Rouzer C A, Sabourin M, Skinner T L, Thompson E J, Wood T O, Chmurny G N, Klose J R, Roman J M, Smith R H, Michejda C J
Department of Chemistry, Western Maryland College, Westminster 21157, USA.
Chem Res Toxicol. 1996 Jan-Feb;9(1):172-8. doi: 10.1021/tx9500639.
(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.
（甲基氨基甲酰基）三氮烯已被证明在许多生物系统中是有效的癌症化疗药物。由于它们的化学稳定性，其体内活性很可能是代谢活化过程的结果。先前的研究表明，1-（2-氯乙基）-3-甲基-3-（甲基氨基甲酰基）三氮烯（CMM）和1-（2-氯乙基）-3-苄基-3-（甲基氨基甲酰基）三氮烯（CBzM）在NADPH存在下被大鼠肝脏微粒体代谢，生成母体化合物的（（羟甲基）氨基甲酰基）三氮烯类似物。目前的研究表明，这两种化合物在氯乙基取代基处也会被氧化，生成氯乙醛和一种取代脲。就CBzM的代谢而言，47%的代谢母体化合物以苄基甲基脲的形式回收，8%以苄基脲的形式回收，26%以（（羟甲基）氨基甲酰基）三氮烯和氨基甲酰基三氮烯代谢物的形式回收。这些结果表明氯乙基是代谢的首选初始位点。在含有初始浓度为300 microM CBzM的反应混合物中，产生了78 microM氯乙醛，相比之下，由300 microM CMM代谢产生的氯乙醛为58 microM。氯乙醛是一种已知的诱变DNA烷基化剂，其形成可能解释了这些化合物的生物活性。
