Chemical synthesis and cytotoxic properties of N-alkylcarbamic acid thioesters, metabolites of hepatotoxic formamides.
Chemical synthesis and cytotoxic properties of N-alkylcarbamic acid thioesters, metabolites of hepatotoxic formamides.
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N-烷基氨基甲酸硫酯（肝毒性甲酰胺的代谢物）的化学合成和细胞毒性特性。
DOI：
10.1021/tx00014a006
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发表时间：
1990
影响因子：
4.1
通讯作者：
Gescher,A
中科院分区：
文献类型：
--
作者：
Han,DH;Pearson,PG;Baillie,TA;Dayal,R;Tsang,LH;Gescher,A
合成了n -甲基甲酰胺和n -乙基甲酰胺的s链半胱氨酸和谷胱甘肽缀合物及其一系列甲酯衍生物，并通过* H NMR、13C NMR、FAB- ms和FAB串联质谱法对其进行了表征。体外细胞毒性试验表明，当培养浓度超过1 mM时，所有标题偶联物对分离的小鼠肝细胞都有毒性，并且当存在10-100µ时，它们可以作为小鼠TLX5淋巴瘤细胞的有效生长抑制剂。在培养液中加入谷胱甘肽（10 mM）后，上述两种效应均被逆转。n -烷基氨基甲酸硫酯缀合物是在哺乳动物系统中n -烷基甲酰胺代谢过程中形成的，可能是母体甲酰胺抗肿瘤和/或肝毒性活性的重要介质，可能是通过它们在细胞膜上释放异氰酸乙酯的能力来实现的。
The S-linked cysteine and glutathione conjugates of N-methylformamide and N-ethylform-amide, together with a series of methyl ester derivatives thereof, have been synthesized and characterized by* H NMR, 13C NMR, FAB-MS, and FAB tandem mass spectrometry. In vitro cytotoxicity assays showed that all of the title conjugates were toxic to isolated mouse hepatocytes when incubated at concentrations in excess of 1 mM and that they served as potent growth inhibitors of murine TLX5 lymphoma cells when present at levels of 10-100 µ. Both of these effects were reversed by the addition to incubation media of glutathione (10 mM). The possibility is raised that N-alkylcarbamic acid thioester conjugates, which are formed during the metabolism of N-alkylformamides in mammalian systems, may act as important mediators of the anti-neoplastic and/or hepatotoxic activity of the parent formamides, possibly through their ability to liberatemethyl isocyanate at cell membranes.