Novel Sulfide Releasing Agents for Ischemic Injury

用于缺血性损伤的新型硫化物释放剂

• 批准号: 8629076
• 负责人: DAVID JOSEPH LEFER
• 金额: $ 38.86万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-17 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629076
• 关键词: Acute; Acute myocardial infarction; Address; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptotic; Biological; Biological Models; Biology; Biomedical Research; Carbon Monoxide; Cardiac; Cations; Cells; Chemical Agents; Chemistry; Chronic; Clinical; Data; Dendrimers; Detection; Development; Disease; Down-Regulation; Drug Kinetics; Exhibits; Future; Generations; Goals; Heart failure; Hydrogen Sulfide; Hypoxia; In Vitro; Infarction; Injury; Investigation; Lead; Left Ventricular Function; Life; Light; Measures; Metabolism; Methods; Mitochondria; Modeling; Modification; Monitor; Mus; Muscle Cells; Myocardial Ischemia; Myocardium; Nitric Oxide; Oxidative Stress; Oxygen Consumption; Pharmacology; Physiology; Problem Solving; Production; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Respiration; Series; Signaling Molecule; Solid; Structure-Activity Relationship; Sulfhydryl Compounds; Sulfides; Testing; Therapeutic; Time; Vasodilation; base; cytotoxicity; design; dithiol; drug development; improved; in vivo; in vivo Model; novel; phosphorodithioic acid; protective effect; public health relevance; research study; tool

Abstract Hydrogen sulfide (H2S) is a newly recognized signaling molecule with very potent cytoprotective actions. The fields of H2S physiology and pharmacology have been rapidly growing in recent years, but a number of fundamental issues must be addressed to advance our understanding of the biology and clinical potential of H2S in the future. It is important to study the chemistry and pharmacology of exogenous H2S, to be aware of the limitations associated with the choice of chemical agents used to generate H2S in vitro and in vivo. In this regard, synthetic H2S-releasing agents (i.e. H2S donors) are important research tools and potentially very valuable therapeutic candidates for drug development. However, currently available H2S donors are very limited in terms of research use or clinical development since those compounds are very short-lived and the timing and amount of H2S release is largely uncontrollable. To solve these problems, we have recently developed four types of new H2S donors based on N-mercapto, perthiol, gem-dithiol, and phosphorodithioate templates. H2S generations from these donors can be controlled by different mechanisms and the rates of H2S generation can be regulated upon structural modifications. We also found that the administration of H2S donors at the time of reperfusion significantly decreased infarct size and preserved left ventricular function in an in vivo murine model of myocardial ischemia/reperfusion injury. In this project, we plan to develop a toolbox of long-lasting and controllable H2S releasing agents and apply them to explore the pharmacology of H2S under pathological disease states in in vitro and in vivo model systems. Three Specific Aims will be pursued: 1) to design, synthesize, and evaluate controllable H2S donors, 2) to screen the activities of synthetic H2S donors under in vitro conditions; and 3) to examine the cardioprotective actions of donors in acute myocardial ischemia/reperfusion (MI/R) injury and chronic heart failure. We believe that the proposed research will expand our understanding of the chemistry/pharmacology of H2S and provide valuable tools and information to facilitate H2S biomedical research.

抽象的 硫化氢 (H2S) 是一种新近被认可的信号分子，具有非常有效的作用 细胞保护作用。 H2S生理学和药理学领域在近年来迅速发展 近年来，但必须解决一些基本问题以增进我们的理解 未来 H2S 的生物学和临床潜力。学习化学很重要 外源性 H2S 的药理学，要了解与化学物质选择相关的局限性 用于在体外和体内产生 H2S 的试剂。在这方面，合成的 H2S 释放剂（即 H2S 供体）是重要的研究工具和潜在非常有价值的药物治疗候选者 发展。然而，目前可用的 H2S 供体在研究用途或 临床开发，因为这些化合物的寿命非常短，并且 H2S 的时间和数量 释放在很大程度上是不可控的。为了解决这些问题，我们最近开发了四种类型 基于 N-巯基、全硫醇、偕二硫醇和二硫代磷酸酯模板的新 H2S 供体。硫化氢 这些供体的世代可以通过不同的机制和 H2S 的速率来控制 可以通过结构修饰来调节生成。我们还发现，管理部门 再灌注时 H2S 供体显着减小了梗塞面积并保留了左心室 在心肌缺血/再灌注损伤的体内小鼠模型中发挥作用。在这个项目中，我们计划 开发长效可控H2S释放剂工具箱并应用于探索 体外和体内模型系统中病理疾病状态下 H2S 的药理学。 将追求三个具体目标：1）设计、合成和评估可控的 H2S 供体， 2）体外条件下筛选合成H2S供体的活性； 3）检查 供体在急性心肌缺血/再灌注（MI/R）损伤和慢性损伤中的心脏保护作用 心脏衰竭。我们相信，拟议的研究将扩大我们对 H2S 的化学/药理学，并提供有价值的工具和信息来促进 H2S 生物医学研究。