Quantitation of the molecular mechanisms of biological synergism in a mixture of DNA-acting aromatic drugs.

It is suggested that the widely reported biological synergism of a mixture of DNA-targeting aromatic drug molecules both in vivo and in vitro can be explained, in part, at the molecular level by competition between two basic mechanisms: the 'interceptor' (hetero-association between Drug1 and Drug2) and 'protector' mechanisms (complexation of Drug1 and Drug2 on DNA-binding sites). In the present work a complete analytical methodology has been developed to quantify these processes, providing an estimate of the relative importance of the interceptor/protector mechanisms using just a set of equilibrium association constants. The general methodology may be applied to other molecules with receptors for aromatic drugs.

Complexation of daunomycin with a DNA oligomer in the presence of an aromatic vitamin (B2) determined by NMR spectroscopy.

The effect of simultaneous binding of the anthracycline antibiotic Daunomycin (DAU) and the Vitamin B2 derivative, Flavin-mononucleotide (FMN), with the DNA oligomer, d(TGCA)2, in solution has been investigated quantitatively by 1I-NMR spectroscopy (500 MHz). The equilibrium reaction constants and the thermodynamical parameters (DeltaH, DeltaS) of the hetero-association FMN-DAU and complexation of FMN with d(TGCA)2 have been determined by analysis of the concentration and temperature dependences of chemical shifts of the aromatic protons in terms of a competitive binding model. A criterion for discrimination between hetero-association and DNA complexation has been developed and applied to the analysis of the simultaneous binding of the antibiotic and the vitamin with DNA.