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
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science . Some of the calculations were carried out at the Computer Center, Institute for Molecular Science at Okazaki, Japan. We thank the computational facility for generous allotments of computer time.
Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
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
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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 -