Exploration of novel macrocyclic dipeptide N-benzyl amides as proteasome inhibitors

As proteasome inhibitors, a series of novel macrocyclic dipeptide N-benzyl amides were designed, synthesized and evaluated. Most of them exhibited potent proteasome inhibition and excellent anti-proliferative activity against RPMI 8226, MM1S, and MV-4-11 cell lines. As the most distinguished one among this series, compound 23h displayed potent and selective proteasome inhibitory potency (IC₅₀: β5c = 29 nM, β5i = 35 nM, β_1c, β_2c,β_1i,β_2i > 10 μM), excellent anti-proliferative activity against RPMI 8226, MM1S, and MV-4-11 cell lines with IC₅₀ values of 18 nM, 15 nM, and 21 nM, respectively, as well as favorable metabolic stability in human liver microsomes (HLMs), highlighting that it is a promising lead compound for further development of proteasome inhibitors.