Structural basis for the binding of antitumor anthracycline antibiotics to model membranes: circular dichroism...

Circular dichroism was used to compare the binding of several anthracycline antitumor antibiotics to sonicated phosphatidylcholine vesicles. Daunorubicin analogues, differing from the parent by structural changes in the amino sugar moiety of the molecule, were tested both with vesicles that contained negatively charged phospholipids and with neutral vesicles. The self-association properties of the analogues were also investigated. Binding to negatively charged vesicles was not strictly dependent on electrostatic interactions, since the characteristics of daunorubicin binding were totally different from those of Adriamycin (doxorubicin). Furthermore, the cardiotoxicity of these molecules did not have its origin in their quantitatively preferential electrostatic binding to negatively charged cardiolipin-containing membranes: DR-19, a daunorubicin derivative having lower cardiotoxicity than the parent compound, which bound to negatively charged vesicles in a manner quite similar to that of Adriamycin, whereas DR-10, another daunorubicin derivative with higher cardiotoxicity, bound poorly to negatively charged vesicles.