SYNTHETIC MODELS OF DEOXYRIBONUCLEIC-ACID COMPLEXES WITH ANTI-MALARIAL COMPOUNDS - COMPARATIVE ULTRAVIOLET AND PROTON MAGNETIC-RESONANCE STUDY OF QUINOLINE-BASE, QUINOLINE-QUINOLINE, AND BASE-BASE STACKING INTERACTIONS

Stacking schemes have been proposed for the mode of binding of the antimalarial drug chloroquine with nucleic acids. In relation to this problem, we have devised synthetic models to evaluate, in the absence of the complicating factors present in the DNA-chloroquine complex, the relative stacking tendency of various aromatic rings involved in the binding process, i.e., the purine nucleotide bases, adenine and guanine, and the aromatic part of chloroquine and 7-substituted analogues. In the model compounds, the rings under study are linked by a flexible trimethylene chain. These systems exhibit in solution a folded ⇋unfolded equilibrium, which reflects the strength of the interaction. This equilibrium was studied by hypochromism measurement in the UV and by Fourier transform magnetic resonance spectroscopy. We thus show that in our models the ring-ring stacking interaction between the aromatic ring of chloroquine (4-amino-7-chloroquinoline) and the monomeric nucleotide bases, adenine and guanine, is of the same order of magnitude as that observed between two identical aminoquinoline rings and that between two adenine molecules. In the analogous series of 7-substituted 4-aminoquinolines, our results point to a higher tendency for the 7-C1 compound than for the 7-Br and 7-H analogues to stack with purines. These results are discussed in view of the different binding schemes proposed for the chloroquine-DNA complex. © 1979, American Chemical Society. All rights reserved.