| There has been a resurgence of interest in the nitroxyl (HNO/NO -) system since it has been demonstrated as a potential alternative to current treatments of cardiac failure. Currently, HNO donors are limited in both number and release rate under physiologically relevant conditions. This thesis covers the development and optimization of HNO donors as well as the controlled release of HNO. The focus of this work is the ability to release HNO at variable rates from seconds to hours under physiological conditions. The development of N,O-bis acylated hydroxylamines into optimal donors with tunable HNO release required utilization of various mechanistic techniques such as by-product, kinetic, and isotopic analysis.;Chapter 1 begins with a discussion of HNO, current HNO donors, and tools utilized to probe their decomposition. Chapter 2 is a review which addresses acyl nitroso species, bis-heteroatom substituted amides, and controlled release, which are all important aspects of the decomposition and HNO generation of donors designed and evaluated in this thesis. Chapter 3 discusses the design and evaluation of N,O-bis-acylated hydroxylamine donors and the optimization and tunability of HNO release. Chapter 4 describes the synthetic approaches to the HNO donors discussed in Chapter 3. Chapter 5 focuses on the utilization of intramolecular cyclization-elimination pathways to vary the HNO release rate from a known HNO donor. Chapter 6 discusses miscellaneous targets attempted for new HNO donors as well as future synthetic targets for new HNO donors based on findings in Chapter 3. |
