Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities
Journal
Journal of enzyme inhibition and medicinal chemistry
Journal Volume
38
Journal Issue
1
Pages
2212326
Date Issued
2023-12
Author(s)
Chu, Jung-Chun
Tseng, Hui-Ju
Lee, Sung-Bau
Hsu, Kai-Cheng
Liang, Ru-Hao
Lin, Tony Eight
Gao, Nain-Chu
Chen, Liang-Chieh
Lu, Wan-Hsun
Wang, Andrew H-J
Huang, Wei-Jan
Abstract
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.
Subjects
Histone deacetylase (HDAC); neuron cells; phenoxazine; structure-activity relationship (SAR)
SDGs
Type
journal article