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Synthesis, Biological Evaluation, and Computer‐Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors
Author(s) -
Zhang Song,
Huang Weibin,
Li Xiaonan,
Yang Zhicheng,
Feng Binghong
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12554
Subject(s) - histone deacetylase , hydroxamic acid , chemistry , docking (animal) , lead compound , histone deacetylase inhibitor , glioma , hdac8 , cell culture , pharmacology , stereochemistry , biochemistry , histone , cancer research , in vitro , biology , medicine , genetics , nursing , gene
The synthesis and biological evaluation of a novel series of compounds based on suberoylanilide hydroxamic acid ( SAHA ) had been designed as potential histone deacetylase inhibitors ( HDAC is). Molecular docking studies indicated that our derivatives had better fitting in the binding sites of HDAC 8 than SAHA . Compounds 1–5 were synthesized through the synthetic routes. In biological test, compounds also showed good inhibitory activity in HDAC enzyme assay and more potent growth inhibition in human glioma cell lines ( MGR 2, U251, and U373). A representative compound, N3F, exhibited better inhibitory effect ( HDAC , IC 50 = 0.1187 μ m ; U251, IC 50 = 0.8949 μ m ) and lower toxicity for human normal cells ( LO 2, IC 50 = 172.5 μ m and MRC 5, IC 50 = 213.6 μ m ) compared with SAHA ( HDAC , IC 50 = 0.8717 μ m ; U251, IC 50 = 8.938 μ m ; LO 2, IC 50 = 86.52 μ m and MRC 5, IC 50 = 81.02 μ m ). In addition, N3F obviously increased Beclin‐1 and Caspase‐3 and 9 as well as inhibited Bcl‐2 in U251 cells. All of our results indicated that these SAHA cap derivatives could serve as potential lead compounds for further optimization. In addition, N3F and N2E both displayed promising profile as antitumor candidates for the treatment of human glioma.