Alkylation of DNA by 1,3-dialkyl-3-acyltriazenes: correlation of biological activity with chemical behavior.
The reactions of calf thymus DNA with four 1,3-dialkyl-3-acyltriazenes were studied alone or in the presence of pig liver esterase in pH 7.4 phosphate buffer for varying lengths of time. The best alkylating agent in the absence of esterase was determined to be 1,3-dimethyl-3-carbethoxytriazene (DMC), followed in order by 1-(2-hydroxyethyl)-3-methyl-3-carbethoxytriazene (HMC), 1-(2-hydroxyethyl)-3-methyl-3-acetyltriazene (HMA), and 1-(2- chloroethyl)-3-methyl-3-carbethoxytriazene (CMC). This order is the same as that for the rate of decomposition of the various acyltriazenes in pH 7.5 phosphate buffer. The extent of calf thymus DNA alkylation by CMC was found to be dependent on both the reaction buffer and the ionic strength of the medium. Alkylation by CMC alone in low ionic strength glycine buffer produced large quantities of 7-(2-chloroethyl)guanine and 7-(2-hydroxyethyl)guanine. The products of DNA alkylation observed at neutral pH are consistent with N(2)-N(3) heterolysis of the triazene, resulting in the N(1) alkyldiazonium ion as the sole alkylating species. In the presence of esterase, CMC showed an enhanced rate of product formation. Furthermore, the product distribution shifted dramatically from mainly hydroxyethylation to predominantly methylation. CMC is postulated to undergo initial enzymatic deacylation, leading to two different alkyldiazonium ions which competitively alkylate DNA. HMC, on the other hand, was little affected by the esterase. The enzyme-catalyzed reaction showed a small increase in methylation and a smaller decrease in hydroxyethylation.(ABSTRACT TRUNCATED AT 250 WORDS)
Kroeger-Koepke
M B
MB
Molecular Aspects of Drug Design Section, NCI-Frederick Cancer Research and Development Center, Maryland 21702.
Michejda
C J
CJ
Smith
R H
RH
D000477:Alkylating Agents / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D002417:Cattle; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004950:Esterases / Q000378:metabolism; D007700:Kinetics; D014226:Triazenes / Q000737:chemistry* / Q000378:metabolism
D000477:Alkylating Agents; D014226:Triazenes; D004247:DNA; D004950:Esterases