Kinetics of the conjugation of aniline mustards with glutathione and thiosulfate
Kinetics of the conjugation of aniline mustards with glutathione and thiosulfate
复制标题
DOI：
10.1016/s0009-2797(97)00036-7
复制
发表时间：
1997-06-06
影响因子：
5.1
通讯作者：
Hamill, TG
中科院分区：
文献类型：
--
作者：
Gamcsik, MP;Millis, KK;Hamill, TG
使用核磁共振光谱法测定取代的苯胺类化合物、美法仑、苯丁酸氮芥和p-（N，N-双（2-氯乙基））甲苯胺与谷胱甘肽和硫代硫酸盐的非酶促缀合的速率。使用这种方法，可以直接监测药物的消失以及单硫醚和双硫醚缀合物的形成。对于谷胱甘肽缀合，形成第一和第二氮丙啶中间体的速率常数相似。在硫代硫酸盐缀合的情况下，形成第一氮丙啶鎓中间体的速率常数大于形成第二氮丙啶鎓的速率常数。这表明亲核试剂的类型对这些双官能多聚体的总体烷基化活性具有显著影响。可以鉴定由p-（N：N-双（[2-C-13]-2-氯乙基））甲苯胺与谷胱甘肽和硫代硫酸盐之间的反应形成的双硫醚加合物，并且产物中C-13标记的混乱提供了烷基化必须通过氮丙啶中间体发生的强有力证据。(C)1997爱思唯尔科学爱尔兰有限公司
The rates of the non-enzymatic conjugation of the substituted aniline mustards, melphalan, chlorambucil and p-(N,N-bis(2-chloroethyl))toluidine with glutathione and thiosulfate were determined using nuclear magnetic resonance spectroscopy. Using this method, the disappearance of drug and the formation of both the mono-thioether and bis-thioether conjugates can be monitored directly. For glutathione conjugation, the rate constants for the formation of the first and second aziridinium intermediates were similar. With thiosulfate conjugation, the rate constant for the formation of the first aziridinium intermediate is greater than the rate constant for the formation of the second aziridinium. This demonstrates that the type of nucleophile has a significant influence on the overall alkylating activity of these bifunctional mustards. The bisthioether adduct formed from the reaction between p-(N:N-bis([2-C-13]-2-chloroethyl))toluidine and glutathione and thiosulfate can be identified and scrambling of the C-13 label in the product provides strong evidence that the alkylation must occur through an aziridinium intermediate. (C) 1997 Elsevier Science ireland Ltd.