7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines

Nitrosamines are potent carcinogens and toxicants in the rat and potential genotoxins in humans. They are metabolically activated by hydroxylation at an alpha-carbon atom with respect to the nitrosoamino group, catalyzed by cytochrome P450. However, there has been little systematic investigation of the structure-mutagenic activity relationship of N-nitrosamines. Herein, we evaluated the mutagenicity of a series of 7-azabicyclo[2.2.1] heptane N-nitrosamines and related monocyclic nitrosamines by using the Ames assay. Our results show that the N-nitrosamine functionality embedded in the bicyclic 7-azabicylo[2.2.1] heptane structure lacks mutagenicity, that is, it is inert to alpha-hydroxylation, which is the trigger of mutagenic events. Further, the calculated alpha-C-H bond dissociation energies of the bicyclic nitrosamines are larger in magnitude than those of the corresponding monocyclic nitrosamines and N-nitrosodimethylamine by as much as 20-30 kcal/mol. These results are consistent with lower alpha-C-H bond reactivity of the bicyclic nitrosamines. Thus, the 7-azabicyclo[2.2.1] heptane structural motif may be useful for the design of nongenotoxic nitrosamine compounds with potential biological/medicinal applications. (C) 2011 Elsevier Ltd. All rights reserved.