Relationship between NMR Shielding and Heme Binding Strength for a Series of 7-Substituted Quinolines

• Published in: The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment, & general theory Vol. 110; no. 25; pp. 7787 - 7792
• Main Authors: Casabianca, Leah B, de Dios, Angel C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 29-06-2006
• Subjects: Computer Simulation; Heme - chemistry; Magnetic Resonance Spectroscopy - methods; Magnetic Resonance Spectroscopy - standards; Models, Chemical; Molecular Structure; Quinolines - chemistry; Reference Standards; Sensitivity and Specificity; Stereoisomerism
• ISSN: 1089-5639; 1520-5215
• DOI: 10.1021/jp061320t

Chemical shielding tensors are calculated for the carbons in a series of 4-aminoquinolines with different substituents at the 7-position. The σ11 component is used as a measure of the relative π-electron density at each carbon. By comparing the π-electron density at each carbon with the log K of binding to heme (Kaschula et al. J. Med. Chem. 2002, 45, 3531), the drug-heme association is found to increase with increasing π-electron density at the carbons meta to the substituent and with decreasing π-electron density at the carbons ortho and para to the substituent. The greatest change in π-electron density is at the ortho carbons, and log K increases with a decrease in π-electron density on the ring containing the substituent, which corresponds to an increase in the π-dipole between the two rings. An examination of the solution structures of the π−π complexes formed by amodiaquine and quinine with heme (Leed et al. Biochemistry 2002, 41, 10245. de Dios et al. Inorg. Chem. 2004, 43, 8078) shows that the π-dipoles in each drug and in the porphyrin ring of heme may be paired. The chloro-substituted compound has an association constant that is an order of magnitude higher than the other compounds in the series, but the π-electron density at the ring containing the substituent is not correspondingly low. This lack of correlation indicates that the Cl-substituted compound may be binding to heme in a manner that differs from the other compounds in the series.