Dai Q H, Zhong R G
Center for Chemistry & Bioengineering of Cancer, Beijing Polytechnic University.
Sci China B. 1989 Jul;32(7):776-90.
In this paper, it is evidenced by the quantitative structure-carcinogenic activity relationship (QSCAR) and the pattern recognition treatment of N-nitroso compounds (NNC) that the key step of carcinogenesis induced by NNC is the cross-linking on the complementary base pair of DNA, through the bifunctional alkylation between alpha-carbon and another carbon within the same chain. The alkylation by the alpha-carbon atom is through the diazonium salt, but that by the atom other than the alpha-position is through the active ester formed from the hydroxylated metabolite of the chain. Therefore, the alkylation by the beta-position of NNC, or by its gamma-position, under suitable conditions, of which the distances from the alpha-position both approach 2.80-3.00 A, would be the most favourable positions along with the alpha-position for the cross-linking to occur between the complementary base pairs of DNA, which will yield the carcinogenic activity of NNC. The above conception of bifunctional alkylation can reduce the QSCAR of NNC to a reasonable structure-chemical reactivity relationship under the complex biological conditions, and is the successful extension of the Di-region theory to the carcinogenesis mechanism of the important NNC series. In the light of the above viewpoint, for 153 NNCs including the nitrosamines and nitrosamides which have been tested reliably with animals, the correct discrimination ratio by quantitative pattern recognition according to carcinogenic activity indexes divided into 5 degrees comes up to as high as 97%.
本文通过对N-亚硝基化合物（NNC）的定量构效关系（QSCAR）和模式识别处理证明，NNC致癌作用的关键步骤是DNA互补碱基对之间的交联，这是通过同一条链内α-碳与另一个碳原子之间的双功能烷基化实现的。α-碳原子的烷基化是通过重氮盐进行的，而α-位以外的原子的烷基化是通过由该链的羟基化代谢产物形成的活性酯进行的。因此，在合适的条件下，NNC的β-位或γ-位的烷基化，其与α-位的距离均接近2.80 - 3.00 Å，将是与α-位一起最有利于在DNA互补碱基对之间发生交联的位置，这将产生NNC的致癌活性。上述双功能烷基化的概念可以将NNC的QSCAR简化为复杂生物条件下合理的结构 - 化学反应性关系，并且是双区理论对重要NNC系列致癌机制的成功扩展。根据上述观点，对于153种已在动物身上进行可靠测试的包括亚硝胺和亚硝酰胺在内的NNC，根据致癌活性指标分为5度进行定量模式识别的正确判别率高达97%。
