Synthesis and Biological Evaluation of ortho-Aryl N-Hydroxycinnamides as Potent Histone Deacetylase (HDAC) 8 Isoform-Selective Inhibitors

• Published in: ChemMedChem 2012-10, Vol.7 (10), p.1815-1824
• Main Authors: Huang, Wei-Jan, Wang, Yi-Ching, Chao, Shi-Wei, Yang, Chen-Yui, Chen, Liang-Chieh, Lin, Mei-Hsiang, Hou, Wen-Chi, Chen, Mei-Yu, Lee, Tai-Lin, Yang, Ping, Chang, Chung-I
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - toxicity; Binding Sites; Cell Line, Tumor; Cell Survival - drug effects; Cinnamates - chemical synthesis; Cinnamates - chemistry; Cinnamates - toxicity; cinnamides; Cytotoxicity; Drug Design; epigenetics; Half-Life; HeLa Cells; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - toxicity; histone deacetylases; Histone Deacetylases - metabolism; Humans; isoform-selective inhibitors; Molecular Docking Simulation; molecular modeling; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - metabolism
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201200300

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 IC50 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. Spec‐HDAC‐ular! Several ortho‐aryl N‐hydroxycinnamides with potent HDAC8 inhibitory activity were synthesized by knowledge‐based design combined with molecular modeling techniques. One compound, (E)‐N‐hydroxy‐4‐methoxy‐2‐(biphenyl‐4‐yl)cinnamide (22 d), exhibited higher cellular effects than PCI34051 on several human lung cancer cells. The results suggest that this compound may be used as a tool to probe the physiological role of HDAC8.