Breydo Leonid, Gates Kent S
Departments of Chemistry and Biochemistry, University of Missouri-Columbia, 65211, USA.
J Org Chem. 2002 Dec 13;67(25):9054-60. doi: 10.1021/jo020568l.
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(3df,p)//B3LYP/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).
硫醇与链黑菌素（1）中含有的1,2 - 二硫杂环戊烷 - 3 - 酮1 - 氧化物杂环反应，会使这种抗肿瘤抗生素转化为一种DNA烷基化环锍离子（5）。虽然该反应中形成的产物已通过一种机制得以解释，该机制涉及硫醇对1,2 - 二硫杂环戊烷 - 3 - 酮1 - 氧化物环的中心亚磺酰硫（S2'）的初始进攻，但该杂环的羰基碳（C3'）和亚磺酰硫（S1'）也被认为是亲电的。因此，重要的是要考虑硫醇在这些位点的亲核进攻是否可能导致抗生素的破坏或转化为其环锍离子形式。为了解决这个问题，我们使用计算方法研究了甲硫醇盐对链黑菌素中发现的1,2 - 二硫杂环戊烷 - 3 - 酮1 - 氧化物杂环的简单类似物中三个亲电中心的进攻。计算在MP2/6 - 311 + G(3df,p)//B3LYP/6 - 31G理论水平下进行，并考虑了溶剂效应。结果表明，硫醇介导的链黑菌素活化的最合理机制涉及硫醇盐首先进攻抗生素的1,2 - 二硫杂环戊烷 - 3 - 酮1 - 氧化物杂环的S2'位置，随后转化为1,2 - 氧硫杂环戊烷 - 5 - 酮中间体（3）。
