Identification of Novel β ‐Lactam Derivatives as Proteasome Inhibitors for Antitumor Therapy

A series of dipeptidic proteasome inhibitors with β ‐lactam as the C ‐terminus was designed and synthesized. Biochemical evaluations of their effects on chymotrypsin‐like (CT‐L) activity revealed that some of them had inhibitory activity against the proteasome, with IC 50 values in the micromolar range. Based on the enzymatic results, structure–activity relationships (SAR) were discussed in detail. Some potent compounds were further selected for antiproliferative assays toward multiple cancer cell lines, with compounds 66 and 78 demonstrating activity against RS4;11 cells and IC 50 values of less than 1 μM. Additionally, cellular mechanistic studies indicated that these effects were linked to their ability to inhibit proteasome signal pathways and to induce apoptosis in RS4;11 cells, as demonstrated by flow cytometry. Collectively, these results illustrate that compound 66 is a potent proteasome inhibitor with significant potential as an antitumor agent.