Discovery of class i histone deacetylase inhibitors based on romidpesin with promising selectivity for cancer cells

Kuojun Zhang, Yiwu Yao, Zhengchao Tu, Chenzhong Liao, Zhen Wang, Yatao Qiu, Dong Chen, Dale J. Hamilton, Zheng Li, Sheng Jiang

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Aim: Class I histone deacetylases (HDACs) are considered to be promising anticancer targets, but selective inhibition of class I HDAC isoforms remains a challenge. Methods & results: Previously, we obtained a selective class I HDAC inhibitor 9 based on a macrocyclic HDAC inhibitor Romidpesin. As our continuous efforts, a library of novel cyclicdepsipeptides based on 9 was established using a convergent synthesis strategy. The most active compounds 10, 16 and 19 selectively inhibit class I HDACs and exhibit promising nanomolar antiproliferative activities against several cancer cell lines with excellent selectivity toward cancer cells over normal cells. Besides, compound 10 demonstrates excellent antitumor effects in human prostate carcinoma PC3 xenograft models with no observed toxicity. Conclusion: These cyclicdepsipeptides show great therapeutic potential as novel anticancer agents for clinical translation.

Original languageEnglish (US)
Pages (from-to)311-323
Number of pages13
JournalFuture Medicinal Chemistry
Volume12
Issue number4
Early online dateNov 29 2019
DOIs
StatePublished - Feb 2020

Keywords

  • antitumor
  • class I histone deacetylases
  • cyclic depsipeptides
  • inhibitor
  • structure-activity relationship

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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