1,3-Dimethyl-3-acyltriazenes: Synthesis and chemistry of a novel class of biological methylating agents

Richard H. Smith, Andrew F. Mehl, Anne Hicks, Cheryl L. Denlinger, Lisa Kratz, A. Wesley Andrews, Christopher J. Michejda

Research output: Contribution to journalArticle

Abstract

The synthesis and hydrolytic decomposition of 1,3-dimethyl-3-(diethoxyphosphinyl)triazene (DMP), 1,3-dimethyl-3-carboethoxytriazene (DMC), 1,3-dimethyl-3-acetyltriazene (DMA), and 1,3-dimethyl-3-(N-methyl-carbamoyl)triazene (DMM) are described. The kinetics of hydrolysis of DMP and DMC were investigated in aqueous buffers as a function of pH. DMP was found to be subject to acid catalysis up to pH 4.5 but then followed uncatalyzed kinetics up to pH 11.5. DMC, on the other hand, was catalyzed by acid at pH 9.5. It exhibited uncatalyzed kinetics in the intervening pH region. DMA and DMM also appear to follow uncatalyzed kinetics in the vicinity of neutral pH. The order of reactivity of the four triazenes at pH 7.5 was found to be DMP > DMC > DMA > DMM. The mechanism of the hydrolytic decomposition in the uncatalyzed region is seen as a direct dissociation of the acyltriazenes to the methyldiazonium ion and the respective acylamidyl onions. The intermediacy of the methyldiazonium ion during the decomposition of DMC was established by deuterium exchange studies when the decomposition was carried out in deuterium oxide buffers. The four triazenes were tested in a bacterial mutagenesis assay by using the His- strains of Salmonella typhimurium. DMP, DMC, and DMA were found to be directly acting mutagens in strains that require a base substitution to revert to wild type. These results are consistent with the methyldiazonium ion acting as the ultimate mutagen. The mutagenicity of DMC was enhanced by porcine liver esterase, which suggested that this enzyme was capable of hydrolyzing the carboethoxy group to release the highly reactive dimethyltriazene.

Original languageEnglish (US)
Pages (from-to)3751-3757
Number of pages7
JournalJournal of Organic Chemistry
Volume51
Issue number20
StatePublished - 1986
Externally publishedYes

Fingerprint

Triazenes
Decomposition
Kinetics
Mutagens
Ions
Buffers
Deuterium Oxide
Mutagenesis
Salmonella
Acids
Deuterium
Esterases
Liver
Catalysis
Hydrolysis
Assays
Ion exchange
Substitution reactions
Enzymes

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Smith, R. H., Mehl, A. F., Hicks, A., Denlinger, C. L., Kratz, L., Andrews, A. W., & Michejda, C. J. (1986). 1,3-Dimethyl-3-acyltriazenes: Synthesis and chemistry of a novel class of biological methylating agents. Journal of Organic Chemistry, 51(20), 3751-3757.

1,3-Dimethyl-3-acyltriazenes : Synthesis and chemistry of a novel class of biological methylating agents. / Smith, Richard H.; Mehl, Andrew F.; Hicks, Anne; Denlinger, Cheryl L.; Kratz, Lisa; Andrews, A. Wesley; Michejda, Christopher J.

In: Journal of Organic Chemistry, Vol. 51, No. 20, 1986, p. 3751-3757.

Research output: Contribution to journalArticle

Smith, RH, Mehl, AF, Hicks, A, Denlinger, CL, Kratz, L, Andrews, AW & Michejda, CJ 1986, '1,3-Dimethyl-3-acyltriazenes: Synthesis and chemistry of a novel class of biological methylating agents', Journal of Organic Chemistry, vol. 51, no. 20, pp. 3751-3757.
Smith, Richard H. ; Mehl, Andrew F. ; Hicks, Anne ; Denlinger, Cheryl L. ; Kratz, Lisa ; Andrews, A. Wesley ; Michejda, Christopher J. / 1,3-Dimethyl-3-acyltriazenes : Synthesis and chemistry of a novel class of biological methylating agents. In: Journal of Organic Chemistry. 1986 ; Vol. 51, No. 20. pp. 3751-3757.
@article{5f9837efe5864a3f9ab8d019bc8f17f3,
title = "1,3-Dimethyl-3-acyltriazenes: Synthesis and chemistry of a novel class of biological methylating agents",
abstract = "The synthesis and hydrolytic decomposition of 1,3-dimethyl-3-(diethoxyphosphinyl)triazene (DMP), 1,3-dimethyl-3-carboethoxytriazene (DMC), 1,3-dimethyl-3-acetyltriazene (DMA), and 1,3-dimethyl-3-(N-methyl-carbamoyl)triazene (DMM) are described. The kinetics of hydrolysis of DMP and DMC were investigated in aqueous buffers as a function of pH. DMP was found to be subject to acid catalysis up to pH 4.5 but then followed uncatalyzed kinetics up to pH 11.5. DMC, on the other hand, was catalyzed by acid at pH 9.5. It exhibited uncatalyzed kinetics in the intervening pH region. DMA and DMM also appear to follow uncatalyzed kinetics in the vicinity of neutral pH. The order of reactivity of the four triazenes at pH 7.5 was found to be DMP > DMC > DMA > DMM. The mechanism of the hydrolytic decomposition in the uncatalyzed region is seen as a direct dissociation of the acyltriazenes to the methyldiazonium ion and the respective acylamidyl onions. The intermediacy of the methyldiazonium ion during the decomposition of DMC was established by deuterium exchange studies when the decomposition was carried out in deuterium oxide buffers. The four triazenes were tested in a bacterial mutagenesis assay by using the His- strains of Salmonella typhimurium. DMP, DMC, and DMA were found to be directly acting mutagens in strains that require a base substitution to revert to wild type. These results are consistent with the methyldiazonium ion acting as the ultimate mutagen. The mutagenicity of DMC was enhanced by porcine liver esterase, which suggested that this enzyme was capable of hydrolyzing the carboethoxy group to release the highly reactive dimethyltriazene.",
author = "Smith, {Richard H.} and Mehl, {Andrew F.} and Anne Hicks and Denlinger, {Cheryl L.} and Lisa Kratz and Andrews, {A. Wesley} and Michejda, {Christopher J.}",
year = "1986",
language = "English (US)",
volume = "51",
pages = "3751--3757",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
number = "20",

