Synthesis of peptide fluoromethyl ketones and the inhibition of human cathepsin B

Abstract

Peptide fluoromethyl ketones have been synthesized for the first time. The inhibitor 3-( N-benzyloxycarbonylphenylalanylamido)- dl-1-fluoro-2-butanone (Z-Phe-AlaCH 2F) was found to be a 30-fold more potent inactivator of human cathepsin B than 3-( N-benzyloxycarbonylphenylalanylamido)- l-1-diazo-2-butanone (Z-Phe-AlaCHN 2), but less reactive than 3-( N-benzyloxycarbonylphenylalanylamido)- l-1-chloro-2-butanone (Z-Phe-AlaCH 2Cl). The fluoromethyl ketone's increased potency over the diazomethyl ketone is mainly due to its tighter binding to cathepsin B, with little difference between their respective k 3 values. Both Z-Phe-AlaCH 2 and Z-Phe-AlaCH 2F were quite stable to high concentrations of dithiothreitol, while Z-Phe-AlaCH 2Cl was rapidly destroyed by the thiol.