NEW STUDIES IN MOLECULAR RECOGNITION

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New Studies in Molecular Recognition; Synthetic "hosts" that bind particular "guests" have tremendous potential to benefit human health. The major, continuing objective of our work in host-guest chemistry/molecular recognition is to discover principles and strategies that will enhance understanding of weak noncovalent interactions and facilitate their application to problems of biomedical significance. In the next budget period, we propose to accomplish this objective by studying hosts that complex guests using hydrogen bonding or pi-stacking in three very different environments: (1) on the surface of chromatographic supports, (2) in the major groove of double helical DNA, and (3) inside dendrimers. With the advent of combinatorial approaches to drug design and the use of combinatorial methods in other areas of molecular recognition research, there is an increasing demand for rapid and accurate measures of binding affinities. One project will determine the generality of a previously developed HPLC method of simultaneously measuring complexation free energies and enthalpies of multiple guests/analytes. Toward this end, several new chemically bonded stationary phases (CBSPs) will be developed using hosts that complex guests in polar solvents including water. A second project involves developing a host for GC and AT base-pairs that can recognize pyrimidines within a DNA triplex. Thus, new DNA bases will be synthesized that are capable of simultaneously hydrogen bonding both bases of an AT or GC base-pair. These novel bases will be ribosylated, converted to phosphoramidites, and incorporated into oligonucleotides using automated methods of DNA synthesis. The ability of these bases to sequence selectively recognize double helical DNA through triple-helix formation will be determined. The objective of this work is a general method of sequence-specific DNA recognition through triplex formation. The regulation of genes by sequence selective triplex formation ia a potential biomedical application of tremendous significance. A final project involves the synthesis and study of hosts that are surrounded by dendrons. These dendritic hosts may have a relatively invariant microenvironment that allows them to function in a wide range of solvents, including water. Such structures may ultimately serve as highly specific drug delivery vehicles.