Arylamines are considered to be carcinogens; however mechanistic detail of their reaction with DNA is still unknown. Currently it is accepted that the mechanism involves the highly reactive arylnitrenium ions. Theoretical calculations support the direct reaction between guanine C8 and arylnitreniums. While others suggest that guanine N7 first reacts with the arylnitrenium yielding N7 adducts, which then rearrange intramolecularly to the C8 substituted product. Here, we have proposed an alternative reaction mechanism that does not involve the arylnitrenium intermediates. In the initial step, N7 reacts with the activated arylamine through an S<sub>N</sub>2’ mechanism. This intermediate cyclizes followed by a ring-opening elimination to yield the final C8 substituted product. Theoretical calculations were done using B3LYP/6-31+G(d) and the CPCM aqueous solvation model. Models for the guanine base; 1-methylimidazole, imidazole, guanine and 9-methylguanine were used. The highly mutagenic 2-aminothiazole was used as the model for arylamines. The rate limiting step is predicted to be the initial substitution reaction forming the N7 adduct. This N7 adduct will readily cyclize to a 5 membered ring intermediate, which is deprotonated at C8 resulting in the ring opening to form the final C8 substituted product. The maximum barrier after the initial S<sub>N</sub>2’ rate limiting step is 16±10 kcal/mol for the 9-methylguanine and 2-aminothiazole model system. Acid constants for a variety of nitreniums to the nitrene are predicted to be acidic suggesting that the lifetime of nitreniums in the cellular environment would be exceedingly small. The acid constants and the singlet-triplet gap for the nitreniums will be presented.

Tandem substitution-cyclization-elimination reaction that can account for the mutagenicity of arylamines without the need of nitrenium ions

249th National Meeting (2015)

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