Synthetic Receptors for Anions, Salts and Neutral Molecules

阴离子、盐和中性分子的合成受体

• 批准号: 0208024
• 负责人: Bradley Smith
• 金额: $ 34.2万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0208024&HistoricalAwards=false
• 关键词: Synthetic; Receptors; Anions; Salts; Neutral

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.

该实验研究计划的总体目标是设计和合成具有有用超分子功能的有机受体分子，并采用分析、生物化学和物理化学方法来评估设计的成功性。目前的提案有三个研究目标，建立在上一个赠款周期的发现。离子对的结构和反应性一直是化学研究的一个重要课题，然而，大多数研究都因离子对固有的不稳定性而变得复杂。主要研究者已经开发出合成受体，其在非极性溶剂中结合并溶解分离的接触离子对。这些配合物提供了一个独特的机会，使用NMR和X射线晶体学表征离子对结构和动力学。要解决的主要问题是如何生物学上重要的，各向异性的阴离子与π电子密度，如RCO 2-，CN-，N3-，和NO3-，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π电子形成氢键。另一个目标是开发氯盐的合成膜转运载体。在生物学上，阴离子转运是几乎所有细胞中普遍存在的过程，并且有缺陷的Cl-转运与许多疾病状态有关。一个例子是囊性纤维化，这是一种遗传性疾病，每2000名白人中就有1人患有这种疾病。一些研究人员认为合成氯离子导体具有作为治疗剂的潜力。作为检验这一假设的第一步，将合成低分子量盐载体，并评估其选择性运输氯化钠或氯化钾穿过囊泡膜的能力。最后，史密斯教授将展示轮烷如何用于新的前药策略。将采用阴离子模板法制备具有含冠醚轮和含缩醛轴的互锁分子轮烷。分子设计允许轮烷轮与提高组织选择性靶向的分子实体缀合。因此，轮烷轮可以被认为是一种新型的药物载体，具有靶点识别能力，以及还原活化的药物释放触发器。有了这个奖项，有机和大分子化学计划（OMC）将支持圣母大学的布拉德利史密斯教授的研究。Smith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，例如在膜转运和控制释放前药系统中的应用。该研究可作为囊性纤维化的潜在治疗剂和作为治疗肿瘤或癌症的控释前药为社会提供益处。该计划的一个重要人力资源成果是项目工作人员（学生和博士后）接受广泛的多学科培训，使他们能够成功地追求一系列科学职业选择。