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- Title
Synthesis, Biological Evaluation, and Computer-Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors.
- Authors
Zhang, Song; Huang, Weibin; Li, Xiaonan; Yang, Zhicheng; Feng, Binghong
- Abstract
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 ( HDACis). Molecular docking studies indicated that our derivatives had better fitting in the binding sites of HDAC8 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 ( MGR2, U251, and U373). A representative compound, N3F, exhibited better inhibitory effect ( HDAC, IC50 = 0.1187 μ m; U251, IC50 = 0.8949 μ m) and lower toxicity for human normal cells ( LO2, IC50 = 172.5 μ m and MRC5, IC50 = 213.6 μ m) compared with SAHA ( HDAC, IC50 = 0.8717 μ m; U251, IC50 = 8.938 μ m; LO2, IC50 = 86.52 μ m and MRC5, IC50 = 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.
- Subjects
HISTONE deacetylase inhibitors; COMPUTER-assisted drug design; HYDROXAMIC acids; GLIOMA treatment; CANCER cell proliferation; MOLECULAR docking; BINDING sites
- Publication
Chemical Biology & Drug Design, 2015, Vol 86, Issue 4, p795
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12554