Rebeccamycin analogues as anti-cancer agents.
Rebeccamycin, a microbial metabolite possessing a maleimide indolo[2,3-a]carbazole framework with a carbohydrate moiety attached to one of the indole nitrogens, is a well-known topoisomerase I inhibitor. This review reports the various total syntheses of rebeccamycin and structure-activity relationship studies on rebeccamycin analogues. Rebeccamycin analogues were prepared either by semi-synthesis from the natural metabolite or by total synthesis. Different families of rebeccamycin analogues were obtained by modifications at the imide heterocycle, dechlorination and substitutions on the indole moieties, modifications of the sugar residue, construction of dimers, coupling the sugar unit to the second indole nitrogen, changing indolo[2,3-a]carbazole skeleton to indolo[2,3-c]carbazole, replacing one or both indole moieties by 7-azaindole units. The biological activities of the rebeccamycin analogues are described. According to their chemical structure, the analogues can inhibit topoisomerase I and/or kinases. From the structure-activity relationships, some important rules were established. Several compounds exhibit stronger antiproliferative activities than the natural metabolite with IC(50) values in the nanomolar range. Some analogues, especially those possessing azaindole moieties, are much more selective than rebeccamycin toward the tumour cell lines tested.
Prudhomme
Michelle
M
Université Blaise Pascal, Synthèse et étude de systèmes à intérêt biologique, UMR 6504 du CNRS, 24, avenue des Landais, 63177, Aubière, France. mprud@chimtp.univ-bpclermont.fr
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002227:Carbazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D059004:Topoisomerase I Inhibitors; C053339:rebeccamycin; D011493:Protein Kinase C