Capranico G, Binaschi M
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, 20133 Milan, Italy.
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):185-94. doi: 10.1016/s0167-4781(98)00135-3.
Chemical agents able to interfere with DNA topoisomerases are widespread in nature, and some of them have clinical efficacy as antitumor or antibacterial drugs. Drugs which have as a target DNA topoisomerases could be divided into two categories: poisons and catalytic inhibitors. Classical topoisomerase poisons stimulate cleavage in a sequence-selective manner, yielding drug-specific cleavage intensity pattern. The mechanisms of drug interaction with DNA topoisomerases, the DNA sequence selectivity of the action of topoisomerase II poisons and the identification of structural determinants of their activity have suggested that topoisomerase II poisons may fit into a specific pharmacophore, constituted by a planar ring system with DNA intercalation or intercalation-like properties, and protruding side chains interfering with the protein side of the covalent enzyme-DNA complex. The complete definition of the diverse pharmacophores of topoisomerase II poisons will certainly be of value for the design of new agents directed to specific genomic sites, and more effective in the treatment of human cancer.
能够干扰DNA拓扑异构酶的化学制剂在自然界中广泛存在，其中一些作为抗肿瘤或抗菌药物具有临床疗效。以DNA拓扑异构酶为靶点的药物可分为两类：毒药和催化抑制剂。经典的拓扑异构酶毒药以序列选择性的方式刺激切割，产生药物特异性的切割强度模式。药物与DNA拓扑异构酶相互作用的机制、拓扑异构酶II毒药作用的DNA序列选择性以及其活性结构决定因素的鉴定表明，拓扑异构酶II毒药可能适合一种特定的药效基团，该药效基团由具有DNA嵌入或类似嵌入性质的平面环系统以及干扰共价酶-DNA复合物蛋白质侧的突出侧链组成。拓扑异构酶II毒药不同药效基团的完整定义对于设计针对特定基因组位点且在治疗人类癌症方面更有效的新型药物肯定具有价值
