Development of New, Physiologically Useful Nitroxyl (HNO) Donors

Nitroxyl;HNO;Chemistry

Guthrie, Daryl AustinToscano, John P. ;

Johns Hopkins University

关键词: Nitroxyl;    HNO;    Chemistry;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/37918/GUTHRIE-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Heart failure, defined as the inability of the heart to pump enough blood to supply the metabolic demands of the body, affects more than 23 million people worldwide with total annual costs in 2013 of $32 billion in the US alone.In in vitro and in vivo models of failing hearts, HNO has been shown to improve both vasorelaxation and myocardial contractility via unique mechanisms leading to enhanced intracellular Ca2+ cycling.Due to its inherent reactivity as a biologically relevant reactive intermediate, HNO must be generated in situ through the use of donor compounds, but very few physiologically useful HNO donors exist.HNO, an ;;aldehyde mimetic”, was used as a reagent to synthesize a variety of HNO donors in what can be considered an N-selective HNO-aldol reaction in up to quantitative yields with bimolecular rate constants reaching 8 × 105 M–1s–1.The hydroxylamino–X (HAX) general class of HNO donors, where X is based on Meldrum’s acid (HAMA), barbituric acid (HABA), or pyrazolone (HAPY), is capable of releasing HNO quantitatively under nonenzymatic, physiological conditions, with the rate and amount of HNO released being dependent mainly on the nature of the carbon-based leaving group.Experimental and computational investigations suggest that the HNO release rate correlates with HAX and X–H pKa.