title: Total synthesis of the lipid mediator PD1n-3 DPA: configurational assignments and anti-inflammatory and pro-resolving actions.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, University of Oslo , PO Box 1068, Blindern, N-0316 Oslo, Norway.
authors.forename: Marius
authors.initials: M
authors.lastname: Aursnes
authors.forename: Jørn E
authors.initials: JE
authors.lastname: Tungen
authors.forename: Anders
authors.initials: A
authors.lastname: Vik
authors.forename: Romain
authors.initials: R
authors.lastname: Colas
authors.forename: Chien-Yee C
authors.initials: CY
authors.lastname: Cheng
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Trond V
authors.initials: TV
authors.lastname: Hansen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002853:Chromatography, Liquid; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000737:chemistry*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D000893:Anti-Inflammatory Agents; D005231:Fatty Acids, Unsaturated; C487679:protectin D1; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid; C026219:docosapentaenoic acid