Recent developments of rebeccamycin analogues as topoisomerase I inhibitors and antitumor agents

DNA topoisomerases are essential for the survival of prokaryotic and eukary otic 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, an alogues of the bacterial metabolite rebeccamycin. These compounds possess a n indolocarbazole chromophore onto which is attached a sugar residue. Impor tant structure-activity relationships studies in this series have helped to understand the role of the carbohydrate moiety which is absolutely necessa ry for topoisomerase I poisoning, the influence of the stereochemistry (alp ha or beta) of its linkage to indole, the influence of the functionalities and substitutions on the sugar moiety and on the aromatic framework have be en investigated. In addition to their action on DNA, rebeccamycin analogues may inhibit the SR kinase activity of topoisomerase I and therefore consti tute a unique family of topoisomerase I poisons quite different from the we ll known camptothecins.