A THEORETICAL-STUDY OF THE MECHANISM OF OXYGEN-BINDING BY MODEL ANTHRAQUINONES .2. QUANTUM-MECHANICAL STUDIES OF THE ENERGETICS OF OXYGEN-BINDING TO MODEL ANTHRAQUINONES

Anthracycline derivatives, which constitute an important class of anti tumor drugs, exhibit undesirable cardiotoxicity owing to their mediati on in the process of oxygen reduction to the superoxide anion radical. Earlier work showed that this mediation could be facilitated by the f ormation of complexes with the 1DELTA(g), oxygen molecule prior to red uction. In this paper, we investigate the energetics of the possible p eroxides formed by a series of model anthraquinones: 1,4-dihydroxyl- ( quinizarin), 1,8-dihydroxyl-, 1-hydroxy-8-methoxy-, 1,8-dimethoxy-, 1, 4,5-trimethoxy- and 1,4-dihydroxy-5-methoxy-9,10-anthracenedione, as w ell as of daunorubicin and demethoxydaunorubicin, by semi-empirical qu antum-mechanical MNDO and PM3 methods, and limited STO-3G ab initio ca lculations. It was found that the oxygen-binding site is determined by three factors: the high electron density and high HOMO coefficients o n the carbon atoms to which oxygen binds, the minimum loss of conjugat ion within the anthraquinone moiety on oxygen binding and the minimum number of bonds to other heavy atoms of the oxygen-binding carbons (th e steric effect). For different molecules, the energy of the most stab le oxygen complex is the greatest for compounds with the lowest ioniza tion potential. On the basis of this and our earlier studies, it was c oncluded that the anthracycline derivatives with reduced ability to bi nd oxygen and, therefore, reduced cardiotoxicity, should possess a hig h symmetry of II-electron density distribution, a high ionization pote ntial and have all of the oxygen-binding sites condensed to other ring s or substituted by bulky groups.