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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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

Fingerprint

Nitrosamines
Hydroxylation
7-azabicyclo(2.2.1)heptane
Dimethylnitrosamine
Heptanes
Mutagens
Structure-Activity Relationship
Carcinogens
Cytochrome P-450 Enzyme System
Rats
Assays
Carbon
Atoms

Keywords

  • Ames test
  • Bond dissociation energy
  • Mutagenicity
  • Nitrosamines

ASJC Scopus subject areas

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

Cite this

7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines. / Ohwada, Tomohiko; Ishikawa, Satoko; Mine, Yusuke; Inami, Keiko; Yanagimoto, Takahiro; Karaki, Fumika; Kabasawa, Yoji; Otani, Yuko; Mochizuki, Masataka.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 8, 15.04.2011, p. 2726-2741.

Research output: Contribution to journalArticle

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, vol. 19, no. 8, pp. 2726-2741. https://doi.org/10.1016/j.bmc.2011.02.049
Ohwada, Tomohiko ; Ishikawa, Satoko ; Mine, Yusuke ; Inami, Keiko ; Yanagimoto, Takahiro ; Karaki, Fumika ; Kabasawa, Yoji ; Otani, Yuko ; Mochizuki, Masataka. / 7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 8. pp. 2726-2741.
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