Specificity of DNA Alkylation by 1-(2-Chloroethyl)-3-alkyl-3-acyltriazenes Depends on the Structure of the Acyl Group: Kinetic and Product Studies

The reactions of calf thymus DNA with ten 1-(2-chloroethyl)-3-alkyl-3-acyltriazenes of varying acyl side chain structure were studied alone, or in the presence of porcine liver esterase in pH 7.0 phosphate buffer. In several of the key triazenes, the acyl substituent contained a free carboxylic acid...

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Bibliographic Details
Published in:	Chemical research in toxicology Vol. 9; no. 2; pp. 466 - 475
Main Authors:	Kroeger Smith, Marilyn B, Schmidt, Brigitte F, Czerwinski, Grzegorz, Taneyhill, Lisa A, Snyder, Emily J, Kline, Adam M, Michejda, Christopher J, Smith, Richard H
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 01-03-1996
Subjects:	Alkylating Agents - chemistry Alkylating Agents - pharmacology Alkylation Animals Cattle DNA - drug effects DNA - metabolism Kinetics Magnetic Resonance Spectroscopy Models, Chemical Thymus Gland Triazenes - chemistry Triazenes - metabolism Triazenes - pharmacology
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Summary:	The reactions of calf thymus DNA with ten 1-(2-chloroethyl)-3-alkyl-3-acyltriazenes of varying acyl side chain structure were studied alone, or in the presence of porcine liver esterase in pH 7.0 phosphate buffer. In several of the key triazenes, the acyl substituent contained a free carboxylic acid group. With esterase present in the reaction mixture, the resultant levels of DNA alkylation could be correlated with the kinetic rates of decomposition of the triazenes. Under these conditions, the predominant pathway of decomposition involved deacylation of the parent triazene and eventual production of an alkanediazonium ion. This intermediate subsequently alkylated DNA−guanine to give 7-alkylguanine as the principal reaction product. In the absence of esterase, the order of DNA alkylation for all of the acyltriazenes did not correlate with their respective rates of decomposition, leading to the conclusion that the triazenes did not decompose by the expected mode of uncatalyzed N(2)−N(3) heterolyic cleavage. The major DNA alkylation product from the N(3)-methyltriazenes was 7-methylguanine, instead of the expected 7-(chloroethyl)- and 7-(hydroxyethyl)guanine products, which suggested that the acyl group was being hydrolyzed. However, acyltriazenes with an N(3)-benzyl group rather than a methyl in this position produced very little 7-benzylguanine product, contrary to prediction. An alternative mechanism involving internally assisted hydrolysis of the side chain ester is proposed to explain these results. NMR product analysis and computational studies were carried out to lend support to the postulated mechanism.
Bibliography:	istex:514EB6FA8A86B7462B05DF35FAD5494B0E12DC04 Abstract published in Advance ACS Abstracts, February 1, 1996. ark:/67375/TPS-XMCN7LXK-9 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0893-228X 1520-5010
DOI:	10.1021/tx950155y