1. Syntheses, biochemical and biological evaluation of staurosporine analogues from the microbial metabolite rebeccamycin.
- Author
-
Anizon F, Moreau P, Sancelme M, Voldoire A, Prudhomme M, Ollier M, Sevère D, Riou JF, Bailly C, Fabbro D, Meyer T, and Aubertin AM
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents pharmacology, Anti-Infective Agents chemical synthesis, Anti-Infective Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Line, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Evaluation Studies as Topic, Humans, Magnetic Resonance Spectroscopy, Protein Kinase C antagonists & inhibitors, Spectrophotometry, Infrared, Staurosporine chemical synthesis, Staurosporine pharmacology, Structure-Activity Relationship, Topoisomerase I Inhibitors, Tumor Cells, Cultured, Aminoglycosides, Anti-Bacterial Agents chemistry, Carbazoles, Indoles, Staurosporine analogs & derivatives
- 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.
- Published
- 1998
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