Hinokitiol, a selective inhibitor of the platelet-type isozyme of arachidonate 12-lipoxygenase.
Hinokitiol (4-isopropyltropolone), a constituent of Japanese cypress, reversibly inhibited platelet-type 12-lipoxygenase with an IC(50) of 0.1 microM, and the enzyme activity was almost lost at 1 microM. The compound was much less active with other lipoxygenase enzymes with higher IC(50) values (leukocyte-type 12-lipoxygenase, 50 microM; soybean lipoxygenase, 17 microM; 15-lipoxygenase-1, >100 microM; 5-lipoxygenase, 17 microM). Hinokitiol up to 100 microM had almost no effect on cyclooxygenases-1 and -2. Their structure-activity relationship examined with various tropolone derivatives indicated the requirements of the 2-hydroxyl group and 4-alkyl group for the potent and selective inhibition of platelet-type 12-lipoxygenase.
Suzuki
H
H
Department of Biochemistry, Tokushima University School of Medicine, Kuramoto-cho, Tokushima, 770-8503, Japan. suzuki@basic.med.tokushima-u.ac.jp
Ueda
T
T
Juránek
I
I
Yamamoto
S
S
Katoh
T
T
Node
M
M
Suzuki
T
T
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007962:Leukocytes / Q000201:enzymology; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D039821:Monoterpenes; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013997:Time Factors; D014197:Trees / Q000737:chemistry; D014334:Tropolone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D039821:Monoterpenes; D014334:Tropolone; D001092:Arachidonate 12-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C009479:beta-thujaplicin