Synthesis and biological evaluation of C-4 substituted phenoxazine-bearing hydroxamic acids with potent class II histone deacetylase inhibitory activities.
Journal of enzyme inhibition and medicinal chemistry(2023)
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 exhibited the most potent class II HDAC inhibition (IC= 3-870 nM). Notably, it protected neuron cells from HO-induced neuron damage at sub-μM concentrations, but with no significant cytotoxicity. These findings show that compound is a lead compound for further development of anti-neurodegenerative agents.
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关键词
hydroxamic acids,synthesis,phenoxazine-bearing
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