2. Academic Validation
  3. Design, synthesis and biological evaluation of coumarin-based N-hydroxycinnamamide derivatives as novel histone deacetylase inhibitors with anticancer activities

Design, synthesis and biological evaluation of coumarin-based N-hydroxycinnamamide derivatives as novel histone deacetylase inhibitors with anticancer activities

  • Bioorg Chem. 2020 Aug;101:104023. doi: 10.1016/j.bioorg.2020.104023.
Jiaoli Ding 1,  Jing Liu 2,  Zhipeng Zhang 1,  Jie Guo 1,  Maojun Cheng 1,  Yang Wan 1,  Rikang Wang 1,  Yuanying Fang 1,  Zhiyu Guan 3,  Yi Jin 1,  Sai-Sai Xie 4
Affiliations

Affiliations

  • 1 National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, PR China.
  • 2 School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, PR China.
  • 3 School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, PR China. Electronic address: adlaiguan@126.com.
  • 4 National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, PR China. Electronic address: xiesaisainanchang@hotmail.com.
PMID: 32650178 DOI: 10.1016/j.bioorg.2020.104023
Abstract

A series of novel coumarin-based N-hydroxycinnamamide derivatives were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds showed potent HDAC inhibitory activity and significant antiproliferative activity against human Cancer cell lines MCF-7, HepG2, HeLa and HCT-116. Among them, compound 14f displayed the most potent HDAC inhibition, especially against HDAC1 with IC50 value of 0.19 μM, which was better than that of SAHA (IC50 = 0.23 μM). It also showed the strongest antiproliferative activity towards HeLa cells and more than 26-fold selectivity for HDAC1 compared with HDAC6. Molecular docking studies revealed the possible binding modes of compound 14f into the two isoforms and provided a reasonable explanation for the selectivity. In addition, compound 14f could inhibit colony formation, upregulate the acetylation level of histone H3, and induce Apoptosis and cell cycle arrest at G2/M phase in HeLa cells. Taken together, these results highlighted that compound 14f might be a promising HDAC Inhibitor for Cancer therapy.

Keywords

Antiproliferative activity; Coumarin; Histone deacetylase; Inhibitors; N-hydroxycinnamamide.

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