Synthesis and 5-lipoxygenase inhibitory activity of 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid analogs

A series of eicosatetraenes (2-24) were designed, synthesized, and evaluated in vitro for inhibitory activity against 5-lipoxygenase (20000g supernatant from homogenized rat basophilic leukemia cells). All compounds were found to be active with the potencies (IC50's) ranging from 0.19 to 97 mic...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1987-07, Vol.30 (7), p.1177-1186
Main Authors: Kerdesky, Francis A. J, Schmidt, Steven P, Holms, James H, Dyer, Richard D, Carter, George W, Brooks, Dee W
Format: Article
Language:English
Subjects:
Animals
Arachidonate Lipoxygenases - antagonists & inhibitors
Arachidonic Acids - chemical synthesis
Arachidonic Acids - pharmacology
Leukotrienes
Lipoxygenase Inhibitors
Rats
Structure-Activity Relationship
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Summary:A series of eicosatetraenes (2-24) were designed, synthesized, and evaluated in vitro for inhibitory activity against 5-lipoxygenase (20000g supernatant from homogenized rat basophilic leukemia cells). All compounds were found to be active with the potencies (IC50's) ranging from 0.19 to 97 microM. Compounds containing the hydroxamic acid functionality (10-12) exhibited the best activity (IC50 = 0.19-2.8 microM). The most potent inhibitor was 5-[(hydroxyamino)carbonyl]methyl]-6,8,11,14-eicosatetraenoic acid (11), which was 10 times more active than the C-1 hydroxamates of arachidonic acid or 5-HETE. Cyclization of the linear eicosanoids 2 and 14 in the C-1 to C-5 region produced compounds (21 and 24, respectively) with several-fold greater potency.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00390a010