Development and Application of Carbonyl Sulfide-Based Donors for HS Delivery.

In addition to nitric oxide and carbon monoxide, hydrogen sulfide (HS) 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 HS, interest in developing HS donors as both research tools and potential therapeutics has led to the growth of different HS-releasing strategies. Many HS investigations in model systems use direct inhalation of HS gas or aqueous solutions of NaSH or NaS; however, such systems do not mimic endogenous HS production. This stark contrast drives the need to develop better sources of caged HS. To address these limitations, different small organosulfur donor compounds have been prepared that release HS 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 HS directly. To address these needs, our group has pioneered the development of carbonyl sulfide (COS) releasing compounds as a new class of HS 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 HS by the ubiquitous enzyme carbonic anhydrase (CA). In addition, this design enables access to key control compounds that release CO/HO rather than COS/HS, which enables delineation of the effects of COS/HS from the organic donor byproducts. In this Account, we highlight a library of first-generation COS/HS donors based on self-immolative thiocarbamates developed in our lab and also highlight challenges related to HS 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 HO/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 -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 HS, 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 HS 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 HS donors, which we anticipate will help to advance our understanding of the rapidly emerging chemical biology of HS and COS.