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Synthesis and biological evaluation of ortho-aryl N-hydroxycinnamides as potent histone deacetylase (HDAC) 8 isoform-selective inhibitors.

Abstract
Histone deacetylases (HDACs) are a family of enzymes that play a crucial role in biological process and diseases. In contrast to other isozymes, HDAC8 is uniquely incapable of histone acetylation. In order to delineate its physiological function, we developed HDAC8-selective inhibitors using knowledge-based design combined with structural modeling techniques. Enzyme inhibitory analysis demonstrated that some of the resulting compounds (22 b, 22 d, 22 f, and 22 g) exhibited anti-HDAC8 activity superior to PCI34051, a known HDAC8-specific inhibitor, with IC(50) values in the range of 5-50 nM. Among them, compound 22 d showed antiproliferative effects toward several human lung cancer cell lines (A549, H1299, and CL1-5); it exhibited cytotoxicity against human lung CL1-5 cells similar to that of SAHA yet without significant cytotoxicity for normal IMR-90 cells. Expression profiling of HDAC isoforms in three cancer cell lines indicated that the HDAC8 level in CL1-5 is higher than that in H1299 and CL1-1 cells, a result consistent with the differential cytotoxicity of compound 22 d. These results suggest the effectiveness of our design concept, which may lead to a tool compound for studying the specific role of HDAC8 in cellular biological processes.
AuthorsWei-Jan Huang, Yi-Ching Wang, Shi-Wei Chao, Chen-Yui Yang, Liang-Chieh Chen, Mei-Hsiang Lin, Wen-Chi Hou, Mei-Yu Chen, Tai-Lin Lee, Ping Yang, Chung-I Chang
JournalChemMedChem (ChemMedChem) Vol. 7 Issue 10 Pg. 1815-24 (Oct 2012) ISSN: 1860-7187 [Electronic] Germany
PMID22907916 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Chemical References
  • Amides
  • Cinnamates
  • Histone Deacetylase Inhibitors
  • Repressor Proteins
  • HDAC8 protein, human
  • Histone Deacetylases
Topics
  • Amides (chemical synthesis, chemistry, toxicity)
  • Binding Sites
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Cinnamates (chemical synthesis, chemistry, toxicity)
  • Drug Design
  • Half-Life
  • HeLa Cells
  • Histone Deacetylase Inhibitors (chemical synthesis, chemistry, toxicity)
  • Histone Deacetylases (metabolism)
  • Humans
  • Molecular Docking Simulation
  • Repressor Proteins (antagonists & inhibitors, metabolism)

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