Pyranthiones/Pyrones: "Click and Release" Donors for Subcellular Hydrogen Sulfide Delivery and Labeling**.

Hydrogen sulfide (H2S), one of the most important gasotransmitters, plays a critical role in endogenous signaling pathways of many diseases. However, developing H2S donors with both tunable release kinetics and high release efficiency for subcellular delivery has been challenging. Here, we describe a click and release reaction between pyrone/pyranthiones and bicyclononyne (BCN). This reaction features a release of CO2/COS with second‐order rate constants comparable to Strain‐Promoted Azide‐Alkyne Cycloaddition reactions (SPAACs). Interestingly, pyranthiones showed enhanced reaction rates compared to their pyrone counterparts. We investigated pyrone biorthogonality and demonstrated their utility in protein labeling applications. Moreover, we synthesized substituted pyranthiones with H2S release kinetics that can address the range of physiologically relevant H2S dynamics in cells and achieved quantitative H2S release efficiency in vitro. Finally, we explored the potential of pyranthiones as H2S/COS donors for mitochondrial‐targeted H2S delivery in living cells. [ABSTRACT FROM AUTHOR]