Significance: Hydrogen sulfide (H 2 S) is an important biological signaling molecule involved in many physiological processes. These diverse roles have led researchers to develop contemporary methods to deliver H 2 S under physiologically relevant conditions and in response to various stimuli. Recent Advances: Different small-molecule donors have been developed that release H 2 S under various conditions. Key examples include donors activated in response to hydrolysis, to endogenous species, such as thiols, reactive oxygen species, and enzymes, and to external stimuli, such as photoactivation and bioorthogonal chemistry. In addition, an alternative approach to release H 2 S has utilized the catalyzed hydrolysis of carbonyl sulfide (COS) by carbonic anhydrase to generate libraries of activatable COS-based H 2 S donors. Critical Issues: Small-molecule H 2 S donors provide important research and pharmacological tools to perturb H 2 S levels. Key needs, both in the development and in the use of such donors, include access to new donors that respond to specific stimuli as well as donors with well-defined control compounds that allow for clear delineation of the impact of H 2 S delivery from other donor byproducts. Future Directions: The abundance of reported small-molecule H 2 S donors provides biologists and physiologists with a chemical toolbox to ask key biological questions and to develop H 2 S-related therapeutic interventions. Further investigation into different releasing efficiencies in biological contexts and a clear understanding of biological responses to donors that release H 2 S gradually (e.g., hours to days) versus donors that generate H 2 S quickly (e.g., seconds to minutes) is needed. Antioxid. Redox Signal. 32, 96-109.

In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H 2 S) has been recently recognized as an important biological signaling molecule with implications in a wide variety of processes including vasodilation, cytoprotection, and neuromodulation. In parallel to the growing number of reports highlighting the biological impact of H 2 S, interest in developing H 2 S donors as both research tools and potential therapeutics has led to the growth of different H 2 S-releasing strategies. Many H 2 S investigations in model systems use direct inhalation of H 2 S gas or aqueous solutions of NaSH or Na 2 S, however such systems do not mimic endogenous H 2 S production. This stark contrast drives the need to develop better sources of caged H 2 S to be used in biological systems. To address these limitations, different small organosulfur donor compounds have been prepared that release H 2 S in the presence of specific activators or triggers. Such compounds, however, often lack suitable H 2 S-depeleted control compounds, which limits the use of these compounds in probing the effects of H 2 S directly. To address these needs, our group has pioneered the development of carbonyl sulfide (COS) releasing compounds as a new class of H 2 S donor motifs. Inspired by a commonly-used carbamate prodrug scaffold, our approach utilizes selfimmolative thiocarbamates to access controlled release of COS, which is rapidly converted to H 2 S by the ubiquitous enzyme carbonic anhydrase (CA). In addition, this design enables access to key control compounds that release CO 2 /H 2 O rather than COS/H 2 S, which enables delineation of the effects of COS/H 2 S from the organic donor byproducts.In this Account, we highlight a library of first-generation COS/H 2 S donors based on selfimmolative thiocarbamates developed in our lab and also highlight challenges related to H 2 S donor development. We showcase the release of COS in the presence of specific triggers and activators including biological thiols and bioorthogonal reactants for targeted applications. We also demonstrate the design and development of a series of H 2 O 2 / reactive oxygen species (ROS)triggered donors and show that such compounds can be activated by endogenous levels of ROS production. Utilizing approaches in bio-orthogonal activation, we establish that donors functionalized with an o-nitrobenzyl photocage can enable access to light-activated donors.Similar to endogenous production by cysteine catabolism, we also prepared a cysteine-selective COS donor activated by a Strongin-ligation mechanism. In efforts to help delineate potential differences in the chemical biology of COS and H 2 S, we also report a simple esterase-activated *

Hydrogen sulfide (H 2 S) is an important gasotransmitter and biomolecule, and many synthetic small-molecule H 2 S donors have been developed for H 2 S-related research. One important class of triggerable H 2 S donors are self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly converted to H 2 S by the ubiquitous enzyme carbonic anhydrase (CA). Prior studies of esterase-triggered thiocarbamate donors reported significant inhibition of mitochondrial bioenergetics and toxicity when compared to direct sulfide donors, suggesting that COS may function differently than H 2 S. Here, we report a suite of modular esterase-triggered selfimmolative COS donors and include the synthesis, H 2 S release profiles, and cytotoxicity of the developed donors. We demonstrate that the rate of ester hydrolysis correlates directly with the observed cytotoxicity in cell culture, which further supports the hypothesis that COS functions as more than a simple H 2 S shuttle in certain biological systems.

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A novel fluorescent probe design based on the interlocking of a reactive thread in a rigid nanohoop fluorophore is reported. This rotaxane design leads to size-selective sensing of thiolates in organic solution.More broadly, the work suggests the promise of mechanical interlocking to enhance the selectivity of reaction-based probes. File list (2)download file view on ChemRxiv H2S_rotaxane_preprint.pdf (0.93 MiB) download file view on ChemRxiv H2S_rotaxane_SI.pdf (1.47 MiB)