Pyrone and pyranthione scaffolds for click-to-release and biological gas delivery

Click-to-release chemistry provides methods to control molecular activation in biological systems using bioorthogonal reactions. Here, we discuss several classical click-to-release reactions, including Staudinger-Bertozzi-based cleavage systems, 1,3-dipolar cycloaddition-based cleavable systems, and tetrazine-triggered inverse-electron-demand Diels-Alder (IEDDA) cleavage systems. We describe in detail pyrone and pyranthione scaffolds that undergo IEDDA reactions with endo-bicyclo[6.1.0]nonyne (endo-BCN), resulting in the release of carbon dioxide or carbonyl sulfide, with the latter converted to hydrogen sulfide by carbonic anhydrase. We discuss approaches to evaluate the kinetics and bioorthogonality of a pyrone compound library. Finally, we discuss protein labeling, quantitative analysis of hydrogen sulfide release, and mitochondrial hydrogen sulfide imaging in live HeLa cells.