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Rebeccamycin Derivatives as Dual DNA-Damaging Agents and Potent Checkpoint Kinase 1 Inhibitors

Laboratoire SEESIB, Université Blaise Pascal, Unité Mixte de Recherche 6504 du Centre National de la Recherche Scientifique, Aubière, France (C.M., S.M., F.A., P.M., M.P.); Institut de Recherches Servier, Division Recherche Cancérologie, Croissy sur Seine, France (B.P., A.P., R.M.G.); Institut National de la Santé et de la Recherche Médicale U837, Centre de Recherches Jean-Pierre Aubert, Team "Molecular and Cellular Targeting for Cancer Treatment" (P.P., M.-P.H., M.-H.D.-C.) and Université de Lille 2, Lille, France (P.P., M.-P.H., M.-H.D.-C.); and Station Biologique Cell Cycle Group, Roscoff, France (O.L., L.M.)

Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on rebeccamycin derivatives, we have synthesized analogs with the sugar moiety attached to either one or both indole nitrogens. Some analogs, especially those with substitutions at the 6' position of the carbohydrate moiety, exhibit potent inhibitory activity toward checkpoint kinase 1 (Chk1), a kinase that has a major role in the G₂/M checkpoint in response to DNA damage. Some of these compounds retained a genotoxic activity either through intercalation into the DNA and/or by topoisomerase I-mediated DNA cleavage. We explored the structure-activity relationship between these compounds and their multiple targets. These rebeccamycin derivatives represent a novel class of potential antitumor agents that have a dual effect and might selectively induce the death of cancer cells.

Address correspondence to: Prof. Michelle Prudhomme, Université Blaise Pascal, UMR 6504 du CNRS, Laboratoire de Synthèse Et Etudes de Systèmes à Intérêt Biologique, 24 Avenue des Landais, 63177 Aubière, France. E-mail: michelle.prudhomme{at}univ-bpclermont.fr