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. These calculations were supplemented with ab initio calculations, using STO-3G, 4-31G and 6-31G basis sets, on the energetics of oxygen binding to 1,4-dihydroxy and 1,4-diaminobenzene. It was found that for anthraquinones possessing hydroxyl groups, the formation of hydroperoxides is significantly favored energetically compared with the formation of peroxides. In the case of anthraquinones containing only amino groups, the formation of hydroperoxides is less favorable, owing to a greater enthalpy of amino group deprotonation compared with that of hydroxyl group. The effect of electrostatic solvation on the energetics of oxygen addition was also investigated using the Conductor-like Screening Model (COSMO) approach. The effect of solvation on peroxide formation was found to be small, while in the case of hydroperoxides solvation was found to lower the enthalpy of this reaction by approximately 10 kcal/mol for epsilon = 78 (simulating an aqueous environment). Significant stabilization of hydroperoxides was estimated in weakly polar media (epsilon = 4) which can simulate the quinone-reducing center of the mitochondrial NADH dehydrogenase. The enthalpies obtained for oxygen addition to anthraquinones involving the formation of the most stable of the peroxide and hydroperoxide species are in good correlation with the rates of NADPH oxidation stimulated by these compounds and, in turn, with their peroxidating properties. This correlation can be directly implemented in the design of non-peroxidating anthraquinone-derived anti-cancer drugs.

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. It was found that the oxygen-binding site is determined by three factors: the high electron density and high HOMO coefficients on the carbon atoms to which oxygen binds, the minimum loss of conjugation within the anthraquinone moiety on oxygen binding and the minimum number of bonds to other heavy atoms of the oxygen-binding carbons (the steric effect). For different molecules, the energy of the most stable oxygen complex is the greatest for compounds with the lowest ionization potential. On the basis of this and our earlier studies, it was concluded that the anthracycline derivatives with reduced ability to bind oxygen and, therefore, reduced cardiotoxicity, should possess a high symmetry of II-electron density distribution, a high ionization potential and have all of the oxygen-binding sites condensed to other rings or substituted by bulky groups.

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. The present study reports quantum mechanical calculations of the structure and the energies of the possible oxygen complexes of the most simplified model compound: 1,4-benzenediol (1,4-hydroquinone); 2,3-dihydro-2,3-epidioxy-, 2,5-dihydro-2,5-epidioxy- and 1,4-epidioxy-1,4-benzenediol (the 2,3-, 2,5- and 1,4-peroxide). Calculations were carried out with the use of ab initio (STO-3G, 4-31G, and 6-31G) and semiempirical MNDO methods with total geometry optimization. The optimized geometry parameters were found to be in a reasonable agreement with the available crystal data. During the oxygen complex formation with hydroquinone, charge transfer occurs from hydroquinone to the oxygen molecule. Supplementary MNDO calculations have shown that the stability of 2,3-peroxide is increased substantially upon the ionization of one of the hydroxyl groups of hydroquinone prior to oxygen binding, which increases the electron density of the benzene ring. These findings result in a prediction that the anthracycline derivatives with electron-withdrawing substituents in the II-electron moiety should exhibit diminished affinity towards oxygen and, consequently, diminished ability to peroxidation. It has also been found that the relative energies of different peroxides are well represented even in the STO-3G ab initio calculations which will enable the further extension of the study to the complete II-electron moiety of the actual anthracycline derivatives.