A New Class of Serine and Cysteine Protease Inhibitor with Chemotherapeutic Potential

Metastasis of cancer is dependent on a variety of biologically active compounds including serine proteases. Inhibition of proteases such as plasmin is a potential route for both suppression of metastatic lesions and control of primary tumor growth. Synthesis of tetrahydrothiopyran-4-one based inhibitors of plasmin containing either a diamine or amide/amine side chain was undertaken. Initial attempts to produce the inhibitors through amide alkylation and reductive amination proved futile. The diamine inhibitor was finally produced using amine alkylation chemistry. A monoamine side product of this reaction forms the starting material for the other inhibitor. A simple peptide coupling reaction converts the monoamine to the amide/amine inhibitor. Preliminary testing on the crude products shows both inhibitors to have some activity against plasmin with a Ki of 6 mM for the diamine inhibitor and 3 mM for the amide/amine inhibitor.