title: Synthesis of 13(R)-Hydroxy-7Z,10Z,13R,14E,16Z,19Z Docosapentaenoic Acid (13R-HDPA) and Its Biosynthetic Conversion to the 13-Series Resolvins.
abstract: Specialized pro-resolving lipid mediators are biosynthesized during the resolution phase of acute inflammation from n-3 polyunsaturated fatty acids. Recently, the isolation and identification of the four novel mediators denoted 13-series resolvins, namely, RvT1 (1), RvT2 (2), RvT3 (3) and RvT4 (4), were reported, which showed potent bioactions characteristic for specialized pro-resolving lipid mediators. Herein, based on results from LC/MS-MS metabololipidomics and the stereoselective synthesis of 13(R)-hydroxy-7Z,10Z,13R,14E,16Z,19Z docosapentaenoic acid (13R-HDPA, 5), we provide direct evidence that the four novel mediators 1-4 are all biosynthesized from the pivotal intermediate 5. The UV and LC/MS-MS results from synthetic 13R-HDPA (5) matched those from endogenously and biosynthetically produced material obtained from in vivo infectious exudates, endothelial cells, and human recombinant COX-2 enzyme. Stereochemically pure 5 was obtained with the use of a chiral pool starting material that installed the configuration at the C-13 atom as R. Two stereoselective Z-Wittig reactions and two Z-selective reductions of internal alkynes afforded the geometrically pure alkene moieties in 5. Incubation of 5 with isolated human neutrophils gave all four RvTs. The results presented herein provide new knowledge on the biosynthetic pathways and the enzymatic origin of RvTs 1-4.
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo , P.O. Box 1068 Blindern, N-0316 Oslo, Norway.|William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , Charterhouse Square, London, UK , EC1M 6BQ.
authors.forename: Karoline G
authors.initials: KG
authors.lastname: Primdahl
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo , P.O. Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Marius
authors.initials: M
authors.lastname: Aursnes
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , Charterhouse Square, London, UK , EC1M 6BQ.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Walker
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , Charterhouse Square, London, UK , EC1M 6BQ.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London , Charterhouse Square, London, UK , EC1M 6BQ.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo , P.O. Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Trond V
authors.initials: TV
authors.lastname: Hansen
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo , P.O. Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Vik
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators; D008264:Macrophages / Q000378:metabolism; D015394:Molecular Structure; D009504:Neutrophils / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism
chemical_list: D005231:Fatty Acids, Unsaturated; D018836:Inflammation Mediators; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; C026219:docosapentaenoic acid