title: Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton.
abstract: Human sirtuin 2 (SIRT2) is an attractive target molecule for development of drugs to treat neurodegenerative diseases and cancer, because SIRT2 inhibitors have a protective effect against neurodegeneration and an anti-proliferative effect on cancer stem cells. We designed and synthesized a series of benzamide derivatives as SIRT2 inhibitor candidates. Among them, compound 17k showed the most potent SIRT2-inhibitory activity (IC50=0.60μM), with more than 150-fold selectivity over SIRT1 and SIRT3 isoforms (IC50 >100μM).
authors.affiliation: Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Taki
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yotaro
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: m-ishikawa@iam.u-tokyo.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugita
authors.affiliation: Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Computational Protein Science, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Wakai
authors.affiliation: Laboratory of Computational Protein Science, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kitao
authors.affiliation: Laboratory of Membrane Proteins, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Era
authors.initials: E
authors.lastname: Morishita
authors.affiliation: Laboratory of Membrane Proteins, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Toyoshima
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D011994:Recombinant Proteins; C037689:benzamide; D056564:Sirtuin 1; D056565:Sirtuin 2; D056566:Sirtuin 3
keywords: SIRT2; Sirtuin