Antitumor action at the molecular level : a spectroscopic study of the binding of anthracyclines to a model DNA system

Magnetic Circular Dichroism (MCD) spectroscopy has been applied to the study of drug-dinucleotide binding in solution. MCD spectra have been recorded for complexes of the intercalating anthracyclines Aclacinomycin, Carminomycin, and Marcellomycin with the self-complimentary dinucleotide Z'-deoxycytidylyl-CS'—>5')2'-deoxyguanosine (CpG). Optical titrations were also performed to further characterize the binding process. Both single and double stranded dinucleotide binding situations were investigated. It is of interest to define the binding process in terms of the structural features involved. This leads to the identification of three important characteristics governing the anthracycline binding process. The degree of substitution on the amino function of the first sugar is important in hydrogen bond formation. If fully substituted no hydrogen bonding is possible and the binding constant of the anthracycline is reduced. The location of the carbonyl function on the non-planar D ring also controls the availability of hydrogen bonding. If the carbonyl is at the 9 position, hydrogen bonding to the bases is possible. However, if the carbonyl is located at the 10 position then no hydrogen bonding is possible. The presence of an anthraquinone carbonyl which is not perihydroxylated will cause the anthracycline to be much more hydrophobic in nature. This in turn will allow it to penetrate the base stacking region to a greater extent leading to cooperative binding. It is the combination of these structural features which will determine the major stabilizing force involved in the intercalation process, base stacking or hydrogen bonding.