| Synthesis and Biological Evaluation of ortho-Aryl N-Hydroxycinnamides as Potent Histone Deacetylase (HDAC) 8 Isoform-Selective Inhibitors. | |
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MedLine Citation:
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PMID: 22907916 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-8-20 |
Journal Detail:
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Title: ChemMedChem Volume: - ISSN: 1860-7187 ISO Abbreviation: ChemMedChem Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-8-21 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101259013 Medline TA: ChemMedChem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Affiliation:
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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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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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