Smith R H, Scudiero D A, Michejda C J
Laboratory of Chemical and Physical Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21701.
J Med Chem. 1990 Sep;33(9):2579-83. doi: 10.1021/jm00171a036.
Aliphatic triazenes, such as 1,3-dimethyltriazene, are potent biological alkylating agents because they form alkyldiazonium ions. They are also subject to very rapid proteolytic decomposition, even at physiological pH. The acylated analogues 1,3-dialkyl-3-acyltrizenes are much more stable in aqueous solution, but they also give rise to alkyldiazonium ions. Four acylated 1,3-dimethyltriazenes, where the acyl groups were diethylphosphoryl (DMP), carbethoxy (DMC), acetyl (DMA), and N-methylcarbamoyl (DMM), were studied kinetically. Rate-pH profiles indicated that the acyl group had a profound effect on the mechanism of decomposition. The cytotoxic potential of all four compounds was studied in vitro by using the MTT-tetrazolium assay. The compounds had fair-to-good activity against some cell lines, particularly those deficient in methylation repair. In vivo assays of DMC and DMM against several tumor xenografts in nude mice showed promising activity for some cancers, particularly in the case of DMM. In vitro assays were also carried out on three 1-(2-chloroethyl)-3-methyl-3-acyltriazenes. The acyl groups were carbethoxy (CMC), acetyl (CMA), and N-methylcarbamoyl (CMM). The activity of these compounds largely paralleled that of bis(2-chloroethyl)-N-nitrosourea (BCNU), except for those cell lines which exhibited the Rem phenotype; triazenes were more active in those lines than BCNU. The in vivo activity of CMC, CMA, and CMM was tested in the P388 leukemia assay. All three were active but CMC and CMA proved to be rather toxic. CMM was well tolerated and was examined in several tumor xenografts in nude mice. Significant activity was found against MX-1 mammary carcinoma, against LX-1 small cell lung carcinoma, and particularly against LOX amelanotic melanoma, where complete cures were effected. The antineoplastic activity of the acyltriazenes is well-correlated with their chemical behavior.
脂肪族三氮烯，如1,3 - 二甲基三氮烯，是强效的生物烷基化剂，因为它们能形成烷基重氮离子。即使在生理pH值下，它们也会迅速发生蛋白水解分解。酰化类似物1,3 - 二烷基 - 3 - 酰基三氮烯在水溶液中更稳定，但它们也会产生烷基重氮离子。对四种酰化的1,3 - 二甲基三氮烯进行了动力学研究，其中酰基分别为二乙磷酰基（DMP）、乙氧羰基（DMC）、乙酰基（DMA）和N - 甲基氨基甲酰基（DMM）。速率 - pH曲线表明酰基对分解机制有深远影响。通过MTT - 四氮唑测定法在体外研究了所有四种化合物的细胞毒性潜力。这些化合物对某些细胞系具有中等至良好的活性，特别是那些甲基化修复缺陷的细胞系。在裸鼠体内对DMC和DMM针对几种肿瘤异种移植的试验显示，对某些癌症具有有前景的活性，特别是DMM的情况。还对三种1 - (2 - 氯乙基)-3 - 甲基 - 3 - 酰基三氮烯进行了体外试验。酰基分别为乙氧羰基（CMC）、乙酰基（CMA）和N - 甲基氨基甲酰基（CMM）。这些化合物的活性在很大程度上与双(2 - 氯乙基)-N - 亚硝基脲（BCNU）相似，但对于那些表现出Rem表型的细胞系除外；三氮烯在这些细胞系中比BCNU更具活性。在P388白血病试验中测试了CMC、CMA和CMM的体内活性。所有三种都有活性，但CMC和CMA被证明毒性较大。CMM耐受性良好，并在裸鼠体内的几种肿瘤异种移植中进行了研究。发现对MX - 1乳腺癌、LX - 1小细胞肺癌具有显著活性，特别是对LOX无黑色素黑色素瘤，可实现完全治愈。酰基三氮烯的抗肿瘤活性与其化学行为密切相关。
