Chemical synthesis and surface activity of lung surfactant phospholipid analogs. II. Racemic N-substituted diether phospholipids

Abstract

A series of racemic 16:0 disaturated N-substituted diether phosphonolipid analogs of glycerophospholipids have been synthesized and purified. Isosteric methylene substitution at three of the four ester sites (carboxyl, phosphate) of conventional glycerophospholipids enhanced the hydrophobicity of analog compounds compared with dipalmitoyl phosphatidylcholine (DPPC), the major glycerophospholipid component of lung surfactant. Further substitutions at the nitrogen headgroup also contributed to hydrophobicity/hydrophilicity characteristics, as well as allowing graded variations in headgroup size among the members of the diether phosphonolipid analog series. Interfacial property studies showed that these compounds had significant differences in surface activity characteristics compared with DPPC, including increased adsorption and respreading facility, plus an enhanced ability to generate low surface tension (< 1 to 4 mN/m) on an oscillating bubble apparatus at 37°C. In addition, pressure-volume mechanical studies in surfactant-deficient excised rat lungs showed that the diether phosphonate analog of DPPC could partially restore pressure-volume characteristics toward normal, both as a pure component and in binary could partially restore pressure-volume characteristics toward normal, both as a pure component and in binary mixtures with palmitoyl-oleoyl phosphatidylglycerol. These findings suggest that selected analog compounds, synthesized with relatively small structural modifications from biologic glycerophospholipids, may have eventual applications as components of synthetic exogenous lung surfactants. Of more immediate importance, analog molecules with defined structural variations are convenient molecular probes for developing structure-surface activity correlates for phospholipid-like surfactants and for investigating the specificity of interactions between glycerophospholipids and other compounds such as proteins.