Development and Application of Carbonyl Sulfide-Based Donors for H 2 S Delivery

Conspectus 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 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 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 self-immolative 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 self-immolative 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 bio-orthogonal 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 donor, which demonstrated fast COS-releasing kinetics and inhibition of mitochondrial respiration in BEAS-2B cells. Additional investigations revealed that COS release rates and cytotoxicity correlated directly within this series of compounds with different ester motifs. In more recent and applied applications of this H 2 S donation strategy, we also highlight the development of donors that generate either a colorimetric or fluorescent optical response upon COS release. Overall, the work described in this Account outlines the development and initial application of a new class of H 2 S donors, which we anticipate will help to advance our understanding of the rapidly emerging chemical biology of H 2 S and COS.