title: Design, synthesis, and biological activity of NCC149 derivatives as histone deacetylase 8-selective inhibitors.
abstract: We recently discovered N-hydroxy-3-[1-(phenylthio)methyl-1H-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.
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun, Nishitakatsukasa-cho, Kita-ku, Kyoto 603-8334 (Japan); PRESTO (Japan) Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan). suzukit@koto.kpu-m.ac.jp.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Nobusuke
authors.initials: N
authors.lastname: Muto
authors.forename: Masashige
authors.initials: M
authors.lastname: Bando
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.forename: Ayako
authors.initials: A
authors.lastname: Masaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Ri
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ota
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C000592886:N-hydroxy-3-(1-(phenylthio)methyl-1H-1,2,3-triazol-4-yl)benzamide; D012097:Repressor Proteins; D014230:Triazoles; C409470:HDAC8 protein, human; D006655:Histone Deacetylases
keywords: T-cell lymphomas; anticancer agents; histone deacetylase; inhibitors; isozyme selectivity