Hetero‐association of caffeine and theophylline with purine and pyrimidine in aqueous solutions studied by ¹H NMR chemical shift measurements

Abstract

The interaction of caffeine and theophylline with purine and pyrimidine was studied in deuterium oxide at 35 "C by measuring the concentration-dependent selective changes in the chemical shifts of the N-methyl protons of the xanthine derivatives. Using a competitive dimer model, the equilibrium constants give a decreasing tendency for hetero-association within the series caffeine-purine (2.97 f 0.15 1 mol-') > theophylline-purine (2.44 & 0.10 I mol-') > caffeine-pyrimidine (1.18 f 0.20 1 mol-') > theophylline-pyrimidine (0.70 0.08 I mol-I), and the upfield dimer shifts suggest a plane-to-plane arrangement.

Complexation of Biologically Active Aromatic Compounds with DNA in the Presence of Theophylline

“…It is found in Table 1 that the magnitudes of the equilibrium constants of THP-ligand hetero-association are in general similar to those for the hetero-association of CAF with the same ligands, although being somewhat higher (except for the NOV-THP system). In previous work [19,20], it was shown that the absence of the 7-methyl group in the structure of THP molecules should lead to more compact stacking of the aromatic chromophores than in CAF. In the case of the sandwich-type hetero-association discussed in this work, compact stacking will always result in effective dispersive interactions of aromatic chromophore currents and, as a consequence, may lead to the increase in the hetero-association constant of THP compared to CAF with the same aromatic drugs.…”

“…However, caffeine is not the only methylxanthine compound present in significant amounts in human blood plasma on consumption of caffeinated food. There are also relatively large amounts of caffeine derivatives such as paraxanthine, theophylline and theobromine [1], which, in principle, can act as effective interceptors of aromatic BACs, though there is little known about the hetero-association of these compounds with BACs and their influence on drug-DNA binding except a few reports of the complexation of theophylline with the dye Acridine Orange [14], and some nucleotide derivatives [18][19][20][21]. Theophylline (THP, Fig.…”

Hetero-association of aromatic molecules in aqueous solution

“…Quantitative parameters of the hetero-association in solution of various combinations of derivatives of nucleic acid bases have been reported for purine-purine, purine-pyrimidine and pyrimidine-pyrimidine interactions [27,70,71,[83][84][85][86][87][88][89]. Derivatives of nucleic acid bases tend to form stacking-type complexes in aqueous solutions with minor contribution, if any, from in-plane hydrogen-bonding (base-pairing), as deduced from the monotonic shift of aromatic protons to lower frequency in NMR [70,83,85,86,88,89] or the hypochromic effect in UV-vis spectroscopy [90][91][92] on increasing concentration or decreasing 16 M.P. Evstigneev temperature, and also supported by high-level quantum-chemical computations [93][94][95][96].…”

“…It was found that K h for the interaction of purine derivatives is, on average, higher than that for purine-pyrimidine which, in turn, is much greater than for pyrimidine-pyrimidine interactions [23,84,87,98]. Based on these results, it was concluded that hetero-association of derivatives of nucleic acid bases in water is largely governed by van der Waals interactions between the molecules in hetero-complexes, which are known to correlate with the dimensions of aromatic portion of the interacting molecules [11,86,87]. This conclusion is supported by the fact that on average the magnitude of thermodynamical parameters increases with the number of overlapping aromatic rings in the hetero-complex, viz.…”

“…The tendency to hetero-association was found to depend strongly on the type of substituents; for example, K h increases with methylation of purine and pyrimidine bases, which was interpreted in terms of either greater hydrophobic or van der Waals contribution to the thermodynamics of complexation [70,[83][84][85][86]98]. However, methylation also leads to alterations in the structures of 1:1 hetero-complexes due to the steric demands to accommodate the methyl group within the complex (an increase in distance and induction of partial overlap between the chromophores) [85,101].…”