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 IC50 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 IC50 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.