Synthesis and Biological Evaluation of ortho-Aryl N-Hydroxycinnamides as Potent Histone Deacetylase (HDAC) 8 Isoform-Selective Inhibitors

Wei 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

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 (22b, 22d, 22f, and 22g) exhibited anti-HDAC8 activity superior to PCI34051, a known HDAC8-specific inhibitor, with IC50 values in the range of 5-50nM. Among them, compound 22d 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 22d. 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.

Original languageEnglish
Pages (from-to)1815-1824
Number of pages10
JournalChemMedChem
Volume7
Issue number10
DOIs
Publication statusPublished - Oct 2012

    Fingerprint

Keywords

  • Cinnamides
  • Epigenetics
  • Histone deacetylases
  • Isoform-selective inhibitors
  • Molecular modeling

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this