Selective Molecular Recognition of Biological and Medicinal Guests in Water by Cucurbit[n]uril Hosts

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My proposed research program involves continuing investigations of supramolecular host-guest complexes (molecules inside other molecules) of the cucurbit[n]uril (CB[n], n = 5-8,10,14) host molecules with guests of biological and medicinal interest. The work will provide a better understanding of the weak non-covalent forces governing the selective molecular recognition of guest molecules in water, with a consideration of potential applications of CB[n] as hosts for drug delivery and release, drug reversal, the recognition of disease biomarkers, and remediation of drugs and metabolites which are toxic to the aquatic ecology. The cyclic CB[n] hosts are comprised of a hydrophobic cavity accessed through two constrictive polar portals. The CB[7] host in particular forms extraordinary stable complexes in water with guests which can position positive charges at each opening and fill the internal cavity such that all of the ‘high energy’ water molecules are displaced. Positive charges on molecules of biological and medicinal interest are ubiquitous and often serve to provide selective recognition by other molecules including receptor proteins.  The guest pKa (ground state) and pKa* (excited state) values (acid strength) increase for protonated guests within CB[n] hosts, and ongoing studies are focussed on selective tuning of absorption and emission properties of cationic aromatic dye guests by simultaneous controls of host and acid concentrations. Some of these guests behave as a “super” photoacid with an excited state pKa* < 0, and their absorption and emission spectra change significantly with addition of CB[7] (thus are potentially useful as guests for assays). We will also continue our studies on the selective complexations of drug molecules containing basic nitrogen functional groups, all of which are protonated at physiological pH levels. There have been few investigations to date on the inclusion of neutral guests in CB[n] hosts.  We will investigate acylic and cyclic ethers (useful fuel oxygenates, but harmful to the environment), and amine boranes (hydrogen storage materials), which form relatively stable host-guest complexes with CB[7] in water. The research will also include studies on how fast the CB[7] host-guest complexes form and dissociate, with neutral and cationic guests, using NMR and conventional and stopped-flow absorption and emission methods. Features of mechanistic interest include the role of the constrictive portals and the ability of simple cations to “cap” these portals, and medium effects such as pH. An understanding of the kinetics and mechanisms of the capture and release of these guests by CB[n] is important in the potential applications listed above. The research program will provide excellent training of highly qualified chemists in the interdisciplinary field of supramolecular chemistry to have future impact in academic or industrial research.