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

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

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.

Citation

Yao, H., Xu, F., Wang, G., Xie, S., Li, W., Yao, H., …Xu, S. (2019). Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors. European Journal of Medicinal Chemistry, 167, 485-498. https://doi.org/10.1016/j.ejmech.2019.02.014

• Journal Article Type: Article
• Acceptance Date: Feb 4, 2019
• Online Publication Date: Feb 12, 2019
• Publication Date: Apr 1, 2019
• Deposit Date: Feb 20, 2019
• Publicly Available Date: Feb 13, 2020
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Electronic ISSN: 1768-3254
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 167
• Pages: 485-498
• DOI: https://doi.org/10.1016/j.ejmech.2019.02.014
• Keywords: Organic Chemistry; Pharmacology; Drug Discovery; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/1572758
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523419301242
• Additional Information: This article is maintained by: Elsevier; Article Title: Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors; Journal Title: European Journal of Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ejmech.2019.02.014; Content Type: article; Copyright: Crown Copyright © 2019 Published by Elsevier Masson SAS. All rights reserved.
• Contract Date: Feb 20, 2019