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Synthesis, Mode of Action, and Biological Activities of Rebeccamycin Bromo Derivatives

1999; American Chemical Society; Volume: 42; Issue: 10 Linguagem: Inglês

10.1021/jm980702n

1520-4804

Pascale Moreau, Fabrice Anizon, Martine Sancelme, Michelle Prudhomme, Danièle Sevère, Jean‐François Riou, Jean‐François Goossens, Jean‐Pierre Hénichart, Christian Bailly, Emmanuel Labourier, Jamal Tazzi, Doriano Fabbro, Thomas Meyer, A.‐M. Aubertin,

Bioactive Compounds and Antitumor Agents

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.