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Synthesis and Biological Evaluation of ortho-Aryl N-Hydroxycinnamides as Potent Histone Deacetylase (HDAC) 8 Isoform-Selective Inhibitors.
MedLine Citation:
PMID:  22907916     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-20
Journal Detail:
Title:  ChemMedChem     Volume:  -     ISSN:  1860-7187     ISO Abbreviation:  ChemMedChem     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101259013     Medline TA:  ChemMedChem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Affiliation:
Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Xing St., Taipei 110 (Taiwan, Republic of China). wjhuang@tmu.edu.tw.
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