Synthesis and Mechanistic Studies on the Reactions of Photoactive Nitrosyl Hydride (HNO) Precursors with Biological Reductants

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With this award the Chemistry of Life Processes Program is funding Dr. Nicola Brasch and Dr. Paul Sampson from Kent State University to synthesize and study the reactivity of two new classes of HNO donors with the goal of rapidly generating HNO via photocleavage of an O-protecting group followed by facile HNO elimination. There is an urgent need for HNO donors which rapidly generate HNO, given that HNO reacts rapidly with biomolecules in addition to reacting rapidly with itself. Although it is well established that HNO reduces biomolecules, the redox potential of the HNO,2H+/NH2OH couple suggests that HNO could also be a versatile oxidant. The plan is to utilize laser flash photolysis for HNO release from these precursors to study the kinetics and mechanism of reactions between HNO and three important classes of biological reductants. This proposal brings together an interdisciplinary team of researchers with expertise in kinetics and mechanism, organic synthesis, and laser flash photolysis. HNO (nitrosyl hydride) is attracting increasing attention as a species potentially formed in biological systems, and also shows potential in treating cardiovascular disease. However, understanding the chemical and biological properties of HNO is hampered by the fact that HNO itself is not stable, requiring the development of compounds that decompose to release HNO; HNO donor molecules. In this research novel HNO donor molecules are being targeted, with the goal of achieving the rapid release of HNO upon exposure to laser light. If successful, this research will provide masked HNO-precursors as tools for the Chemical Biology and Medicinal Chemistry communities. The research will provide multi-disciplinary training to undergraduate and graduate students as part of this multi-faceted research team. A new seminar course for junior undergraduate Chemistry majors will also be developed in which students will learn to critically evaluate scientific literature and give effective oral presentations.