STEROL-POLYAMINE CONJUGATES AS SYNTHETIC IONOPHORES

A design principle has been devised for the construction of sterol-pol yamine conjugates that function as synthetic ionophores. For feasibili ty studies, a prototype (1) was synthesized from 3 beta-hydroxybisnor- 5-cholenic acid via sequential activation of its carboxylic acid moiet y, condensation with spermine, and sulfation of the 3 beta-hydroxyl gr oup. Closely related analogues were also prepared in which the termina l amine group was acetylated (2), the 3 beta-hydroxyl group was left u nsulfated (3), and each of the two remaining secondary amines was repl aced with oxygen atoms (4). Incorporation of each conjugate into egg p hosphatidylglycerol-based vesicles showed that 1 functions as an ionop hore by discharging a pH difference across the vesicle membrane, but t hat 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 a s membrane-bound monomer and that dimers are the active species that a re responsible for ion transport. Comparative experiments have also sh own that 1 exhibits greater activity in negatively charged phospholipi d membranes relative to ones that are electrically neutral. The implic ations of these findings, with regard to the design of new classes of antibacterial agents, are briefly discussed.