Ab initio computations were carried out at MP2/6-311＋G(d,p) level to study the mechanism of the formation of DNA alkylation agents from the metabolism of 3,5-dimethyl-1-nitrosopiperazine (DMNP) and its derivatives. The influence of the substituent groups of the N’ atom was investigated in the formation of the two alkylation centers on the α- and γ-positions of the DMNP metabolites. The relationship between the formational activities of the two active centers and the carcinogenic potency of the parent compounds was also explained. The results show that the parent compounds are inclined to exhibit higher carcinogenic activity when their α-position and γ-position metabolites are easier to produce the active electrophilic intermediates. However, if one alkylation center is blocked, the carcinogenic potency of the compounds is decreased obviously. Therefore, the carcinogenecity of DMNP was supposed to depend on the synergetic alkylation of the α- and the γ-positions. It is necessary to consider the alkylating activity of these two alkylation centers and the relationship between them in the appraisement of the carcinogenecity of DMNP.

Key words: N-nitrosopiperazine, carcinogenic mechanism, alkylation activity, ab initio