Synthesis, biological evaluation, and molecular modeling studies of rebeccamycin analogues modified in the carbohydrate moiety.
A new series of indolocarbazole glycosides containing disaccharides were synthesized and their in vitro antiproliferative activity was evaluated against three human cancer cell lines (A2780, H460, and GLC4). Cytotoxicity appeared to be remarkably affected by the regio- and stereochemical features of the disaccharide moiety. In vivo antitumor activity of the compounds studied, two of which having IC(50)<100 nm, was determined using ovarian cancer cell line A2780 xenografted on nude mice. One compound showed an efficacy similar to that of the reference compound edotecarin, though with a lower long-lasting activity. The topoisomerase I inhibitory properties of some compounds were also examined. Molecular dynamics simulations of the ternary topoisomerase I-DNA-ligand complexes were performed to analyze the structural features of topoisomerase I poisoning with this class of indolocarbazoles. A plausible explanation of their biological behavior was provided. These theoretical results were compared with the recently published crystal structure of an indolocarbazole monosaccharide bound to the covalent human topoisomerase I-DNA complex.
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D004187:Disaccharides / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008024:Ligands; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D004187:Disaccharides; D007211:Indoles; D008024:Ligands; D059004:Topoisomerase I Inhibitors; C053339:rebeccamycin