Replacement of phenyl substituents at phosphorus by hexyl ones in 2-(2-hydroxyaryl)vinylphosphonium salts can tune the nature of the induced proton transport through lipid membranes.

2-(2-hydroxyaryl)vinylphosphonium salts are zwitterionic protonophores previously shown to induce proton transport across lipid membranes via cyclic deprotonation and protonation of the hydroxyl group. Here, we examine the impact of the kind of substituents at phosphorus on the protonophoric activity of these compounds. In particular, replacement of all the three phenyl groups at the phosphorus atom of the 2-(2-hydroxyaryl)vinyl(triphenyl)phosphonium salt (2HVPPh3) by hexyl chains (2HVPHex3) led to a tremendous increase in electric current induced by the phosphonium salt across planar bilayer lipid membranes (BLM). Remarkably, the BLM conductance quadratically increased with increasing 2HVPHex3 concentration, whereas a linear concentration dependence of the BLM current was observed for 2HVPPh3, 2HVPHexPh2 ((hexyl)diphenyl) and 2HVPHex2Ph ((dihexyl)phenyl), i.e., in the presence of at least one phenyl substituent at the phosphorus atom. Proton selectivity of the 2HVPHex3-induced electric current was close to perfect in membranes formed of diphytanylphosphatidylcholine with the decreased dipole potential, but rather low in membranes formed of the usual synthetic lipid - diphytanoylphosphatidylcholine. We hypothesize that the proton transport across BLM is carried out by 2HVPHex3 dimers. By contrast, the uncoupling activity of 2HVPHex3 in isolated rat liver mitochondria was observed at similar concentrations, as found for the compounds with phenyl substituents, thereby indicating that dimers do not play a key role in the uncoupling process. At the same time, the rate of 2HVPHex3-induced mitochondrial swelling under the deenergized conditions in potassium acetate medium, reflecting the protonophoric activity of the compound in mitochondria, significantly exceeded that for other compounds.