title: 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.
abstract: 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.
authors.affiliation: Institute of Physics, Nicholas Copernicus University, Toruń, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Jeziorek
authors.forename: D
authors.initials: D
authors.lastname: Dyl
authors.forename: A
authors.initials: A
authors.lastname: Liwo
authors.forename: W
authors.initials: W
authors.lastname: Woźnicki
authors.forename: A
authors.initials: A
authors.lastname: Tempczyk
authors.forename: E
authors.initials: E
authors.lastname: Borowski
mesh_terms: D004735:Energy Transfer; D006873:Hydroquinones / Q000737:chemistry / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011789:Quantum Theory; D013481:Superoxides / Q000737:chemistry / Q000378:metabolism
chemical_list: D006873:Hydroquinones; D013481:Superoxides; D010100:Oxygen; C031927:hydroquinone