Design, synthesis and docking studies of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids

A series of novel dipeptidyl boronic acid proteasome inhibitors constructed from alpha alpha- and alpha beta-amino acids were designed and synthesized. Their structures were elucidated by H-1 NMR, C-13 NMR, LC-MS and HRMS. These compounds were evaluated for their beta 5 subunit inhibitory activities of human proteasome. The results showed that dipeptidyl boronic acid inhibitors composed of aa- amino acids were as active as bortezomib. Interestingly, the activities of those derived from ab-amino acids lost completely. Of all the inhibitors, compound 22 (IC50 = 4.82 nM) was the most potent for the inhibition of proteasome activity. Compound 22 was also the most active against three MM cell lines with IC50 values less than 5 nM in inhibiting cell growth assays. Molecular docking studies displayed that 22 fitted very well in the beta 5 subunit active pocket of proteasome. (C) 2016 Published by Elsevier Ltd.