Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities

Autor: Jung-Chun Chu, Hui-Ju Tseng, Sung-Bau Lee, Kai-Cheng Hsu, Ling-Wei Hsin, Ru-Hao Liang, Tony Eight Lin, Nain-Chu Gao, Liang-Chieh Chen, Wan-Hsun Lu, Andrew H.-J Wang, Wei-Jan Huang
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 38, Iss 1 (2023)
Druh dokumentu: article
ISSN: 14756366
1475-6374
1475-6366
DOI: 10.1080/14756366.2023.2212326
Popis: 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.
Databáze: Directory of Open Access Journals
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