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

Tomohiko Ohwada, Satoko Ishikawa, Yusuke Mine, Keiko Inami, Takahiro Yanagimoto, Fumika Karaki, Yoji Kabasawa, Yuko Otani, Masataka Mochizuki

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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.

Original languageEnglish
Pages (from-to)2726-2741
Number of pages16
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number8
DOIs
Publication statusPublished - 2011 Apr 15

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Keywords

  • Ames test
  • Bond dissociation energy
  • Mutagenicity
  • Nitrosamines

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Ohwada, T., Ishikawa, S., Mine, Y., Inami, K., Yanagimoto, T., Karaki, F., Kabasawa, Y., Otani, Y., & Mochizuki, M. (2011). 7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines. Bioorganic and Medicinal Chemistry, 19(8), 2726-2741. https://doi.org/10.1016/j.bmc.2011.02.049