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Novel thiourea-based sirtuin inhibitory warheads.

ABSTRACT: N(?)-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(?)-thiocarbamoyl-lysine with its terminal NH2 mono-substituted with alkyl and aryl groups, we found that N(?)-methyl-thiocarbamoyl-lysine and N(?)-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(?)-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(?)-thiocarbamoyl-lysine.

SUBMITTER: Zang W

PROVIDER: S-EPMC4636340 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Novel thiourea-based sirtuin inhibitory warheads.

Zang Wenwen W Hao Yujun Y Wang Zhenghe Z Zheng Weiping W

Bioorganic & medicinal chemistry letters 20150530 16

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 ...[more]

PMID: 26081291

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