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Design, synthesis and biological evaluation of 3, 4-disubstituted-imidazolidine-2, 5-dione derivatives as HDAC6 selective inhibitors.

Abstract
HDAC6 isoform selective inhibitors can be pursued as an alternative to pan-HDACs inhibitors due to their therapeutic effect and low toxicity. Efforts of the structure optimization of our previous compound 10c (IC50 = 4.4 nM) resulted in a new series of 3, 4-disubstituted-imidazolidine-2, 5-dione based HDAC6 inhibitors with better HDAC6 inhibitory activities and improved selectivities. The most potent compound 71 exhibited a low nanomolar HDAC6 inhibitory activity (IC50 = 2.1 nM) and showed 5545-fold, 5864-fold as well as 1638-fold selectivity relative to HDAC1, HDAC2 and HDAC8, respectively. Western blot analysis further confirmed that compound 71 selectively increased the acetylation level of α-tubulin without affecting histone H3. Moreover, compound 71 also possesses good properties in term of caspase-3 activation, apoptosis induction, anti-proliferative activity, cytotoxicity and plasma stability. Therefore, compound 71 can be applied in cancer therapy or used as a lead compound to develop more potent HDAC6 selective inhibitor.
AuthorsTao Liang, Junxin Xue, Zefu Yao, Yang Ye, Xinying Yang, Xuben Hou, Hao Fang
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 221 Pg. 113526 (Oct 05 2021) ISSN: 1768-3254 [Electronic] France
PMID33992929 (Publication Type: Journal Article)
CopyrightCopyright © 2021 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Histone Deacetylase Inhibitors
  • Imidazolidines
  • HDAC6 protein, human
  • Histone Deacetylase 6
Topics
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Design
  • Histone Deacetylase 6 (antagonists & inhibitors, metabolism)
  • Histone Deacetylase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Humans
  • Imidazolidines (chemical synthesis, chemistry, pharmacology)
  • Molecular Structure
  • Structure-Activity Relationship

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