Specificity of DNA Alkylation by 1-(2-Chloroethyl)-3-alkyl-3-acyltriazenes Depends on the Structure of the Acyl Group: Kinetic and Product Studies
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- 作者：Marilyn B. Kroeger Smith ; Brigitte F. Schmidt ; Grzegorz Czerwinski ; Lisa A. Taneyhill ; Emily J. Snyder ; Adam M. Kline ; Christopher J. Michejda ; and Richard H. Smith ; Jr.
- 刊名：Chemical Research in Toxicology
- 出版年：1996
- 出版时间：February 1996
- 年：1996
- 卷：9
- 期：2
- 页码：466 - 475
- 全文大小：351K
- 年卷期：v.9,no.2(February 1996)
- ISSN：1520-5010
文摘
The reactions of calf thymus DNA with ten1-(2-chloroethyl)-3-alkyl-3-acyltriazenes of varyingacyl side chain structure were studied alone, or in the presence ofporcine liver esterase in pH7.0 phosphate buffer. In several of the key triazenes, the acylsubstituent contained a freecarboxylic acid group. With esterase present in the reactionmixture, the resultant levels ofDNA alkylation could be correlated with the kinetic rates ofdecomposition of the triazenes.Under these conditions, the predominant pathway of decompositioninvolved deacylation ofthe parent triazene and eventual production of an alkanediazonium ion.This intermediatesubsequently alkylated DNA-guanine to give 7-alkylguanine as theprincipal reaction product.In the absence of esterase, the order of DNA alkylation for all ofthe acyltriazenes did notcorrelate with their respective rates of decomposition, leading to theconclusion that thetriazenes did not decompose by the expected mode of uncatalyzedN(2)-N(3) heterolyic cleavage.The major DNA alkylation product from theN(3)-methyltriazenes was 7-methylguanine,insteadof the expected 7-(chloroethyl)- and 7-(hydroxyethyl)guanineproducts, which suggested thatthe acyl group was being hydrolyzed. However, acyltriazenes withan N(3)-benzyl group ratherthan a methyl in this position produced very little 7-benzylguanineproduct, contrary toprediction. An alternative mechanism involving internally assistedhydrolysis of the side chainester is proposed to explain these results. NMR product analysisand computational studieswere carried out to lend support to the postulatedmechanism.