Synthesis and biological evaluation of ortho-aryl N-hydroxycinnamides as potent histone deacetylase (HDAC) 8 isoform-selective inhibitors.
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.
Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Xing St., Taipei 110, Taiwan, Republic of China. wjhuang@tmu.edu.tw
Wei-Jan
WJ
Huang
Yi-Ching
YC
Wang
Shi-Wei
SW
Chao
Chen-Yui
CY
Yang
Liang-Chieh
LC
Chen
Mei-Hsiang
MH
Lin
Wen-Chi
WC
Hou
Mei-Yu
MY
Chen
Tai-Lin
TL
Lee
Ping
P
Yang
Chung-I
CI
Chang
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D015195:Drug Design; D006207:Half-Life; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases