Determinants of nucleic acid adduct formation.
Although N-aryl- or N-acetyl-N-arylnitrenium ions are considered the reactive species in the attack of many aromatic amines or amides on biologic macromolecules, a coherent picture explaining the variety of reactions of the ultimate carcinogens from which they are derived has not been established. Self-consistent field-molecular orbital calculations were used to attempt to understand the reactions of 3 ultimate carcinogens in the aromatic amine class. The MINDO/3 calculations for the cations resulting from loss of acetate from 3-acetoxyxanthine, N-acetoxy-2-fluorenylacetamide (N-AcO-2-FAA) and N-acetoxy-4-acetamidostilbene show that these cations are unlikely to exist in a triplet state, contrary to experimental data which could be interpreted otherwise. Iterative extended Hückel theory calculations for these cations show that the reactions which suggested a triplet state may be explained on the basis of hard/soft-acid/base theory. Electrostatic potential maps combined with frontier orbital theory suggest a coherent explanation for the variety of reactions of N-AcO-2-FAA. The use of the polyelectronic perturbation theory has previously been shown to predict correctly the major product of reaction between guanosine and 5 ultimate carcinogens. I have shown here that the unmodified theory (using Hückel molecular orbital theory) further predicts the major product of reaction between DNA and N-hydroxy-2-naphthyl-amine, but that it predicts secondary products incorrectly.
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives*; D000099:Acetoxyacetylaminofluorene / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D002151:Calorimetry; D002273:Carcinogens / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D008968:Molecular Conformation; D013267:Stilbenes / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000378:metabolism*
D002273:Carcinogens; D013267:Stilbenes; D014970:Xanthines; C006363:N-acetoxy-4-acetylaminostilbene; D000099:Acetoxyacetylaminofluorene; C033992:3-acetoxyxanthine; D004247:DNA; D015073:2-Acetylaminofluorene