Nitroxyl and Nitric Oxide Producing Reactions of Hydroxyurea and Related Compound

本研究的长期目标是进一步开发和了解羟脲及其相关化合物的硝基（HNO）和一氧化氮（NO）生成反应。羟基脲已获得临床批准用于镰状细胞病的治疗，令人兴奋的工作揭示了HNO/NO在镰状细胞病的病理生理和治疗中的重要作用。先前由该基金资助的研究发现，c -亚硝基和硝基（HNO）是羟基脲生成NO的重要成分。基于c -亚硝基化合物的新型HNO/NO供体的开发将定义具有独特心血管特性的新结构实体。本研究的目的是基于c -亚硝基化合物作为称职的HNO和供体具有独特的生物学效应的假设。与该假设相关的具体研究目的是：i)通过考察反应动力学、反应产物、结构要求以及酶的激活/抑制程度，确定c -亚硝基化合物衍生的HNO与已鉴定的含血红素蛋白过氧化氢酶、可溶性鸟苷酸环化酶和细胞色素P450的反应；ii)通过制备和表征c -亚硝基化合物作为NO/HNO供体，确定c -亚硝基化合物是否作为NO/HNO供体；iii)确定这些新的NO/HNO供体与生物靶分子和组织的相互作用，包括血红蛋白、可溶性鸟苷酸环化酶、过氧化氢酶、过氧化物酶体增殖激活受体γ （PPAR）、预收缩血管和心脏组织。这些研究目标的实现将通过化学合成和表征，生化和生物物理分析以及生理学研究的顺序结合来实现。这些研究的结果应该提高我们使用HNO/NO供体治疗镰状细胞病、其他贫血和充血性心力衰竭的能力。

The long-term goal of the proposed research is to further develop and understand the nitroxyl (HNO) and nitric oxide (NO) producing reactions of hydroxyurea and related compounds. Hydroxyurea has gained clinical approval for treatment of sickle cell disease and exciting work reveals important roles for HNO/NO in both the pathophysiology and treatment of this disease. Previously studies funded by this grant identify C-nitroso species and nitroxyl (HNO) as important components in NO formation from hydroxyurea. The development of new HNO/NO donors based upon C-nitroso compounds will define new structural entities with unique cardiovascular properties. This research goal is based on the hypothesis that C-nitroso compounds act as competent HNO and donors with unique biological effects. The specific research aims in relation to this hypothesis are: i) To determine the reaction of C-nitroso compound-derived HNO with the identified heme-containing proteins catalase, soluble guanylate cyclase and cytochrome P450 by examining the kinetics, reaction products and structural requirements of these reactions as well as the extent of enzyme activation/inhibition; ii) to determine whether C-nitroso compounds act as NO/HNO donors by preparing and characterizing these compounds as NO/HNO donors; and iii) to determine the interaction of these new NO/HNO donors with biological target molecules and tissues, including hemoglobin, soluble guanylate cyclase, catalase, the peroxisomal proliferator-activated receptor gamma (PPAR), pre-constricted blood vessels and cardiac tissue. The achievement of these research goals will be approached through the sequential combination of chemical synthesis and characterization, biochemical and biophysical analysis and physiological study. The results from these studies should enhance our ability to use HNO/NO donors as treatments for sickle cell disease, other anemias and congestive heart failure. .