Reversible phosphorylation of proteins plays an important role in intracellular signal transduction. Recently we started a project for the development of highly specific inhibitors of the biologically significant protein tyrosine phosphatases and dual-specificity phosphatases. Here we report an asymmetric synthesis of RK-682 (6) which has been reported as a potent inhibitor of a dual-specificity phosphatase VHR, and the absolute stereochemistry of RK-682 was determined to be (R) (Scheme 1). This efficient and versatile synthetic method enabled to generate a tetronic acid library containing various RK-682 analogs. Inhibition of VHR by these novel compounds was first evaluated. The structure-activity relationship suggests that hydrophobic side chain at C3 position is quite important (Table 1). To find a potential therapeutics, we next focused on phosphatases involved in the regulation of cell proliferation. Although RK-682 showed strong inhibition of VHR, its inhibitions to several other phosphatases tested were weak. Screening of the library identified several compounds which inhibit biologically important phosphatases. For example, compound 10 showed inhibition of dual-specificity phosphatases Cdc25A and Cdc25B, which are key enzymes of cell cycle progression. Compound 17 inhibited CD45, a receptor-type tyrosine phosphatase which is involved in T cell and B cell activation. It was also found that compounds 18 and 19 inhibit PTH-stimulated IL-6 production of MC3T3-E1 cells.
