Novel thiourea-based sirtuin inhibitory warheads

[Display omitted] Nε-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 Nε-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups,...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2015-08, Vol.25 (16), p.3319-3324
Main Authors: Zang, Wenwen, Hao, Yujun, Wang, Zhenghe, Zheng, Weiping
Format: Article
Language:English
Subjects:
Deacetylation
Deacylation
Enzyme Activation - drug effects
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Humans
Inhibitory warhead
Molecular Structure
Nε-Carboxyethyl-thiocarbamoyl-lysine
Nε-Methyl-thiocarbamoyl-lysine
SIRT1
SIRT2
SIRT3
SIRT5
Sirtuin
Sirtuin 1 - antagonists & inhibitors
Sirtuin 2 - antagonists & inhibitors
Thiourea - chemistry
Thiourea - pharmacology
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Summary:[Display omitted] Nε-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 Nε-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that Nε-methyl-thiocarbamoyl-lysine and Nε-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, Nε-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 Nε-thiocarbamoyl-lysine.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.05.058