Journal
JOURNAL OF NATURAL PRODUCTS
Volume 77, Issue 4, Pages 910-916Publisher
AMER CHEMICAL SOC
DOI: 10.1021/np4009865
Keywords
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Funding
- Norwegian Research Council (KOSK II)
- School of Pharmacy, University of Oslo
- Norwegian Research Council
- National Institutes of Health GM Grant [PO1GM095467]
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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.
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