Investigating the Reactivities and Stabilities of Protic Small Molecule Bioregulators

Abstract

Protic small molecule bioregulators (PSMBs) are a class of molecules that serve important roles in biology and are essential for maintaining various physiological processes. PSMBs are defined by their physiological relevance and protic nature, as opposed to gasotransmitters, which are narrow in definition, focus on physical state, and exclusively include CO, NO, and H2S. While gasotransmitters are known for their toxicity at unregulated high concentrations, at low physiological concentrations they are essential bioregulators. PSMBs, however, often are less toxic and also participate in important bioregulatory processes including cellular signaling, cardioprotection, vasodilation, angiogenesis, and inducing anti-/pro- inflammatory responses, among many others. Many PSMBs are the result of intermolecular gasotransmitter crosstalk and/or are regarded as gasotransmitter storage vehicles as they can release gasotransmitters upon their decomposition.

The physiological pathways that PSMBs are involved in are under investigation, however their distinct molecular reactivities and stabilities are still not well understood. Herein, Chapter 1 gives a brief review of select PSMBs and their relevance in biology, endogenous generation, and crosstalk mechanisms. Building off the importance of PSMBs, Chapter II discusses the modes of interconversion between SNO– and SSNO–, two PSMBs that are regarded as H2S and NO crosstalk species. Reported are new experimental insights into the fundamental reaction chemistry of pathways to form SNO− and SSNO−, including mechanisms for proton-mediated interconversion. In addition, new modes of reactivity are demonstrated with other sulfur- containing potential crosstalk species, including carbonyl sulfide (COS). Additionally, Chapters III & IV discuss the stabilities of several PSMBs and other anions using molecular recognition with various rationally designed synthetic C–H hydrogen bonding anion receptors. Using a series of imidazole and imidazolium host molecules, the role of preorganization and charge on anion binding is investigated using both solution-state as well as solid-state characterization methods. The anions investigated range from PSMBs such as HS–, NO2–, and NO3–, to more commonly studied anions within the supramolecular community, Cl– and Br–. Finally, Chapter V summarizes the impact of this work in the field as well as current outlooks and future perspectives on the molecular reactivities and stabilities of PSMBs.

Supplemental materials for Chapters II–IV can be found in the appendices.This dissertation includes previously published and unpublished co-authored materials.