Abstract
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.
Footnotes
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This work was supported by grants to M.-H.D.-C. from the Ligue Nationale contre le Cancer, Comité du Nord. We are grateful to the Institut de Recherches sur le Cancer de Lille (IRCL), the Conseil Régional Nord-Pas de Calais, and the Association pour la Recherche contre le Cancer (ARC) for a PhD fellowship to P.P. This research was supported by grants from the EEC (FP6-2002-Life Sciences and Health, PRO-KINASE Research Project) (to L.M.), the “Cancéropole Grand-Ouest” grant (to L.M.), and the “Ligue Nationale contre le Cancer (Comité du Finistère)” (to L.M.).
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ABBREVIATIONS: Chk1, Checkpoint kinase 1; CPT, camptothecin; Nck, nicked; Rel, relaxed; Sc, supercoiled; NB506, 6N-formylamido-12,13-dihydro-1,11-dihydroxy-13-(β-d-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]-5,7(6H)-dione.
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↵1 Current affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada.
- Received May 29, 2008.
- Accepted September 2, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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