D. A. Veselkov

1H NMR investigation of the hetero-association of aromatic molecules in aqueous solution: factors involved in the stabilization of complexes of daunomycin and acridine drugs

Hetero-association of the anthracycline drug, daunomycin (DAU), with typical mutagens, the acridine dyes proflavine (PF) and acridine orange (AO), has been studied by 500 MHz 1H NMR spectroscopy as a function of concentration and temperature in 0.1 mol dm−3 phosphate buffered aqueous solutions at pD = 7.1. The results have been analysed in terms of a statistical-thermodynamical model of hetero-association of aromatic molecules, described previously [Davies, D. B., Veselkov, D. A., and Veselkov, A. N., 1999, Molec. Phys., 97, 439], but generalized in this work, so that there is no limitation on the magnitudes of the self-association constants of the interacting molecules. Expressions suitable for the analysis of NMR parameters of both components in the mixed solution have been developed enabling both the structural and thermodynamic properties of hetero-association to be determined. The magnitude of the equilibrium constant for hetero-association of PF + DAU is found to be substantially higher than the self-association constants of these molecules, whereas that for hetero-association of AO + DAU is intermediate between the equilibrium constants of self-association of AO and DAU. Intermolecular cross-peaks observed in 2D-ROESY spectra of PF + DAU mixed solutions are consistent with formation of a hetero-association complex in which an intermolecular hydrogen bond can form between either of the 3,6-diamino groups of the PF chromophore and the 9-MeCO group of DAU, which is in contrast to AO + DAU hetero-association, where such hydrogen bonds are unable to form. Quantitative structural and thermodynamical analysis of PF + DAU complexation is consistent with an intermolecular hydrogen bond contributing to the stability of the hetero-complex in aqueous solution. The NMR results show that hydrophobic interactions play a substantial role in the stabilization of the AO-DAU complex, characterized by a relatively small entropy change on complexation, compared to the PF-DAU hetero-complex, which is mainly stabilized by hydrogen bond and dispersive van der Waals interactions.

A general nuclear magnetic resonance analysis of hetero-association of aromatic molecules in aqueous solution

A general nuclear magnetic resonance analysis of a statistical-thermodynamical model of hetero-association of aromatic molecules in solution has been developed to take “edge effects” into consideration, i.e., the dependence of proton chemical shifts on the position of the molecule situated inside or at the edge of the aggregate. This generalized approach is compared with a previously published model, where an average contribution to proton shielding is considered irrespective of the position of the molecule in the stack. Association parameters have been determined from experimental concentration and temperature dependences of 500 MHz proton chemical shifts of the hetero-association of the acridine dye, proflavine, and the phenanthridinium dye, ethidium bromide, in aqueous solution. Differences in the parameters in the range 10%–30% calculated using the basic and generalized approaches have been found to depend substantially on the magnitude of the equilibrium hetero-association constant Khet—the larger th...

Structure and thermodynamics of the hetero-association of aromatic molecules in aqueous solution determined by NMR spectroscopy

A statistical-thermodynamical model of hetero-association, in which molecules form indefinite aggregates for both self-association and hetero-association, has been developed in this work to analyse the NMR parameters of component molecules in mixed solutions. The NMR analysis has been used to investigate the hetero-association of the phenanthridinium drug molecules, ethidium bromide (EB) and propidium iodide (PI), and the method has been shown to be self-consistent by the same results being given for two independent sets of experiments having either PI or EB constant and the other varied. The magnitudes of the hetero-association parameters (equilibrium reaction constants and thermodynamic parameters, entropy and free energy) for the phenanthridinium drugs, PI and EB, are found to be intermediate between those observed for self-association of these molecules, whereas the enthalpy of hetero-association of EB + PI is similar to that for self-association of these molecules in solution. The most favourable str...

