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Development and Application of Carbonyl Sulfide-Based Donors for $H_{2}$S Delivery
| Content Provider | Scilit |
|---|---|
| Author | Levinn, Carolyn M. Cerda, Matthew M. Pluth, Michael D. |
| Copyright Year | 2019 |
| Abstract | 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. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047812/pdf |
| Ending Page | 2731 |
| Page Count | 9 |
| Starting Page | 2723 |
| ISSN | 00014842 |
| e-ISSN | 15204898 |
| DOI | 10.1021/acs.accounts.9b00315 |
| Journal | Accounts of Chemical Research |
| Issue Number | 9 |
| Volume Number | 52 |
| Language | English |
| Publisher | American Chemical Society (ACS) |
| Publisher Date | 2019-08-07 |
| Access Restriction | Open |
| Subject Keyword | Journal: Accounts of Chemical Research Biochemistry and Molecular Biology New Class Donor Development Carbonyl Sulfide Based Donors Triggers and Activators |
| Content Type | Text |
| Resource Type | Article |
| Subject | Chemistry Medicine |
