Structure of Molecular Assembles of Bioactive Natural Products Formed in Biomembranes

两性霉素B（AmB）是已知的组装在一起，并形成跨生物膜的离子通道。选择性毒性通常是由于其对麦角固醇的亲和力高于胆固醇。为了更好地理解离子通道结构和分子间相互作用，我们制备了各种AmB衍生物并测量了它们的活性。AmB二聚体的氨基之间通过短链共价连接，显示出比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取向的。AmB-固醇缀合物也被设计并检查离子通道活性。AmB-麦角固醇偶联物比AmB-胆固醇同源物显示更强的离子通道活性，表明AmB和麦角固醇之间更强的货车德瓦尔斯相互作用有助于更高的离子通道活性。最后，我们制备了AmB的构象限制衍生物，其中氨基和羧基与不同长度的烷基链桥接。这些衍生物成功地为我们提供了关于AmB糖部分在膜中的活性构象的信息。这些衍生物现在被标记为^<13>C和/或^<19>F，以利用固体NMR探测AmB离子通道的分子结构。Ampidinols是甲藻源多烯多羟基化合物，主要利用NMR方法研究其膜透化作用模式。多羟基和聚烯烃部分在离子通道衬里的形成和膜中的结合中起作用。详细的NOE测量在膜模拟系统阐明，中心部分的amphidinols采取发夹构象，这应该是，至少部分，占其强大的生物活性。

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.