The 26S proteasome is a multicatalytic protease complex that plays an essential role inintracellular protein degradation. We have synthesized and tested a series of arecoline peptidederivatives where the peptide portion derives from a screening of tripeptide sequences, andthe arecoline moiety has been considered as a potential substrate for catalytic threonine.Derivatives 17−19 are the best compounds of the series, showing chymotryptic-like (β5)inhibition (IC50 ≅ 1 μM) and favorable pharmacokinetic properties.
