Synthetic Receptors for Anions, Salts and Neutral Molecules

这个实验研究计划的总体目标是设计和合成具有有用的超分子功能的有机受体分子，并使用分析、生化和物理化学方法来评估设计的成功。目前的提案有三个研究目标，这些目标建立在前一个赠款周期中的发现的基础上。几十年来，离子对的结构和反应活性一直是一个重要的化学研究课题，然而，由于离子对固有的不稳定性，使得大多数研究变得复杂。首席研究人员已经开发出合成受体，可以在非极性溶剂中结合和增溶孤立的接触离子对。这些配合物提供了一个独特的机会来表征离子对的结构和动力学使用核磁共振和X射线结晶学。需要解决的主要问题是具有pi-电子密度的生物重要的各向异性阴离子，如RCO2-、CN-、N3-和NO3-，如何同时与受体NH残基和结合的金属阳离子相互作用。假设受体NH残基与阴离子pi-电子形成氢键。另一个目标是开发用于氯盐的合成膜传输载体。生物学上，阴离子转运是几乎所有细胞中普遍存在的过程，而有缺陷的氯离子转运与许多疾病状态有关。囊性纤维化就是一个例子，这是一种遗传性疾病，在2000年的高加索人中有1人患有此病。一些研究人员认为，合成的氯离子导体具有作为治疗剂的潜力。作为验证这一假设的第一步，将合成低分子量盐载体，并评估其选择性地通过囊泡膜运输氯化钠或氯化钾的能力。最后，史密斯教授将演示轮烷如何用于新的前药策略。将使用阴离子模板方法来制备被称为轮烷的互锁分子，这些分子带有含冠醚的轮子和含缩醛的轴。分子设计允许轮烷轮与提高组织选择性靶向性的分子实体结合。因此，轮烷轮可以被认为是一种新型的药物载体，它配备了目标识别能力，以及还原激活的药物释放触发器。有了这个奖，有机和高分子化学计划(OMC)将支持圣母大学的布拉德利·史密斯教授的研究。史密斯教授在超分子化学领域的工作在生物化学中有许多潜在的应用，例如在膜传输和控制释放前药系统中的应用。这项研究可能会作为囊性纤维化的潜在治疗剂和作为对照释放的用于治疗肿瘤或癌症的前体药物而对社会产生好处。该项目的一个重要人力资源成果是，项目工作人员(学生和博士后)接受了广泛的多学科培训，使他们能够成功地从事一系列科学的职业选择。

The general goal of this experimental research program is to design and synthesize organic receptor molecules with useful supramolecular functions, and to employ analytical, biochemical and physical chemistry methods to evaluate the success of the designs. The current proposal has three research objectives that build on discoveries made in the previous grant cycle. The structure and reactivity of ion-pairs has been a major chemical research topic for many decades, however, the majority of studies have been complicated by the inherent lability of the ion-pairs. The principal investigator has developed synthetic receptors that bind and solubilize isolated contact ion-pairs in non-polar solvents. These complexes provide a unique opportunity to characterize ion-pair structure and dynamics using NMR and X-ray crystallography. The major question to be addressed is how do biologically important, anisotropic anions with pi -electron density such as RCO2-, CN-, N3-, and NO3-, simultaneously interact with receptor NH residues and the bound metal cation. It is hypothesized that the receptor NH residues form hydrogen bonds with anion pi -electrons.Another objective is to develop synthetic membrane transport carriers for chloride salts. Biologically, anion transport is a ubiquitous process in nearly all cells and defective Cl- transport is related to a number of disease states. One example is cystic fibrosis, an inherited disease that afflicts 1 in 2000 Caucasians. Some researchers think that synthetic Cl- conductors have potential as therapeutic agents. As a first step towards testing this hypothesis, low-molecular-weight salt carriers will be synthesized and evaluated for their abilities to selectively transport sodium chloride or potassium chloride across vesicle membranes. And finally, Professor Smith will demonstrate how rotaxanes can be used in novel prodrug strategies. An anion template method will be employed to prepare interlocked molecules known as rotaxanes with crown ether-containing wheels and acetal-containing axles. The molecular design allows conjugation of the rotaxane wheels with molecular entities that improve tissue-selective targeting. Thus, the rotaxane wheel can be thought of as a novel drug carrier that is equipped with target recognition capability, as well as a reductively activated drug-release trigger.With this Award, the Organic and Macromolecular Chemistry Program (OMC) will support the research of Professor Bradley Smith of the University of Notre Dame. Professor Smith's work in the supramolecular chemistry field has many potential applications in biochemistry, such as uses in membrane transport and control released prodrug systems. The research may offer benefits to society as potential therapeutic agents for cystic fibrosis and as control released prodrugs for curing tumors or cancers. An important human resources outcome of this program is that the project workers (students and postdoctoral associates) receive broad multidisciplinary training, which enables them to successfully pursue a range of scientific career choices.