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Synthesis and Biological Evaluation of ortho ‐Aryl N ‐Hydroxycinnamides as Potent Histone Deacetylase (HDAC) 8 Isoform‐Selective Inhibitors
Author(s) -
Huang WeiJan,
Wang YiChing,
Chao ShiWei,
Yang ChenYui,
Chen LiangChieh,
Lin MeiHsiang,
Hou WenChi,
Chen MeiYu,
Lee TaiLin,
Yang Ping,
Chang ChungI
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201200300
Subject(s) - hdac8 , acetylation , cytotoxicity , histone deacetylase , isozyme , gene isoform , histone , chemistry , enzyme , biochemistry , cell culture , a549 cell , cancer research , cell , biology , in vitro , genetics , gene
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 n M . 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.