Structure–Activity Relationship and Rational Design of 3,4-Dephostatin Derivatives as Protein Tyrosine Phosphatase Inhibitors

Several alkyl- and O-methylated-3,4-dephostatin were synthesized and evaluated for their inhibitory activity toward protein tyrosine phosphatase. Alkyl chains with a length up to that of the pentyl group gave tolerable inhibition, whereas methylation of hydroxyl groups resulted in a decrease in the activity. Based on the structure–activity relationship and X-ray crystallographic analysis of C215S PTP1B–phosphotyrosine containing peptide complex, the mode of binding of 3,4-dephostatins to the active site was speculated with the aid of calculation. Several hydrogen bonds and CH/π interactions were suggested to be important for inhibition of PTPase. A novel nitroso-free methoxime compound was designed so that all the attractive interactions were maintained. The methoxime compound was synthesized and shown to inhibit PTP1B.