2. Academic Validation
  3. Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors

Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors

  • Eur J Med Chem. 2021 Jul 5:219:113419. doi: 10.1016/j.ejmech.2021.113419.
Kai-Cheng Hsu 1,  Jung-Chun Chu 2,  Hui-Ju Tseng 2,  Chia-I Liu 3,  Hao-Ching Wang 4,  Tony Eight Lin 5,  Hong-Sheng Lee 6,  Ling-Wei Hsin 7,  Andrew H-J Wang 4,  Chien-Huang Lin 8,  Wei-Jan Huang 9
Affiliations

Affiliations

  • 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 2 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 3 School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 4 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 5 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 6 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 7 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 8 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: chlin@tmu.edu.tw.
  • 9 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: wjhuang@tmu.edu.tw.
PMID: 33845233 DOI: 10.1016/j.ejmech.2021.113419
Abstract

The pathogenesis of Alzheimer's disease (AD) has been associated with dysregulation of histone deacetylases (HDACs). Previously, acridine-based HDAC inhibitors have shown potential in ameliorating HDAC activity and enhancing neurite outgrowth. In this study, the acridine ring was modified using various phenothiazine derivatives. Several resulting compounds exhibited potent enzyme-inhibiting activity towards class II HDACs when compared to the clinically approved HDAC Inhibitor SAHA. Compound 4f demonstrated the highest class II HDAC inhibition (IC50 = 4.6-600 nM), as well as promotion of neurite outgrowth. Importantly, compound 4f displayed no cytotoxicity against neuron cells. Compound 4f was further evaluated for cellular effects. Altogether, these findings show a potential strategy in HDAC inhibition for treatment of the Neurological Disease.

Keywords

Alzheimer’s disease; Histone deacetylase; Neurite outgrowth; Phenothiazine.

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