Self-association of the antitumour agent novatrone (mitoxantrone) and its hetero-association with caffeine

The self-association of the antitumour drug, novatrone, NOV (mitoxantrone) and its hetero-association with caffeine (CAF) have been investigated by 1D and 2D 500 MHz 1H NMR spectroscopy. Two-dimensional homonuclear correlation NMR spectroscopy (2D TOCSY and 2D ROESY) has been used for complete assignment of proton signals and for a qualitative analysis of the mutual arrangements of the aromatic drug molecules in the aggregates. The structural and thermodynamical parameters of molecular self- and hetero-association of the aromatic compounds have been determined from measurements of the NMR chemical shifts of the drug protons as a function of concentration and temperature. The self-association of NOV has been analysed using both the indefinite cooperative and non-cooperative models, and the hetero-association of NOV and CAF has been analysed in terms of a statistical-thermodynamical model, in which molecules form indefinite aggregates for both self- and hetero-association. The magnitudes of parameters (equilibrium reaction constants, enthalpy (ΔH) and entropy (ΔS)) have been calculated for self-association of NOV and its complexation with CAF; at 318 K the equilibrium constant for self-association of NOV is 12400 (±4000) l mol−1 and for hetero-association with CAF is 256 (±30) l mol−1. The most favourable structures of the NOV dimer and the 1∶1 NOV–CAF hetero-association complexes have been determined from the calculated limiting values of the induced chemical shifts of the drug protons.

The Self-Association of Antibiotic Actinocyl-bis(3-dimethylaminopropylamine) in Aqueous Solution: A 1H NMR Analysis

The self-association of the synthetic antibiotic actinocyl-bis(3-dimethylaminopropylamine) was studied in aqueous solution by one- and two-dimensional 1H NMR spectroscopy at 500 MHz. The two-dimensional homonuclear correlation NMR techniques (TOCSY and ROESY) were used to completely assign all the proton signals of the antibiotic and to quantitatively analyze the mutual arrangement of the antibiotic molecules in their aggregates. The concentration and temperature dependences of proton chemical shifts were used to determine the equilibrium constants and the thermodynamic parameters (ΔH and ΔS) of the self-association, as well as the limiting values of proton chemical shifts in associates. The experimental results were analyzed using both the indefinite noncooperative and cooperative models of the molecular self-association. The calculated value of the cooperativity coefficient (σ ≈ 1.1) for our synthetic antibiotic confirmed a substantially lower anticooperative effect at the aggregation of its molecules in comparison with that of the antitumor antibiotic actinomycin D (σ ≈ 1.5). We calculated the most favorable structure of the dimeric associate of the synthetic antibiotic in aqueous solution and found that, like in the actinomycin D dimer, the antiparallel orientation of the phenoxazone chromophore planes of interacting molecules is characteristic of its dimer.

Heteroassociation of Caffeine with the Antibiotic Actinocyl- bis(3-dimethylaminopropylamine) in Aqueous Solution: 1H NMR Analysis

The heteroassociation of caffeine (CAF) and the synthetic antibiotic actinocyl-bis(3-dimethylaminopropylamine) (ACT) was studied in aqueous solution by one- and two-dimensional 1H NMR spectroscopy at 500 MHz. The equilibrium reaction constants, thermodynamic parameters (ΔH and ΔS) of ACT heteroassociation with CAF, the limiting values of proton chemical shifts of their molecules in the heteroassociation complex, and the spatial structure of the ACT–CAF complex were determined from the experimental dependences of proton chemical shifts of the aromatic molecules on concentration and temperature. The parameters of CAF heteroassociation with the phenoxazone antibiotic actinomycin D and its synthetic analogue ACT were comparatively analyzed and conclusions were made on the crucial role of stacking interactions of the chromophores of CAF and the phenoxazone antibiotics in the formation of the heterocomplexes in aqueous solution.

Thermodynamic analysis of self-association of actinocin bis(2-dimethylaminoethyl)amide in aqueous solution by 1H NMR spectroscopy

Self-association of a synthetic antibiotic, actinocin bis(2-dimethylaminoethyl)amide (ActII), in aqueous solution was studied by one- and two-dimensional 1H NMR spectroscopy (500 MHz).