Interaction between aromatic antibiotics and vitamins: 1H NMR study of heteroassociation of nicotinamide and anthracycline antitumor antibiotics

Abstract

The interaction between anthracycline antitumor antibiotics daunomycin and novatrone and the vitamin nicotinamide has been investigated by one- and two-dimensional 1H NMR spectroscopy (500 MHz). Due to significant differences in structures of the chromophores of interacting molecules, a two-site heteroassociation model has been developed, allowing the arrangement of one and two nicotinamide molecules on the chromophore of the antibiotic. The equilibrium association constant, thermodynamical parameters (deltaH, deltaS) of the heteroassociation of nicotinamide with daunomycin and novatrone and the induced proton chemical shifts in the heterocomplexes have been determined from the concentration and temperature dependences of proton chemical shifts of interacting molecules. The most favorable structures of 1:1 nicotinamide--daunomycin and nicotinamide-novatrone heteroassociation complexes have been determined using both the molecular mechanics methods (X-PLOR software) and the calculated values of induced proton chemical shifts. Analysis of the results obtained allows one to conclude that two nicotinamide molecules cannot simultaneously bind on one side of the chromophore of antibiotic. Heterocomplexes of the vitamin with the antibiotics with a stoichiometry 1:1 are mainly stabilized by the stacking of aromatic chromophores.