title: Synthesis of 6-F-ergosterol and its influence on membrane-permeabilization of amphotericin B and amphidinol 3.
abstract: Two well-known antifungals, amphotericin B (AmB) and amphodinol 3 (AM3), are thought to exert antifungal activity by forming ion-permeable channels or pores together with sterol molecules. However, detailed molecular recognitions for AmB-sterol and AM3-sterol in lipid bilayers have yet to be determined. Toward (19)F NMR-based investigation of the molecular recognition underlying their potent antifungal activity, we synthesized 6-fluoro-ergosterol in five steps via ring opening of (5α,6α)-epoxide of ergosterol acetate with using novel combination of TiF(4) and n-Bu(4)N(+)Ph(3)SiF(2)(-). Then we evaluated its activity of promoting pore formation of AmB and AM3, and found that pore formation of AmB was barely promoted by 6-F-ergosterol in clear contrast to the dramatic promotion effect of unmodified ergosterol, whereas AM3 activity was markedly enhanced in the presence of 6-F-ergosterol, which was comparable to that of unmodified ergosterol. These results indicate that the introduction of an F atom at C6 position of ergosterol plays an inhibitory role in interacting with AmB, but it is not the case with AM3.
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kasai
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Matsumori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ueno
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nonomura
authors.forename: Shinya
authors.initials: S
authors.lastname: Yano
authors.forename: Murata
authors.initials: M
authors.lastname: Michio
authors.forename: Tohru
authors.initials: T
authors.lastname: Oishi
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000666:Amphotericin B / Q000737:chemistry*; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D008081:Liposomes / Q000737:chemistry; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry*; D000095722:Amphidinols
chemical_list: D000475:Alkenes; D000666:Amphotericin B; D004875:Ergosterol; D008081:Liposomes; D011714:Pyrans; C557398:6-fluoroergosterol; C438973:amphidinol 3; D000095722:Amphidinols