Amphotericin B Mimics: A Sterol-Based Ionophore

Abstract

A sterol-polyether conjugate, 5-androstene3j3,17j3-bis[(oxycarbonyl)hexaethylene glycol] (l), has been synthesized via condensation of the bis-chloroformate derivative of 5-androstene-3j3,17j3-diol with hexaethylene glycol mono(triphenylmethy1 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 pressurearea isotherm of 1, generated at the air-water interface, indicates a limiting area of ca. 60 A2 per molecule. This value is fully consistent with a model in which the sterol nucleus (ca. 40 A2) and one pendant polyether chain (ca. 20 A2) 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 23Na 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.

A simple method to identify supramolecules in action: Hill coefficients for exergonic self‐assembly

“…3,4 Effective concentrations EC 50 promise reasonable approximations of the stability of supramolecules, whereas Hill coefficients n > 1 demonstrate their existence and reveal their stoichiometry. These insights are particularly desirable in situations where the complexity of the system of interest hinders more precise analysis.…”

“…Incompatibility of Hill analysis with exergonic self-assembly because of insufficient c M has been suggested to account for these confusing Hill coefficients. 3,4 Compatibility with Hill analysis, therefore, reveals endergonic self-assembly, and Hill coefficients n > 1 indicate the stoichiometry of unstable supramole-cules that exist besides an excess of monomer. Stable supramolecules with n ¼ 1, however, are overlooked in Hill plots and misinterpreted as monomers.…”

The effect of twin‐tailed sidearms on sodium cation transport in synthetic hydraphile cation channels

“…1 H-NMR: δ 1.26 (bs, 14H), 1.35-1.50 (m, 2H), 1.55-1.65 (m, 2H), 2.28 (t, J = 7.5 Hz, 2H), 2.47 (t, J = 7.5 Hz, 2H), 2.81 (m, 8H), 3.50-3.70 (m, 20H), 7.20-7.30 (m, 5H); 13 C-NMR: δ~24. 8,27.0,27.0,27.3,29.0,29.1,29.3,29.4,33.9,51.3,53.6,53.8,55.9,59.8,69.9,70.6,126.8,128.1,128.8,139.7,4,10,16-diaza-cyclooctadec-7-yl)-dodecanoic Acid (HOOC(CH 2 ) 11 <N18N>CH 2 Ph, 5).…”

“…1 H-NMR: δ 0.88 (t, J = 6.9 Hz, 6H), 1.26 (bs, 42H), 1.56 (m, 4H), 3.20-3.35 (m, 4H), 4.01 (s, 2H); 13 C-NMR: δ 14.0, 22. 5,26.7,26.8,27.2,29.0,29.2,29.3,29.4,29.5,31.8,41.2,46.1,48.2,4,10,-dodecanoyl]-1,4,10,13-tetraoxa-7,16-diaza-cyclooctadec-7-yl}-12-oxo-dodecyl)-1,4, 10,13-tetraoxa-7,16-diaza-cyclooctadec-7-yl To a solution of chloroacetamide 9 ( 0.083 g , 0.192 mmol) in acetonitrile (20 mL) was added tris(macrocyclic) diamide 8 (0.100, 0.087 mmol), KI (20 mg), and Na 2 CO 3 (0.055 g, 0.55 mmol). The reaction mixture was heated to reflux for 48 hours.…”

“…1 H-NMR: δ 0.88 (t, J = 6.6 Hz, 6H), 1.26 (bs, 104H), 1.42-1.59 (m, 16H), 2.32 (t, J = 7.5 Hz, 4H), 2.68-2.75 (m, 16H), 2.93 (t, J = 5.5 Hz, 4H), 3.27 (t, J = 7.5 Hz, 8H), 3.46 (bs, 4H), 3.63 (bs, 64H); 13 C-NMR: δ 14.0, 22. 5, 23.5, 25.2, 26.7, 27.2, 27.7, 29.2, 29.3, 29.4, 29.5, 29.5, 31.8, 33.02, 46.7, 47.3, 48.7, 51.8, 53.8, 54.8, 56.6, 66.9, 67.4, 68.4, 69.0, 69.9, 70.3, 70.4, 70.7, 70.8, 170.8, 173.4 (12)(13)(14)(15)(16)4,10,-dodecyl]-1,4, 10,13-tetraoxa-7,16-diaza-cyclooctadec-7-yl}-dodecyl)-1,4,10,13-tetraoxa-7,16-diaza-cyclooctadec-7-yl To a solution of tetraamide 10 (0.200 g, 0.103 mmol) in THF (5 mL), BH 3 •THF (3 mL, 2 M in THF) was added and the resulting solution was stirred at room temperature for 72 hours. The reaction mixture was cooled to 5 °C, quenched with ice-water, and the solvent removed in vacuo.…”