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Total Synthesis of the Lipid Mediator PD1(n-3 DPA): Configurational Assignments and Anti-inflammatory and Pro-resolving Actions

[Image: see text] The polyunsaturated lipid mediator PD1(n-3 DPA) (5) was recently isolated from self-resolving inflammatory exudates of 5 and human macrophages. Herein, the first total synthesis of PD1(n-3 DPA) (5) is reported in 10 steps and 9% overall yield. These efforts, together with NMR data...

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Detalles Bibliográficos
Autores principales: Aursnes, Marius, Tungen, Jørn E., Vik, Anders, Colas, Romain, Cheng, Chien-Yee C., Dalli, Jesmond, Serhan, Charles N., Hansen, Trond V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society and American Society of Pharmacognosy 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000582/
https://www.ncbi.nlm.nih.gov/pubmed/24576195
http://dx.doi.org/10.1021/np4009865
Descripción
Sumario:[Image: see text] The polyunsaturated lipid mediator PD1(n-3 DPA) (5) was recently isolated from self-resolving inflammatory exudates of 5 and human macrophages. Herein, the first total synthesis of PD1(n-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 PD1(n-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 mediators and pathways.