Activation of leinamycin by thiols: A theoretical study
Activation of leinamycin by thiols: A theoretical study
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DOI：
10.1021/jo020568l
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发表时间：
2002-12-13
影响因子：
3.6
通讯作者：
Gates, KS
中科院分区：
文献类型：
--
作者：
Breydo, L;Gates, KS
硫醇与莱那霉素中发现的1，2-二硫戊环-3-酮1-氧化物杂环反应（1）导致这种抗肿瘤抗生素转化为DNA烷基化表锍离子（5）。虽然在该反应中形成的产物已经通过涉及硫醇对1，2-二硫戊环-3-酮1-氧化物环的中心硫基硫（S2 '）的初始攻击的机理合理化，但是该杂环的羰基碳（C3'）和亚磺酰基硫（S1 '）也被预期是亲电的。因此，重要的是要考虑在这些位点上硫醇的亲核攻击是否可能导致抗生素的破坏或转化为表锍离子形式。为了解决这个问题，我们已经使用了计算方法来检查攻击的甲基硫醇的三个亲电中心在一个简单的类似物的1，2-二硫戊环-3-酮1-氧化物杂环中发现的莱那霉素。在MP2/6-311+G（3dfp）//B3 LY-P/6- 31 G * 理论水平下进行计算，包括溶剂效应。结果表明，硫醇介导的雷那霉素活化的最合理机制涉及抗生素1，2-二硫杂环戊烷-3-酮1-氧化物杂环的S2 '-位上的硫醇盐的初始攻击，然后转化为1，2-氧硫杂环戊烷-5-酮中间体（3）。
Reaction of thiols with the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin (1) results in the conversion of this antitumor antibiotic to a DNA-alkylating episulfonium ion (5). While the products formed in this reaction have been rationalized by a mechanism involving initial attack of thiol on the central sulfenyl sulfur (S2') of the 1,2-dithiolan-3-one 1-oxide ring, the carbonyl carbon (C3') and the sulfinyl sulfur (S1') of this heterocycle are also expected to be electrophilic. Therefore, it is important to consider whether nucleophilic attack of thiol at these sites might contribute either to destruction of the antibiotic or conversion to its episulfonium ion form. To address this question, we have used computational methods to examine the attack of methyl thiolate on each of the three electrophilic centers in a simple analogue of the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin. Calculations were performed at the MP2/6-311+G(3dfp)//B3LY-P/6-31G* level of theory with inclusion of solvent effects. The results indicate that the most reasonable mechanism for thiol-mediated activation of leinamycin involves initial attack of thiolate at the S2'-position of the antibiotic's 1,2-dithiolan-3-one 1-oxide heterocycle, followed by conversion to the 1,2-oxathiolan-5-one intermediate (3).