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

Kai-Cheng Hsu; Jung-Chun Chu; Hui-Ju Tseng; Chia-I Liu; Hao-Ching Wang; Tony Eight Lin; Hong-Sheng Lee; Ling-Wei Hsin; Andrew H-J Wang; Chien-Huang Lin; Wei-Jan Huang

doi:10.1016/j.ejmech.2021.113419

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. Epub 2021 Apr 1.

Authors

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.

MeSH terms

Acetylation / drug effects
Alzheimer Disease / drug therapy
Alzheimer Disease / pathology
Binding Sites
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Drug Design
Histone Deacetylase Inhibitors / chemical synthesis*
Histone Deacetylase Inhibitors / metabolism
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylase Inhibitors / therapeutic use
Histone Deacetylases / chemistry*
Histone Deacetylases / genetics
Histone Deacetylases / metabolism
Histones / metabolism
Humans
Hydroxamic Acids / chemistry*
Molecular Docking Simulation
Neurites / drug effects
Neurites / physiology
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / metabolism
Neuroprotective Agents / pharmacology
Neuroprotective Agents / therapeutic use
Oxidative Stress / drug effects
Phenothiazines / chemistry*
Phenothiazines / metabolism
Phenothiazines / pharmacology
Phenothiazines / therapeutic use
Structure-Activity Relationship
Tubulin / metabolism

Substances

Histone Deacetylase Inhibitors
Histones
Hydroxamic Acids
Neuroprotective Agents
Phenothiazines
Tubulin
Histone Deacetylases
phenothiazine