Novel thiourea-based sirtuin inhibitory warheads

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Zang, Wenwen¹  Hao, Yujun^2,3  Wang, Zhenghe^2,3  Zheng, Weiping¹ 

[1] Jiangsu Univ, Sch Pharm, Zhenjiang 212013, Jiangsu, Peoples R China

[2] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA

关键词: Sirtuin;    SIRT1;    SIRT2;    SIRT3;    SIRT5;    Deacetylation;    Deacylation;    Inhibitory warhead;    N-epsilon-Methyl-thiocarbamoyl-lysine;    N-epsilon-Carboxyethyl-thiocarbamoyl-lysine;   

DOI  :  10.1016/j.bmcl.2015.05.058

来源: Elsevier

【 摘 要 】

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. (C) 2015 Elsevier Ltd. All rights reserved.

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