Rebeccamycin derivatives as dual DNA damaging agents and potent checkpoint kinase 1 inhibitors. - Archive ouverte HAL Access content directly
Journal Articles Molecular Pharmacology Year : 2008

Rebeccamycin derivatives as dual DNA damaging agents and potent checkpoint kinase 1 inhibitors.

Paul Peixoto
Marie-Paule Hildebrand
  • Function : Author
Marie-Helene David-Cordonnier
  • Function : Author
Olivier Lozach

Abstract

Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on rebeccamycin derivatives, we have synthesized analogues with the sugar moiety attached to either one or both indole nitrogens. Some analogues, 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.
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Dates and versions

hal-00319800 , version 1 (09-09-2008)

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Christelle Marminon, Fabrice Anizon, Pascale Moreau, Bruno Pfeiffer, Alain Pierre, et al.. Rebeccamycin derivatives as dual DNA damaging agents and potent checkpoint kinase 1 inhibitors.. Molecular Pharmacology, 2008, 74 (6), pp.1620-1629. ⟨10.1124/mol.108.049346⟩. ⟨hal-00319800⟩
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