RT Journal Article
SR Electronic
T1 Rebeccamycin Derivatives as Dual DNA-Damaging Agents and Potent Checkpoint Kinase 1 Inhibitors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1620
OP 1629
DO 10.1124/mol.108.049346
VO 74
IS 6
A1 Marminon, Christelle
A1 Anizon, Fabrice
A1 Moreau, Pascale
A1 Pfeiffer, Bruno
A1 Pierré, Alain
A1 Golsteyn, Roy M.
A1 Peixoto, Paul
A1 Hildebrand, Marie-Paule
A1 David-Cordonnier, Marie-Hélène
A1 Lozach, Olivier
A1 Meijer, Laurent
A1 Prudhomme, Michelle
YR 2008
UL http://molpharm.aspetjournals.org/content/74/6/1620.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics