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 language | English |
|---|---|
| Pages (from-to) | 2726-2741 |
| Number of pages | 16 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 19 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2011 Apr 15 |
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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 journal › Article
}
TY - JOUR
T1 - 7-Azabicyclo[2.2.1]heptane as a structural motif to block mutagenicity of nitrosamines
AU - Ohwada, Tomohiko
AU - Ishikawa, Satoko
AU - Mine, Yusuke
AU - Inami, Keiko
AU - Yanagimoto, Takahiro
AU - Karaki, Fumika
AU - Kabasawa, Yoji
AU - Otani, Yuko
AU - Mochizuki, Masataka
PY - 2011/4/15
Y1 - 2011/4/15
N2 - 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.
AB - 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.
KW - Ames test
KW - Bond dissociation energy
KW - Mutagenicity
KW - Nitrosamines
UR - http://www.scopus.com/inward/record.url?scp=79954425141&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79954425141&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2011.02.049
DO - 10.1016/j.bmc.2011.02.049
M3 - Article
C2 - 21435887
AN - SCOPUS:79954425141
VL - 19
SP - 2726
EP - 2741
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 8
ER -