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Bio-orthogonal Click-and-Release Strategy for H2S Generation

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Abstract:
Hydrogen sulfide (H2S) has been known as a gaseous pollutant with the smell of rotten eggs, exhibiting lethal effects and toxicity which can lead to reversible unconsciousness, eye irritation, and respiratory irritation. However, H2S naturally occurs in mammalian cells due to enzymatic activity (ex: CBS, CSE, and MST). Research has revealed that H2S can target different ion channels and modify various physiological functions. In fact, inadequate levels of H2S are linked to a variety of diseases including Down syndrome, Alzheimer’s disease, diabetes, and liver cirrhosis, establishing H2S as the third endogenous gaseous transmitter. Thus, chemicals that can precisely supply H2S in biological systems are useful research tools and potential therapeutics. While previous discoveries from other groups have also accomplished H2S delivery, these chemical donors have faced challenges of biocompatibility, such as requiring large quantities of organic solvents to dissolve. Recently, we discovered that pyran-2-thione can react with strained alkynes utilizing a click-and-release strategy, yielding an unstable cycloadduct intermediate to subsequently release COS. In physiological conditions, carbonic anhydrase (CA), an enzyme facilitating the equilibrium between carbonic acid and CO2 + H2O, hydrolyzes COS to yield CO2 and H2S, thus achieving a potential bio-orthogonal delivery of H2S. Using DFT calculations, we predicted potential diene substrates to release the COS payload after a Diels–Alder/retro-Diels-Alder reaction with a strained alkyne dienophile (a bicyclo[6.1.0]nonyne). These predictions were subsequently verified by experimental data to be viable H2S donors in physiological conditions, with pyran-2-thione and its 5-methyl ester derivative as optimal candidates. Further applications of click-and-release reactions are under investigation.

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Citation

Pan, Tony, Cui, Qi, and Xian, Ming, "Bio-orthogonal Click-and-Release Strategy for H2S Generation" (2022). Summer Research Symposium. Brown Digital Repository. Brown University Library. https://doi.org/10.26300/d3b2-ym71

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  • Summer Research Symposium

    Each year, Brown University showcases the research of its undergraduates at the Summer Research Symposium. More than half of the student-researchers are UTRA recipients, while others receive funding from a variety of Brown-administered and national programs and fellowships and go …
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