The distribution of substituted phenols into lipid vesicles

Abstract

It is shown that solute partitioning into phospholipid liposomes is relevant to the study of structure–biological activity relationships. Data on the thermodynamics of such partitioning are reviewed, from which it is clear that the magnitude of the enthalpy (ΔH_tr) and entropy (ΔS_tr) of transfer varies greatly with the solute. Results are reported on the partitioning of a series of phenol and anisole solutes into cyclohexane, octan-1-ol and dimyristoylphosphatidylcholine (DMPC) liposomes below their phase transition temperature. For all three systems, ΔH_tr and ΔS_tr were derived from van't Hoff plots. Whereas partitioning into octan-1-ol was always associated with a loss of enthalpy and was enthalpy driven for a number of solutes, transfer of these same compounds into cyclohexane led to an increase in enthalpy and was entropy driven. These differences are related to the hydrogen-bonding properties of the solutes and the fact that octan-1-ol but not cyclohexane can hydrogen-bond. Surprisingly, all the solutes partitioned to a greater extent into the DMPC liposomes at 22 °C than into the organic solvents on a mole fraction basis. The free energy of transfer (ΔG_tr) into liposomes was more closely related to that for octan-1-ol than for cyclohexane. Differential scanning calorimetry demonstrated that as little as 1% mol 4-methylphenol per mole DMPC caused some broadening of the liposome phase transition and reduced the enthalpy of transition. This perturbation of the gel structure was probably also responsible for the very large ΔH_tr and ΔS_tr observed for this and other solutes partitioning into the liposomes. Larger substituent groups than methyl did not always lead to increased values of enthalpy and entropy of transfer, as might have been expected. Inter alia substituent effects are discussed in terms of their interaction with phospholipid via hydrogen bonding, their steric effects and their effects on the pK_a and hence hydrogen-bonding ability of the phenolic hydroxy group. The results from the phenols and a number of substituted anisoles suggest that hydrogen bonding between solute and phospholipid is an important factor affecting thermodynamics of partitioning. In free-energy terms both octan-1-ol and DMPC liposomes appear to be equally good models for the partitioning of a small number of phenols into red blood-cell membranes. It is concluded that in thermodynamic terms neither octan-1-ol nor cyclohexane is a good model for the gel phase of DMPC liposomes.