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.

Isotope sensitive branching and kinetic isotope effects in the reaction of deuterated arachidonic acids with human 12- and 15-lipoxygenases.

Lipoxygenases (LOs) catalyze lipid peroxidation and have been implicated in a number of human diseases connected to oxidative stress and inflammation. These enzymes have also attracted considerable attention due to large kinetic isotope effects (30-80) for the rate-limiting hydrogen abstraction step with linoleic acid (LA) as substrate. Herein, we report kinetic isotope effects (KIEs) in the reactions of three human LOs (platelet 12-hLO, reticulocyte 15-hLO-1, and epithelial 15-hLO-2) with arachidonic acid (AA).

Synthesis of 7-thiaarachidonic acid as a mechanistic probe of prostaglandin H synthase-2.

The mechanism by which prostaglandin synthase converts arachidonic acid to prostaglandin G(2), creating five new chiral centers in the process, is still incompletely understood. The first radical intermediate has been characterized by EPR spectroscopy but subsequent proposed intermediates have not succumbed to detection. We report the synthesis of 7-thiaarachidonic acid designed to stabilize one of the proposed radical intermediates, which may allow its detection.

Synthesis of site-specifically deuterated arachidonic acid derivatives containing a remote tritium radiolabel.

The synthesis of arachidonic acid derivatives containing site-specifically incorporated deuterium atoms and also a remote tritium label are described. Deuterium incorporation at the C11 and/or C15 position was achieved using Wittig chemistry, while the radiolabel was introduced at a remote position using [(3)H]NaBH(4) as the radiolabel source. These compounds can be used to measure secondary kinetic isotope effects for both cyclooxygenase and lipoxygenase enzymes under aerobic turnover with high precision.

Synthesis of site-specifically labeled arachidonic acids as mechanistic probes for prostaglandin H synthase.

[structure: see text] Prostaglandin H synthase catalyzes the first committed step in the biosynthesis of prostaglandins and thromboxane. Herein we report the synthesis of four site-specifically labeled arachidonic acids for investigation of the radical intermediate formed during this enzymatic reaction. Two compounds were prepared using a common C9-C11 fragment, while another target was synthesized using a previously reported advanced intermediate.

Enzymatic hydrogen atom abstraction from polyunsaturated fatty acids.

The oxidation of polyunsaturated fatty acids such as arachidonic and linoleic acid initiates a plethora of cell signaling pathways in animals and plants. The chemistry of the enzymatic oxidation has been investigated for several enzymes, most notably prostaglandin synthase and the lipoxygenases, revealing many surprises and impressive examples of enzymatic control of hydrogen atom abstraction and subsequent oxygenation.

Mechanistic investigation of a novel vitamin B(12)-catalyzed carbon [bond] carbon bond forming reaction, the reductive dimerization of arylalkenes.

In the presence of catalytic vitamin B(12) and a reducing agent such as Ti(III)citrate or Zn, arylalkenes are dimerized with unusual regioselectivity forming a carbon [bond] carbon bond between the benzylic carbons of each coupling partner. Dimerization products were obtained in good to excellent yields for mono- and 1,1-disubstituted alkenes. Dienes containing one aryl alkene underwent intramolecular cyclization in good yields.