Synthetic Transmembrane Channels:  Functional Characterization Using Solubility Calculations, Transport Studies, and Substituent Effects

Dibenzyldiaza-18-crown-6 (PhCH2〈N18N〉CH2Ph, 1), di(dodecyldiaza-18-crown-6 (C12H25〈N18N〉C12H25, 2), HOOC(CH2)11〈N18N〉(CH2)11COOH (3), 〈18N〉(CH2)12〈N18N〉(CH2)12〈N18〉 (4), 〈N18N〉(CH2)12〈N18N〉(CH2)12〈N18N〉 (5), C12H25〈N18N〉(CH2)12〈N18N〉(CH2)12〈N18N〉C12H25 (6), PhCH2〈N18N〉(CH2)12〈N18N〉(CH2)12〈N18N〉CH2Ph (7), 4-(p-MeOC6H4CH2〈N18N〉C12)2〈N18N〉 (8), (p-NO2C6H4CH2〈N18N〉C12)2〈N18N〉 (9), and [chol-O-(CH2)2〈N18N〉C12]2〈N18N〉 (10) were studied. Octanol−water partition coefficients were determined for 1, 6, 7, 8, 10, and 3-cholestanyl-OCOCH2〈N18N〉(CH2)12〈N18N〉(CH2)12〈N18N〉COCH2O-3-cholestanyl (11). All were found to favor octanol, and by implication the phospholipid bilayer membrane, by at least 104-fold. Transport of Na+ was assessed in both a phospholipid bilayer and in a bulk CHCl3 membrane phase. Addition of ionophores to the latter was found in some cases to strongly enhance CHCl3 phase hydration. An attempt to correlate transport rates determined in the two systems failed, suggesting that the carrier mechanism, required in the CHCl3 phase, does not apply to the tris(macrocyclic) compounds in the bilayer. Sodium transport rates were also assessed for these compounds by using the bilayer clamp technique. Although Na+ flux rates thus determined for 7−9 in the phospholipid bilayer did not correlate with results obtained by the 23Na-NMR technique, the traces are similar to those obtained with protein channels, further supporting the function of tris(macrocycle)s as channel formers.