Syntheses and Properties of 1-Methyl-3-phenylaminobenzimidazolium Salts, Models of DNA Adducts of N7-Arylaminodeoxyguanosinium Salt

• Published in: Chemical research in toxicology Vol. 13; no. 10; pp. 993 - 1001
• Main Authors: Kaiya, Toyo, Fujiwara, Tomoko, Kohda, Kohfuku
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-10-2000
• Subjects: 1-methyl-3-phenylaminobenzimidazolium; Amines - chemical synthesis; Amines - chemistry; Arylaminodeoxyguanosinium; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Deoxyguanosine - analogs & derivatives; Deoxyguanosine - chemical synthesis; Deoxyguanosine - chemistry; DNA Adducts - chemical synthesis; DNA Adducts - chemistry; Hot Temperature; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Models, Chemical
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx0000724

When arylaminating carcinogens are administered to cells, they mainly generate the C8-arylamino-2‘-deoxyguanosine adduct in DNA. A mechanism for this was proposed in which N7-arylaminated 2‘-deoxyguanosine acts as an intermediate; however, it remained unclear whether this is actually the case. To elucidate the mechanisms involved in the generation of this adduct, a series of 5-substituted 1-methylbenzimidazole derivatives were used as models of the imidazole moiety of 2‘-deoxyguanosine. Syntheses of a series of 5-substituted (CH3, H, F, CF3, or NO2) 1-methyl-3-phenylaminobenzimidazolium salts (7) and their related compounds were carried out, and the chemical characteristics of these products were examined. Heating compound 7 at 80 °C for 48 h in H2O/MeOH provided 5-substituted 1-methyl-2-oxo-2,3-dihydrobenzimidazoles but only when this compound contained a CF3 or NO2 substituent. Compound 7 decomposed in alkaline media, and its rate of decomposition increased when this compound had a stronger electron-withdrawing substituent. The product obtained under these conditions was 4-substituted N 1-methyl-2-phenylazoaniline. On the other hand, when 1-methyl-3-(4-nitrophenylamino)benzimidazolium salt was treated under the same conditions as described above, it generated a demethylated product, 1-(4-nitrophenylamino)benzimidazole, when heated in H2O/MeOH and N 1-formyl-N 1-methyl-2-phenylazoaniline when treated in alkaline media. When the chemical characteristics of 3-phenylamino and 3-amino groups were compared using 3-substituted 1-methyl-5-(trifluoromethyl)benzimidazoles, the 3-phenylamino derivative was found to be more reactive.