Prudhomme M
Laboratoire de Synthese, Electrosynthèse et Etude de Systèmes à Interet Biologique, Universite Blaise Pascal, UMR 6504 du CNRS, Aubiere, 63177, France.
Curr Med Chem. 2000 Dec;7(12):1189-212. doi: 10.2174/0929867003374138.
DNA topoisomerases are essential for the survival of prokaryotic and eukaryotic organisms. Topoisomerases inhibitors, due to their capacity to induce DNA breaking, can exhibit interesting antitumor properties. While there are many potent antitumor agents which target topoisomerase II, relatively few families of specific topoisomerase I inhibitors have been identified. The present review describes a new family of topoisomerase I inhibitors, analogues of the bacterial metabolite rebeccamycin. These compounds possess an indolocarbazole chromophore onto which is attached a sugar residue. Important structure-activity relationships studies in this series have helped to understand the role of the carbohydrate moiety which is absolutely necessary for topoisomerase I poisoning, the influence of the stereochemistry (alpha or beta) of its linkage to indole, the influence of the functionalities and substitutions on the sugar moiety and on the aromatic framework have been investigated. In addition to their action on DNA, rebeccamycin analogues may inhibit the SR kinase activity of topoisomerase I and therefore constitute a unique family of topoisomerase I poisons quite different from the well known camptothecins.
DNA拓扑异构酶对于原核生物和真核生物的生存至关重要。拓扑异构酶抑制剂由于其诱导DNA断裂的能力，可展现出有趣的抗肿瘤特性。虽然有许多靶向拓扑异构酶II的强效抗肿瘤药物，但已鉴定出的特异性拓扑异构酶I抑制剂家族相对较少。本综述描述了一类新的拓扑异构酶I抑制剂，即细菌代谢产物瑞贝克霉素的类似物。这些化合物具有一个吲哚并咔唑发色团，上面连接有一个糖残基。该系列中重要的构效关系研究有助于理解碳水化合物部分的作用，其对于拓扑异构酶I中毒是绝对必要的，研究了其与吲哚连接的立体化学（α或β）的影响、糖部分和芳香骨架上官能团及取代基的影响。除了对DNA的作用外，瑞贝克霉素类似物可能会抑制拓扑异构酶I的SR激酶活性，因此构成了一类独特的拓扑异构酶I毒物，与著名的喜树碱截然不同。
