P65. Acyloxy nitroso compounds as hno donors, without the release of nitrite, and their reactions with thiol and heme proteins

摘要

Nitroxyl (HNO/NO~-) is the reduced relative of nitric oxide (NO), a biologically relevant signaling agent. Nitroxyl has distinct biological properties when compared to NO and is a potential treatment of myocardial reperfusion injury and congestive heart failure. Nitroxyl must be generated from donors, and a limited number of these compounds exist. Angeli’s salt (AS) is the most widely used HNO donor, but at physiological pH, nitrite is also formed during decomposition of AS. The synthesis of new HNO donors is an objective of this research, specifically acyloxy nitroso compounds. Acyloxy nitroso compounds act as HNO donors through ester hydrolysis to give an unstable intermediate that decomposes to HNO, without generation of nitrite. Varying the R group of the ester portion of these structures varies the stability and reactivity of these compounds, while addition of esterase to water-soluble acyloxy nitroso compounds increases the rate of hydrolysis. These compounds react with thiols and inhibit the thiol containing enzyme aldehyde dehydrogenase (ALDH). Acyloxy nitroso compounds also react with the heme protein myoglobin (Mb). Better understanding of the reaction of HNO with thiol and heme proteins will further the use of HNO donors as therapies.