title: Syntheses, biochemical and biological evaluation of staurosporine analogues from the microbial metabolite rebeccamycin.
abstract: The indolocarbazole antibiotics staurosporine and rebeccamycin (1) are potent antitumor drugs targeting protein kinase C and topoisomerase I, respectively. To obtain staurosporine analogues from rebeccamycin, different structural modifications were performed: coupling of the sugar moiety to the second indole nitrogen, dechlorination and then reduction of the imide function to amide. The newly synthesized compounds (3-6) were tested for their abilities to bind to DNA and to inhibit topoisomerase I and protein kinase C. Their antiproliferative effects in vitro against B16 melanoma and P388 leukemia (including the related P388CPT cell line resistant to camptothecin) as well as their anti-HIV-1 and antimicrobial activities against various strains of microorganisms were determined. The cytotoxicity of the dechlorinated imide analogue 5 correlates well with its DNA binding and anti-topoisomerase I activities. These findings provide guidance for the development of new topoisomerase I-targeted antitumor indolocarbazoles equipped with a carbohydrate attached to the two indole nitrogens.
authors.affiliation: Université Blaise Pascal, Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504, Aubière, France.
authors.forename: F
authors.initials: F
authors.lastname: Anizon
authors.forename: P
authors.initials: P
authors.lastname: Moreau
authors.forename: M
authors.initials: M
authors.lastname: Sancelme
authors.forename: A
authors.initials: A
authors.lastname: Voldoire
authors.forename: M
authors.initials: M
authors.lastname: Prudhomme
authors.forename: M
authors.initials: M
authors.lastname: Ollier
authors.forename: D
authors.initials: D
authors.lastname: Sevère
authors.forename: J F
authors.initials: JF
authors.lastname: Riou
authors.forename: C
authors.initials: C
authors.lastname: Bailly
authors.forename: D
authors.initials: D
authors.lastname: Fabbro
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.forename: A M
authors.initials: AM
authors.lastname: Aubertin
mesh_terms: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002227:Carbazoles; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D006801:Humans; D007211:Indoles; D009682:Magnetic Resonance Spectroscopy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013055:Spectrophotometry, Infrared; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D059004:Topoisomerase I Inhibitors; C053339:rebeccamycin; D011493:Protein Kinase C; D019311:Staurosporine