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, beta 1, beta 2 and beta 5, containing a caspaselike, 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 beta 5 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(1) values in the sub-micromolar to micromolar range. These compounds were also tested against bovine pancreatic alpha-chymotrypsin and human cathepsin B and L, revealing a good selectivity for the target enzyme over these related enzymes.