Mechanism of action of the nitrosoureas--V. Formation of O6-(2-fluoroethyl)guanine and its probable role in the crosslinking of deoxyribonucleic acid.
Mechanism of action of the nitrosoureas--V. Formation of O6-(2-fluoroethyl)guanine and its probable role in the crosslinking of deoxyribonucleic acid.
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亚硝基脲类药物的作用机制--V．
DOI：
10.1016/0006-2952(83)90420-3
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发表时间：
1983
影响因子：
5.8
通讯作者：
Ludlum,DB
中科院分区：
文献类型：
--
作者：
Tong,WP;Kirk,MC;Ludlum,DB
已显示暴露于2-卤代乙基亚硝基脲的DNA含有化学交联1-（N3-脱氧胞苷基），2-（N1-脱氧鸟苷基）-乙烷[W. P. Tong，M.C.柯克和D.B. Ludlum，Cancer Res.43，3102（1982）]。我们假设这种结构是由鸟嘌呤的6位上的2-卤代乙基的初始攻击，随后与胞嘧啶的分子内重排和二次交联反应形成的。我们现在已经证明，与N-（2-氟乙基）-N′-环己基-N-亚硝基脲反应的DNA含有O 6-（2-氟乙基）鸟嘌呤，从而证明了所提出的机制中的第一步发生。此外，O 6-（2-氟乙基）鸟苷水解成N1-（2-羟乙基）鸟苷，表明发生了必要的摩尔内重排。这两个观察结果大大加强了所提出的2-卤代乙基亚硝基脲交联DNA的途径。
DNA which has been exposed to 2-haloethylnitrosoureas has been shown to contain the chemical crosslink 1-(N3-deoxycytidyl), 2-(N1-deoxyguanosinyl)-ethane [W.P. Tong, M.C. Kirk and D.B. Ludlum,Cancer Res.43, 3102 (1982)]. We have hypothesized that this structure is formed by an initial attack of a 2-haloethyl group on the 6 position of guanine followed by an intramolecular rearrangement and secondary crosslinking reaction with cytosine. We have now shown that DNA which had been reacted withN-(2-fluoroethyl)-N′-cyclohexyl-N-nitrosourea containedO6-(2-fluoroethyl) guanine and have thus demonstrated that the first step in the proposed mechanism occurs. Furthermore,O6-(2-fluoroethyl)guanosine hydrolyzed toN1-(2-hydroxyethyl)guanosine, showing that the necessary intramolar rearrangement occurs. These two observations greatly strengthen the proposed route to DNA crosslinking by the 2-haloethylnitrosoureas.