Design, synthesis, and biological evaluation of novel naphthoquinone derivatives with CDC25 phosphatase inhibitory activity.

Marie-Priscille Brun (1) , Emmanuelle Braud (1) , Delphine Angotti (1) , Odile Mondésert (2) , Muriel Quaranta (2) , Matthieu Montes (1) , Maria A. Miteva (1) , Nohad Gresh (1) , Bernard Ducommun (2) , Christiane Garbay (1)

1 PMC - UMR_S 648 - Pharmacochimie Moléculaire et Cellulaire
2 LBCMCP - Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération

CDC25 dual-specificity phosphatases are essential key regulators of eukaryotic cell cycle progression and the CDC25A and B isoforms are over-expressed in different tumors and related cancer cell lines. CDC25s are now considered to be interesting targets in the search for novel anticancer agents. We describe new compounds derived from vitamin K3 that inhibit CDC25B activity with IC50 values in the low micromolar range. These naphthoquinone derivatives also display antiproliferative activity on HeLa cells as expected for CDC25 inhibitors and inhibit cell growth in a clonogenic assay at submicromolar concentrations. They increase inhibitory tyrosine 15 phosphorylation of CDK and induce the cleavage of PARP, a hallmark of apoptosis.

Domaines: Biologie cellulaire

Marie-Priscille Brun, Emmanuelle Braud, Delphine Angotti, Odile Mondésert, Muriel Quaranta, et al.. Design, synthesis, and biological evaluation of novel naphthoquinone derivatives with CDC25 phosphatase inhibitory activity.. Bioorganic and Medicinal Chemistry, 2005, 13 (16), pp.4871-9. ⟨10.1016/j.bmc.2005.05.005⟩. ⟨hal-00317419⟩