Reactive sulfane sulfur species such as persulfides (RSSH) and H₂S₂ are important redox regulators and closely linked to H₂S signaling. H₂S is a gasotransmitter involved in multiple essential physiological processes, including the regulation of vasorelaxation and mediation of neurotransmission, but recent studies have implicated H₂S₂as the actual mediator in some of the biological phenomena previously thought to be regulated by H₂S. However, the study of H₂S₂ is still challenging in biological settings due to its instability, high reactivity, and the lack of suitable donors to produce it. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which could specifically convert H₂S to HSOH, and then to H₂S₂ in the presence of excess H₂S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) could be oxidized to reform TTS by biological oxidants. TTS was studied experimentally and computationally. TTS could be conjugated to proteins to achieve specific delivery for localized H₂S₂formation, and the combination of TTS and H₂S led to highly efficient protein persulfidation. When TTS was applied in conjunction with established H₂S donors, the corresponding donors of H₂S₂ were obtained. Cell-based studies revealed that TTS could effectively increase intracellular sulfane sulfur levels and act as a mimic of sulfide:quinone oxidoreductase (SQR) by effectively converting intracellular H₂S to H₂S₂. Considering these promising findings, analogues of TTS were also synthesized, and comparative experimental studies have demonstrated their potential as compounds to more specifically boost the reactivity of H₂S through HSOH/H₂S₂conversion. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

Takaaki Akaike

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