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

• Published in: Bioorganic & medicinal chemistry letters 2016-04, Vol.26 (8), p.1958-1962
• Main Authors: Shi, Jingmiao, Lei, Meng, Wu, Wenkui, Feng, Huayun, Wang, Jia, Chen, Shanshan, Zhu, Yongqiang, Hu, Shihe, Liu, Zhaogang, Jiang, Cheng
• Format: Article
• Language: English
• Subjects: Amino Acids - chemistry; Amino Acids - pharmacology; Boronic Acids - chemical synthesis; Boronic Acids - chemistry; Boronic Acids - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cytotoxicity; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Dipeptidyl boronic acid; Docking study; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Docking Simulation; Molecular Structure; Proteasome Endopeptidase Complex - metabolism; Proteasome inhibitor; Proteasome Inhibitors - chemical synthesis; Proteasome Inhibitors - chemistry; Proteasome Inhibitors - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.03.007

A series of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα and αβ amino acids were designed and synthesized. [Display omitted] A series of novel dipeptidyl boronic acid proteasome inhibitors constructed from αα- and αβ-amino acids were designed and synthesized. Their structures were elucidated by 1H NMR, 13C NMR, LC–MS and HRMS. These compounds were evaluated for their β5 subunit inhibitory activities of human proteasome. The results showed that dipeptidyl boronic acid inhibitors composed of αα-amino acids were as active as bortezomib. Interestingly, the activities of those derived from αβ-amino acids lost completely. Of all the inhibitors, compound 22 (IC50=4.82nM) 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 5nM in inhibiting cell growth assays. Molecular docking studies displayed that 22 fitted very well in the β5 subunit active pocket of proteasome.