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 chem otherapeutic agents in a number of biological systems. Because of thei r chemical stability, it is likely that their activity in vivo is the result of a metabolic activation process. Previous studies have shown that -chloroethyl)-3-methyl-3-(methylcarbamoyl)triazene (CMM) and -chl oroethyl)-3-benzyl-3-(methylcarbamoyl)triazene (CBzM) are metabolized by rat liver microsomes in the presence of NADPH to yield the ((hydrox ymethyl)carbamoyl)triazene analogs of the parent compounds. The presen t studies show that both compounds are also oxidized at the chloroethy l substituent to yield chloroacetaldehyde and a substituted urea. In t he 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 carbamo yltriazene metabolites. These results suggest that the chloroethyl gro up is the favored initial site of metabolism. In reaction mixtures con taining intitial concentrations of 300 mu M CBzM, 78 mu M chloroacetal dehyde was produced, as compared to 58 mu M chloroacetaldehyde produce d from the metabolism of 300 mu M CMM. The formation of chloroacetalde hyde, a known mutagenic DNA alkylating agent, may explain the biologic al activity of these compounds.