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.
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Authors | Tao Liang, Junxin Xue, Zefu Yao, Yang Ye, Xinying Yang, Xuben Hou, Hao Fang |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 221
Pg. 113526
(Oct 05 2021)
ISSN: 1768-3254 [Electronic] France |
PMID | 33992929
(Publication Type: Journal Article)
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Copyright | Copyright © 2021 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Histone Deacetylase Inhibitors
- Imidazolidines
- HDAC6 protein, human
- Histone Deacetylase 6
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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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