title: Rebeccamycin derivatives as dual DNA-damaging agents and potent checkpoint kinase 1 inhibitors.
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 G(2)/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.
authors.affiliation: Laboratoire SEESIB, Université Blaise Pascal, Unité Mixte de Recherche 6504 du Centre National de la Recherche Scientifique, Aubière, France. michelle.prudhomme@univ-bpclermont.fr
authors.forename: Christelle
authors.initials: C
authors.lastname: Marminon
authors.forename: Fabrice
authors.initials: F
authors.lastname: Anizon
authors.forename: Pascale
authors.initials: P
authors.lastname: Moreau
authors.forename: Bruno
authors.initials: B
authors.lastname: Pfeiffer
authors.forename: Alain
authors.initials: A
authors.lastname: Pierré
authors.forename: Roy M
authors.initials: RM
authors.lastname: Golsteyn
authors.forename: Paul
authors.initials: P
authors.lastname: Peixoto
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Hildebrand
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Michelle
authors.initials: M
authors.lastname: Prudhomme