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Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton.
Bioorg Med Chem. 2015 Jan 15; 23(2):328-39.BM

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).

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Publisher Full Text (DOI)

Authors+Show Affiliations

Sakai T
Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Matsumoto Y
Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Ishikawa M
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.
Sugita K
Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Hashimoto Y
Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Wakai N
Laboratory of Computational Protein Science, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Kitao A
Laboratory of Computational Protein Science, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Morishita E
Laboratory of Membrane Proteins, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Toyoshima C
Laboratory of Membrane Proteins, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Hayashi T
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.
Akiyama T
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.

MeSH

BenzamidesBinding SitesDrug DesignHistone Deacetylase InhibitorsHumansMolecular Docking SimulationProtein BindingProtein Structure, TertiaryRecombinant ProteinsSirtuin 1Sirtuin 2Sirtuin 3Structure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25515955

Citation

Sakai, Taki, et al. "Design, Synthesis and Structure-activity Relationship Studies of Novel Sirtuin 2 (SIRT2) Inhibitors With a Benzamide Skeleton." Bioorganic & Medicinal Chemistry, vol. 23, no. 2, 2015, pp. 328-39.
Sakai T, Matsumoto Y, Ishikawa M, et al. Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton. Bioorg Med Chem. 2015;23(2):328-39.
Sakai, T., Matsumoto, Y., Ishikawa, M., Sugita, K., Hashimoto, Y., Wakai, N., Kitao, A., Morishita, E., Toyoshima, C., Hayashi, T., & Akiyama, T. (2015). Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton. Bioorganic & Medicinal Chemistry, 23(2), 328-39. https://doi.org/10.1016/j.bmc.2014.11.027
Sakai T, et al. Design, Synthesis and Structure-activity Relationship Studies of Novel Sirtuin 2 (SIRT2) Inhibitors With a Benzamide Skeleton. Bioorg Med Chem. 2015 Jan 15;23(2):328-39. PubMed PMID: 25515955.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton. AU - Sakai,Taki, AU - Matsumoto,Yotaro, AU - Ishikawa,Minoru, AU - Sugita,Kazuyuki, AU - Hashimoto,Yuichi, AU - Wakai,Nobuhiko, AU - Kitao,Akio, AU - Morishita,Era, AU - Toyoshima,Chikashi, AU - Hayashi,Tomoatsu, AU - Akiyama,Tetsu, Y1 - 2014/12/02/ PY - 2014/10/27/received PY - 2014/11/18/revised PY - 2014/11/19/accepted PY - 2014/12/18/entrez PY - 2014/12/18/pubmed PY - 2015/9/9/medline KW - SIRT2 KW - Sirtuin SP - 328 EP - 39 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 23 IS - 2 N2 - 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). SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/25515955/Design_synthesis_and_structure_activity_relationship_studies_of_novel_sirtuin_2__SIRT2__inhibitors_with_a_benzamide_skeleton_ DB - PRIME DP - Unbound Medicine ER -