Novel Sulfide Releasing Agents for Ischemic Injury

摘要 硫化氢(H_2S)是新近发现的一种功能非常强大的信号分子 细胞保护作用。硫化氢生理学和药理学领域在#年迅速增长。 但是，必须解决一些根本性问题，以增进我们的理解 未来硫化氢的生物学和临床潜力。学习化学和化学是很重要的 外源性硫化氢的药理学，意识到与选择化学物质相关的限制 用于在体外和体内产生硫化氢的试剂。在这方面，合成的硫化氢释放剂(即 硫化氢供体)是重要的研究工具和潜在的非常有价值的候选药物 发展。然而，目前可用的硫化氢捐赠者在研究用途或 由于这些化合物的寿命很短，临床进展以及硫化氢的时间和数量 释放在很大程度上是无法控制的。为了解决这些问题，我们最近开发了四种类型的 基于N-硫醇、硫醇、GEM-二硫醇和硫代磷酸盐模板的新的硫化氢供体。硫化氢 这些供体的世代可以通过不同的机制和硫化氢的速率来控制 可以在结构修改时对生成进行调节。我们还发现，美国政府 再灌流时供者硫化氢显著缩小心肌梗死面积并保存左心室 在活体小鼠心肌缺血/再灌注损伤模型中的作用。在这个项目中，我们计划 开发长效可控硫化氢释放剂工具箱并应用于探索 病理性疾病下硫化氢的药理作用在体外和体内模型系统中的状态。 将追求三个具体目标：1)设计、合成和评估可控的硫化氢供体， 2)在体外条件下筛选合成的硫化氢供体的活性；以及3)检测 供体在急性心肌缺血再灌注损伤和慢性心肌损伤中的心脏保护作用 心力衰竭。我们相信，拟议的研究将扩大我们对 硫化氢的化学/药理学，并提供有价值的工具和信息来促进硫化氢 生物医学研究。

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.