Synthesis and 5-lipoxygenase inhibitory activities of eicosanoid compounds

Abstract

Ten eicosanoid compounds [7,7-ethanoarachidonic acid (3), (8Z,11Z,14Z)-cis-5,6-methano-8,11,14-eicosatrienoic acid (5,6-methanoarachidonic acid, 6), (6E,8Z,11Z,14Z)-5-(hydroxymethyl)6,8,11,14-eicosatetraenoic acid (9), methyl (6E,8Z,11Z,14Z)-5-oxo-6,8,11,14-eicosatetraenoate (11), methyl (7E,9E,11Z,14Z)-trans-5,6-epithio-7,9,11,14-eicosatetraenoate (5,6-epithioleukotriene A4, 12), (5E,7E,9Z,12Z)-trans-3,4-methano-5,7,9,12-octadecatetraenoic acid (15), (7E,9E,11Z,14Z)-trans-5,6-methano-7,9,11,14-eicosatetraenoic acid (18), (8E,10E,12Z,15Z)-trans-6,7-methano-8,10,12,15-heneicosatetraenoic acid (21), cis-5,6-methanoeicosanoic acid (23), and trans-5,6-methanoeicosanoic acid (25)], methyl (6E,8Z,11Z,14Z)-5-hydroxy-6,8,11,14-eicosatetraenoate (5-HETE, 10), leukotriene A4 (26) and (5S,6E,8E,10E,12RS,14E)-5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-diHETE, 27) were prepared and their inhibitory activities against the 5-lipoxygenase from guinea pig polymorphonuclear leukocytes were tested. 5,6-Methanoleukotriene A4 (18) was especially a potent and specific inhibitor of the 5-lipoxygenase without inhibiting the cyclooxygenase and the 12-lipoxygenase. Leukotriene A4, 5-HETE, and 5,12-diHETE also have inhibitory activities against the 5-lipoxygenase at micromolar concentrations, which can regulate the formation of slow-reacting substance of anaphylaxis intracellulary.