2. Academic Validation
  3. Design, synthesis and biological evaluation of novel isoindolinone derivatives as potent histone deacetylase inhibitors

Design, synthesis and biological evaluation of novel isoindolinone derivatives as potent histone deacetylase inhibitors

  • Eur J Med Chem. 2019 Apr 15:168:110-122. doi: 10.1016/j.ejmech.2019.02.032.
Xin Chen 1,  Shuang Zhao 2,  Hongmei Li 2,  Xin Wang 3,  Aixin Geng 2,  Hao Cui 2,  Tao Lu 4,  Yadong Chen 5,  Yong Zhu 6
Affiliations

Affiliations

  • 1 Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China.
  • 2 School of Science, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 3 School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 4 School of Science, China Pharmaceutical University, Nanjing, 210009, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China.
  • 5 School of Science, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: ydchen@cpu.edu.cn.
  • 6 School of Science, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: zhuyong@cpu.edu.cn.
PMID: 30802729 DOI: 10.1016/j.ejmech.2019.02.032
Abstract

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.

Keywords

Antiproliferation; HDAC inhibitor; Isoindolinone; Structural optimization; Synthesis.

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