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，具有非常强的细胞保护作用。近年来，H2S生理学和药理学领域迅速发展，但必须解决一些基本问题，以促进我们对未来H2S生物学和临床潜力的理解。重要的是要研究外源性H2S的化学和药理学，了解与用于在体外和体内产生H2S的化学试剂的选择相关的限制。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的非常有价值的治疗药物开发的候选人。然而，目前可用的H2S供体在研究用途或临床开发方面非常有限，因为这些化合物非常短，并且H2S释放的时间和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类型的新的H2S供体基于N-巯基，过硫醇，偕二硫醇，和二硫代磷酸酯模板。来自这些供体的H2S生成可以通过不同的机制来控制，并且H2S生成的速率可以在结构修饰后进行调节。我们还发现，在心肌缺血/再灌注损伤的体内小鼠模型中，在再灌注时给予H2S供体显著降低了梗死面积并保留了左心室功能。在本项目中，我们计划开发一种长效和可控的H2S释放剂工具箱，并将其应用于体外和体内模型系统中病理疾病状态下H2S的药理学研究。本研究的目的有三：1）设计、合成和评价可控H2S供体; 2）在体外条件下筛选合成H2S供体的活性; 3）检测供体在急性心肌缺血/再灌注（MI/R）损伤和慢性心力衰竭中的心脏保护作用。我们相信，拟议的研究将扩大我们的化学/药理学的H2S的理解，并提供有价值的工具和信息，以促进H2S的生物医学研究。

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.