Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton

Taki Sakai; Yotaro Matsumoto; Minoru Ishikawa; Kazuyuki Sugita; Yuichi Hashimoto; Nobuhiko Wakai; Akio Kitao; Era Morishita; Chikashi Toyoshima; Tomoatsu Hayashi; Tetsu Akiyama

doi:10.1016/j.bmc.2014.11.027

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. doi: 10.1016/j.bmc.2014.11.027. Epub 2014 Dec 2.

Authors

Affiliations

¹ Laboratory of Bioorganic Chemistry, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
² 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.
³ Laboratory of Computational Protein Science, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁴ Laboratory of Membrane Proteins, Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁵ 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.

PMID: 25515955
DOI: 10.1016/j.bmc.2014.11.027

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).

Keywords: SIRT2; Sirtuin.

MeSH terms

Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / metabolism
Binding Sites
Drug Design*
Histone Deacetylase Inhibitors / chemical synthesis*
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / metabolism
Humans
Molecular Docking Simulation
Protein Binding
Protein Structure, Tertiary
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Sirtuin 1 / antagonists & inhibitors
Sirtuin 1 / metabolism
Sirtuin 2 / antagonists & inhibitors*
Sirtuin 2 / genetics
Sirtuin 2 / metabolism
Sirtuin 3 / antagonists & inhibitors
Sirtuin 3 / metabolism
Structure-Activity Relationship

Substances

Benzamides
Histone Deacetylase Inhibitors
Recombinant Proteins
benzamide
Sirtuin 1
Sirtuin 2
Sirtuin 3