Synthesis, Biological Evaluation, and Computer-Aided Drug Designing of New Derivatives of Hyperactive Suberoylanilide Hydroxamic Acid Histone Deacetylase Inhibitors

Song Zhang, Weibin Huang, Xiaonan Li, Zhicheng Yang, Binghong Feng*

*Corresponding author for this work

Research output: Contribution to journalArticle

8 Scopus citations

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 μm; U251, IC50 = 0.8949 μm) and lower toxicity for human normal cells (LO2, IC50 = 172.5 μm and MRC5, IC50 = 213.6 μm) compared with SAHA (HDAC, IC50 = 0.8717 μm; U251, IC50 = 8.938 μm; LO2, IC50 = 86.52 μm and MRC5, IC50 = 81.02 μm). 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.

Original languageEnglish (US)
Pages (from-to)795-804
Number of pages10
JournalChemical Biology and Drug Design
Volume86
Issue number4
DOIs
StatePublished - Oct 1 2015

Keywords

  • Bcl-2
  • Beclin-1
  • Caspase-3, 9
  • histone deacetylase inhibitor
  • human normal cells (LO2 and MRC5)
  • proliferation inhibition of human glioma cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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