}

TY - JOUR

T1 - 1,3-Dimethyl-3-acyltriazenes

T2 - Synthesis and chemistry of a novel class of biological methylating agents

AU - Smith, Richard H.

AU - Mehl, Andrew F.

AU - Hicks, Anne

AU - Denlinger, Cheryl L.

AU - Kratz, Lisa

AU - Andrews, A. Wesley

AU - Michejda, Christopher J.

PY - 1986

Y1 - 1986

N2 - The synthesis and hydrolytic decomposition of 1,3-dimethyl-3-(diethoxyphosphinyl)triazene (DMP), 1,3-dimethyl-3-carboethoxytriazene (DMC), 1,3-dimethyl-3-acetyltriazene (DMA), and 1,3-dimethyl-3-(N-methyl-carbamoyl)triazene (DMM) are described. The kinetics of hydrolysis of DMP and DMC were investigated in aqueous buffers as a function of pH. DMP was found to be subject to acid catalysis up to pH 4.5 but then followed uncatalyzed kinetics up to pH 11.5. DMC, on the other hand, was catalyzed by acid at pH 9.5. It exhibited uncatalyzed kinetics in the intervening pH region. DMA and DMM also appear to follow uncatalyzed kinetics in the vicinity of neutral pH. The order of reactivity of the four triazenes at pH 7.5 was found to be DMP > DMC > DMA > DMM. The mechanism of the hydrolytic decomposition in the uncatalyzed region is seen as a direct dissociation of the acyltriazenes to the methyldiazonium ion and the respective acylamidyl onions. The intermediacy of the methyldiazonium ion during the decomposition of DMC was established by deuterium exchange studies when the decomposition was carried out in deuterium oxide buffers. The four triazenes were tested in a bacterial mutagenesis assay by using the His- strains of Salmonella typhimurium. DMP, DMC, and DMA were found to be directly acting mutagens in strains that require a base substitution to revert to wild type. These results are consistent with the methyldiazonium ion acting as the ultimate mutagen. The mutagenicity of DMC was enhanced by porcine liver esterase, which suggested that this enzyme was capable of hydrolyzing the carboethoxy group to release the highly reactive dimethyltriazene.

AB - The synthesis and hydrolytic decomposition of 1,3-dimethyl-3-(diethoxyphosphinyl)triazene (DMP), 1,3-dimethyl-3-carboethoxytriazene (DMC), 1,3-dimethyl-3-acetyltriazene (DMA), and 1,3-dimethyl-3-(N-methyl-carbamoyl)triazene (DMM) are described. The kinetics of hydrolysis of DMP and DMC were investigated in aqueous buffers as a function of pH. DMP was found to be subject to acid catalysis up to pH 4.5 but then followed uncatalyzed kinetics up to pH 11.5. DMC, on the other hand, was catalyzed by acid at pH 9.5. It exhibited uncatalyzed kinetics in the intervening pH region. DMA and DMM also appear to follow uncatalyzed kinetics in the vicinity of neutral pH. The order of reactivity of the four triazenes at pH 7.5 was found to be DMP > DMC > DMA > DMM. The mechanism of the hydrolytic decomposition in the uncatalyzed region is seen as a direct dissociation of the acyltriazenes to the methyldiazonium ion and the respective acylamidyl onions. The intermediacy of the methyldiazonium ion during the decomposition of DMC was established by deuterium exchange studies when the decomposition was carried out in deuterium oxide buffers. The four triazenes were tested in a bacterial mutagenesis assay by using the His- strains of Salmonella typhimurium. DMP, DMC, and DMA were found to be directly acting mutagens in strains that require a base substitution to revert to wild type. These results are consistent with the methyldiazonium ion acting as the ultimate mutagen. The mutagenicity of DMC was enhanced by porcine liver esterase, which suggested that this enzyme was capable of hydrolyzing the carboethoxy group to release the highly reactive dimethyltriazene.

UR - http://www.scopus.com/inward/record.url?scp=0023023177&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023023177&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:0023023177

VL - 51

SP - 3751

EP - 3757

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 20

ER -