کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1356202 | 981096 | 2011 | 16 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: 7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines 7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines](/preview/png/1356202.png)
Nitrosamines are potent carcinogens and toxicants in the rat and potential genotoxins in humans. They are metabolically activated by hydroxylation at an α-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 α-hydroxylation, which is the trigger of mutagenic events. Further, the calculated α-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 α-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.
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Journal: Bioorganic & Medicinal Chemistry - Volume 19, Issue 8, 15 April 2011, Pages 2726–2741