Inhibitors of the chymotrypsin-like activity of proteasome based on di- and tri-peptidyl α-keto aldehydes (glyoxals)

A series of peptidyl α-keto aldehydes (glyoxals) have been synthesised as putative inhibitors of the chymotryptic-like activity of proteasome. The most potent peptides, Cbz-Leu-Leu-Tyr-COCHO and Bz-Leu-Leu-Leu-COCHO, function as slow-binding reversible inhibitors, exhibiting final K i values of approximately 3.0 nM. These are among the lowest values so far reported for (tri)peptide-based aldehyde-releated inhibitors. A series of peptidyl α-keto aldehyde (glyoxal) inhibitors, of general structure I, have been synthesised and tested against the chymotryptic-like activity of proteasome. The most active members of this series exhibit K i values in the low nanomolar range, thus ranking them among the most potent proteasome inhibitors ever reported.