Uncovering the role of exogenous sulfide through novel donors and radioactive tracers
Creators: name: Brown, Eric Michael
Publisher: name: University of Iowa
Year: 2022
Subjects: public abstract

description: Hydrogen sulfide was recently categorized as a gasotransmitter in humans and plants, and it has been shown to act upon dozens to hundreds of enzymatic pathways in vivo. Due to this property, hydrogen sulfide exhibits beneficial effects in living systems when applied exogenously. The work outlined in this thesis describes improvements made towards synthetic hydrogen sulfide releasing donors, and their applications in living systems.
description: A series of dialkyldithiophosphates were synthesized from P2S5 using commercially available alcohols and thiols for use in agriculture to increase harvest yield and protect plants against environmental stressors. These compounds degrade slowly in water to release hydrogen sulfide. The other byproducts from degradation in water include the corresponding alcohol or thiol and phosphoric acid. Depending on the alcohol or thiol used, these degradation products can be safe and natural in the environment, a highly desired trait that many of the common hydrogen sulfide releasing chemicals, such as GYY-4137 and sodium hydrosulfide, do not possess. Another highly desired attribute of dialkyldithiophosphates is the ability to tune the rate of release of hydrogen sulfide. Rate constants of the degradation of these chemicals in water at 85 °C were obtained and the results show a highly tunable hydrogen sulfide release profile that span 4 orders of magnitude. Hydrogen sulfide was also quantified using a hydrogen sulfide electrode, which demonstrated a highly tunable release profile. As it is unlikely all plants require the same amount of hydrogen sulfide to achieve beneficial effects, the ability to easily tune the rate of release of hydrogen sulfide is a significant property of these chemicals. To demonstrate its potential use in agriculture, corn grown on an industrial scale was dosed with dibutyldithiophosphate at a loading of 2 kg/acre and a 6.4% increase in harvest yield was observed.
description: This thesis also describes research completed on polysulfides. Polysulfide compounds exist naturally in the body and are known to produce hydrogen sulfide as well as powerful antioxidant persulfides in the presence of thiols. Despite the known importance of polysulfides, little is known about their stability, and there are conflicting results on the concentration of polysulfides in vivo. To test their stabilities and hydrogen sulfide release profiles, trisulfides from N-acetylcysteine, cysteine, and glutathione, as well as the tetrasulfide from N-acetylcysteine were synthesized. The stabilities of these compounds were investigated in aqueous conditions under various conditions ranging from alkaline and acidic environments to being in the presence of amines and metals. It was found that these polysulfide compounds degrade rapidly in the presence of amines with half-lives ranging from 1.5 minutes to 2.9 hours. The trisulfides of cysteine and glutathione were unstable at more alkaline pH values due to the deprotonation of the ammonium group exposing the amine. N-Acetylcysteine was stable at all pH ranges tested due to the amide group masking the amine. It is known that polysulfides release hydrogen sulfide in the presence of thiols, and the hydrogen sulfide release from these polysulfides in the presence of cysteine was quantified using a hydrogen sulfide electrode, which showed near quantitative amount of hydrogen sulfide release from each chemical with peaking times under 1 hour for each. The results from this work indicate polysulfides are likely a short-lived species in vivo and exist in small concentrations.
description: Lastly, synthetic pathways to synthesize the radioactive hydrogen sulfide donors discussed above were developed to utilize these donors in living systems. Incorporating radioactive sulfur into hydrogen sulfide releasing donors would allow for more accurate tracking in vivo, and improve our understanding of not only the role of hydrogen sulfide in living systems, but also its therapeutic mechanism. Synthetic pathways to the radioactive hydrogen sulfide
description: donors were developed from radioactive sodium sulfate. The pathway to the amino acid trisulfides proceeded in 4 steps, while the pathway to dialkyldithiophosphates was achieved in 2 steps. Along with trisulfides and dialkyldithiophosphates, the pathway to the hydrogen sulfide donor GYY-4137 as a radioactive hydrogen sulfide source was also developed and required a two-step pathway.