Synthesis of 11-thialinoleic acid and 14-thialinoleic acid, inhibitors of soybean and human lipoxygenases

Cyril Jacquot, Chris M. McGinley, Erik Plata, Theodore R. Holman, Wilfred A. Van Der Donk

Research output: Contribution to journalArticlepeer-review

Abstract

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 Ki values of 22 and 35 μM, respectively. On the other hand, 11-thialinoleic acid was a noncompetitive inhibitor with respect to arachidonic acid with Kis and Kii values of 48 and 36 μM, respectively. 11-Thialinoleic acid was also a noncompetitive inhibitor of human 15-lipoxygenase-1 with arachidonic acid (Kis = 11.4 μM, Kii = 18.1 μM) or linoleic acid as substrate (Kis = 20.1 μM, Kii = 20.0 μM), and a competitive inhibitor of human 12-lipoxygenase with arachidonic acid as substrate (Ki = 2.5 μM). The presence of inhibitor did not change the regioselectivity of soybean lipoxygenase-1, human 12- or 15-lipoxygenase-1.

Original languageEnglish (US)
Pages (from-to)4242-4252
Number of pages11
JournalOrganic and Biomolecular Chemistry
Volume6
Issue number22
DOIs
StatePublished - 2008

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Synthesis of 11-thialinoleic acid and 14-thialinoleic acid, inhibitors of soybean and human lipoxygenases'. Together they form a unique fingerprint.

Cite this