Molecular characterization of drug/drug carrier interaction through investigation on a crown ether/cation system

An innovative methodology for characterizing host-guest type drug/drug carrier interactions has been developed. In this methodology, experimental data is used in conjunction with computational chemistry to provide an in-depth chemically intuitive understanding of these systems. In particular, quantum mechanic (QM) calculations coupled with natural bond orbital (NBO) analysis is shown to be effective for the interpretation of experimental observations.;The crown ether/metal ion system was selected as a model for a drug/drug carrier system. The interactions between 12-crown-4 (12C4) and Li+ or benzo-12-crown-4 (b12C4) and Li+ were characterized using NMR spectroscopy, X-ray crystallography and theoretical calculations. The apparent association constants were determined through NMR 7Li titration experiments. b12C4/Li+ displayed a 1:1 complexation while 12C4/Li+ displayed a mixture of 1:1 and 2:1 complexation in acetonitrile-d3. Water was demonstrated to significantly weaken the crown ether/Li+ complexation. A novel water variation experiment was designed to obtain the apparent association constant(s) in the absence of water. The main stabilizing orbital interaction during complexation was found to be that the ether oxygen lone pair electrons donate electron density to the Li+ 2s empty orbital. The 1:1 association constant for 12C4/Li+ was an order of magnitude larger than b12C4/Li+ complexation in a water free environment. This was in part due to an ether oxygen lone pair electron density delocalization into b12C4 benzene ring. The difference between the observed experimental and theoretical 13C chemical shifts was determined to be within 1-2 ppm. Through an extensive conformational analysis of 12C4, the lowest energy conformer from Merck Molecular Force Field was determined to remain lowest after further QM optimization.;Four novel crystal structures were obtained for the 12C4 (or b12C4)/Li + systems including 1:1, 2:1 and 3:2 sandwich structures. Through comparing the original crystal structures with their corresponding gas phase optimal structures, the crystal structures can, with proper care, be utilized as starting point for computation studies and facilitate the search for the global minimum on the potential energy surface. A significant finding was that crystal lattice effects can be captured, in part, by selecting just the nearest neighbors of primary importance in computational studies.