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C J Michejda

Publications and source records attributed to C J Michejda.

58 records · Page 4Linked to original sources
PubMedDate not supplied

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)

Alkylating Agents↗
PubMedDate not supplied

Oxidative metabolism of 1-(2-chloroethyl)-3-alkyl-3- (methylcarbamoyl)triazenes: formation of chloroacetaldehyde and relevance to biological activity.

(Methylcarbamoyl)triazenes have been shown to be effective cancer chemotherapeutic agents in a number of biological systems. Because of their chemical stability, it is likely that their activity in vivo is the result of a metabolic activation process. Previous studies have shown that 1-(2-chloroethyl)-3-methyl-3-(methylcarbamoyl)triazene (CMM) and 1-(2-chloroethyl)-3-benzyl-3-(methylcarbamoyl)triazene (CBzM) are metabolized by rat liver microsomes in the presence of NADPH to yield the ((hydroxymethyl)carbamoyl)triazene analogs of the parent compounds. The present studies show that both compounds are also oxidized at the chloroethyl substituent to yield chloroacetaldehyde and a substituted urea. In the case of CBzM metabolism, 47% of the metabolized parent compound was recovered as benzylmethylurea, 8% was recovered as benzylurea, and 26% was recovered as the ((hydroxymethyl)carbamoyl)-triazene and carbamoyltriazene metabolites. These results suggest that the chloroethyl group is the favored initial site of metabolism. In reaction mixtures containing initial concentrations of 300 microM CBzM, 78 microM chloroacetaldehyde was produced, as compared to 58 microM chloroacetaldehyde produced from the metabolism of 300 microM CMM. The formation of chloroacetaldehyde, a known mutagenic DNA alkylating agent, may explain the biological activity of these compounds.

Acetaldehyde↗
PubMedDate not supplied

Base sequence selectivity in the alkylation of DNA by 1,3-dialkyl-3-acyltriazenes.

The base sequence selectivity of DNA alkylation for a series of structurally related 1,3-dialkyl-3-acyltriazenes was examined with calf thymus DNA or polymers containing the sequences GGG, CGC, TGT, and AGA. The reaction products at the N7 and the O6 positions of guanine were identified, quantitated, and then correlated with the decomposition rates of the triazenes, 1-(2-chloroethyl)-3-methyl-3-carbethoxy- (CMC), 1-(2-chloroethyl)-3-methyl-3-acetyl- (CMA), 1-(2-hydroxyethyl)-3-methyl-3-carbethoxy- (HMC), 1-(2-hydroxyethyl)-3-methyl-3-acetyl- (HMA), and 1,3-dimethyl-3-acetyl- (DMA). The results of these studies revealed that DNA sequences with runs of purines were more reactive toward alkylation by all of the triazenes tested, irrespective of whether the alkylation was measured by N7, O6, or total guanine adducts. Within this generalization, the (hydroxyethyl)triazenes showed a preference for the AGA sequence, while the (chloroethyl)triazenes favored the GGG sequence. The structure of the 3-acyl group of the triazene also played a role in the extent of alkylation of a particular sequence of DNA. Both the (chloroethyl)- and the (hydroxyethyl)triazenes produced higher alkylation product yields for the 3-carbethoxytriazenes as compared with the 3-acetyl derivatives for most of the sequences examined. These overall patterns correlated well with the order of decomposition of the triazenes at 37 degrees C: HMC > DMA > HMA > CMC > CMA. This study has demonstrated how varying the structure of 1,3-dialkyl-3-acyltriazenes can modulate DNA alkylation, a finding which may be important in the design of new triazene antitumor agents.

Alkylation↗