（GA（4）T（4）C）（2）双链体的三种Terbenzimidazole类似物的明显小沟结合亲和力遵循与上述配体诱导的人TOP1-中毒的定性相似的层次即5PTB> TB> 5NIBB。总的来说，我们的结果表明，DNA小沟结合，而不是DNA展开，在苯并咪唑对TOP1的中毒中很重要。 [参考：44]

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