Sterol−Polyamine Conjugates as Synthetic Ionophores

Abstract

A design principle has been devised for the construction of sterol−polyamine conjugates that function as synthetic ionophores. For feasibility studies, a prototype (1) was synthesized from 3β-hydroxybisnor-5-cholenic acid via sequential activation of its carboxylic acid moiety, condensation with spermine, and sulfation of the 3β-hydroxyl group. Closely related analogues were also prepared in which the terminal amine group was acetylated (2), the 3β-hydroxyl group was left unsulfated (3), and each of the two remaining secondary amines was replaced with oxygen atoms (4). Incorporation of each conjugate into egg phosphatidylglycerol-based vesicles showed that 1 functions as an ionophore by discharging a pH difference across the vesicle membrane, but that 2, 3, and 4 do not. A kinetic analysis of the ionophoric activity of 1 has provided evidence that the majority of the conjugate exists as membrane-bound monomer and that dimers are the active species that are responsible for ion transport. Comparative experi...