Molecular modeling of singlet-oxygen binding to anthraquinones in relation to the peroxidating activity of antitumor anthraquinone drugs.

Anthraquinone derivatives are important anti-cancer drugs possessing, however, undesirable peroxidating and, in consequence, cardiotoxic properties. This results from the mediation by these compounds of the one-electron reduction processes of the oxygen molecule, which produces the highly toxic superoxide anion radical and other active oxygen species. This article summarizes the results of our studies on the molecular aspects of the mechanism of anthraquinone-mediated peroxidation which were carried out using enzymatic-assay, electrochemical, and quantum-mechanical methods.

Enthalpy of oxygen addition to anthraquinone derivatives determines their ability to mediate NADH oxidation.

Anthraquinone derivatives are important anti-cancer drugs possessing undesirable cardiotoxic properties related to their peroxidating activity. Previous studies have suggested that this activity can be caused by the binding of a singlet oxygen molecule to an anthraquinone, followed by the one-electron reduction of the complex formed, and its further dissociation into anthraquinone and the superoxide anion radical. In this study, we have carried out semi-empirical PM3 calculations of the energetics of the formation of peroxides and hydroperoxides from hydroxy, amino and imino derivatives of 9,10-anthracenedione.

A theoretical study of the mechanism of oxygen binding by model anthraquinones. Part II. Quantum-mechanical studies of the energetics of oxygen binding to model anthraquinones.

Anthracycline derivatives, which constitute an important class of antitumor drugs, exhibit undesirable cardiotoxicity owing to their mediation in the process of oxygen reduction to the superoxide anion radical. Earlier work showed that this mediation could be facilitated by the formation of complexes with the 1 delta g oxygen molecule prior to reduction. In this paper, we investigate the energetics of the possible peroxides 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 well as of daunorubicin and demethoxydaunorubicin, by semi-empirical quantum-mechanical MNDO and PM3 methods, and limited STO-3G ab initio calculations.

A theoretical study of the mechanism of oxygen binding by model anthraquinones. I: Quantum mechanical evaluation of the oxygen-binding sites of 1,4-hydroquinone.

The undesirable cardiotoxicity of some important classes of antitumor drugs, such as anthracycline derivatives, is caused by their mediation of the one-electron reduction processes of the oxygen molecule which produces the highly toxic superoxide anion radical. Recent studies enable the conclusion to be drawn that the first and rate-limiting stage of this process is the formation of complexes of the drug anthraquinone moiety with 1 delta g molecular oxygen. The complexes can easily undergo one-electron reduction, whose product dissociates into the unchanged drug molecule and the superoxide anion radical.