Anizon F, Moreau P, Sancelme M, Voldoire A, Prudhomme M, Ollier M, Sevère D, Riou J F, Bailly C, Fabbro D, Meyer T, Aubertin A M
Université Blaise Pascal, Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, UMR 6504, Aubière, France.
Bioorg Med Chem. 1998 Sep;6(9):1597-604. doi: 10.1016/s0968-0896(98)00096-0.
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.
