Syntheses, biochemical and biological evaluation of staurosporine analogues from the microbial metabolite rebeccamycin.
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.
Anizon
F
F
Université Blaise Pascal, Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504, Aubière, France.
Moreau
P
P
Sancelme
M
M
Voldoire
A
A
Prudhomme
M
M
Ollier
M
M
Sevère
D
D
Riou
J F
JF
Bailly
C
C
Fabbro
D
D
Meyer
T
T
Aubertin
A M
AM
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
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