A simple method for the preparation of (5Z, 8Z, 11Z, 14Z)-16-hydroxyeicosa-5,8,11,14-tetraenoic acid enantiomers and the corresponding 14,15-dehydro analogues: Role of the 16-hydroxy group for the lipoxygenase reaction

(5Z,8Z,11Z,13E)-15-Hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) is not well oxygenated by arachidonate 15-lipoxygenases because of two structural reasons: (i) it contains a hydrophilic OH-group in close proximity to its methyl end and (ii) it lacks the bisallylic methylene at C(13). We synthesi...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2002-07, Vol.10 (7), p.2335-2343
Main Authors: IVANOV, Igor V, ROMANOV, Stepan G, GROZA, Nataliya V, NIGAM, Santosh, KUHN, Hartmut, MYAGKOVA, Galina I
Format: Article
Language:English
Subjects:
Chromatography, High Pressure Liquid
Hydroxyeicosatetraenoic Acids - chemical synthesis
Hydroxyeicosatetraenoic Acids - chemistry
Hydroxyeicosatetraenoic Acids - pharmacology
Lipoxygenase - chemistry
Lipoxygenase Inhibitors - chemical synthesis
Lipoxygenase Inhibitors - chemistry
Lipoxygenase Inhibitors - pharmacology
Spectrum Analysis
Stereoisomerism
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Summary:(5Z,8Z,11Z,13E)-15-Hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) is not well oxygenated by arachidonate 15-lipoxygenases because of two structural reasons: (i) it contains a hydrophilic OH-group in close proximity to its methyl end and (ii) it lacks the bisallylic methylene at C(13). We synthesized racemic (5Z,8Z,11Z,14Z)-16-hydroxy-5,8,11,14-eicosatetraenoic acid (16-HETE) which still contains the bisallylic C(13), separated the enantiomers reaching an optical purity of >99% and tested them as substrates for 5- and 15-lipoxygenases. Our synthetic pathway, which is based on stereospecific hydrogenation of a polyacetylenic precursor, yielded substantial amounts (30%) of 14,15-dehydro-16-HETE in addition to 16-HETE. When 16-HETE was tested as lipoxygenase substrate, we found that it is well oxygenated by the soybean 15-lipoxygenase and by the recombinant human 5-lipoxygenase. Analysis of the reaction products suggested an arachidonic acid-like alignment at the active site of the two enzymes. In contrast, the product pattern of 16-HETE methyl ester oxygenation by the soybean lipoxygenase (5-lipoxygenation) may be explained by an inverse head to tail substrate orientation.
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(02)00024-X