Novel Sulfide Releasing Agents for Ischemic Injury

描述（由申请人提供）：硫化氢（H2S）是一种新发现的信号分子，具有非常有效的细胞保护作用。近年来，H2S生理学和药理学领域发展迅速，但为了进一步了解H2S的生物学和临床潜力，必须解决一些基本问题。研究外源性H2S的化学和药理学是很重要的，要意识到用于在体外和体内产生H2S的化学试剂的选择的局限性。在这方面，合成H2S释放剂（即H2S供体）是重要的研究工具，也是药物开发中潜在的非常有价值的治疗候选者。然而，目前可用的H2S供体在研究使用或临床开发方面非常有限，因为这些化合物的寿命非常短，H2S释放的时间和数量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基于n -巯基、perthiol、gem-dithiol和phospodithiate模板的新型H2S供体。来自这些供体的H2S生成可以通过不同的机制来控制，H2S的生成速率可以通过结构修饰来调节。我们还发现，在小鼠心肌缺血/再灌注损伤模型中，在再灌注时给予H2S供体可显著降低梗死面积并保留左心室功能。在本项目中，我们计划开发一个长效可控的H2S释放剂工具箱，并应用其在体外和体内模型系统中探索病理状态下H2S的药理学作用。研究的三个具体目标是：1)设计、合成和评估可控H2S供体；2)筛选合成H2S供体在体外条件下的活性；3)观察急性心肌缺血/再灌注（MI/R）损伤和慢性心力衰竭时供体的心脏保护作用。我们相信这项研究将扩大我们对H2S化学/药理学的理解，并为H2S生物医学研究提供有价值的工具和信息。

DESCRIPTION (provided by applicant): 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.