Structure, thermotropic phase behavior and membrane interaction of N-acyl-β-alaninols. Homologs of stress-combating N-acylethanolamines

Abstract

β-Alaninol and its derivatives were reported to exhibit interesting biological and pharmacological activities and showed potential application in formulating drug delivery vehicles. In the present study, we report the synthesis and characterization of N-acyl-β-alaninols (NABAOHs) bearing saturated acyl chains (n = 8–20) with respect to thermotropic phase behavior, supramolecular organization and interaction with diacylphosphatidylcholine, a major membrane lipid. Results obtained from DSC and powder XRD studies revealed that the transition temperatures (Tt), transition enthalpies (ΔHt), transition entropies (ΔSt) and d-spacings of NABAOHs show odd-even alteration. A linear dependence was observed in the values of ΔHt and ΔSt on the acyl chain length, independently for even and odd acyl chains in both dry and hydrated states; further, the even chainlength molecules exhibited higher values than the odd chainlength series. The crystals structures of N-lauroyl-β-alaninol and N-palmitoyl-β-alaninol, solved in monoclinic system in the P21/c space group, show that the NABAOHs adopt a tilted bilayer structure. A number of NH⋯O, O—H⋯O, and C—H⋯O hydrogen bonds between the hydroxyl and amide moieties of the head groups of NABAOH molecules belonging to adjacent and opposite layers stabilize the overall supramolecular organization of the self-assembled bilayer system. DSC studies on the interaction of N-myristoyl-β-alaninol (NMBAOH) with dimyristoylphosphatidylcholine (DMPC) indicate that these two lipids mix well up to 45 mol% NMBAOH, whereas phase separation was observed at higher contents of NMBAOH. Transmission electron microscopic studies reveal that mixtures containing 20−50 mol% NMBAOH form stable ULVs of 90−150 nm diameter, suitable for use in drug delivery applications.