Abstract
To develop potent histone deacetylase inhibitors as antitumor agents, structural modification was performed. The synthesized molecules were tested by enzymatic inhibition assay and anti-proliferation assay. Several molecules show improved activities in the enzymatic inhibition assay. However, in the MTT assays, all these derived molecules have limited performance compared with SAHA. The IC50 values of molecule ((S)-N-(6-(hydroxyamino)-6-oxohexyl)-4-(3-(2-oxo-1-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethyl)ureido)benzamide, L8) which has the best enzymatic inhibition activity (with an IC50 value of 11.7 nm and 967 nm against Hela nucleus extract and HDAC8, respectively) were calculated compared with SAHA. Molecular docking was performed to predict the binding mode of molecule L8 in the active site of HDAC2 and HDAC8. Hydrophobic interaction, chelate binding, electrostatic attraction and H-bond interaction in combination make contribution to the ligand-receptor interactions.
Keywords:
Anti-tumor; histone deacetylase; inhibitor; structural modification.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Catalytic Domain / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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HeLa Cells
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Histone Deacetylase 2 / antagonists & inhibitors*
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Histone Deacetylase 2 / metabolism
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Histone Deacetylase Inhibitors / chemical synthesis
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Histone Deacetylase Inhibitors / chemistry
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / metabolism
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Humans
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Hydroxamic Acids / chemical synthesis
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology*
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Ligands
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Molecular Structure
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Phenylurea Compounds / chemical synthesis
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Phenylurea Compounds / chemistry
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Phenylurea Compounds / pharmacology*
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Repressor Proteins / antagonists & inhibitors*
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Repressor Proteins / metabolism
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Structure-Activity Relationship
Substances
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Ligands
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N-(6-(hydroxyamino)-6-oxohexyl)-4-(3-(2-oxo-1-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethyl)ureido)benzamide
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Phenylurea Compounds
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Repressor Proteins
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HDAC2 protein, human
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HDAC8 protein, human
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Histone Deacetylase 2
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Histone Deacetylases