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

作者：Suzuki Takayoshi^*; Khan Mohammed Naseer Ahmed; Sawada Hideyuki; Imai Erika; Itoh Yukihiro; Yamatsuta Katsura; Tokuda Natsuko; Takeuchi Jun; Seko Takuya; Nakagawa Hidehiko; Miyata Naoki

来源：Journal of Medicinal Chemistry, 2012, 55(12): 5760-5773.

DOI：10.1021/jm3002108

Selective inhibitors of human sirtuin 2 (SIRT2), a deacetylase, are candidate therapeutic agents for neurodegenerative diseases such as Parkinson%26apos;s disease and Huntington%26apos;s 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%26apos;-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 alpha-tubulin acetylation in human colon cancer HCT116 cells, indicating selective inhibition of SIRT2 in the cells. These 3%26apos;-phenethyloxy-2-anilinobenzamide derivatives represent an entry into a new class of SIRT2-selective inhibitors.

• 出版日期2012-6-28