ANTHRACYCLINE COPPER(II) COMPLEXES - STRUCTURE-DEPENDENT COORDINATION PATTERN AS EVIDENCED BY ELECTRON-SPIN-RESONANCE

The copper(II) coordination properties of different anthracycline antitumor agents were studied by ESR spectroscopy. Three classes of drugs have been identified: (i) adria-like, which contains adriamycin, daunomycin, 4′-deoxydaunomycin, 4′-deoxy- 4′-iododaunomycin and 4-demethoxydaunomycin; (ii) 4′-epiadria-like, which contains 4′-epiadriamycin, 4′-epidaunomycin, 4-demethoxy-6-deoxydaunomycin and 4-demethoxy-11-deoxydaunomycin; and (iii) border-line type, which contains carminomycin, 6-O- methylcarminomycin, 11-deoxycarminomycin and 6- deoxycarminomycin. They have been characterized by their different Cu(II) chelation properties. The adria-like class members give rise to multi- nuclear complexes, where both the CO and COH functionalities of both sides of the hydroxyanthra- quinone system are involved in the coordination. By contrast, the 4′-epiadria-like drugs form monomeric Cu(II) complexes because of the unavailability of the C(6)OH group. The border-line type compounds yield more than one monomeric Cu(II)adduct because of the presence of OH at the C(4) position. All Cu(II) derivatives are characterized by a very strong ligand field, the unpaired electron lying in the dx2-y2 orbital. The onset of comptexation is oxygen dependent and this is related to the σ and π bond properties of the anthracycline ligand.