含吩噻嗪衍生物的羟肟酸的合成及生物评价作为有效的 II 类组蛋白去乙酰化酶抑制剂。
Synthesis and biological evaluation of phenothiazine derivative-containing hydroxamic acids as potent class II histone deacetylase inhibitors.
机构信息
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.
Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
出版信息
Eur J Med Chem. 2021 Jul 5;219:113419. doi: 10.1016/j.ejmech.2021.113419. Epub 2021 Apr 1.
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 (IC = 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.
阿尔茨海默病（AD）的发病机制与组蛋白去乙酰化酶（HDACs）的失调有关。先前，吖啶基 HDAC 抑制剂已显示出在改善 HDAC 活性和促进神经突生长方面的潜力。在这项研究中，使用各种吩噻嗪衍生物修饰了吖啶环。与临床批准的 HDAC 抑制剂 SAHA 相比，几种衍生化合物对 II 类 HDAC 表现出很强的酶抑制活性。化合物 4f 对 II 类 HDAC 的抑制作用最强（IC=4.6-600 nM），同时也促进了神经突的生长。重要的是，化合物 4f 对神经元细胞没有细胞毒性。进一步评估了化合物 4f 的细胞作用。总的来说，这些发现为治疗神经疾病的 HDAC 抑制提供了一种潜在的策略。
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