Carbonothioate-Triggered Cascade Cyclization Enables High-Specificity Fluorescence Imaging of Hydrogen Polysulfides.

Hydrogen polysulfides (H2Sn; n > 1) are critical redox signaling molecules. While the biological functions of H2Sn have received much attention, their exact action mechanisms are still poorly understood due to the lack of reliable detection methods. In this context, fluorescent probes for H2Sn are emerging as powerful chemical tools to aid in unraveling its contributions to biology. Currently, most available H2Sn probes are prone to interference from biothiols or hydrogen sulfide (H2S). To address this challenge, herein, we report a unique carbonothioate-based trigger utilizing a cascade cyclization reaction for specific detection of H2Sn. Using this strategy, eight new fluorescent probes (CTP 1-8) were prepared and evaluated. Among them, CTP-8 not only enables highly sensitive and selective detection of H2Sn but also allows visualization of H2Sn fluctuations in living cells and mice. Significantly, we demonstrate for the first time the fluorescence imaging of endogenous H2Sn dynamics in insulin-resistant cells and type 2 diabetes mellitus (T2DM) mice. Besides, this carbonothioate-based trigger could also be potentially utilized in other fluorescent dye scaffolds that possess an optically tunable phenolic hydroxyl group. This work provides a useful approach for further investigations of H2Sn biology as well as future probe development.