Evaluation of Sulfone Analogs of Cpd 5 as Cdc25 Inhibitors

Abstract

The search for less toxic and more effective anticancer agents has involved a detailed mechanistic investigation of the cell cycle and possible critical enzymes as rational targets. Recently, the observation that Cdc25A and Cdc25B as important cell cycle regulators are proto-oncogenes and are overexpressed in many cancer cells has made them as attractive drug targets. Among the Cdc25 inhibitors, several quinoid compounds, including Compound 5 (Cpd 5, or 2(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone), was found to be a selective and partial-competitive inhibitor of Cdc25, and was markedly less active against PTP1B, VHR and MKP-1. More recently, computer docking studies of Cpd 5 to Cdc25A showed that the sulfur atom of Cpd 5 is close to the cysteine of the enzyme active site in the best conformation. The redox properties of the naphthoquinones can also generate toxic oxygen species, which may cause toxicity to normal tissues and thus reduce their therapeutic attractiveness. In present study, Cpd 5 analogs with the sulfone as an isostatic group of one of the carbonyl group were synthesized as illustrated in Scheme 1. Acylation of the addition product of thiophenol and methyl crotonate in polyphosphoric acid (PPA) yielded 2. After oxidation of 2 with H2O2 in acetic acid at 100 C, the resulting 3 was