Synthesis of 11-thialinoleic acid and 14-thialinoleic acid, inhibitors of soybean and human lipoxygenases.
Lipoxygenases catalyse the oxidation of polyunsaturated fatty acids and have been invoked in many diseases including cancer, atherosclerosis and Alzheimer's disease. Currently, no X-ray structures are available with substrate or substrate analogues bound in a productive conformation. Such structures would be very useful for examining interactions between substrate and active site residues. Reported here are the syntheses of linoleic acid analogues containing a sulfur atom at the 11 or 14 positions. The key steps in the syntheses were the incorporation of sulfur using nucleophilic attack of metallated alkynes on electrophilic sulfur compounds and the subsequent stereospecific tantalum-mediated reduction of the alkynylsulfide to the cis-alkenylsulfide. Kinetic assays performed with soybean lipoxygenase-1 showed that both 11-thialinoleic acid and 14-thialinoleic acid were competitive inhibitors with respect to linoleic acid with K(i) values of 22 and 35 microM, respectively. On the other hand, 11-thialinoleic acid was a noncompetitive inhibitor with respect to arachidonic acid with K(is) and K(ii) values of 48 and 36 microM, respectively. 11-Thialinoleic acid was also a noncompetitive inhibitor of human 15-lipoxygenase-1 with arachidonic acid (K(is) = 11.4 microM, K(ii) = 18.1 microM) or linoleic acid as substrate (K(is) = 20.1 microM, K(ii) = 20.0 microM), and a competitive inhibitor of human 12-lipoxygenase with arachidonic acid as substrate (K(i) = 2.5 microM). The presence of inhibitor did not change the regioselectivity of soybean lipoxygenase-1, human 12- or 15-lipoxygenase-1.
Jacquot
Cyril
C
Department of Chemistry, Roger Adams Laboratory, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, IL 61801, USA.
McGinley
Chris M
CM
Plata
Erik
E
Holman
Theodore R
TR
van der Donk
Wilfred A
WA
D016718:Arachidonic Acid / Q000378:metabolism; D001667:Binding, Competitive; D055162:Biocatalysis; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D019787:Linoleic Acid / Q000138:chemical synthesis* / Q000494:pharmacology*; D008041:Linoleic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D008084:Lipoxygenase / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013025:Glycine max / Q000201:enzymology*; D013379:Substrate Specificity
C533402:11-thialinoleic acid; C533404:14-thialinoleic acid; D007527:Isoenzymes; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D019787:Linoleic Acid; D008084:Lipoxygenase