Synthesis and properties of novel bifunctional nitrosamines with ω-chloroalkyl groups

Satoko Ishikawa, N. Saitoh, M. Mochizuki

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Novel N-nitroso-N-(acetoxymethyl)-ω-chloroalkylamines were synthesized and their chemical and biological properties were evaluated. The nitrosamines were expected to decompose through ω-chloroalkyldiazohydroxides in aqueous solution, and then to alkylate various cellular macromolecules. N-Nitroso-N-(acetoxymethyl)-2-chloroethylamine rapidly decomposed in aqueous solution, and the reaction rate was apparently independent of the pH of the solution. On the other hand, the rate of decomposition of chloropropyl and chlorobutyl homologs was pH-dependent, and increased in alkaline solution. When mutagenicity was assayed in Salmonella typhimurium TA1535 and TA92 for preliminary evaluation, all three compounds were directly mutagenic. The mutagenicity in Salmonella typhimurium TA1535, which can detect base-pair change mutation, clearly showed that these compounds induced DNA alkylation in vivo. The increase of alkyl chain length in chloroalkyl compounds increased the mutagenic activity, and the activities were stronger than those of the corresponding simple α-acetoxy nitrosamines lacking a chloro group, N-nitroso-N-(acetoxymethyl)alkylamines. Furthermore, the positive result in TA92 suggested that chlorinated nitrosamines cross-linked DNA like antitumor chloroethylnitrosoureas and that they are expected to be new lead compounds for antitumor agents.

Original languageEnglish
Pages (from-to)1500-1503
Number of pages4
JournalChemical and Pharmaceutical Bulletin
Volume48
Issue number10
Publication statusPublished - 2000

Fingerprint

Nitrosamines
Salmonella
Salmonella typhimurium
Lead compounds
DNA
Alkylation
Macromolecules
Chain length
Base Pairing
Antineoplastic Agents
Reaction rates
Decomposition
Mutation

Keywords

  • ω-chloroalkyl nitrosamine
  • Antitumor agent
  • DNA alkylation
  • DNA cross-linking
  • Mutagenicity

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Drug Discovery
  • Pharmacology

Cite this

Synthesis and properties of novel bifunctional nitrosamines with ω-chloroalkyl groups. / Ishikawa, Satoko; Saitoh, N.; Mochizuki, M.

In: Chemical and Pharmaceutical Bulletin, Vol. 48, No. 10, 2000, p. 1500-1503.

Research output: Contribution to journalArticle

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N2 - Novel N-nitroso-N-(acetoxymethyl)-ω-chloroalkylamines were synthesized and their chemical and biological properties were evaluated. The nitrosamines were expected to decompose through ω-chloroalkyldiazohydroxides in aqueous solution, and then to alkylate various cellular macromolecules. N-Nitroso-N-(acetoxymethyl)-2-chloroethylamine rapidly decomposed in aqueous solution, and the reaction rate was apparently independent of the pH of the solution. On the other hand, the rate of decomposition of chloropropyl and chlorobutyl homologs was pH-dependent, and increased in alkaline solution. When mutagenicity was assayed in Salmonella typhimurium TA1535 and TA92 for preliminary evaluation, all three compounds were directly mutagenic. The mutagenicity in Salmonella typhimurium TA1535, which can detect base-pair change mutation, clearly showed that these compounds induced DNA alkylation in vivo. The increase of alkyl chain length in chloroalkyl compounds increased the mutagenic activity, and the activities were stronger than those of the corresponding simple α-acetoxy nitrosamines lacking a chloro group, N-nitroso-N-(acetoxymethyl)alkylamines. Furthermore, the positive result in TA92 suggested that chlorinated nitrosamines cross-linked DNA like antitumor chloroethylnitrosoureas and that they are expected to be new lead compounds for antitumor agents.

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