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

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

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12 Citations (Scopus)

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.

Original language	English
Article number	113419
Journal	European Journal of Medicinal Chemistry
Volume	219
DOIs	https://doi.org/10.1016/j.ejmech.2021.113419
Publication status	Published - Jul 5 2021

Keywords

Alzheimer's disease
Histone deacetylase
Neurite outgrowth
Phenothiazine

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2021.113419

https://www.sciencedirect.com/science/article/pii/S0223523421002683

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Hsu, K.-C., Chu, J.-C., Tseng, H.-J., Liu, C.-I., Wang, H.-C., Lin, T. E., Lee, H.-S., Hsin, L.-W., Wang, A. H.-J., Lin, C.-H., & Huang, W.-J. (2021). Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors. European Journal of Medicinal Chemistry, 219, Article 113419. https://doi.org/10.1016/j.ejmech.2021.113419

Hsu, K-C, Chu, J-C, Tseng, H-J, Liu, C-I, Wang, H-C, Lin, TE, Lee, H-S, Hsin, L-W, Wang, AH-J , Lin, C-H & Huang, W-J 2021, 'Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors', European Journal of Medicinal Chemistry, vol. 219, 113419. https://doi.org/10.1016/j.ejmech.2021.113419

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

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",

author = "Kai-Cheng Hsu and Jung-Chun Chu and Hui-Ju Tseng and Chia-I Liu and Hao-Ching Wang and Lin, {Tony Eight} and Hong-Sheng Lee and Ling-Wei Hsin and Wang, {Andrew H.-J.} and Chien-Huang Lin and Wei-Jan Huang",

note = "Funding Information: We gratefully acknowledge the support from the Ministry of Science and Technology ( MOST108-2320-B-038 -036 and MOST108-2320-B-038-058-MY3 ) in Taiwan. This research was also partially supported by the Taiwan Protein Project (Grant No. MOST105-0210-01-12-01 and Grant No. MOST106-0210-01-15-04 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Masson SAS",

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AU - Hsu, Kai-Cheng

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AU - Wang, Hao-Ching

AU - Lin, Tony Eight

AU - Lee, Hong-Sheng

AU - Hsin, Ling-Wei

AU - Wang, Andrew H.-J.

AU - Lin, Chien-Huang

AU - Huang, Wei-Jan

N1 - Funding Information: We gratefully acknowledge the support from the Ministry of Science and Technology ( MOST108-2320-B-038 -036 and MOST108-2320-B-038-058-MY3 ) in Taiwan. This research was also partially supported by the Taiwan Protein Project (Grant No. MOST105-0210-01-12-01 and Grant No. MOST106-0210-01-15-04 ). Publisher Copyright: © 2021 Elsevier Masson SAS

PY - 2021/7/5

Y1 - 2021/7/5

N2 - 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.

AB - 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.

KW - Alzheimer's disease

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KW - Neurite outgrowth

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

Abstract

Keywords

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