2. Academic Validation
  3. Design, synthesis and biological evaluation of novel non-peptide boronic acid derivatives as proteasome inhibitors

Design, synthesis and biological evaluation of novel non-peptide boronic acid derivatives as proteasome inhibitors

  • Eur J Med Chem. 2017 Mar 10:128:180-191. doi: 10.1016/j.ejmech.2017.01.034.
Ying Ge 1,  Aibo Li 1,  Jianwei Wu 1,  Haiwei Feng 1,  Letian Wang 1,  Hongwu Liu 1,  Yungen Xu 2,  Qingxiang Xu 3,  Li Zhao 4,  Yuyan Li 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, Nanjing 210008, China. Electronic address: xqx008dg@sina.com.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhaolicpu@126.com.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: yuyanli@cpu.edu.cn.
PMID: 28182990 DOI: 10.1016/j.ejmech.2017.01.034
Abstract

A novel series of non-peptide Proteasome inhibitors bearing the 1, 4-naphthoquinone scaffold and boronic acid warhead was developed. In the biological evaluation on the chymotrypsin-like activity of human 20S Proteasome, five compounds showed IC50 values in the nanomolar range. Docking experiments into the yeast 20S Proteasome rationalized their biological activities and allowed further optimization of this interesting class of inhibitors. Within the cellular proliferation inhibition assay and western blot analysis, compound 3e demonstrated excellent anti-proliferative activity against solid tumor cells and clear accumulation of ubiquitinated cellular proteins. Furthermore, in the microsomal stability assay compound 3e demonstrated much improved metabolic stability compared to bortezomib, emerging as a promising lead compound for further design of non-peptide Proteasome inhibitors.

Keywords

1, 4-naphthoquinones; Docking studies; Non-peptide boronic acid; Proteasome inhibitors.

Figures