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Novel hydroxyl naphthoquinones with potent Cdc25 antagonizing and growth inhibitory properties

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.