Design, Synthesis, and Biological Activity of NCC149 Derivatives as Histone Deacetylase 8‐Selective Inhibitors

Abstract We recently discovered N ‐hydroxy‐3‐[1‐(phenylthio)methyl‐1 H ‐1,2,3‐triazol‐4‐yl]benzamide (NCC149) as a potent and selective histone deacetylase 8 (HDAC8) inhibitor from a 151‐member triazole compound library using a click chemistry approach. In this work, we present a series of NCC149 derivatives bearing various aromatic linkers that were designed and synthesized as HDAC8‐selective inhibitors. A series of in vitro assays were used to evaluate the newly synthesized compounds, four of which showed HDAC8 inhibitory activity similar to that of NCC149, and one of which displayed HDAC8 selectivity superior to that of NCC149. In addition, these top four compounds induced the increase of acetylated cohesin (an HDAC8 substrate) in HeLa cells in a dose‐dependent manner, indicating inhibition of HDAC8 in the cells. While none of these compounds enhanced the acetylation of H3K9 (a substrate of HDAC1 and 2), only one compound refrained from increasing α‐tubulin acetylation, a substrate of HDAC6, indicating that this compound is more selective for HDAC8 than the other derivatives. Furthermore, this HDAC8‐selective inhibitor suppressed the growth of T‐cell lymphoma cells more potently than did NCC149. These findings are useful for the further development of HDAC8‐selective inhibitors.