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

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.
Jingmiao Shi 1,  Meng Lei 2,  Wenkui Wu 3,  Huayun Feng 2,  Jia Wang 4,  Shanshan Chen 4,  Yongqiang Zhu 5,  Shihe Hu 4,  Zhaogang Liu 4,  Cheng Jiang 6
Affiliations

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.

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