title: 7-azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines.
abstract: 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.
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. ohwada@mol.f.u-tokyo.ac.jp
authors: Tomohiko
authors: T
authors: Ohwada
authors: Satoko
authors: S
authors: Ishikawa
authors: Yusuke
authors: Y
authors: Mine
authors: Keiko
authors: K
authors: Inami
authors: Takahiro
authors: T
authors: Yanagimoto
authors: Fumika
authors: F
authors: Karaki
authors: Yoji
authors: Y
authors: Kabasawa
authors: Yuko
authors: Y
authors: Otani
authors: Masataka
authors: M
authors: Mochizuki
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D006536:Heptanes / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D009152:Mutagenicity Tests; D009153:Mutagens; D009602:Nitrosamines / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D006536:Heptanes; D009153:Mutagens; D009602:Nitrosamines