Asymmetric Synthesis of Lysine Analogues with Reduced Basicity, and their Incorporation into Proteasome Inhibitors

Most known β2 selective proteasome inhibitor suffer from relatively poor cell permeability as the result of a net positive charge caused by the basic moiety at P1. Here we describe the synthesis of oligopeptide vinyl sulfones that contain different amino acids bearing amino groups with reduced basicity at P1 and/or P3. For this, we developed the first enantioselective synthesis of lysine(4-ene) and lysine(4-yn). These amino acids, as well as histidine and diaminopropionic acid-glycine, were incorporated at the P1 and/or P3 position of oligopeptide vinyl sulfones. All inhibitors inhibit β2, however, with loss of potency compared to our most potent and selective β2 inhibitor, LU-102. These results notwithstanding, our study described here provides important insights for the future design of β2 selective proteasome inhibitors.