JPCA, de Dios, CS tensoirs in 4-aminoquinolines; heme-drug interactions

J. Phys. Chem. A, ASAP Article 10.1021/jp061320t S1089-5639(06)01320-X
Web Release Date: June 6, 2006

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

Leah B. Casabianca and Angel C. de Dios*

Department of Chemistry, Georgetown University, 37th and O Streets NW, Washington, DC 20057

Abstract:

Chemical shielding tensors are calculated for the carbons in a series of 4-aminoquinolines with different substituents at the 7-position. The 11 component is used as a measure of the relative -electron density at each carbon. By comparing the -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 -electron density at the carbons meta to the substituent and with decreasing -electron density at the carbons ortho and para to the substituent. The greatest change in -electron density is at the ortho carbons, and log K increases with a decrease in -electron density on the ring containing the substituent, which corresponds to an increase in the -dipole between the two rings. An examination of the solution structures of the - 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 -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 -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.