Nitroxyl and Nitric Oxide Producing Reactions of Hydroxyurea and Related Compound

拟议研究的长期目标是进一步开发和了解羟基尿素和相关化合物产生氮氧基(HNO)和一氧化氮(NO)的反应。羟基脲已被临床批准用于治疗镰状细胞病，令人振奋的工作揭示了HNO/NO在该病的病理生理和治疗中的重要作用。此前，由这笔赠款资助的研究发现，C-亚硝基和硝基(HNO)是羟基尿素生成NO的重要成分。基于C-亚硝基化合物的新的HNO/NO供体的开发将定义具有独特心血管性质的新的结构实体。本研究的目的是基于C-亚硝基化合物作为具有独特生物效应的活性HNO和供体的假设。与这一假说相关的具体研究目的是：i)通过检测这些反应的动力学、反应产物和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、可溶性鸟苷环化酶和细胞色素P450的反应；ii)通过制备和表征这些化合物作为NO/HNO供体来确定C-亚硝基化合物是否作为NO/HNO供体；以及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、可溶性鸟苷环化酶、过氧化氢酶、过氧化物体增殖物激活受体γ(PPAR)、预收缩的血管和心脏组织。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研究的顺序相结合来实现。这些研究的结果应该会增强我们使用HNO/NO供体治疗镰状细胞疾病、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. .