Relationship between NMR shielding and heme binding strength for a series of 7-substituted quinolines.
Chemical shielding tensors are calculated for the carbons in a series of 4-aminoquinolines with different substituents at the 7-position. The sigma(11) component is used as a measure of the relative pi-electron density at each carbon. By comparing the pi-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 pi-electron density at the carbons meta to the substituent and with decreasing pi-electron density at the carbons ortho and para to the substituent. The greatest change in pi-electron density is at the ortho carbons, and log K increases with a decrease in pi-electron density on the ring containing the substituent, which corresponds to an increase in the pi-dipole between the two rings. An examination of the solution structures of the pi-pi 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 pi-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 pi-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.
Casabianca
Leah B
LB
Department of Chemistry, Georgetown University, Washington, DC 20057, USA.
de Dios
Angel C
AC
D003198:Computer Simulation; D006418:Heme / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods* / Q000592:standards*; D008956:Models, Chemical; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry*; D012015:Reference Standards; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
D011804:Quinolines; D006418:Heme