Expanding the Sulfur Chemical Toolbox: Synthesis and Study of Small Molecule Carbonyl Sulfide Donors and Hydrogen Sulfide Probes

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dc.contributor.advisorPluth, Michael
dc.contributor.authorLevinn, Carolyn
dc.date.accessioned2021-04-29T14:51:11Z
dc.date.issued2021-04-29
dc.description.abstractHydrogen sulfide (H2S) has recently been recognized as an important biological signaling molecule, with roles in regulating many biological processes, including neuromodulation and inflammation, as well as many disease states, such as diabetes and Alzheimer’s disease. Due to these diverse biological functions, there is great interest in better understanding the complex roles of H2S in biology and studying how we can utilize this molecule as a potential therapeutic. To accomplish these goals, researchers need chemical tools, such as H2S donors and probes, that act with precision in biological settings. The research presented in this dissertation falls into primarily two aims: 1) obtaining a better mechanistic understanding of the thiocarbamate COS/H2S donor scaffold and developing novel COS/H2S donors, and 2) studying and applying H2S detection motifs to novel H2S probes. Chapter I is an introduction into the biological roles of H2S. Chapter II is a review of current H2S donor molecules with an emphasis on COS delivering systems. Chapter III expands upon previously reported cytotoxic esterase-triggered thiocarbamate donors, demonstrating that the observed toxicity and rate of COS release can be attenuated predictably by changing the rate of ester hydrolysis, but not through electronic modulation of the payload. Chapter IV uses N-methylation to investigate the mechanism of COS release from thiocarbamates and shows that electron poor payloads have a more complex reaction landscape than previously recognized. Additionally, Chapter IV describes the application of the N-alkylation strategy to the development of dithiocarbamate CS2 donors and oligomeric COS donors. Chapter V reports the development of a COS-releasing Alzheimer’s prodrug. To address aim 2, Chapter VI provides an overview of detection methods and probes for H2S. Chapter VII details using a chemiluminescent core to survey different H2S-senstitive triggering motifs and reports a bright platform for aqueous detection of H2S. Chapter VIII demonstrates using a nanohoop rotaxane as a fluorescent probe for H2S. Chapter IX summarizes where the field of H2S research currently stands, and includes a broader scientific policy argument that highlights the need for increased transparency and destigmatization around publishing failed results across all of science. This dissertation includes previously published and unpublished co-authored materials.en_US
dc.description.embargo2022-03-17
dc.identifier.urihttps://hdl.handle.net/1794/26197
dc.language.isoen_US
dc.publisherUniversity of Oregon
dc.rightsAll Rights Reserved.
dc.subjectCarbonyl Sulfideen_US
dc.subjectDeliveryen_US
dc.subjectDetectionen_US
dc.subjectHydrogen Sulfideen_US
dc.subjectSmall Moleculeen_US
dc.subjectSynthesisen_US
dc.titleExpanding the Sulfur Chemical Toolbox: Synthesis and Study of Small Molecule Carbonyl Sulfide Donors and Hydrogen Sulfide Probes
dc.typeElectronic Thesis or Dissertation
thesis.degree.disciplineDepartment of Chemistry and Biochemistry
thesis.degree.grantorUniversity of Oregon
thesis.degree.leveldoctoral
thesis.degree.namePh.D.

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