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

Keiko Inami, Satoko Ishikawa, Masataka Mochizuki, Satoko Ishikawa

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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-phosphono-oxy, 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. Key words: N-nitrosodialkylamine, metabolic activation, mutagenesis.

Original languageEnglish
Pages (from-to)97-104
Number of pages8
JournalGenes and Environment
Volume31
Issue number4
DOIs
Publication statusPublished - 2009

Fingerprint

Nitrosamines
Mutagens
Research
Chemical Models
DNA
Alkylating Agents
Hydroxylation
mutagen
nitrosamine
Mutagenesis
Cytochrome P-450 Enzyme System
cytochrome
chemical property

ASJC Scopus subject areas

  • Social Psychology
  • Genetics
  • Environmental Science (miscellaneous)

Cite this

Activation Mechanism of N-Nitrosodialkylamines as Environmental Mutagens and Its Application to Antitumor Research. / Inami, Keiko; Ishikawa, Satoko; Mochizuki, Masataka; Ishikawa, Satoko.

In: Genes and Environment, Vol. 31, No. 4, 2009, p. 97-104.

Research output: Contribution to journalArticle

@article{5d584b7b986a4e9897304b34c507e552,
title = "Activation Mechanism of N-Nitrosodialkylamines as Environmental Mutagens and Its Application to Antitumor Research",
abstract = "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-phosphono-oxy, 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. Key words: N-nitrosodialkylamine, metabolic activation, mutagenesis.",
author = "Keiko Inami and Satoko Ishikawa and Masataka Mochizuki and Satoko Ishikawa",
year = "2009",
doi = "10.3123/jemsge.31.97",
language = "English",
volume = "31",
pages = "97--104",
journal = "Genes and Environment",
issn = "1880-7046",
publisher = "The Japanese Environmental Mutagen Society",
number = "4",

}

TY - JOUR

T1 - Activation Mechanism of N-Nitrosodialkylamines as Environmental Mutagens and Its Application to Antitumor Research

AU - Inami, Keiko

AU - Ishikawa, Satoko

AU - Mochizuki, Masataka

AU - Ishikawa, Satoko

PY - 2009

Y1 - 2009

N2 - 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-phosphono-oxy, 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. Key words: N-nitrosodialkylamine, metabolic activation, mutagenesis.

AB - 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-phosphono-oxy, 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. Key words: N-nitrosodialkylamine, metabolic activation, mutagenesis.

UR - http://www.scopus.com/inward/record.url?scp=84992721568&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84992721568&partnerID=8YFLogxK

U2 - 10.3123/jemsge.31.97

DO - 10.3123/jemsge.31.97

M3 - Article

AN - SCOPUS:84992721568

VL - 31

SP - 97

EP - 104

JO - Genes and Environment

JF - Genes and Environment

SN - 1880-7046

IS - 4

ER -