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 experiments have also shown that 1 exhibits greater activity in negatively charged phospholipid membranes relative to ones that are electrically neutral. The implications of these findings, with regard to the design of new classes of antibacterial agents, are briefly discussed.