title: Novel thiourea-based sirtuin inhibitory warheads.
abstract: N(ε)-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(ε)-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that N(ε)-methyl-thiocarbamoyl-lysine and N(ε)-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(ε)-methyl-thiocarbamoyl-lysine was found in the study to be a ∼ 2.5-18.4-fold stronger SIRT1/2/3 inhibitory warhead than its lead warhead N(ε)-thiocarbamoyl-lysine.
authors.affiliation: School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zang
authors.affiliation: Department of Genetics & Genome Sciences and Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Genetics & Genome Sciences and Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, PR China. Electronic address: wzheng@ujs.edu.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zheng
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D056564:Sirtuin 1; D056565:Sirtuin 2; D013890:Thiourea
keywords: Deacetylation; Deacylation; Inhibitory warhead; N(ε)-Carboxyethyl-thiocarbamoyl-lysine; N(ε)-Methyl-thiocarbamoyl-lysine; SIRT1; SIRT2; SIRT3; SIRT5; Sirtuin