Quantitative pattern recognition for structure-carcinogenic activity relationship of N-nitroso compounds based upon Di-region theory.

Abstract

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%.