The role of amine in the mechanism of pentathiepin (polysulfur) antitumor agents
The role of amine in the mechanism of pentathiepin (polysulfur) antitumor agents
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DOI：
10.1021/ja027416s
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发表时间：
2003-01-15
影响因子：
15
通讯作者：
Greer, A
中科院分区：
文献类型：
--
作者：
Brzostowska, EM;Greer, A
提出了一个计算和实验研究，这提供了第一个证据表明，胺有机会参与五硫杂环己烷的成键，以促进其分解。这项研究从机制上洞察了五硫肽生物活性的产生过程。伯胺或仲胺将允许在最近的硫(S1)处与五硫杂环进行分子内加成反应。相反，叔胺可逆地加到S1上，因为氮不能通过去质子化失去它的正电荷。这就排除了胺的推广步骤。表征了一个能量低的过程，对应于由伯胺或仲胺的亲核活化引发的S-3-IOSS。用降冰片烯进行的一项捕集研究支持了S-3单元转移对五硫杂环己烷的脱硫作用。该胺可增强天然产物伐沙星1和李索克林毒素A 2的反应性，增加了对五硫肽激活途径的理解，并可能提供新的设计概念，具有潜在的此类杀生剂的应用。
A computational and experimental study is presented, which provides the first evidence that amine has an opportunity to engage in bonding with pentathiepin to promote its decomposition. The study provides mechanistic insight into the process that gives rise to pentathiepin biological activity. Primary or secondary amine will allow for an intramolecular addition to the pentathiepin ring at the nearest sulfur (S1). In contrast, tertiary amine adds reversibly to S1, because nitrogen cannot lose its positive charge by deprotonation. This precludes the amine promotion step. An energetically low-lying process is characterized, corresponding to S-3-Ioss triggered by nucleophilic activation with a primary or secondary amine. Pentathiepin desulfurization via S-3-unit transfer is supported by a trapping study with norbornene. That the amine may confer an enhanced reactivity in the natural products varacin, 1, and lissoclinotoxin A, 2, adds to the understanding of the pathway for pentathiepin activation and may provide new design concepts that have potential applications for this class of biocides.