Photoactivation of an inhibitor of the 12/15-lipoxygenase pathway.
Lipoxygenases are lipid-peroxidizing enzymes that have been implicated in the pathogenesis of inflammatory diseases and lipoxygenase inhibitors may be developed as anti-inflammatory drugs. Structure comparison with known lipoxygenase inhibitors has suggested that (2Z)-2-(3-benzylidene)-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester might inhibit the lipoxygenase pathway but we found that it exhibited only a low inhibitory potency for the pure 12/15-lipoxygenase (IC(50) = 0.7 mM). However, photoactivation, which induces a Z-to-E isomerization of the double bond, strongly augmented the inhibitory potency and an IC(50) value of 0.021 mM was determined for the pure E isomer. Similar isomer-specific differences were observed with the recombinant enzyme and its 12-lipoxygenating Ile418Ala mutant, as well as in intracellular lipoxygenase activity. Structure modeling of the enzyme/inhibitor complex suggested the molecular reasons for this isomer specificity. Since light-induced isomerization may proceed in the skin, such photoreactive compounds might be developed as potential drugs for inflammatory skin diseases.
Herre
Stephan
S
Institute of Chemistry, Technical University Berlin, Germany.
Schadendorf
Torsten
T
Ivanov
Igor
I
Herrberger
Christian
C
Steinle
Wencke
W
Rück-Braun
Karola
K
Preissner
Robert
R
Kuhn
Hartmut
H
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D002851:Chromatography, High Pressure Liquid; D007536:Isomerism; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000528:radiation effects*; D009682:Magnetic Resonance Spectroscopy; D010777:Photochemistry; D011817:Rabbits; D013329:Structure-Activity Relationship
C475064:12-15-lipoxygenase; D016859:Lipoxygenase Inhibitors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase