Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases.

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Kai-Cheng Hsu, Yun-Yi Huang, Jung-Chun Chu, Yu-Wen Huang, Jing-Lan Hu, Tony Eight Lin, Shih-Chung Yen, Jing-Ru Weng, Wei-Jan Huang
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引用次数: 0

Abstract

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.

对 IIa 类组蛋白去乙酰化酶具有更好选择性的含吩噻嗪的正苯基苯基羟肟酸的合成和生物学评价。
IIa类组蛋白去乙酰化酶(HDAC)与多种癌症的肿瘤发生有关。此前,我们设计了苯羟肟酸 LH4f 作为一种强效 IIa 类 HDAC 抑制剂。然而,它对 I 类和 IIb 类 HDAC 也有非选择性抑制作用。为了提高该化合物对 IIa 类 HDAC 的选择性,选择性 HDAC7 抑制剂 1 的正苯基被并入 LH4f 中苯基羟肟酸的正交位置。与 LH4f 相比,大多数所得化合物对 IIa 类 HDAC 的选择性都有大幅提高。值得注意的是,化合物 7 g 对 HDAC9 的抑制作用最强,其 IC50 值为 40 nM。分子建模进一步确定了化合物 7 g 与 HDAC9 结合的关键相互作用。化合物 7 g 能明显抑制多种人类癌细胞,诱导细胞凋亡,调节 Caspase 相关蛋白和 p38,并造成 DNA 损伤。这些发现表明,IIa 类 HDAC 抑制剂有可能成为开发癌症治疗药物的先导化合物。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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