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

Abstract

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.

• Authors: Marie-Priscille Brun, Emmanuelle Braud, Delphine Angotti, Odile Mondésert, Muriel Quaranta, Matthieu Montes, Maria Miteva, Nohad Gresh, Bernard Ducommun, Christiane Garbay
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 13 Issue 16 Pg. 4871-9 (Aug 15 2005) ISSN: 0968-0896 [Print] England
• PMID: 15921913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Enzyme Inhibitors
• Naphthoquinones
• Recombinant Proteins
• Vitamin K 3
• CDC25B protein, human
• cdc25 Phosphatases

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (antagonists & inhibitors)
• Cell Line, Tumor
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• HeLa Cells
• Humans
• Inhibitory Concentration 50
• Models, Molecular
• Naphthoquinones (chemical synthesis, chemistry, pharmacology)
• Recombinant Proteins (antagonists & inhibitors, chemistry, metabolism)
• Vitamin K 3 (analogs & derivatives, pharmacology)
• cdc25 Phosphatases (antagonists & inhibitors, chemistry, metabolism)