A Post-PKS oxidation of the amphotericin B skeleton predicted to be critical for channel formation is not required for potent antifungal activity
A Post-PKS oxidation of the amphotericin B skeleton predicted to be critical for channel formation is not required for potent antifungal activity
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DOI：
10.1021/ja075739o
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发表时间：
2007-11-14
影响因子：
15
通讯作者：
Burke, Martin D.
中科院分区：
文献类型：
--
作者：
Palacios, Daniel S.;Anderson, Thomas M.;Burke, Martin D.
临床上重要的抗霉菌剂阿替西霉素B代表了通道形成小分子的典型实例。用于阿替西霉素B通道的自组装的主要模型预测C（41）羧酸根和C（3 '）铵离子形成对稳定性至关重要的分子间盐桥/氢键。我们在此报告了一种灵活的降解合成途径，使这些基团中的一个或两个从阿氏菌素B中去除。我们进一步证明了与广泛的NMR实验，删除这些基团不改变多烯大环内酯骨架的构象。如主要模型所预测的，缺乏含有C（3 '）铵离子的真菌胺糖的阿替霉素B衍生物对酿酒酵母完全无活性。然而，令人惊讶的是--并且与当前模型强烈矛盾的是--缺少C（41）羧酸酯的阿替西霉素B衍生物至少与天然产物等效。总的来说，这些发现表明，必须显著修正阿替霉素B作用机制的主要模型--要么C（41）羧酸盐不需要通道形成，要么通道形成不需要抗真菌活性。
The clinically vital antimycotic agent amphotericin B represents the archetypal example of a channel-forming small molecule. The leading model for self-assembly of the amphotericin B channel predicts that the C(41) carboxylate and the C(3') ammonium ions form intermolecular salt bridges/hydrogen bonds that are critical for stability. We herein report a flexible degradative synthesis pathway that enables the removal of either or both of these groups from amphotericin B. We further demonstrate with extensive NMR experiments that deleting these groups does not alter the conformation of the polyene macrolide skeleton. As predicted by the leading model, amphotericin B derivatives lacking the mycosamine sugar that contains the C(3') ammonium ion are completely inactive against Saccharomyces cerevisiae. However, strikingly-and in strong contradiction with the current model-the amphotericin B derivative lacking the C(41) carboxylate is at least equipotent to the natural product. Collectively, these findings demonstrate that the leading model for the mechanism of action of amphotericin B must be significantly revised-either the C(41) carboxylate is not required for channel formation or channel formation is not required for antifungal activity.