Novel hydroxyl naphthoquinones with potent Cdc25 antagonizing and growth inhibitory properties.

Abstract	Cdc25 phosphatases are important in cell cycle control and activate cyclin-dependent kinases (Cdk). Efforts are currently under way to synthesize specific small-molecule Cdc25 inhibitors that might have anticancer properties. NSC 95397, a protein tyrosine phosphatase antagonist from the National Cancer Institute library, was reported to be a potent Cdc25 inhibitor. We have synthesized two hydroxyl derivatives of NSC 95397, monohydroxyl-NSC 95397 and dihydroxyl-NSC 95397, which both have enhanced activity for inhibiting Cdc25s. The new analogues, especially dihydroxyl-NSC 95397, potently inhibited the growth of human hepatoma and breast cancer cells in vitro. They influenced two signaling pathways. The dual phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) was induced, likely due to inhibition of the ERK phosphatase activity in Hep 3B cell lysate but not the dual specificity ERK phosphatase MKP-1. They also inhibited Cdc25 enzymatic activities and induced tyrosine phosphorylation of the Cdc25 target Cdks. Addition of hydroxyl groups to the naphthoquinone ring thus enhanced the potency of NSC 95397. These two new compounds may be useful probes for the biological functions of Cdc25s and have the potential for disrupting the cell cycle of growing tumor cells.
Authors	Vincent P Peyregne, Siddhartha Kar, Seung W Ham, Meifang Wang, Ziqiu Wang, Brian I Carr
Journal	Molecular cancer therapeutics (Mol Cancer Ther) Vol. 4 Issue 4 Pg. 595-602 (Apr 2005) ISSN: 1535-7163 [Print] United States
PMID	15827333 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	2,3-bis(2-hydroxyethylsulfanyl)-(1,4)-5,8-dihydroxynaphthoquinone 2,3-bis(2-hydroxyethylsulfanyl)-(1,4)-5-hydroxynaphthoquinone 2,3-bis(2-hydroxyethylsulfanyl)-(1,4)naphthoquinone Antineoplastic Agents Cell Cycle Proteins Flavonoids Immediate-Early Proteins Naphthoquinones Tyrosine DNA Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Phosphoprotein Phosphatases Protein Phosphatase 1 CDC25B protein, human CDC25C protein, human DUSP1 protein, human Dual Specificity Phosphatase 1 Protein Tyrosine Phosphatases cdc25 Phosphatases 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Topics	Antineoplastic Agents (pharmacology) Biotinylation Blotting, Western Breast Neoplasms (drug therapy) Carcinoma, Hepatocellular (drug therapy) Cell Cycle Proteins (metabolism) Cell Line, Tumor Cell Proliferation Cell-Free System DNA (chemistry) Dual Specificity Phosphatase 1 Flavonoids (pharmacology) Flow Cytometry Humans Immediate-Early Proteins (metabolism) Immunoprecipitation Mitogen-Activated Protein Kinase 1 (metabolism) Mitogen-Activated Protein Kinase 3 (metabolism) Naphthoquinones (pharmacology) Phosphoprotein Phosphatases (metabolism) Phosphorylation Protein Phosphatase 1 Protein Tyrosine Phosphatases (metabolism) Signal Transduction Time Factors Transfection Tyrosine (chemistry) cdc25 Phosphatases (metabolism)

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