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