Interaction of anthracycline antibiotics with biopolymers: 9. Comparative study of the interaction kinetics of daunomycin, adriamycin and iremycin with DNA

Abstract

The interaction kinetics of the three anthracycline antibiotics, daunomycin, adriamycin and iremycin, with calf thymus DNA has been investigated using the temperature-jump technique. Experimental data obtained at high binding ratio have been fitted by a kinetic theory which, for the binding of large ligands to a linear polymer chain, takes into account both nearest-neighbour ligand interaction and the overlap of potential binding sites. The kinetics of such cooperative binding according to a single-step mechanism can be described completely by two independent microscopic parameters, namely one rate constant and a kinetic cooperativity parameter. Both these parameters have been determined for the three anthracyclcine antibiotics, making use of the known equilibrium binding parameters. The association rate constant in the singly contiguous case turns out to be almost the same for all three antibiotics ( 7 × 10 6 to 8 × 10 6 1 mol −1 s −1 ), while the corresponding dissociation rate constant ranges from 3.5 s −1 for adriamycin to 10 s −1 for daunomycin and about 35 s −1 for iremycin. The different equilibrium binding constants thus correspond to different mean attachment times of the antibiotics at the polymer chain, which positively correlate with the inhibitory action of these drugs on in vitro DNA synthesis. Nearest-neighbour interaction in the case of adriamycin-DNA binding kinetics implies that adriamycin molecules dissociate from an isolated binding site nine times more frequently than from a site between two adjacent ligands.