title: Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3.
abstract: Uncontrolled inflammation is now considered to be a link between many widely occurring diseases. Thus, controlling the innate inflammatory response and its local chemical mediators has been receiving increasing attention. We recently identified a novel family of eicosapentaenoic acid (EPA)-derived mediators produced by eosinophils, denoted as resolvin E3 (RvE3), that possess potent anti-inflammatory actions both in vitro and in vivo. Carbons at 17 and 18 positions are asymmetric and thus the molecule has a total of four potential stereoisomers. Here, we assigned the stereochemistry of the conjugated double bonds and chirality of alcohols present in two natural isomers of RvE3 with four different stereoisomers prepared by total organic synthesis. The complete structures of two natural isomers of RvE3 were determined to be 17R,18S- and 17R,18R-dihydroxy-5Z,8Z,11Z,13E,15E-EPA, respectively. These natural isomers prepared by total organic synthesis displayed a potent anti-inflammatory action by limiting neutrophil infiltrations both in vitro and in vivo. The unnatural stereoisomers were much less active compared with the natural isomers, demonstrating the stereoselective action of RvE3.
authors.affiliation: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Isobe
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Urabe
authors.forename: Hidenori
authors.initials: H
authors.lastname: Todoroki
authors.forename: Koji
authors.initials: K
authors.lastname: Masuda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry; D002464:Cell Migration Inhibition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives*; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D010538:Peritonitis / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C583424:17,18-dihydroxyeicosapentaenoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D015118:Eicosapentaenoic Acid; D001093:Arachidonate 15-Lipoxygenase