Novel thiourea-based sirtuin inhibitory warheads

作者：Zang, Wenwen; Hao, Yujun; Wang, Zhenghe; Zheng, Weiping^*

来源：Bioorganic & Medicinal Chemistry Letters, 2015, 25(16): 3319-3324.

DOI：10.1016/j.bmcl.2015.05.058

• Sirtuin
• SIRT1
• SIRT2
• SIRT3
• SIRT5
• Deacetylation
• Deacylation
• Inhibitory warhead
• N-epsilon-Methyl-thiocarbamoyl-lysine
• N-epsilon-Carboxyethyl-thiocarbamoyl-lysine

N-epsilon-Thiocarbamoyl-lysine was recently demonstrated by our laboratory to be a potent catalytic mechanism- based SIRT1/2/3 inhibitory warhead, in the current study, among the prepared analogs of N-epsilon-thiocarbamoyl- lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that N-epsilon-methyl- thiocarbamoyl-lysine and N-epsilon-carboxyethyl-thiocarbamoyl-lysine, respectively, also behaved as strong inhibitory warheads against SIRT1/2/3 and SIRT5, typical deacetylases and deacylase in the human sirtuin family, respectively. Moreover, N-epsilon-methyl-thiocarbamoyl-lysine was found in the study to be a similar to 2.5-18.4-fold stronger SIRT1/2/3 inhibitory warhead than its lead warhead N-epsilon-thiocarbamoyl-lysine.

• 出版日期2015-8-15
• 单位江苏大学