Esterase-Activated\nHydrogen Sulfide Donors with Self-Reporting\nFluorescence Properties and Highly Tunable Rates of Delivery

Hydrogen sulfide (H<sub>2</sub>S) has emerged as a significant\nbiomolecule with diverse activities, akin to other gaseous signaling\nmolecules such as nitric oxide (NO) and carbon monoxide (CO). In the\npresent study, we report on the development of esterase-activated\ndonors that track their direct cellular donation of H<sub>2</sub>S\nby enlisting a cyclization reaction onto a thioamide that forms a\nfluorogenic byproduct. This simple donor design provides a noninvasive\nmethod for monitoring the biological delivery and activity of H<sub>2</sub>S, along with access to a library of compounds with highly\nvariable rates of H<sub>2</sub>S delivery. These studies culminated\nwith the identification of a slow-release, yet highly efficient, donor\n(<b>ZL-DMA-Ph</b>) that was shown to self-report its gradual\nand continuous cellular donation of H<sub>2</sub>S for up to 24 h\nwhich, in addition to better mimicking the natural biosynthesis of\nH<sub>2</sub>S, provided impressive cytoprotection in a cellular cardiotoxicity\nmodel, even at submicromolar concentrations. In total, these findings\nindicate that the esterase-triggered fluorogenic donors identified\nin this study will offer new opportunities for exploring the chemical\nbiology and therapeutic potential of exogenous H<sub>2</sub>S supplementation.