3,5-二甲基-亚硝基哌嗪代谢物对DNA烷化作用的理论研究

Theoretical Studies on the Mechanism of DNA Alkylation by the Metabolites of 3,5-Dimethyl-1-nitrosopiperazine

用从头计算法在MP2/6-311+G(d,p)水平上对3,5-二甲基-亚硝基哌嗪(DMNP)及其类似物经代谢生成DNA烷化剂的机理进行了研究.探讨了N'原子上取代基的变化对DMNP代谢物生成α-位和γ-位两个烷化中心的影响,解释了两个烷化中心的生成活性与化合物的致癌性之间的关系.结果表明,α-位和γ-位代谢物越容易生成活泼亲电中间体,其母体化合物的致癌活性越高.但如果有一个烷化中心丧失活性,就会明显减弱化合物的致癌活性.因此,DMNP类化合物的致癌性取决于其α-位和γ-位的协同烷化作用,在评价DMNP的致癌强度时需同时考虑两个烷化中心的烷化能力以及二者之间的关系.

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.