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

Animals; Antineoplastic Agents/chemistry/pharmacology; Carbazoles/chemistry/pharmacology; Cell Proliferation/drug effects; DNA/chemistry; DNA Cleavage/drug effects; DNA Damage; Drug Screening Assays, Antitumor; Humans; Mice; Protein Kinase Inhibitors/chemistry/pharmacology; Protein Kinases/metabolism; Structure-Activity Relationship; Topoisomerase I Inhibitors

Abstract :

[en] 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.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Marminon, Christelle

Anizon, Fabrice

Moreau, Pascale

Pfeiffer, Bruno

Pierre, Alain

Golsteyn, Roy M

Peixoto, Paul

Hildebrand, Marie-Paule

David-Cordonnier, Marie Hélène

Lozach, Olivier

Meijer, Laurent

Prudhomme, Michelle

Language :

English

Title :

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

Publication date :

2008

Journal title :

Molecular Pharmacology

ISSN :

0026-895X

eISSN :

1521-0111

Publisher :

American Society for Pharmacology and Experimental Therapeutics, Bethesda, United States - Maryland

Volume :

Issue :

Pages :

1620-9

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 03 March 2011

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