Résumé
Oxidized phospholipids (OxPLs) containing oxidized fatty acids (oxylipins) are increasingly recognized as pleiotropic lipid mediators. Further understanding of structure-activity relationships of OxPLs is hampered by the complexity of their synthesis. Although dozens of individual free oxylipins are commercially available, their attachment to the phospholipid scaffold requires multiple synthetic steps and relatively harsh conditions leading to the decomposition of sensitive oxylipins. In this work we describe a simple synthesis of OxPLs containing oxylipins bound at the sn-2-position via an amide bond that is characteristic of sphingophospholipids. Activation of oxylipins and attachment to the phospholipid scaffold are performed under mild conditions and characterized by high yield. The sn-1 residue is bound through an alkyl bond, which is a common bond present in a large proportion of naturally occurring phospholipids. Alkyl-amide OxPLs are phospholipase A1/A2-resistant, which improves their biological stability. We found that alkyl-amide phosphatidylcholines (OxPCs) containing either linear or prostane cycle oxylipins inhibited proinflammatory action of LPS and increased endothelial cellular barrier in vitro and in mouse models. The effects of alkyl-amide- and regular diacyl-OxPCs developed in a similar range of concentrations. We hypothesize that alkylamide OxPLs may become a useful tool for deeper analysis of the structure-activity relationship of OxPLs.