Metal Coordination Compounds as Reporters for Biological NO

这个无机、生物无机和有机金属化学项目的奖项支持麻省理工学院的Stephen J. Lippard教授探索一氧化氮（NO）与过渡金属配合物的基本化学。一个主要的目标是生产明亮的荧光化学传感器，在一氧化氮与金属中心反应时发出可见光，最终用于导入活细胞，以时间和位置敏感的方式跟踪一氧化氮的产生和扩散。最低限度，有无反应和发光模块。高级结构将包含一个靶向单元，以允许附着到特定的细胞位点。概述了实现检测生物NO所需的适当化学反应的策略。一种方法依赖于NO从发射猝灭金属中心取代荧光团的能力。配体与金属的解离可以恢复其荧光，并且可以很容易地监测该过程。另一种策略是切换含有结合荧光团的金属离子的氧化或自旋状态，以恢复荧光。杂蒽酮家族的荧光团，包括发光荧光素和相关平台，以及可溶性荧光共轭聚合物（CPs），将被制备，结合金属结合的部分来完成这种化学反应。荧光素衍生物和CPs有几个优点，特别是激发和发射波长向近红外方向移动，优化了生物相容性，高消光系数和量子产率，导致了明亮的探针。通过对这些金属-荧光团配合物与NO的结构、物理性质和反应动力学的详细研究，将寻求使反应快速、可逆并与活细胞中遇到的环境相容的方法。特别令人感兴趣的是通讯神经元之间的突触间隙中的受体，在那里NO被认为是大脑学习和记忆形成过程中的逆行递质。NO的细胞靶点还包括金属离子或它们在金属蛋白中的配体，这些金属蛋白在信号转导、基因表达和催化中起作用。本文将系统地研究NO与非血红素铁硫酸配合物、铁硫簇和锌硫酸配合物反应的结构、形成机制和相互转化。这些研究结果将为解释活细胞中金属蛋白与NO之间的生化反应及其信号转导提供分子基础。了解一氧化氮的生理和病理功能将对化学、生物学和医学产生重大影响，通过阐明一氧化氮诱导的病理和神经元变化背后的化学反应的性质。该项目的研究生和博士后研究人员是麻省理工学院本科生研究机会参与者的导师，他们协助进行实验。

This award in the Inorganic, Bioinorganic and Organometallic Chemistry Program supports Provessor Stephen J. Lippard at the Massachusetts Institute of Technology to explore the fundamental chemistry of nitric oxide (NO) with transition metal complexes. A major goal is to produce bright fluorescent chemosensors that emit visible light upon reaction of nitric oxide with a metal center, ultimately for introduction into living cells to track the production and diffusion of NO in a time- and position-sensitive manner. Minimally, there are NO-reactive and light-emitting modules. Advanced constructs will contain a targeting unit to allow attachment to specific cellular loci. Strategies are outlined to achieve the appropriate chemistry required to detect biological NO. One approach relies upon the ability of NO to displace a fluorophore from an emission-quenching metal center. Dissociation of the ligand from the metal restores its fluorescence and the process can be readily monitored. Another tactic is to toggle the oxidation or spin state of the metal ion containing the bound fluorophore in such a manner as to restore the fluorescence. Fluorophores of the xanthenone family, including the brightly emitting fluorescein and related platforms, as well as soluble fluorescent conjugated polymers (CPs), will be prepared that incorporate metal-binding moieties to accomplish this chemistry. Fluorescein derivatives and CPs offer several advantages, notably excitation and emission wavelengths shifted toward the near-IR, which optimize biocompatibility, and high extinction coefficients and quantum yields, which result in bright probes. By conducting detailed studies of the structures, physical properties, and reaction kinetics of these metal-fluorophore complexes with NO, methods will be sought to make the reactions fast, reversible, and compatible with the environment encountered in living cells. Of particular interest are receptors in the synaptic cleft between communicating neurons, where NO is proposed to function as a retrograde transmitter during learning and memory formation in the brain. Cellular targets of NO also include metal ions or their ligands in metalloproteins that function in signal transduction, gene expression, and catalysis. The structures, mechanism of formation, and interconversion of species generated in the reactions of NO with non-heme iron-thiolate complexes, ironsulfur clusters, and zinc-thiolate complexes will be systematically investigated. The results of these studies will provide a molecular basis for interpreting the biochemical reactions of metalloproteins with NO that transduce its signals in living cells. Understanding the physiological and pathological functions of NO would have a major impact on chemistry, biology and medicine by elucidating the nature of chemical reactions that underlie NO-induced pathologies and neuronal changes. Graduate and postdoctoral researchers on the project are mentors to undergraduate research opportunity participants at MIT who assist in carrying out the experiments.