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

项目摘要 虽然小分子细胞内金属催化剂（SIMcat）提供了潜在的强大的新方法， 操纵生物系统，其发展的几个科学障碍不幸地限制了它们的发展。 用于生命科学研究。该项目的长期目标是建立一个全面的SIMcat 发现计划，重点是他们的发展和翻译，从反应瓶的生活系统。 本研究的总体目标是：1）确定快速获得的重要因素， 选择性和生物相容性的转移氢化SIMCats;和2）为 醛超负荷的补救。我们对催化转移氢化反应的SIMCAT感兴趣 因为它们模仿了在所有生命形式中普遍存在的重要氧化还原酶。我们的核心假设是 这些合成酶模拟物可用于中和体内有毒醛， 抗氧化剂（例如谷胱甘肽）可自由地隔离损害细胞和组织的活性氧物质。 该项目的基本原理是，通过选择性地将有毒醛转化为无毒醇， 氢化SIMCat可以补充自然界对氧化应激的防御系统。SIMCAT是 由于其催化连续反应的能力， 与在每次反应时被消耗的常规醛清除剂不同，具体目标1、 将测试各种半夹心金属配合物的活性， 将进行构效关系和动力学/热力学研究，以获得化学见解 转化为催化行为。在具体目标2中，SIMcat的催化速率、形态和分布 将确定活细胞。这一目标将通过利用单分子超 分辨率显微镜和比率荧光成像技术，以可视化SIMCat“在行动中”。在 具体目标3、转移氢化SIMCats保护神经母细胞瘤细胞和斑马鱼的能力 对醛毒性进行评价。SIMCAT解毒的功效和醛选择性 将试剂与常规化学计量的醛捕集剂进行比较。我们的重要性 研究是发展合成方法，专门用于发现新的 SIMcat不仅考虑化学反应性和底物选择性，还考虑生物相容性。的 我们研究的创新之处在于应用有机金属配合物保护细胞免受化学物质的侵害。 有毒物质的催化能力。我们希望这项工作将有助于简化SIMcat 发现过程，并导致新的方法来补救醛超载，这可能具有重要的 与治疗人类氧化应激相关疾病的治疗相关性。

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.