Activation Mechanism of N-Nitrosodialkylamines as Environmental Mutagens and Its Application to Antitumor Research

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  • Inami Keiko
    Tokyo University of Science, Faculty of Pharmaceutical Sciences Kyoritsu University of Pharmacy
  • Ishikawa Satoko
    Tokyo University of Science, Faculty of Pharmaceutical Sciences Keio University Faculty of Pharmacy
  • Mochizuki Masataka
    Tokyo University of Science, Faculty of Pharmaceutical Sciences Kyoritsu University of Pharmacy

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説明

Carcinogenic and mutagenic N-nitrosodialkylamines exist in our environment. In order to study the biological and chemical properties of the activated form of carcinogenic N-nitrosodialkylamines, highly unstable α-hydroxy nitrosamines were synthesized through deoxygenation of the corresponding α-hydroperoxy nitrosamines. Furthermore, active nitrosamines such as α-hydroperoxy, α-phosphonooxy, and α-acetoxy nitrosamines were also synthesized along with alkanediazohydroxides, which are activated products of α-hydroxy nitrosamines. The activity of all these active nitrosamines is highly dependent upon the alkyl groups in the N-nitrosodialkylamines. We demonstrate that α-hydroxylation is the key step in the metabolic activation of N-nitrosodialkylamines. Using chemical models for cytochrome P450, we isolated a mutagenic agent capable of alkylating DNA. Based on the chemistry of N-nitrosamines, we found some new possible anticancer lead compounds that have an N-nitroso group as an alkylating moiety and tricyclic aromatic rings as a DNA intercalating moiety.<br>

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