期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 168, 期 -, 页码 110-122出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.02.032
关键词
HDAC inhibitor; Antiproliferation; Isoindolinone; Synthesis; Structural optimization
资金
- Chinese Universities Scientific Fund [2452017174]
- Scientific Startup Foundation for Doctors of Northwest AF University [2452016146]
- Natural Science Foundation of Jiangsu Province, China [BK20180573s]
Histone deacetylases (HDACs) as appealing targets for the treatment of many diseases has been studied extensively and its use in cancer care is the most important. Here, we developed a series of novel derivatives containing isoindolinone skeleton. Twelve compounds demonstrated nanomolar IC50 values against HDAC1, and the best compounds were 5a (65.6 nM), 5b (65.1 nM) and 13a (57.9 nM). In vitro, 5a and 5b also showed potent antiproliferative activities against several cancer cell lines, in particular 5b, which behaved better than approved drug chidamide. Morever, enzyme inhibition and western blot assay established 5b to be a selective inhibitor for HDAC1-3. Molecular docking was performed to rationalize the high potency of isoindolinones. Additionally, 5b had more appropriate drug metabolism in human liver microsome (HLM) compared with chidamide and moderate pharmacokinetics properties. These results indicated that 5b was worthy of further biological studies. (C) 2019 Elsevier Masson SAS. All rights reserved.
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