Design of Modular Receptors for Ion and Molecule Recognition

项目总结/摘要 该研究计划的首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基乙炔基和P，N-杂环受体。与大多数 荧光阴离子传感器，这些传感器包含固有的荧光骨架，而不是侧基 荧光团单位这项研究将解决下一代发展中的基本问题， 阴离子的分子探针和结合剂，并集中在三个主要领域：（1）合成和 研究新的识别基序和支架，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 氯化物探针 提出的受体也将有助于提供一个基本的了解阴离子协调 化学.阴离子越来越被认为是有问题的环境污染物，并且对于 自然界中的许多过程，从蛋白质和DNA的三级结构发展到“协同”， 金属在蛋白质中的结合，以及它们在生物过程中日益被理解的作用， 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 通道也可能参与多种疾病途径的机制（例如，囊性纤维化， 骨硬化症、阿尔茨海默病、癌症等）。这项研究将提供基本的洞察力， 目标阴离子的新方法（“阴离子-π型”相互作用，C-H···阴离子氢键），并可能提供 在阴离子配位中具有新的选择性。在分子水平上理解阴离子结合是至关重要的 如果人们希望阐明阴离子在更复杂的生物过程中的作用，那么这一点就很重要。 本课题的具体目标是：（1）合成和研究一系列阴离子受体 其表现出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 荧光P，N-杂环作为阴离子结合剂;（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/裂解物测定中筛选成功的候选物。我们将调查 该项目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;主体-客体滴定以量化结合相互作用的能量学;线性自由能 关系和动力学同位素效应，以了解阴离子结合相互作用的基本性质; 和各种光谱技术来评估溶液形态。合作将使筛选 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， 本计画所开发之离子交换膜，可广泛应用于研究阴离子稳态与离子传输之研究。

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.