Differential binding of the enantiomers of chloroquine and quinacrine to polynucleotides: Implications for stereoselective metabolism

Abstract

Interaction of the antimalarial drugs quinacrine and chloroquine with DNA has been studied extensively in order to understand the origin of their biological activity. These studies have shown that they bind to DNA through an intercalative mode and show little sequence specificity. All previous experiments were carried out using the racemic form of these drugs. We have investigated the binding of the enantiomeric forms of quinacrine and chloroquine to synthetic polynucleotides poly(dA-dT).poly(dA-dT) and poly(dG-dC).poly (dG-dC), and found interesting differences in their binding parameters. Quinacrine enantiomers have a much higher binding affinity for the two polynucleotides compared to those of chloroquine. The negative enantiomers were found to have higher binding affinity than the positive ones. The binding constant for the binding of quinacrine(-) to poly(dG-dC).poly(dG-dC) was found to be about 3 times that of quinacrine(+). The differences in these binding affinities were further confirmed by equilibrium dialysis of the complexes of the polynucleotides with the racemic form of the drugs, which resulted in the enrichment of the dialysate with the positive enantiomer. CD spectra of the enantiomers and their polynucleotide complexes are reported. Changes in the fluorescence properties of quinacrine in the presence of the two polynucleotides are also described. Biological implications of these findings are discussed.

Arene–Ru(II)–chloroquine complexes interact with DNA, induce apoptosis on human lymphoid cell lines and display low toxicity to normal mammalian cells

“…The effects of both CQDP and 6 on the secondary structure of CT DNA have been reported [57,76] and they agree with our results. CQDP is a chiral molecule and the (+) and (−) enantiomers give mirror image CD spectra [57], which explains the lack of CD bands for the racemate used in our experiments.…”

“…CQDP is a chiral molecule and the (+) and (−) enantiomers give mirror image CD spectra [57], which explains the lack of CD bands for the racemate used in our experiments. Additionally, it has been determined by both spectrophotometric titrations and CD spectroscopy of pure CQDP enantiomers that the (−) enantiomer has a higher binding affinity for a given polynucleotide than the (+) one, with a ratio of 1.29 and 1.28 for poly (dG-dC).poly (dG-dC) and poly (dA-dT).poly (dA-dT) respectively [57]. This preferential binding of (−)-CQDP causes a change in the enantiomeric composition of the remaining drug not-bound to DNA, thus generating optical activity due to excess of free (+) CQDP.…”

“…As far as the mechanism of action is concerned, DNA can be considered a potential target for the Ru-CQ compounds because (i) CQ binds to DNA through intercalation [50–56], along with electrostatic interactions of the ionic side chain with the DNA phosphate groups [57–59]; and (ii) the related compounds [Ru(η 6 -arene)(X)(Y–Z)] exert their antitumor action through covalent binding of Ru to DNA. It was thus important to investigate the interactions of our compounds with DNA and to establish any possible relevance to antitumor behavior.…”

New Hopes from Old Drugs: Revisiting DNA-Binding Small Molecules as Anticancer Agents

“…Quinacrine has two optical isomers (enantiomers) with a chiral center in the middle section of its ‘tail’ [104]. This results in two different positions of the tail in the minor groove: the S -enantiomer tail is directed against the direction of the minor groove, while the R -enantiomer tail is positioned along the minor groove (Figure 2A).…”

Clearing the complexity: immune complexes and their treatment in lupus nephritis

“…46 We recently demonstrated that the binding of anti-dsDNA antibodies as measured by the modified Farr assay is reduced by the addition of hydroxychloroquine in vitro. 47 This effect is likely to be due to the high protein-binding capacity of hydroxychloroquine, 48 and intercalation of DNA (if sharing this property with chloroquine), 49,50 potentially modifying critical autoepitopes. Whether this affects the pathogenesis of human lupus nephritis is unknown.…”