The Development of Fluorescent Probes and Slow-Releasing H2S Donors for Studying Biological H2S
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Hydrogen sulfide (H2S) is an essential small molecule in human physiology. Although quite toxic, H2S is produced endogenously and performs important regulatory functions in the cardiovascular, immune, nervous, and respiratory systems. Varied interactions with intracellular thiols, reactive oxidants, and protein transition-metal centers are highly dynamic and sensitive to fluctuations in redox homeostasis. Furthermore, H2S is implicated in a number of diseases such as cancer, neurodegeneration, and heart disease. Hence, exogenously delivered H2S as a therapeutic agent is an active area of intrigue and research. The complexity and interconnectivity of these processes has stimulated the development of advanced chemical tools with which to study biological H2S, including reaction-based fluorescent probes and slow-releasing H2S donors. Toward these goals, I present several significant advances in the fields of H2S detection and delivery. An azide reduction-based probe, MeRho-Az, provides a rapid >1,000-fold fluorescence response when treated with H2S. MeRho-Az is sufficiently sensitive to detect endogenous H2S in C6 cells and was used to image H2S in live zebrafish larvae using light sheet fluorescence microscopy, representing the first analyte-responsive experiments with this imaging technology. Using a ratiometric dual-fluorophore fragmentation strategy, NBD-Coum simultaneously detects, differentiates, and measures relative concentration ratios of H2S versus cysteine/homocysteine, two important metabolites in H2S biosynthesis. NBD-Coum was used to monitor changes in redox homeostasis in a simulated sulfur pool and is useful for studying H2S-thiol dynamics. The synthesis and amide-coupling conditions of ADT-NH2, a highly sought dithiolethione H2S donor, allow for hydrolytically stable, H2S-releasing non-steroidal anti-inflammatory drug hybrids. Finally, inspired by polysulfide-containing natural products, functionalized tetrasulfides are a new class of accessible, customizable, and versatile H2S donors with controllable H2S release rates. I hope that by using these investigative tools, chemists and biologists are able to refine our understanding of physiological H2S and exploit H2S activities in disease treatments.