Nitroxyl and Nitric Oxide Producing Reactions of Hydroxyurea and Related Compound

羟基脲及相关化合物的硝氧基和一氧化氮生成反应

• 批准号: 7654799
• 负责人: S BRUCE King
• 金额: $ 32.41万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-06 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7654799
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Achievement; Anemia; Biochemical; Biological; Biological Process; Biology; Blood Pressure; Blood Vessels; Calcium; Cardiac; Cardiovascular system; Chemistry; Clinical; Congestive Heart Failure; Cytochrome P450; Development; Disease; Drug usage; Electrons; Enzyme Activation; Esters; Foundations; Functional disorder; Funding; Goals; Grant; Health; Heart failure; Heme; Hemeproteins; Hemoglobin; Hydroxylamine; Immune response; Kinetics; Learning; Maintenance; Memory; Myocardium; Nitric Oxide; Nitric Oxide Donors; Nitro Compounds; Nitroso Compounds; Physiological; Play; Property; Proteins; Rattus; Reaction; Research; Role; Scheme; Sickle Cell Anemia; Soluble Guanylate Cyclase; Source; Therapeutic; Time; Tissues; Work; base; blood pressure regulation; catalase; chemical synthesis; hydroxyurea; nitroxyl; receptor; research study; response

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. .

该研究的长期目标是进一步开发和了解羟基脲和相关化合物的硝酰基（HNO）和一氧化氮（NO）生成反应，羟基脲已获得临床批准用于治疗镰状细胞病，令人兴奋的工作揭示了重要的意义。 HNO/NO 在该疾病的病理生理学和治疗中的作用之前由该资助资助的研究确定了 C-亚硝基物种和硝酰基 (HNO) 是 NO 形成的重要组成部分。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。该研究目标基于 C-亚硝基化合物作为有效的 HNO 和具有独特生物效应的供体的假设。与该假设相关的具体研究目标是： i) 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 的反应通过检查这些反应的动力学、反应产物和结构要求以及酶激活/抑制的程度，通过制备和表征这些化合物作为NO/HNO供体来确定C-亚硝基化合物是否充当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、过氧化物酶体增殖物激活受体γ（PPAR）、预收缩血管和心脏组织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组合来实现。这些研究的结果应该增强我们的研究成果。能够使用 HNO/NO 供体治疗镰状细胞病、其他贫血和充血性心力衰竭。 。