Novel thiourea-based sirtuin inhibitory warheads

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.