AMPHOTERICIN-B MIMICS - A STEROL-BASED IONOPHORE

A sterol-polyether conjugate, 5-androstene-3 beta,17 beta-bis[(oxycarbonyl)hexaethylene glycol] (1), has been synthesized via condensation of the bis-chloroformate derivative of 5-androstene-3 beta,17 beta-diol with oxyethylene glycol mono(triphenylmethyl ether), followed by deprotection. This conjugate, which is composed of a long and rigid hydrophobic unit, two flexible hydrophilic chains that are linked to the hydrophobic unit, and a pendant polar head group, was designed as a prototype for new classes of compounds that are intended to serve as functional equivalents of the polyene macrolide antibiotic amphotericin B. Analysis of the surface pressure-area isotherm of 1, generated at the air-water interface, indicates a limiting area of ca. 60 Angstrom(2) per molecule. This value is fully consistent with a model in which the sterol nucleus (ca. 40 Angstrom(2)) and one pendant polyether chain (ca. 20 Angstrom(2)) define the collisional area of the surfactant; that is, it supports the existence of a ''folded'' conformation at the air-water interface. Incorporation of 1 into egg PC vesicular membranes leads to ion channel formation, as demonstrated by Na-23 NMR spectroscopy. Operationally, 1 has been found to have an ionophoric activity that-is very similar to that found for a synthetic ''bouquet'' molecule, but significantly less than amphotericin B, itself.