Design, Synthesis, and Biological Activity of a Novel Series of Human Sirtuin-2-Selective Inhibitors

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• 作者：Takayoshi Suzuki ; Mohammed Naseer Ahmed Khan ; Hideyuki Sawada ; Erika Imai ; Yukihiro Itoh ; Katsura Yamatsuta ; Natsuko Tokuda ; Jun Takeuchi ; Takuya Seko ; Hidehiko Nakagawa ; Naoki Miyata
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 28, 2012
• 年：2012
• 卷：55
• 期：12
• 页码：5760-5773
• 全文大小：541K
• 年卷期：v.55,no.12(June 28, 2012)
• ISSN：1520-4804

文摘

Selective inhibitors of human sirtuin 2 (SIRT2), a deacetylase, are candidate therapeutic agents for neurodegenerative diseases such as Parkinson鈥檚 disease and Huntington鈥檚 disease as well as potential tools for elucidating the biological functions of SIRT2. On the basis of homology models of SIRT1 and SIRT2, we designed and prepared a series of 2-anilinobenzamide analogues. Enzyme assays using recombinant SIRT1 and SIRT2 revealed that 3鈥?phenethyloxy-2-anilinobenzamide analogues such as 33a and 33i are potent and selective SIRT2 inhibitors, showing more than 3.5-fold greater SIRT2-inhibitory activity and more than 35-fold greater SIRT2-selectivity compared with AGK2 (3), a previously reported SIRT2-selective inhibitor. Compound 33a also induced a dose-dependent selective increase of 伪-tubulin acetylation in human colon cancer HCT116 cells, indicating selective inhibition of SIRT2 in the cells. These 3鈥?phenethyloxy-2-anilinobenzamide derivatives represent an entry into a new class of SIRT2-selective inhibitors.