2. Academic Validation
  3. Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors

Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors

  • Eur J Med Chem. 2019 Apr 1:167:485-498. doi: 10.1016/j.ejmech.2019.02.014.
Hong Yao 1,  Feijie Xu 1,  Guangyu Wang 1,  Shaowen Xie 1,  Wenlong Li 1,  Hequan Yao 1,  Cong Ma 2,  Zheying Zhu 3,  Jinyi Xu 4,  Shengtao Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
  • 2 State Key Laboratory of Chemical Biology and Drug Discovery, and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong.
  • 3 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
  • 4 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: jinyixu@china.com.
  • 5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: cpuxst@cpu.edu.cn.
PMID: 30784881 DOI: 10.1016/j.ejmech.2019.02.014
Abstract

A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (HSP90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human Cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high HSP90 binding potency (60 nM) and caused degradation of client proteins through ubiquitin Proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast Cancer MCF-7 cells. Flow cytometry and Western blot analyses confirmed that compound 21c caused Apoptosis of MCF-7 cells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7 cells. Taken together, these results suggest that 21c might be a promising lead compound for further development of HSP90 inhibitors.

Keywords

Anticancer; Deguelin; Heat shock protein 90; Structure simplification.

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