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

Jingmiao Shi; Meng Lei; Wenkui Wu; Huayun Feng; Jia Wang; Shanshan Chen; Yongqiang Zhu; Shihe Hu; Zhaogang Liu; Cheng Jiang

doi:10.1016/j.bmcl.2016.03.007

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

Bioorg Med Chem Lett. 2016 Apr 15;26(8):1958-62. doi: 10.1016/j.bmcl.2016.03.007. Epub 2016 Mar 3.

Authors

Jingmiao Shi¹, Meng Lei², Wenkui Wu³, Huayun Feng², Jia Wang⁴, Shanshan Chen⁴, Yongqiang Zhu⁵, Shihe Hu⁴, Zhaogang Liu⁴, Cheng Jiang⁶

Affiliations

¹ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
² College of Science, Nanjing Forestry University, Nanjing 210037, China.
³ College of Life Science, Nanjing Normal University, Nanjing 210023, China.
⁴ Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd, Nanjing 210037, China.
⁵ College of Life Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: zhyqscu@hotmail.com.
⁶ Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jc@cpu.edu.cn.

PMID: 26965867
DOI: 10.1016/j.bmcl.2016.03.007

Abstract

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 (1)H NMR, (13)C 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=4.82 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 β5 subunit active pocket of proteasome.

Keywords: Cytotoxicity; Dipeptidyl boronic acid; Docking study; Proteasome inhibitor; Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / chemistry*
Amino Acids / pharmacology*
Boronic Acids / chemical synthesis
Boronic Acids / chemistry
Boronic Acids / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dipeptides / chemical synthesis
Dipeptides / chemistry
Dipeptides / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Molecular Docking Simulation*
Molecular Structure
Proteasome Endopeptidase Complex / metabolism*
Proteasome Inhibitors / chemical synthesis*
Proteasome Inhibitors / chemistry
Proteasome Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Amino Acids
Boronic Acids
Dipeptides
Proteasome Inhibitors
Proteasome Endopeptidase Complex