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.
Institute of Physics, Nicholas Copernicus University, Toruń, Poland.
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Jeziorek
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Dyl
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Liwo
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Woźnicki
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Tempczyk
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Borowski
D000880:Anthraquinones / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000880:Anthraquinones; D000970:Antineoplastic Agents; D010100:Oxygen