Synthesis, Biological Evaluation of Novel β-Peptidyl Epoxyketone Proteasome Inhibitors

OBJECTIVE To discover novel β-peptidyl epoxyketone proteasome inhibitors, evaluate their enzymatic activities. METHODS According to the binding interactions of lead compound Carfilzomib with proteasome, the epoxyketone group of Carfilzomib was retained in the drug design. A series of novel proteasome inhibitors were designed by combining the retained epoxyketone group, β-amino acid using rational drug design strategies such as amino acid, bioisostere replacement. These compounds were synthesized through condensation, oxidation, reduction reactions, were tested for their enzymatic activities in vitro. RESULTS Totally 8 novel β-peptidyl epoxyketone analogues were synthesized, confirmed by ¹H-NMR, ESI-MS, which exhibited moderate proteasome inhibitory activities. CONCLUSIONS β-Amino acid, which is an important α-amino acid replacement, is anticipated to enrich the structure diversity of proteasome inhibitors.