Bromo analogues of the natural metabolite rebeccamycin with and without a methyl substituent on the imide nitrogen were synthesized. The effects of the drugs on protein kinase C, the binding to DNA, and the effect on topoisomerase I were determined. The drugs’ uptake and their antiproliferative activities against P388 leukemia cells sensitive and resistant to camptothecin, their antimicrobial activity against a Gram-positive bacterium (B. cereus), and their anti-HIV-1 activity were measured and compared to those of the chlorinated and dechlorinated analogues. Dibrominated imide 5 shows a remarkable activity against topoisomerase I, affecting both the kinase and DNA cleavage activity of the enzyme. The marked cytotoxic potency of this compound depends essentially on its capacity to inhibit topoisomerase I.
Synthesis, mode of action, and biological activities of rebeccamycin bromo derivatives
Moreau, P.; Anizon, F.; Sancelme, M.; Prudhomme, M.; Severe, D.; Riou, J. F.; Goossens, J. F.; Henichart, J. P.; Bailly, C.; Labourier, E.; Tazzi, J.; Fabbro, D.; Meyer, T.; Aubertin, A. M.
1999
Journal of Medicinal Chemistry
1999-05-20 / vol 42 / pages 1816-1822
Abstract
0022-2623
Tags
protein-kinase-c; terminal domain; sr proteins; inhibition; advanced colorectal-cancer; antimicrobial properties; antitumor; cleavage; DNA-topoisomerase-i; indolocarbazoles