Development of Transfer Hydrogenation Small-Molecule Intracellular Metal Catalysts (SIMCats) and their Application Toward Toxic Aldehyde Remediation

项目总结 尽管小分子胞内金属催化剂(SIMCats)提供了潜在的强大的新方法 操纵生物系统，但不幸的是，发展它们的几个科学障碍限制了它们 在生命科学研究中的应用。该项目的长期目标是建立一个全面的SIMCat 发现计划，重点是它们的发展和从反应瓶到生命系统的转换。 这项研究的总体目标是：1)确定对获得FAST非常重要的因素， 选择性和生物相容的转移氢化SIMCats；以及2)为 乙醛超载的修复。我们对催化转移加氢反应的SIMCats感兴趣 因为它们模仿所有生命形式中普遍存在的重要氧化还原酶。我们的中心假设是 这些合成酶模拟物可以用来中和体内的有毒醛，从而使内源 抗氧化剂，如谷胱甘肽，可以自由隔离破坏细胞和组织的活性氧类。 这个项目的基本原理是，通过选择性地将有毒的醛转化为无毒的醇，转移 氢化SIMCats可以补充大自然对氧化应激的防御系统。SIMCats是 由于其催化连续反应的能力，有望成为高效的解毒剂 与传统的乙醛清除剂不同，每一次反应都会消耗掉。在具体目标1中， 将测试各种半夹心金属络合物的活性和最有希望的候选者 将接受结构-活性关系和动力学/热力学研究，以获得化学见解 它们的催化行为。在特定目标2中，SIMCats在体内的催化速率、形态和分布 活细胞将被确定。这一目标将通过利用单分子超级 分辨率显微镜和比率荧光成像技术，以可视化的SIMCats“在行动”。在……里面 特异靶3，转移氢化SIMCats保护神经母细胞瘤细胞和斑马鱼的能力 抗乙醛毒性将进行评估。SIMCat的解毒效果和乙醛选择性 将试剂与传统的化学计量比的乙醛捕集器进行比较。我们的重要意义在于 研究是为发现小说而量身定做的综合方法论的发展 SIMCats，它不仅考虑了化学反应和底物的选择性，而且还考虑了生物兼容性。这个 我们研究的创新是应用有机金属络合物来保护细胞免受化学物质的伤害 通过利用毒物的催化能力。我们希望这项工作将有助于简化SIMCat 发现过程并导致补救醛超载的新方法，这可能具有重要的意义 治疗与人类氧化应激相关疾病的相关性。

PROJECT SUMMARY Although small-molecule intracellular metal catalysts (SIMCats) offer potentially powerful new ways to manipulate biological systems, several scientific barriers to their development have unfortunately limited their use in life science research. The long-term goal of this project is to establish a comprehensive SIMCat discovery program that focuses on their development and translation from the reaction flask to living systems. The overall objectives of this research are to 1) identify the factors that are important to obtaining fast, selective, and biocompatible transfer hydrogenation SIMCats; and 2) create new catalytic agents for the remediation of aldehyde overload. We are interested in SIMCats that catalyze transfer hydrogenation reactions because they mimic important redox enzymes that are ubiquitous in all life forms. Our central hypothesis is that these synthetic enzyme mimics could be used to neutralize toxic aldehydes in vivo so that endogenous antioxidants, such as glutathione, are free to sequester reactive oxygen species that damage cells and tissue. The rationale for this project is that by selectively converting toxic aldehydes to non-toxic alcohols, transfer hydrogenation SIMCats could supplement Nature’s defense system against oxidative stress. SIMCats are expected to be highly efficient detoxification agents due to their ability to catalyze continuous reaction turnovers, unlike conventional aldehyde scavengers that get consumed upon each reaction. In Specific Aim 1, a variety of half-sandwich metal complexes will be tested for their activity and the most promising candidates will be subjected to structure-activity relationship and kinetic/thermodynamic studies to obtain chemical insights into their catalytic behavior. In Specific Aim 2, the catalytic rates, speciation, and distribution of SIMCats inside live cells will be determined. This aim will be accomplished by taking advantage of single-molecule super resolution microscopy and ratiometric fluorescence imaging techniques to visualize SIMCats “in action.” In Specific Aim 3, the ability of transfer hydrogenation SIMCats to protect neuroblastoma cells and zebrafish against aldehyde toxicity will be evaluated. The efficacy and aldehyde selectivity of SIMCat detoxification agents will be compared to that of conventional stoichiometric aldehyde traps. The significance of our research is the development of synthetic methodologies that are tailored toward the discovery of novel SIMCats, which considers not only chemical reactivity and substrate selectivity but also biocompatibility. The innovation of our research is the application of organometallic complexes to protect cells against chemical toxicants by exploiting their catalytic capabilities. We expect that this work will help streamline the SIMCat discovery process and lead to new approaches to remedy aldehyde overload, which could have important therapeutic relevance to the treatment of oxidative stress-related diseases in humans.