J. Am. Chem. Soc. 140, 12574–12579 (2018)

As a biological signaling molecule, hydrogen sulfide (H2S) is involved in processes such as vasodilation and angiogenesis. Widely used H2S sources such as sodium hydrosulfide release H2S in a burst, unlike the more gradual release that occurs endogenously. This difference has led researchers to seek other approaches such as chemical tools that produce H2S at slower, more physiologically relevant rates. Drawing inspiration from the native chemical ligation (NCL) reaction between a thioester and an N-terminal cysteine residue to generate an amide bond, Cerda et al. developed an analogous reaction using a thionoester (a structural isomer of thioesters) and cysteine, which produces H2S. The reaction between bis(phenyl) thionoester and free cysteine proceeds via nucleophilic addition and S-to-N acyl transfer, similarly to NCL, and robustly produces H2S, phenol and a stable dihydrothiazole. This reaction is selective for cysteine and homocysteine over other common biological thiols such as reduced glutathione, and proceeds under physiological conditions at rates comparable to those of copper-catalyzed azide–alkyne cycloadditions. Although the utility of the reaction has yet to be demonstrated in cells, it may be useful in the future development of tools for H2S production or for ligation of reactive cysteine residues.

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