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.