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

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

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

机译：含苯甲苯胺衍生物的羟肟酸的合成与生物学评价为有效的II类组蛋白脱乙酰酶抑制剂

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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. (C) 2021 Elsevier Masson SAS. All rights reserved.

机译：阿尔茨海默病（AD）的发病机制与组蛋白去乙酰化酶（HDAC）的失调有关。此前，基于吖啶的HDAC抑制剂已显示出改善HDAC活性和促进神经突起生长的潜力。在这项研究中，使用各种吩噻嗪衍生物对吖啶环进行了修饰。与临床批准的HDAC抑制剂SAHA相比，几种合成化合物对II类HDAC表现出强大的酶抑制活性。化合物4f表现出最高的II类HDAC抑制（IC50=4.6-600 nM），以及促进神经突起生长。重要的是，化合物4f对神经元细胞没有细胞毒性。进一步评估化合物4f的细胞效应。总之，这些发现显示了抑制HDAC治疗神经系统疾病的潜在策略。（c）2021爱思唯尔马松SAS。版权所有。

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来源
《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2021年第1期|共12页
作者
Hsu Kai-Cheng; Chu Jung-Chun; Tseng Hui-Ju; Liu Chia- I; Wang Hao-Ching; Lin Tony Eight; Lee Hong-Sheng; Hsin Ling-Wei; Wang Andrew H-J; Lin Chien-Huang; Huang Wei-Jan;
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作者单位

Taipei Med Univ Coll Med Sci &

Technol Grad Inst Canc Biol &

Drug Discovery Taipei Taiwan;

Taipei Med Univ Coll Pharm PhD Program Drug Discovery &

Dev Ind Taipei Taiwan;

Taipei Med Univ Coll Pharm PhD Program Drug Discovery &

Dev Ind Taipei Taiwan;

Taipei Med Univ Coll Med Sci &

Technol Sch Med Lab Sci &

Biotechnol Taipei Taiwan;

Taipei Med Univ Coll Med Sci &

Technol PhD Program Translat Med Taipei Taiwan;

Taipei Med Univ Coll Med Sci &

Technol Grad Inst Canc Biol &

Drug Discovery Taipei Taiwan;

Taipei Med Univ Coll Med Grad Inst Med Sci Taipei Taiwan;

Natl Taiwan Univ Coll Med Sch Pharm Taipei Taiwan;

Taipei Med Univ Coll Med Sci &

Technol PhD Program Translat Med Taipei Taiwan;

Taipei Med Univ Coll Med Grad Inst Med Sci Taipei Taiwan;

Taipei Med Univ Coll Pharm PhD Program Drug Discovery &

Dev Ind Taipei Taiwan;

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正文语种 eng
中图分类药学;
关键词
Histone deacetylase; Alzheimer's disease; Phenothiazine; Neurite outgrowth;

机译：组蛋白脱乙酰酶;阿尔茨海默病;吩噻嗪;神经突起生长;

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

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