Total Synthesisof the Lipid Mediator PD1n-3 DPA: ConfigurationalAssignments and Anti-inflammatory and Pro-resolvingActions

摘要

The polyunsaturated lipid mediator PD1n-3 DPA (>5) was recently isolated from self-resolving inflammatory exudates of >5 and human macrophages. Herein, the first total synthesis of PD1n-3 DPA (>5) is reported in 10 steps and 9% overall yield. These efforts, together with NMR data of its methyl ester >6, confirmed the structure of >5 to be (7Z,10R,11E,13E,15Z,17S,19Z)-10,17-dihydroxydocosa-7,11,13,15,19-pentaenoic acid. The proposed biosynthetic pathway, with the involvement of an epoxide intermediate, was supported by results from trapping experiments. In addition, LC-MS/MS data of the free acid >5, obtained from hydrolysis of the synthetic methyl ester >6, matched data for the endogenously produced biological material. The natural product PD1n-3 DPA (>5) demonstrated potent anti-inflammatory properties together with pro-resolving actions stimulating human macrophage phagocytosis and efferocytosis. These results contribute new knowledge on the n-3 DPA structure–function of the growing numbers of specialized pro-resolving lipid mediatorsand pathways.