title: An amphotericin B-ergosterol covalent conjugate with powerful membrane permeabilizing activity.
abstract: Amphotericin B-sterol conjugates were synthesized and examined for their membrane permeabilizing activity. Ergosterol and cholesterol, each connected with amphotericin B via an ethylenecarbamate or hexamethylenecarbamate linker, were examined by K(+) flux assays using liposomes and by single-channel recording across phospholipid membrane. Among four conjugates tested, AmB-ergosterol bearing an ethylenecarbamate linker exhibited the most powerful activity, which substantially exceeded that of the cholesterol homolog. Single-channel recording clearly exhibited that the ergosterol conjugate elicited channel current with the conductance of 28 pS, which was comparable with those by AmB, and revealed a higher channel open probability than the cholesterol conjugate. These results imply that direct interaction between amphotericin B and ergosterol is reproduced by their conjugate, which may serve as a model compound for understanding the drug's selective toxicity.
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, 1-16 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Matsumori
authors.forename: Noritsugu
authors.initials: N
authors.lastname: Eiraku
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsuoka
authors.forename: Tohru
authors.initials: T
authors.lastname: Oishi
authors.forename: Michio
authors.initials: M
authors.lastname: Murata
authors.forename: Takaaki
authors.initials: T
authors.lastname: Aoki
authors.forename: Toru
authors.initials: T
authors.lastname: Ide
mesh_terms: D000666:Amphotericin B / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry; D002463:Cell Membrane Permeability / Q000187:drug effects; D004594:Electrophysiology; D004875:Ergosterol / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006860:Hydrogen Bonding; D015394:Molecular Structure
chemical_list: D000666:Amphotericin B; D002118:Calcium; D004875:Ergosterol