SYNTHESIS, CHARACTERIZATION, AND CONFORMATIONAL-ANALYSIS OF DNA-ADDUCTS FROM METHYLATED ANILINES PRESENT IN TOBACCO-SMOKE

The ability of a series of aromatic amines present in tobacco smoke (2 -, 3-, and 4-methylaniline, 2,3- and 2,4-dimethylaniline) to bind to D NA has been investigated by reacting N-(acyloxy)arylamines with dG, dG nucleotides, and DNA. The predominant products from reactions with dG and the nucleotides were characterized as N-(deoxyguanosin-8-yl)aryla mines by spectroscopic and HPLC methods. HPLC and spectroscopic analys es of the modified DNA indicated the same adducts. Analyses of the H-1 and C-13 NMR spectra suggested that the adducts containing a methyl s ubstituent ortho to the arylamine nitrogen had a higher percentage of syn conformers. This observation was supported by theoretical simulati on studies that indicated substantial percentages of low energy syn co nformers, increasing with the substitution pattern in the order para < meta < ortho < ortho,para < ortho,meta. The results demonstrate that, although single-ring arylamines are considered weak carcinogens, thei r electrophilic N-acetoxy derivatives, which are plausible metabolic i ntermediates, react with DNA to yield covalent adducts structurally id entical to those derived from carcinogenic polyarylamines, such as 2-a minofluorene and 4-aminobiphenyl. Furthermore, the conformational pert urbation induced in DNA by the formation of the monoarylamine-DNA addu cts, especially those with an ortho substituent, may contribute to the biological activities of these compounds.