Design of Modular Receptors for Ion and Molecule Recognition

项目摘要/摘要 这项研究计划的主要主题是利用模块化方法来综合 用于阴离子识别的高度共轭的芳乙炔和P，N杂环受体。与大多数人不同 荧光阴离子传感器，这些传感器包含固有的荧光主干，而不是吊坠 荧光团单元。这项研究将解决下一代网络开发中的基本问题 阴离子的分子探针和结合剂，主要集中在三个方面：(1)合成和 研究新的识别基元和支架，以推进我们的模块化设计策略；(2)量化 这些受体与阴离子的相互作用，以及(3)这些化合物作为新的荧光分子的应用 氯化物探头。 建议的受体也将有助于从根本上理解阴离子的配位作用。 化学反应。阴离子越来越被认为是有问题的环境污染物，对 自然界中有许多过程，从形成蛋白质和DNA的三级结构到“协同作用”。 蛋白质中金属的结合，以及它们在生物过程中日益被理解的作用，包括 内吞作用、溶酶体活性和激酶功能等。阴离子结合蛋白与转运蛋白 经络也可参与多种疾病途径的机制(例如，囊性纤维化， 骨质疏松症、阿尔茨海默病、癌症等)。这项研究将为新兴市场提供基本的洞察 以阴离子为目标的新方法(“阴离子-π类型”相互作用，C-H···阴离子氢键)，并可能提供 新的阴离子配位选择性。了解分子水平上的阴离子结合是至关重要的 如果一个人想要阐明阴离子在更复杂的生物过程中的作用，那么它是非常重要的。 本研究的具体目标是：(1)合成和研究一系列阴离子受体。 展示了由模块化设计产生的可调谐的关-开荧光；(2)阐述了一类新的 作为阴离子结合剂的荧光P，N-杂环化合物；(3)开发新的水溶性小分子 用于阴离子的荧光探针，并在细胞/裂解物分析中筛选成功的候选者。我们会调查的 在这个项目上开发的受体首先使用现代物理有机方法，包括：分子建模 用于主体设计；主客体滴定以量化结合相互作用的能量学；线性自由能 相互关系和动力学同位素效应，以了解阴离子结合作用的基本性质； 以及各种光谱技术来评估溶液的形态。协作将支持筛选 成功的宿主分子作为体外和体内应用的分子探针。从长远来看，探测器 本项目的研究成果可广泛用于研究阴离子动态平衡和离子传输的研究人员。

Project Summary/Abstract The overarching theme of this research program is the utilization of a modular approach to synthesize highly-conjugated arylethynyl and P,N-heterocyclic receptors for anion recognition. Unlike the majority of fluorescent anion sensors, these sensors contain an inherently fluorescent backbone as opposed to a pendant fluorophore unit. The research will address fundamental problems in the development of the next generation of molecular probes and binding agents for anions and focuses on three main areas: (1) synthesizing and studying new recognition motifs and scaffolds to advance our modular design strategy; (2) quantifying the interactions of these receptors with anions, and (3) applying these compounds as new fluorescent molecular probes for chloride. The proposed receptors will also help provide a fundamental understanding of anion coordination chemistry. Anions are increasingly recognized as problematic environmental contaminants and are vital to many processes in nature, ranging from developing tertiary structure in proteins and DNA, to “synergistic” binding of metals in proteins, to their increasingly understood role in biological processes including endocytosis, lysosome activity and kinase function, among others. Anion binding proteins and transport channels also may be involved in the mechanisms of a variety of disease pathways (e.g., Cystic Fibrosis, osteopetrosis, Alzheimer's disease, cancers, etc.). This research will provide fundamental insight into emerging new approaches to target anions (“anion-π-type” interactions, C-H···anion hydrogen bonding) and may provide novel selectivity in anion coordination. Understanding anion binding on a molecular level is of paramount importance if one wishes to elucidate the roles of anions in the much more complicated biological processes. The specific aims of the proposed research are: (1) to synthesize and study a series of receptors for anions that exhibit tunable OFF-ON fluorescence resulting from the modular design; (2) to elaborate a new class of fluorescent P,N-heterocycles as anion binding agents; and (3) to develop new water-soluble small molecule fluorescent probes for anions and to screen successful candidates in cell/lysate assays. We will investigate receptors developed on this project first using modern physical organic methods, including: molecular modeling for host design; host-guest titrations to quantify the energetics of binding interactions; linear free energy relationships and kinetic isotope effects to understand the fundamental nature of anion binding interactions; and a variety of spectroscopic techniques to assess solution speciation. Collaborations will enable screening of successful host molecules as molecular probes for in vitro and in vivo applications. In the long term, probes developed in this project can be used broadly by researchers studying anion homeostasis and ion transport.