Selfassociation of daunomycin

Abstract

Daunomycin, a potent anthracycline [anticancer] antibiotic, self-associates in aqueous solution at concentrations > 10 .mu.M. Visible absorbance, sedimentation equilibrium and proton NMR experiments that characterize this self-association are reported. In contrast to earlier reports that the process is a simple dimerization, an indefinite association model best fit the data, with an intrinsic association constant, Ki = 1500 M-1. From the temperature dependence of the observed NMR spectra, an enthalpy of .apprx. 8.0 kcal/mol is calculated. NMR data show that the aromatic protons of the anthracycline portion of the drug are most affected by aggregation, probably due to stacking of the anthracycline rings. Knowledge of the applicable model for the self-association process, and the equilibrium constant that describes the process, enables the quantitative assessment of the possible effects of drug aggregation on the interpretation of drug-DNA binding data. For the ionic conditions most commonly used in such studies, the amount of aggregated daunomycin will be slight and may safely be ignored.