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

Hong Yao, Feijie Xu, Guangyu Wang, Shaowen Xie, Wenlong Li, Hequan Yao, Cong Ma, Zheying Zhu, Jinyi Xu, Shengtao Xu

Research output: Journal article publicationJournal articleAcademic researchpeer-review

7 Citations (Scopus)

Abstract

A series of novel B[sbnd] 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.

Original languageEnglish
Pages (from-to)485-498
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume167
DOIs
Publication statusPublished - 1 Apr 2019

Keywords

  • Anticancer
  • Deguelin
  • Heat shock protein 90
  • Structure simplification

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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