Development of novel peptidomimetics containing a vinyl sulfone moiety as proteasome inhibitors

Proteasome inhibition is a topic of great interest in anticancer research. The proteolytic activity of this multicatalytic complex relies on three subunits, β1, β2 and β5, containing a caspase-like, a trypsin-like and a chymotrypsin-like active site, respectively. Several studies have demonstrated that, of the three activities, the chymotrypsin-like activity was the most necessary for cell viability and protein processing. Thus, most efforts towards the development of proteasome inhibitors have focused on the selective inhibition of the β5 subunit active site. Herein, we report the design and synthesis of a series of conformationally constrained tripeptidyl vinyl sulfones were determined to be good inhibitors of the chymotrypsin-like activity of proteasome, with K(I) values in the sub-micromolar to micromolar range. These compounds were also tested against bovine pancreatic α-chymotrypsin and human cathepsin B and L, revealing a good selectivity for the target enzyme over these related enzymes.