Derivatization and isotope labeling of amphotericin B aiming at elucidation of the ion-channel structure

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Abstract

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 13C and/or 19F to probe the molecular structure of AmB ion channel using solid-state NMR.

Original languageEnglish
Pages (from-to)502-513
Number of pages12
JournalYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
Volume64
Issue number5
Publication statusPublished - May 1 2006
Externally publishedYes

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Amphotericin B
Ion Channels
Isotopes
Labeling
Ergosterol
Derivatives
Conformations
Cholesterol
Sterols
Sugars
Dimers
Molecular structure
Toxicity
Nuclear magnetic resonance
Topology
Membranes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

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title = "Derivatization and isotope labeling of amphotericin B aiming at elucidation of the ion-channel structure",
abstract = "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 13C and/or 19F to probe the molecular structure of AmB ion channel using solid-state NMR.",
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AU - Matsumori, Nobuaki

AU - Oishi, Tohru

AU - Murata, Michio

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N2 - 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 13C and/or 19F to probe the molecular structure of AmB ion channel using solid-state NMR.

AB - 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 13C and/or 19F to probe the molecular structure of AmB ion channel using solid-state NMR.

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