Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Taishogun Nishitakatsukasa-cho, Kita-ku, Kyoto 603-8334, Japan.
J Med Chem. 2012 Jun 28;55(12):5760-73. doi: 10.1021/jm3002108. Epub 2012 Jun 12.
Selective inhibitors of human sirtuin 2 (SIRT2), a deacetylase, are candidate therapeutic agents for neurodegenerative diseases such as Parkinson's disease and Huntington'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'-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 α-tubulin acetylation in human colon cancer HCT116 cells, indicating selective inhibition of SIRT2 in the cells. These 3'-phenethyloxy-2-anilinobenzamide derivatives represent an entry into a new class of SIRT2-selective inhibitors.
基于 SIRT1 和 SIRT2 的同源模型，我们设计并制备了一系列 2-苯胺甲酰胺类似物。使用重组 SIRT1 和 SIRT2 的酶活性测定表明，3'-苯乙氧基-2-苯胺甲酰胺类似物如 33a 和 33i 是强效且选择性的 SIRT2 抑制剂，与先前报道的 SIRT2 选择性抑制剂 AGK2（3）相比，对 SIRT2 的抑制活性高 3.5 倍以上，选择性高 35 倍以上。化合物 33a 还可诱导人结肠癌细胞 HCT116 中 α-微管蛋白乙酰化的剂量依赖性选择性增加，表明其在细胞中对 SIRT2 的选择性抑制作用。这些 3'-苯乙氧基-2-苯胺甲酰胺衍生物代表了一类新型的 SIRT2 选择性抑制剂。
