Design, synthesis and docking studies of novel dipeptidyl boronic acid proteasome inhibitors constructed from alpha alpha - and alpha beta -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 super(1)H NMR, super(13)C 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 alpha alpha -amino acids were as active as bortezomib. Interestingly, the activities of those derived from alpha beta -amino acids lost completely. Of all the inhibitors, compound 22 (IC sub(50) = 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 IC sub(50) 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.