Eicosanoid biosynthesis, inhibition

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). 

Fuscoside B is a lobane diterpenoid isolated from the Caribbean gorgonian Eunicea fusca. It has been evaluated for the inhibitory activities against COX-1, 5-LOX, 12-LOX, PLA2, and other eicosanoid biosynthesis pathways and found only to irreversibly inhibit the 5-LOX pathway with an IC50 value of 10 pM. [141,142]... 

Srivastava, K.C. (1 989) Extracts from two frequently consumed spices - cumin (Cuminum cyminum) and turmeric (Curcuma longa) - inhibit platelet aggregation and alter eicosanoid biosynthesis in human blood platelets. Prostaglandins, Leukotrienes and Essential Fatty Acids 37(1), 57-64. 

In the first part the biosynthesis of fatty acids in skin with its role in barrier function as well as the role of dietary fatty acids on skin cell function and in the treatment of inflammatory skin diseases is presented. The second part deals with skin as a source of proinflammatory eicosanoids, especially with the keratinocyte as a major cellular source. Metabolism of eicosanoids in skin, its role in psoriasis and atopic dermatitis as well as pharmacological inhibition of eicosanoid biosynthesis is reviewed. 

Figure 8.9 Prostaglandins and leukotrienes are potent eicosanoid lipid mediators, derived from phospholipase-released arachidonic acids, that are involved in numerous homeostatic biological functions and inflammation. They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and pharmacological actions are inhibited by clinically relevant nonsteroidal anti-inflammatory drugs.

Inflammation is now recognized as a key process in atherogenesis [Libby, 2002]. The potential for dietary flavonoids to inhibit inflammatory activities is of particular interest. A potential anti-inflammatory feature of the flavonoids is the ability to inhibit the biosynthesis of eicosanoids. Selected phenolic acids and some flavonoids have been shown to inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways [Nijveldt et al., 2001 Takano-Ishikawa et al., 2006], Epicatechin and related flavonoids have been shown to inhibit the synthesis of pro-inflammatory cytokines in vitro [Sanbongi et al., 1997], and plasma metabolites of catechin and quercetin inhibit the adhesion of monocytes to cultured endothelial cells [Koga and Meydani, 2001]. Silymarin has been shown to inhibit the production of inflammatory cytokines, such as interleukin-1, interferon-, and tumor necrosis factor-a (TNFa), from macrophages and T-cells [Matsuda et al., 2005], Some flavonoids can inhibit neutrophil... 

Although PLAj activity is the first step for prostanoid biosynthesis and can limit their availability, it is not the rate-limiting step in prostanoid formation. However, direct inhibition of PLA could potentially block the production of all eicosanoids, making it a desirable target for pharmacological intervention (Yedgar et al., 2000). 

Curcuma extract, volatile oil, and its curcumin components have in vitro and in vivo antiinflammatory activity that may be due to inhibition of eicosanoid (leukotrienes/thrombox-anes) biosynthesis. A fraction of curcuma oil (b.p 80-110 °C) has been demonstrated to have anti-inflammatory and antiarthritic activities in rats. An essential oil-depleted extract is effective against experimental rheumatoid arthritis. Involved targets include NF-kB, che-mokine, COX-2, and others. Curcumin has also been reported to exhibit antiedemic effects in rats (martestdale). 

The mechanistic action of anti-proliferative activity of the mixture of CLA isomers is poorly understood. However, it is, in part, attributed to the alterations in eicosanoid metabolism (27) and/or peroxidation of CLA (7). We believe that eicosanoid metabolism is more strongly altered by tram/tram CLA isomers than cis/tram CLA isomers. The chemical structure of tram/tram CLA isomers closely resembles the straight chain of stearic acid, which is, in turn, preferentially incorporated into the SN-2 position of membrane phospholipids. This might inhibit the process of elongation and desaturation of linoleic acid required for the biosynthesis of arachidonic acid, and thus, alter the eicosanoid metabolisms and/or inhibiting phospholipaseA2 activity. Further research looking for the mechanistic action of anti-proliferative activity of individual CLA isomers is under way. 

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