Structural Effects in Reactivity and Adduct Formation of Polycyclic Aromatic Epoxide and Diol Epoxide Derivatives with DNA: Comparison between 1-Oxiranylpyrene and Benzo[a]pyrenediol Epoxide

Reaction of 1-oxiranylpyrene (1-OP) with DNA and the structures of the covalent and noncovalent complexes formed were studied in aqueous media (5 mM phosphate buffer with 0.1 M NaCl, pH 7) by utilizing the techniques of absorption, fluorescence and linear dichroism spectroscopy in order to gain an understanding of possible structure-activity relationships for polycyclic aromatic hydrocarbon epoxides in tumorigenesis and carcinogenesis, and the results were compared with those obtained for the highly active benzo[a]pyrene diol epoxide (BaPDE). Like BaPDE, 1-OP undergoes acid-catalyzed hydrolysis with the pseudo-first-order rate constant k = 4.6 × 10^-4 s^-1 in the absence of DNA, which is about 10 times slower than in the case of BaPDE. In DNA solutions, this hydrolysis is catalyzed by a rapid formation of a physically bound complex of 1-OP…DNA, which subsequently undergoes either (1) hydrolysis to a diol derivative or (2) formation of a covalent adduct of 1-OP-DNA. The same value of the noncovalent binding constant (K = 4000 M^-1) is obtained for both 1-OP and for BaPDE, which suggests that the π-electron interaction between the pyrenyl moiety and the nucleic acid bases is the dominant factor in the formation of the physical complexes and that the two extra OH groups in BaPDE do not play a significant role in determining the value of the physical binding constant. The most striking difference between the structures of these two adducts is the linear dichroism (LD): unlike the BaPDE-DNA adduct which exhibits positive LD signais, characteristic of external binding sites, 1-OP-DNA adducts exhibit negative LD with the angle of orientation of the pyrenyl chromophore with respect to the DNA helix axis θ = 65 ± 3°, indicating conformations close to, but not identical with, those of dye-DNA intercalation complexes. The lower mutagenic activity of 1-OP relative to that of BaPDE may be related to these differences in the structures of the covalent DNA adducts.