33 アンフォテリシンB誘導体が生体膜中に形成するチャネル複合体(口頭発表の部)

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Amphotericin B (AmB, 1) has been a choice for treatment of systemic fungal infections for over 30 years. Its selective toxicity is generally attributed to the higher affinity for ergosterol as a principal fungal sterol over cholesterol occurring mammalian plasma membranes upon forming an ion-permeable channel, in which AmB together with sterol is thought to self-assemble to shape a barrel-stave complex. Although the structure of this assemblage in biomembranes has been a target of extensive investigations for a long time, the precise picture has not been obtained. To reducie serious side effects of the drug, the mechanism of molecular recognition has to be clarified. As the first step toward this goal, we prepared several AmB dimers and AmB-sterol conjugates, and examined for their channel-forming activity. AmB-sterol conjugates were tested for their K^+ flux activity using phosphatidylcholine (PC) liposome systems. The ergosterol conjugate 2 exhibited the prominent activity, which substantially exceeded that of its cholesterol homologue 3. The results indicate that specific intermolecular recognition between AmB and ergosterol could be reproduced to a certain extent by conjugate 2. AmB-sterol conjugates with a longer linker with C_6-diaminocarbamate showed much weaker K^+-flux activity, which suggests that the amino group of AmB mycosamine resides close to 3-OH of ergosterol in a channel assemblage. Molecular recognition between AmB and PC is known to be essential for ion-channel formation. To examine the effect of the length of fatty acyl chains on ion-channel formation, we prepared AmB-PC conjugates 6 and 7, dimyristoylphosphatidyl-AmB and dilauroyl-phosphatidyl-AmB. Conjugate 7 evidently revealed more potent activity, thus disclosing that a direct interaction between AmB and phospholipids is of great importance in ion-channel formation. AmB dimers with an aminoalkyl-dicarboxylate linker between amino groups of AmB have showed potent ion-permeabilizing activity as reported in the previous Symposium. For feasibility in synthesis, another series of AmB dimers linked via carboxylic acid were prepared and examined for their activity. A dimer with a 1,6-hexanediamine linkage (9) bearing potent hemolytic activity gave rise to large K^+ flux in phospholipid liposomes regardless of the presence or absence of sterols. Some of these conjugates may possibly serve as a molecular probe to investigate the precise mechanism of action for the selective toxicity by AmB. Currently, we attempt to prepare isotope-labeled conjugates for measuring solid state NMR. Interatomic distance estimated from the NMR data would help elucidating the structure of a complicated AmB-ergosterol assemblage formed in membrane. Preliminary experiments of ^<13>C-labeled AmB methyl ester will be related.
天然有機化合物討論会の論文
2002-09-01

33 アンフォテリシンB誘導体が生体膜中に形成するチャネル複合体(口頭発表の部)

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