Total synthesis of the lipid mediator PD1n-3 DPA: configurational assignments and anti-inflammatory and pro-resolving actions
| Autor: | Jesmond Dalli, Chien-Yee C. Cheng, Trond Vidar Hansen, Marius Aursnes, Charles N. Serhan, Anders Vik, Jørn Eivind Tungen, Romain A. Colas |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Docosahexaenoic Acids
Stereochemistry Anti-Inflammatory Agents Pharmaceutical Science Epoxide Stereoisomerism 01 natural sciences Article Analytical Chemistry 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Structure–activity relationship Animals Humans Efferocytosis Nuclear Magnetic Resonance Biomolecular 030304 developmental biology Pharmacology 0303 health sciences Natural product Molecular Structure 010405 organic chemistry Macrophages Organic Chemistry Total synthesis Lipid signaling 0104 chemical sciences Complementary and alternative medicine chemistry Biochemistry Eicosapentaenoic Acid Docosahexaenoic acid Fatty Acids Unsaturated Molecular Medicine Chromatography Liquid |
| Zdroj: | Journal of Natural Products |
| ISSN: | 1520-6025 |
| Popis: | 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 mediators and pathways. |
| Databáze: | OpenAIRE |
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