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

Abstract

Hydrogen 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.