title: Synthesis and anti-inflammatory and pro-resolving activities of 22-OH-PD1, a monohydroxylated metabolite of protectin D1.
abstract: Protectin D1 (PD1 (3)), a C22-dihydroxylated polyunsaturated fatty acid biosynthesized from all-Z-docosahexaenoic acid, belongs to the new family of endogenous mediators referred to as specialized pro-resolving lipid mediators. PD1 (3) is a natural product that displays potent anti-inflammatory properties together with pro-resolving actions including inhibition of polymorphonuclear leukocyte (PMN) infiltration and promotion of macrophage phagocytosis and efferocytosis. Given its potent endogenous actions, this compound has entered several clinical development programs. Little has been reported on the metabolism of PD1 (3). The synthesis and biological evaluations of the ω-22 monohydroxylated metabolite of PD1 (3), named herein 22-OH-PD1 (6), are presented. LC-MS/MS data of the free acid 6, obtained from hydrolysis of the synthetic methyl ester 7, matched data for the endogenously produced 22-OH-PD1 (6). Compound 6 exhibited potent pro-resolving actions by inhibiting PMN chemotaxis in vivo and in vitro comparable to its precursor PD1 (3) and decreased pro-inflammatory mediator levels in inflammatory exudates. The results reported herein provide new knowledge of the metabolism of the protectin class of specialized pro-resolving mediators.
authors.affiliation: School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo , PO Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Jørn E
authors.initials: JE
authors.lastname: Tungen
authors.forename: Marius
authors.initials: M
authors.lastname: Aursnes
authors.forename: Anders
authors.initials: A
authors.lastname: Vik
authors.forename: Sesquile
authors.initials: S
authors.lastname: Ramon
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
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: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects; D053719:Tandem Mass Spectrometry
chemical_list: C000593734:22-OH-PD1 compound; D000893:Anti-Inflammatory Agents; D004952:Esters; D005231:Fatty Acids, Unsaturated; C487679:protectin D1; D004281:Docosahexaenoic Acids