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  3. Design, synthesis, and biological evaluation of indole-based hydroxamic acid derivatives as histone deacetylase inhibitors

Design, synthesis, and biological evaluation of indole-based hydroxamic acid derivatives as histone deacetylase inhibitors

  • Eur J Med Chem. 2022 Jan 5:227:113893. doi: 10.1016/j.ejmech.2021.113893.
Bei-Er Jiang 1,  Jiaxin Hu 2,  Hao Liu 2,  Zhitao Liu 2,  Yu Wen 3,  Mingyao Liu 2,  Han-Kun Zhang 2,  Xiufeng Pang 4,  Li-Fang Yu 5
Affiliations

Affiliations

  • 1 Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China; Navy Medical Research Institute, Second Military Medical University, Shanghai, 200433, PR China.
  • 2 Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China.
  • 3 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China.
  • 4 Drug Discovery Unit, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, PR China. Electronic address: xfpang@bio.ecnu.edu.cn.
  • 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: lfyu@sat.ecnu.edu.cn.
PMID: 34656899 DOI: 10.1016/j.ejmech.2021.113893
Abstract

The equilibrium between histone acetylation and deacetylation plays an important role in Cancer initiation and progression. The histone deacetylases (HDACs) are a class of key regulators of gene expression that enzymatically remove an acetyl moiety from acetylated lysine ε-amino groups on histone tails. Therefore, HDAC inhibitors have recently emerged as a promising strategy for Cancer therapy and several pan-HDAC inhibitors have globally been approved for clinical use. In the present study, we designed and synthesized a series of substituted indole-based hydroxamic acid derivatives that exhibited potent anti-proliferative activities in various tumor cell lines. Among the compounds tested, compound 4o, was found to be among the most potent in the inhibition of HDAC1 (half maximal inhibitory concentration, IC50 = 1.16 nM) and HDAC6 (IC50 = 2.30 nM). It also exhibited excellent in vitro anti-tumor proliferation activity. Additionally, compound 4o effectively increased the acetylation of histone H3 in a dose-dependent manner and inhibited cell proliferation by inducing cell cycle arrest and Apoptosis. Moreover, compound 4o remarkably blocked colony formation in HCT116 Cancer cells. Based on its favorable in vitro profile, compound 4o was further evaluated in an HCT116 xenograft mouse model, in which it demonstrated better in vivo efficacy than the clinically used HDAC Inhibitor, suberanilohydroxamic acid. Interestingly, compound 4k was found to have a preference for the inhibition of HDAC6, with IC50 values of 115.20 and 5.29 nM against HDAC1 and HDAC6, respectively.

Keywords

Antiproliferative; HDAC inhibitors; Hydroxamic acid; Indole.

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