Structure of Molecular Assembles of Bioactive Natural Products Formed in Biomembranes

两性霉素B(Amb)可以聚集在一起，形成跨越生物膜的离子通道。这种选择性毒性通常是因为它对麦角固醇的亲和力高于胆固醇。为了更好地了解离子通道的结构和分子间的相互作用，我们制备了不同的AMB衍生物并测量了它们的活性。氨基之间通过短链共价连接的AMB二聚体表现出比AMB更强的离子通道活性，表明AMB分子的相互拓扑结构是头对头的取向。还设计了AMB-甾醇结合物，并对其离子通道活性进行了检测。AMB-麦角甾醇结合物表现出比AMB-胆固醇同系物更强的离子通道活性，这表明AMB与麦角甾醇之间更强的van der Waals相互作用导致了更高的离子通道活性。最后，我们合成了构象受限的AMB衍生物，其中的氨基和羧基与不同长度的烷基相连。这些衍生物成功地为我们提供了膜上AMB糖基的活性构象信息。这些衍生物现在被标记为^&lt；13&gt；C和/或^&lt；19&gt；F，以固体核磁共振研究AMB离子通道的分子结构。多羟基和聚烯烃部分在离子通道衬里的形成和膜的结合中起作用。在模拟膜体系中详细的NOE测量表明，苯二醇类化合物的中心部分具有发夹构象，这至少是它们具有较强生物活性的原因之一。

Amphotericin B (AmB) is known to assemble together and form an ion channel across biomembranes. The selective toxicity is generally accounted for by its higher affinity for ergosterol than cholesterol. To better understand the ion-channel structure and intermolecular interactions, we prepared various AmB derivatives and measured their activities. AmB dimers which are covalently linked between the amino groups by short chains showed more potent ion-channel activity than that of AmB, indicating that the mutual topology of AmB molecules is a head-to-head orientation. AmB-sterol conjugates were also designed and examined for ion-channel activities. AmB-ergosterol conjugates showed more powerful ion-channel activity than AmB-cholesterol congeners, suggesting that stronger van der Waals interaction between AmB and ergosterol contributes to the higher ion-channel activity. Finally, we prepared conformation-restricted derivatives of AmB, in which the amino and carboxyl groups were bridged with various lengths of alkyl chains. The derivatives successfully gave us information on the active-conformation of the sugar moiety of AmB in membrane. These derivatives are now labeled by ^<13>C and/or ^<19>F to probe the molecular structure of AmB ion channel using solid-state NMR.The mode of membrane permeabilizing action of amphidinols, dinoflagellate-originating polyene-polyhydroxy compounds, was investigated mainly by NMR methods. The polyhydroxy and polyolefinic parts play roles in the formation of ion channel lining and in binding in the membrane. Detailed NOE measurements in membrane-mimicking systems elucidated that the central part of amphidinols takes a hairpin conformation, which should be, at least in part, accounted for their strong biological activities.