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

Autor: Huang WJ; Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Xing St., Taipei 110, Taiwan, Republic of China. wjhuang@tmu.edu.tw, Wang YC, Chao SW, Yang CY, Chen LC, Lin MH, Hou WC, Chen MY, Lee TL, Yang P, Chang CI
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2012 Oct; Vol. 7 (10), pp. 1815-24. Date of Electronic Publication: 2012 Aug 20.
DOI: 10.1002/cmdc.201200300
Abstrakt: 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.
(Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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