Design, synthesis, and biological evaluation of novel naphthoquinone derivatives with CDC25 phosphatase inhibitory activity.
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.
Brun
Marie-Priscille
MP
Laboratoire de Pharmacochimie Moléculaire et Cellulaire INSERM U648-CNRS FRE 2718, UFR Biomédicale, 45 rue des Saints Pères, 75270 Paris Cedex 06, France.
Braud
Emmanuelle
E
Angotti
Delphine
D
Mondésert
Odile
O
Quaranta
Muriel
M
Montes
Matthieu
M
Miteva
Maria
M
Gresh
Nohad
N
Ducommun
Bernard
B
Garbay
Christiane
C
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D024483:Vitamin K 3 / Q000031:analogs & derivatives / Q000494:pharmacology; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D011994:Recombinant Proteins; D024483:Vitamin K 3; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases