Metal Coordination Compounds as Reporters for Biological NO

无机化学、生物无机化学和金属有机化学项目的这一奖项支持麻省理工学院的斯蒂芬·J·利帕德教授探索过渡金属络合物中一氧化氮(NO)的基本化学。一个主要的目标是制造明亮的荧光化学传感器，该传感器在一氧化氮与金属中心反应时发出可见光，最终引入活细胞，以时间和位置敏感的方式跟踪NO的产生和扩散。最低限度，有无反应和发光模块。先进的结构将包含一个靶向单元，以允许连接到特定的细胞基因座。概述了实现检测生物NO所需的适当化学的策略。一种方法依赖于NO将荧光团从发射猝灭的金属中心置换出来的能力。配体从金属上解离后会恢复其荧光，这一过程很容易被监测。另一种策略是以恢复荧光的方式切换包含结合的荧光团的金属离子的氧化或自旋状态。为了完成这一化学过程，将制备黄原酮家族的荧光团，包括发光荧光素及其相关平台，以及可溶的荧光共轭聚合物(CP)。荧光素衍生物和CP具有许多优点，特别是激发和发射波长向近红外方向移动，从而优化了生物相容性，以及高消光系数和量子产率，从而产生明亮的探针。通过对这些金属-荧光团与NO的络合物的结构、物理性质和反应动力学进行详细的研究，将寻求使反应快速、可逆并与活细胞中的环境相容的方法。特别令人感兴趣的是通讯神经元之间突触缝隙中的受体，在那里，一氧化氮被认为在大脑学习和记忆形成过程中作为逆行递质发挥作用。NO的细胞靶标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、基因表达和催化中发挥作用。将系统地研究NO与非血红素硫铁络合物、铁硫簇合物和锌硫酸盐络合物反应产生的物种的结构、形成机理和相互转化。这些研究结果将为解释金属蛋白与NO在活细胞中传递其信号的生化反应提供分子基础。了解NO的生理和病理功能将对化学、生物学和医学产生重大影响，因为它可以阐明NO引起的病理和神经元变化的化学反应的本质。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，他们帮助进行实验。

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.