Design, synthesis and biological evaluation of dipeptides as novel non-covalent 20S proteasome inhibitors.

Based on the interaction modes of the natural 20S proteasome inhibitors , we have previously discovered a dipeptide . To explore the SAR around compound , we designed and synthesized a series of dipeptides () with a fragment-based strategy. Among them, nine compounds showed significant inhibitory activities against the chymotrypsin-like activity of human 20S proteasome with IC values at the submicromolar level, which were comparable or even superior to the parent compound . Meanwhile, they displayed no significant inhibition against trypsin-like and caspase-like activities of 20S proteasome. The results suggested the feasibility to design dipeptides as novel and potent 20S proteasome inhibitors.[Formula: see text].