Therapeutic Delivery of H2S via COS: Small Molecule and Polymeric Donors with Benign Byproducts.
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ABSTRACT:
SUBMITTER: Powell CR
PROVIDER: S-EPMC5074078 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The enzymatic conversion of carbonyl sulfide (COS) to hydrogen sulfide (H2 S) by carbonic anhydrase has been used to develop self-immolating thiocarbamates as COS-based H2 S donors to further elucidate the impact of reactive sulfur species in biology. The high modularity of this approach has provided a library of COS-based H2 S donors that can be activated by specific stimuli. A common limitation, however, is that many such donors result in the formation of an electrophilic quinone methide byproduct during donor activation. As a mild alternative, we demonstrate here that dithiasuccinoyl groups can function as COS/H2 S donor motifs, and that these groups release two equivalents of COS/H2 S and uncage an amine payload under physiologically relevant conditions. Additionally, we demonstrate that COS/H2 S release from this donor motif can be altered by electronic modulation and alkyl substitution. These insights are further supported by DFT investigations, which reveal that aryl and alkyl thiocarbamates release COS with significantly different activation energies.
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Project description:Hydrogen sulfide (H2S) is an important biological mediator, and synthetic H2S donating molecules provide an important class of investigative tools for H2S research. Here, we report esterase-activated H2S donors that function by first releasing carbonyl sulfide (COS), which is rapidly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). We report the synthesis, self-immolative decomposition, and H2S release profiles of the developed scaffolds. In addition, the developed esterase-triggered COS/H2S donors exhibit higher levels of cytotoxicity than equivalent levels of Na2S or the common H2S donors GYY4137 and AP39. Using cellular bioenergetics measurements, we establish that the developed donors reduce cellular respiration and ATP synthesis in BEAS 2B human lung epithelial cells, which is consistent with COS/H2S inhibition of cytochrome c oxidase in the mitochondrial respiratory chain although not observed with common H2S donors at the same concentrations. Taken together, these results may suggest that COS functions differently than H2S in certain biological contexts or that the developed donors are more efficient at delivering H2S than other common H2S-releasing motifs.
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Project description:Significance: Hydrogen sulfide (H2S) is an important biological signaling molecule involved in many physiological processes. These diverse roles have led researchers to develop contemporary methods to deliver H2S under physiologically relevant conditions and in response to various stimuli. Recent Advances: Different small-molecule donors have been developed that release H2S 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 bio-orthogonal chemistry. In addition, an alternative approach to release H2S has utilized the catalyzed hydrolysis of carbonyl sulfide (COS) by carbonic anhydrase to generate libraries of activatable COS-based H2S donors. Critical Issues: Small-molecule H2S donors provide important research and pharmacological tools to perturb H2S 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 H2S delivery from other donor byproducts. Future Directions: The abundance of reported small-molecule H2S donors provides biologists and physiologists with a chemical toolbox to ask key biological questions and to develop H2S-related therapeutic interventions. Further investigation into different releasing efficiencies in biological contexts and a clear understanding of biological responses to donors that release H2S gradually (e.g., hours to days) versus donors that generate H2S quickly (e.g., seconds to minutes) is needed.
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