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

被引:54
作者
Brun, MP
Braud, E
Angotti, D
Mondésert, O
Quaranta, M
Montes, M
Miteva, M
Gresh, N
Ducommun, B
Garbay, C
机构
[1] CNRS, INSERM, U648, FRE 2718,UFR Biomed,Lab Pharmacol Mol & Cellulair, F-75270 Paris, France
[2] Univ Toulouse 3, IFR 109, UMR 5088, Lab Biol Cellulaire & Mol Controle Proliferat, F-31062 Toulouse, France
关键词
cancer; signal transduction; CDC25; phosphatases; naphthoquinones;
D O I
10.1016/j.bmc.2005.05.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 K-3 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. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:4871 / 4879
页数:9
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