Novel thiourea-based sirtuin inhibitory warheads

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.