title: Chemical synthesis and surface activity of lung surfactant phospholipid analogs. II. Racemic N-substituted diether phosphonolipids.
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 (less than 1 to 4 mN/m) on an oscillating bubble apparatus at 37 degrees 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 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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Rhode Island, Kingston 02861.
authors.forename: J G
authors.initials: JG
authors.lastname: Turcotte
authors.forename: W H
authors.initials: WH
authors.lastname: Lin
authors.forename: P E
authors.initials: PE
authors.lastname: Pivarnik
authors.forename: A M
authors.initials: AM
authors.lastname: Sacco
authors.forename: S S
authors.initials: SS
authors.lastname: Shirali
authors.forename: M M
authors.initials: MM
authors.lastname: Bermel
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.forename: R H
authors.initials: RH
authors.lastname: Notter
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004987:Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D008051:Lipid Bilayers; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008954:Models, Biological; D010743:Phospholipids / Q000138:chemical synthesis* / Q000494:pharmacology; D011663:Pulmonary Surfactants / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013500:Surface Tension / Q000187:drug effects
chemical_list: D004987:Ethers; D008051:Lipid Bilayers; D010743:Phospholipids; D011663:Pulmonary Surfactants; C028299:phosphonolipids; D015060:1,2-Dipalmitoylphosphatidylcholine