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 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.
Ivanov
Igor V
IV
M.V. Lomonosov State Academy of Fine Chemical Technology, 117571 Pr. Vernadskogo 86, Moscow, Russian Federation.
Romanov
Stepan G
SG
Groza
Nataliya V
NV
Nigam
Santosh
S
Kuhn
Hartmut
H
Myagkova
Galina I
GI
D002851:Chromatography, High Pressure Liquid; D006893:Hydroxyeicosatetraenoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008084:Lipoxygenase / Q000737:chemistry*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013057:Spectrum Analysis; D013237:Stereoisomerism
C410424:16-hydroxy-5,8,11,14-eicosatetraenoic acid; D006893:Hydroxyeicosatetraenoic Acids; D016859:Lipoxygenase Inhibitors; D008084:Lipoxygenase