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.
Rouzer
C A
CA
Department of Chemistry, Western Maryland College, Westminster 21157, USA.
Sabourin
M
M
Skinner
T L
TL
Thompson
E J
EJ
Wood
T O
TO
Chmurny
G N
GN
Klose
J R
JR
Roman
J M
JM
Smith
R H
RH
Michejda
C J
CJ
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism* / Q000633:toxicity; D001711:Biotransformation; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D014226:Triazenes / Q000378:metabolism* / Q000633:toxicity
D018906:Antineoplastic Agents, Alkylating; D014226:Triazenes; C082496:1-(2-chloroethyl)-3-benzyl-3-(methylcarbamoyl)triazene; C004656:chloroacetaldehyde; D000079:Acetaldehyde