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: beta 5c = 29 nM, beta 5i = 35 nM, beta(1c), beta(2c), beta(1i), beta(2i)> 10 mu M), 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. (C) 2019 Elsevier Masson SAS. All rights reserved.