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首页> 外文期刊>Anti-Cancer Drug Design >Relationships between topoisomerase II inhibition, sequence-specificity and DNA binding mode of dicationic diphenylfuran derivatives.
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Relationships between topoisomerase II inhibition, sequence-specificity and DNA binding mode of dicationic diphenylfuran derivatives.

机译：二磷酸呋喃衍生物的拓扑异构酶II抑制，序列特异性与DNA结合模式之间的关系。

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Four diphenylfuran derivatives possessing different dicationic terminal side chains were used to investigate sequence-specific binding to DNA and poisoning of human topoisomerase II. Footprinting experiments with a range of DNA substrates attest that all four drugs bind selectively to AT-rich sequences in DNA. However, the quantitative analysis of the footprinting profiles reveals significant differences in terms of AT-selectivity according to the nature of the basic side chains. Furimidazoline (DB60) shows a reduced capacity to interact selectively with A.T tetrads compared with furamidine (DB75) and the 3-pentyl-substituted diamidine analogue DB226. DB244, for which the two amidine ends are substituted with a cyclopentyl group, exhibits the most pronounced AT specificity. It binds tightly to sites composed of at least four adjacent AT base pairs, such as 5'-TAAT, AATT and TTTT. At low concentrations (< 2 microM) DB60 is also capable of forming stable complexes with AT sites but at higher concentrations the binding becomes totally non-specific due to additional intercalation of drug molecules into GC-rich sequences. Nevertheless, DB60 is the only drug is the series which stabilizes DNA-topoisomerase II covalent complexes. This compound effectively promotes DNA cleavage by topoisomerase II whereas DB75, DB226 and DB244 have practically no effect. The topoisomerase II poisoning activity of DB60 correlates with its ability to intercalate into GC sites in DNA whereas the three other diphenylfurans essentially behave as typical AT-selective minor groove binders. The study suggests that the antimicrobial activity of the diphenylfurans, which are active against the Pneumocystis carinii pathogen (PCP), depends essentially on their capacity to recognize AT-rich DNA sequences rather than their ability to interfere with topoisomerase II. In contrast, the cytotoxicity of drugs like DB60 would be connected with the formation of intercalation complexes and the stimulation of DNA cleavage by human topoisomerase II.
机译：使用四种具有不同双末端末端侧链的二苯呋喃衍生物来研究与DNA的序列特异性结合以及人类拓扑异构酶II的中毒。用一系列DNA底物进行的足迹实验证明，所有四种药物都选择性地结合到DNA中富含AT的序列上。但是，对足迹轮廓的定量分析显示，根据基本侧链的性质，AT选择性方面存在显着差异。与呋喃啶（DB75）和3-戊基取代的二am类似物DB226相比，呋喃咪唑啉（DB60）与A.T四联体选择性相互作用的能力降低。 DB244的两个am末端被环戊基取代，表现出最明显的AT特异性。它与至少四个相邻的AT碱基对组成的位点紧密结合，例如5'-TAAT，AATT和TTTT。在低浓度（<2 microM）下，DB60也能够与AT位点形成稳定的复合物，但在较高浓度下，由于药物分子进一步插入富含GC的序列中，结合变得完全非特异性。尽管如此，DB60是唯一可稳定DNA-拓扑异构酶II共价复合物的系列药物。该化合物有效地促进拓扑异构酶II的DNA切割，而DB75，DB226和DB244实际上没有作用。 DB60的拓扑异构酶II中毒活性与其插入DNA中GC位点的能力有关，而其他三种二苯呋喃本质上表现为典型的AT选择性小沟结合剂。该研究表明，对卡氏肺孢子虫病原体（PCP）具有活性的联苯呋喃的抗菌活性主要取决于它们识别富含AT的DNA序列的能力，而不是其干扰拓扑异构酶II的能力。相反，药物如DB60的细胞毒性将与插层复合物的形成以及人拓扑异构酶II刺激DNA切割有关。

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