https://scholars.lib.ntu.edu.tw/handle/123456789/641457
標題: | Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities | 作者: | Chu, Jung-Chun Tseng, Hui-Ju Lee, Sung-Bau Hsu, Kai-Cheng LING-WEI HSIN Liang, Ru-Hao Lin, Tony Eight Gao, Nain-Chu Chen, Liang-Chieh Lu, Wan-Hsun Wang, Andrew H-J Huang, Wei-Jan |
關鍵字: | Histone deacetylase (HDAC); neuron cells; phenoxazine; structure-activity relationship (SAR) | 公開日期: | 十二月-2023 | 卷: | 38 | 期: | 1 | 起(迄)頁: | 2212326 | 來源出版物: | Journal of enzyme inhibition and medicinal chemistry | 摘要: | Class II histone deacetylases (HDACs) are considered as potential targets to treat Alzheimer's disease (AD). Previously, C-3 substituted phenothiazine-containing compounds with class II HDAC-inhibiting activities was found to promote neurite outgrowth. This study replaced phenothiazine moiety with phenoxazine that contains many C-3 and C-4 substituents. Some resulting compounds bearing the C-4 substituent on a phenoxazine ring displayed potent class II HDAC inhibitory activities. Structure-activity relationship (SAR) of these compounds that inhibited HDAC isoenzymes was disclosed. Molecular modelling analysis demonstrates that the potent activities of C-4 substituted compounds probably arise from π-π stacked interactions between these compounds and class IIa HDAC enzymes. One of these, compound 7d exhibited the most potent class II HDAC inhibition (IC50= 3-870 nM). Notably, it protected neuron cells from H2O2-induced neuron damage at sub-μM concentrations, but with no significant cytotoxicity. These findings show that compound 7d is a lead compound for further development of anti-neurodegenerative agents. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/641457 | ISSN: | 14756366 | DOI: | 10.1080/14756366.2023.2212326 |
顯示於: | 藥學系 |
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