Rebeccamycin analogues from indolo[2,3-c] carbazole

Glycosylated indolocarbazoles related to the antibiotic rebeccamycin repres ent an important series of antitumor drugs. In the course of structure-acti vity relationship studies, we report the synthesis of two new derivatives c ontaining an indolo[2,3-c]carbazole chromophore instead of the conventional indolo[2,3-a]carbazole unit found in the natural metabolites. The N-methyl ated compound 8 containing one glucose residue behaves as a typical DNA int ercalating agent, as judged from circular and electric linear dichroism mea surements with purified DNA. In contrast, the bis-glycosylated derivative 7 containing a glucose residue on each indole nitrogen has lost its capacity to form stable complexes with DNA. DNA relaxation experiments reveal that the two drugs 7 and 8 have weak effects on human DNA topoisomerase I. The m odified conformation of the indolocarbazole chromophore is detrimental to t he stabilization of topoisomerase I DNA complexes. The lack of potent topoi somerase I inhibition lends to decreased cytotoxicity but, however, we obse rved that the DNA-intercalating mono-glycosyl derivative 8 is about 5 times more cytotoxic than the bis-glycosyl analogue 7. The study suggests that t he naturally-occurring indolo[2,3-a]carbazole skeleton should be preserved to maintain the topoisomerase I inhibitory and cytotoxic activities. (C) 20 01 Elsevier Science Ltd. All rights reserved.