In recent years, hydrogen sulfide (H2S) has garnered interest as the third addition to the gasotransmitter family. Essential to human physiology, H2S has roles in the cardiovascular, nervous, and respiratory systems and perturbations in physiological H2S levels have been correlated to a variety of diseases. As a result, there has been significant interest in the development of H2S-releasing compounds (H2S donors) that can mimic slow, enzymatic production for research and therapeutic applications. While a large library of H2S donors exists, several common drawbacks persist, such as: lack of spatial and temporal control, poorly understood mechanisms of release, uncontrolled kinetics, and low efficiency. These issues significantly limit the biological applications of many H2S donors.
This dissertation describes recent work to provide biocompatible H2S donors with controllable release kinetics using a robust, novel strategy for H2S delivery that relies on rapid enzymatic hydrolysis of carbonyl sulfide (COS) to H2S by the ubiquitous mammalian enzyme carbonic anhydrase (CA). Self-immolative thiocarbamates can be designed to release COS by a variety of stimuli, and in biological milieu this COS is rapidly converted to H2S by CA. This strategy has enabled the development of the first analyte-replacement fluorescent probe for H2S and has become a popular strategy for H2S delivery in a variety of applications. Additionally, the unexpected cytotoxicity profile of enzyme-activated COS/H2S donors has piqued interest in COS chemical biology, and these donors are being used as tools for studying COS itself. This dissertation includes previously published and unpublished coauthored work. / 2021-04-30
| Identifer | oai:union.ndltd.org:uoregon.edu/oai:scholarsbank.uoregon.edu:1794/24522 |
| Date | 30 April 2019 |
| Creators | Steiger, Andrea |
| Contributors | Pluth, Michael |
| Publisher | University of Oregon |
| Source Sets | University of Oregon |
| Language | en_US |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Rights | All Rights Reserved. |
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