US EPA

7485496 

Journal Article 

Discovery of a series of hydroximic acid derivatives as potent histone deacetylase inhibitors 

Zhang, L; Wang, X; Li, X; Zhang, L; Xu, W 

2014 

Yes 

Journal of Enzyme Inhibition and Medicinal Chemistry
ISSN: 1475-6366
EISSN: 1475-6374 

Informa Healthcare 

29 

4 

582-589 

English 

10.3109/14756366.2013.827678 

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 11.7nm and 967nm 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. © 2014 Informa UK Ltd. 

Anti-tumor; Histone deacetylase; Inhibitor; Structural modification; (s) 2 amino n benzyl 2 phenylacetamide hydrochloride; (s) 2 [(tert butoxycarbonyl)amino] 2 phenylacetic acid; (s) 4 (3 (2 (furan 2 ylamino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((2 fluorophenyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((2,4 dichlorophenyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((2,6 diisopropylphenyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hyroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((3 chlorophenyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((3 fluoro 4 methoxyphenyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((3,5 dimethylphenyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((3-bromophenyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((4 (tert butyl)phenyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) 4 [3 (2 ((4 fluorobenzyl)amino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (S) 4 [3 (2 (benzylamino) 2 oxo 1 phenylethyl)ureido] n [6 (hydroxyamino) 6 oxohexyl]benzamide; (s) methyl 6 [4 (3 (2 (benzylamino) 2 oxo 1 phenylethyl)ureido)benzamido]hexanoate; (s) n [6 (hydroxyamino) 6 oxohexyl] 4 [3 (2 ((2 hydroxyphenyl)amino) 2 oxo 1 phenylethyl)ureido]benzamide; (s) n [6 (hydroxyamino) 6 oxohexyl] 4 [3 (2 ((2 methoxyphenyl)amino) 2 oxo 1 phenylethyl)ureido]benzamide; (s) n [6 (hydroxyamino) 6 oxohexyl] 4 [3 (2 (naphthalen 1 ylamino) 2 oxo 1 phenylethyl)ureido]benzamide; (s) n [6 (hydroxyamino) 6 oxohexyl] 4 [3 (2 oxo 1 phenyl 2 ((3 (trifluoromethyl)phenyl)amino)ethyl)ureido]benzamide; (s) n [6 (hydroxyamino) 6 oxohexyl] 4 [3 (2 oxo 1 phenyl 2 (m tolylamino)ethyl)ureido]benzamide; (s) n [6 (hydroxyamino) 6 oxohexyl] 4 [3 (2 oxo 1 phenyl 2 (o tolylamino)ethyl)ureido]benzamide; (s) n [6 (hydroxyamino) 6 oxohexyl] 4 [3 (2 oxo 1 phenyl 2 (p tolyamino)ethyl)ureido]benzamide; (s) tert butyl [2 (benzylamino) 2 oxo 1 phenylethyl]carbamate; antineoplastic agent; histone deacetylase inhibitor; hydroximic acid derivative; methyl 6 aminohexanoate hydrochloride; unclassified drug; vorinostat; carbanilamide derivative; HDAC2 protein, human; HDAC8 protein, human; histone deacetylase; histone deacetylase 2; histone deacetylase inhibitor; hydroxamic acid; ligand; N-(6-(hydroxyamino)-6-oxohexyl)-4-(3-(2-oxo-1-phenyl-2-((3-(trifluoromethyl)phenyl)amino)ethyl)ureido)benzamide; repressor protein; article; controlled study; crystal structure; drug development; drug synthesis; electrospray mass spectrometry; enzyme activity; enzyme inhibition; enzyme inhibition assay; female; HeLa cell line; human; human cell; hydrophobicity; IC 50; molecular docking; MTT assay; priority journal; proton nuclear magnetic resonance; tumor growth; antagonists and inhibitors; chemical structure; chemistry; dose response; drug effects; enzyme active site; metabolism; structure activity relation; synthesis; Catalytic Domain; Dose-Response Relationship, Drug; Drug Discovery; HeLa Cells; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Ligands; Molecular Structure; Phenylurea Compounds; Repressor Proteins; Structure-Activity Relationship