Synthetic Receptors for Anions, Salts and Neutral Molecules

University Of Notre Dame, Notre Dame IN

Investigators

Abstract

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.