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.
Jeziorek
D
D
Institute of Physics, Nicholas Copernicus University, Toruń, Poland.
Dyl
D
D
Liwo
A
A
Ossowski
T
T
Woźnicki
W
W
D000880:Anthraquinones / Q000138:chemical synthesis / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006861:Hydrogen Peroxide / Q000138:chemical synthesis / Q000737:chemistry*; D009243:NAD / Q000737:chemistry*; D010084:Oxidation-Reduction; D010545:Peroxides / Q000138:chemical synthesis / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics
D000880:Anthraquinones; D000970:Antineoplastic Agents; D010545:Peroxides; D009243:NAD; D006861:Hydrogen Peroxide