title: Identification of a potent non-hydroxamate histone deacetylase inhibitor by mechanism-based drug design.
abstract: In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, we synthesized several suberoylanilide hydroxamic acid (SAHA)-based compounds designed on the basis of the catalytic mechanism of HDACs. Among these compounds, 5b was found to be as potent as SAHA. Kinetic enzyme assays and molecular modeling suggested that the mercaptoacetamide moiety of 5b interacts with the zinc in the active site of HDACs and removes a water molecule from the reactive site of the deacetylation.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan. suzuki@phar.nagoya-cu.ac.jp
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Azusa
authors.initials: A
authors.lastname: Matsuura
authors.forename: Akiyasu
authors.initials: A
authors.lastname: Kouketsu
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
mesh_terms: D000081:Acetamides / Q000737:chemistry; D000107:Acetylation; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D000077337:Vorinostat; D015032:Zinc / Q000737:chemistry
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013438:Sulfhydryl Compounds; D000077337:Vorinostat; C030686:acetamide; D015032:Zinc