Lipooxygenases

Horie and coworkers synthesized a series of flavones that showed promising inhibitory activity against archidonate 5-lipooxygenase. This enzyme is responsible for the initiation of bioactive leukotrienes that are chemical mediators of anaphylaxis and inflammation. Under standard K-R conditions o-hydroxyarylketone 66 and anhydride 67 in presence of the corresponding anhydride 68 delivered flavones 69 in yields of 42-65%. Subsequent hydrogenation of 69 afforded the flavone inhibitors 70. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Red wine contains quercetin, rutin, catechin, and epicatechin, among other flavonoids (Frankel and others 1993). Quercetin and other phenolic compounds isolated from wines were found to be more effective than a-tocopherol in inhibiting copper-catalyzed LDL oxidation. It has been determined that quercetin has also several anti-inflammatory effects it inhibits inflammatory cytokine production (Boots and others 2008), inducible NO synthase expression and activation of inflammatory transcription factors (Hamalainen and others 2007), and activity of cyclooxygenase and lipooxygenase (Issa 2006), among others. 

Kuroda, Y. Sera, T., Ogoshi, H., (1991) Regioselectivities and stereoselectivities of singlet oxygen generated by cyclodextrin sandwiched porphyrin sensitization. Lipooxygenase-like activity J. Am. Chem. Soc. 113, 2793-2794. 

Figure 16.24 Major prostaglandin and leukotriene products derived from arachidonic acid via the cyclooxygenase and 5-lipooxygenase pathways. Major enzymes 1, cyclooxygenase 2, hydroperoxidase 1 + 2, prostaglandin endoperoxidase synthetase 3, thromboxane synthetase 4, prostacyclin synthetase 5, 5-lipooxygenase 6, 9-ketoisomerase 7, PGH-PGF2a reductase 8, 11-ketoisomerase 9, PGE reductase 10, PGD reductase. (Reproduced by permission from Nelson NA, Kelly RC, Johnson, RA. Prostaglandins and the arachidonic acid cascade. Chem Eng News August 30-44, 1982.)...

Any reduction in the availability of free AA, by glucocorticoids or other agents, would virtually block all production of products via both the cyclooxygenase and lipooxygenase pathways. 

Another important metabolic pathway for the metabolism of arachidonic acid the 5-lipooxygenase pathway, which leads to a series of compounds callea leukotrienes (LTs). These compounds appear to be essentially, but not exclusively, of a pathophysiologic nature and are formed in various inflammatory cells. 

Both leukotrienes and prostaglandins can originate from arachidonic acid. Lipooxygenase initiates the formation of leukotrienes from arachidonic acid. Eicosapentaenoic acid is a precursor of series 3 prostaglandins, that is, prostaglandins with three double bonds in the side chains. Eicosapentaenoic acid is generated by linolenic acid, an essential fatty acid. 

Antiinflammatory steroids inhibit the release of arachidonic acid from membrane phospholipids by inhibiting a phospholipase A2. If arachidonate is not released, it is not converted to either leukotrienes or prostaglandins. Aspirin, a synthetic antiinflammatory agent, inhibits cyclooxygenase but not lipooxygenase. 

Leukotriene inhibitors, one leukotriene inhibitor blocks leukotriene synthesis by inhibiting the action of 5-lipooxygenase (Zileuton Zyflo). Another blocks leukotriene receptors on the surface of smooth-muscle cells and eosinophils (Montelukast Singulair). 

Eicosanoids, also referred to as icosanoids, are so named because of the 20-carbon constituency that identifies this class of oxygenated lipid molecules. A primary synthetic pathway for these molecules involves the phospholipase-mediated cleavage of a membrane phospholipid to produce arachidonic acid [(all-Z)-ik osa-5,8,ll,14-tetraenoic acid]. From this biologically essential intermediate fatty acid, two major subclasses of eicosanoids can be produced 1) leukotrienes, via the action of lipooxygenases, and 2) prostanoids, via the action of cyclooxygenases (COX-1 and COX-2). Examples of chemical structures for a leukotriene (Fig. la) and three types of prostanoids (Fig. Ib-d) underscore their shared arachidonate origin. 

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