Abrogation of the selectivity of adriamycin for negatively-charged phospholipids by 14-valerate side chain substitution

The impressive affinity of Adriamycin and related anthracycline antibiotics for negatively-charged phospholipids has been implicated in the mechanism of the cardiac toxicity of these drugs. In this report we employ the method of fluorescence anisotropy titration to examine the manner in which 14-valerate side chain substitution modulates anthracycline drug associations with electroneutral vesicles composed of dimyristoyl phosphatidylcholine as well as negatively-charged vesicles composed of dimyristoyl phosphatidylglycerol or a binary mixture of dimyristoyl phosphatidylcholine and cardiolipin. Equilibrium binding data gathered on several anthracycline analogs indicate that incorporation of a hydrophobic valerate side chain abolished the high levels of preferential drug binding to negatively-charged membranes. Thus, we propose that 14-O-acyl substitution may prove to be a useful synthetic modification to prevent the selective accumulation of positively-charged anthracyclines in tissues or membrane domains rich in negatively-charged lipid.