Synthesis of 5- and 6-fluoro derivatives of 5,8,14-eicosatrienoic and 5,8,11,14-eicosatetraenoic acids. Effects of fluorinated arachidonic acids on leukotriene C4 production by macrophages.
The total syntheses of the 5- and 6-fluoro derivatives of 5,8,14-eicosatrienoic (ETA) and arachidonic (AA) acids are described. The fluorinated double bond was introduced using (E)-1,4-dihydroxy-2-fluoro-2-butene obtained through diisobutylaluminium hydride reduction of dimethylfluoromaleate. Recently, 5-fluoro and 6-fluoro arachidonic acids (5-F-AA and 6-F-AA) were found to be effective inhibitors of 5-lipoxygenase in vitro (Nave, J. F.; Jacobi, D.; Gaget, C.; Dulery, B.; Ducep, J. B., Biochem. J. 1991, 278, 549). The effect of these compounds on leukotriene C4 (LTC4) production by intact cells was investigated. Mouse peritoneal macrophages were cultured in the presence of 5-F-AA or 6-F-AA under conditions where AA was found to be efficiently incorporated into cellular phospholipids. Following stimulation with zymosan, macrophages treated with 20 microM 6-F-AA released 30 to 35% less LTC4 than control cells. In contrast, macrophages treated with 20 microM 5-F-AA released 1.5 to 1.8 times more LTC4 than control cells. In competition experiments with [14C]-AA, 5-F-AA modified the distribution profile of [14C]-AA within the various classes of lipids in a way similar to AA. 6-F-AA had a distinct behaviour, producing a more important incorporation of [14C]-AA into the neutral lipid fraction at the expense of the phospholipid fraction than AA and 5-F-AA. 6-F-AA is expected to be an important tool in further studies of the arachidonic acid pathway in vivo.
Ducep
J B
JB
Marion Merrell Dow Research Institute, Strasbourg Research Centre, France.
Nave
J F
JF
Zimmermann
P R
PR
D015126:8,11,14-Eicosatrienoic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005459:Fluorides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D017997:Leukotriene C4 / Q000096:biosynthesis*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure
D001095:Arachidonic Acids; D008055:Lipids; D017997:Leukotriene C4; C047852:5,8,14-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid; D005459:Fluorides