Eicosanoids biosynthesis

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). 

Srivastava KC. (1986). Isolation and effects of some ginger components of platelet aggregation and eicosanoid biosynthesis. Prostaglandins Leukot Med. 25(2-3) 187-98. 

Nicosia S, Patrona C. Eicosanoid biosynthesis and action novel opportunities for pharmacological intervention. EASEB J 1989 3 1941-8. 

A convenient approach to the synthesis of 2-aryl-4-alkyl-13 -triazino[l,2-ajbenzimidazoles 113 from 2-aminobenzimidazole has been reported <98IJC(B)1283>. New 8-cyanopyridothieno[l,23]triazines 114 as inhibitors of nitric oxide and eicosanoid biosynthesis have been described <99JMC4720>. Synthesis of pyridodithienotriazines 115, from dithienopyrimidine derivatives, and their antihistaminic and cytotoxic activities have been reported <98EJM887>. 

Cells of the immune system contribute substantially to eicosanoid biosynthesis during an immune reaction. T and lymphocytes are not primary synthetic sources however, they may supply arachidonic acid to monocyte-macrophages for eicosanoid synthesis. In addition, there is evidence for eicosanoid-mediated cell-cell interaction by platelets, erythrocytes, leukocytes, and endothelial cells. 

Eicosanoid Biosynthesis Eicosanoids Exert Their Action Locally... 

The pathway for the synthesis of dipalmitoyl-phos-phatidylcholine is illustrated in figure 19.5. The starting species of phosphatidylcholine is made by the CDP-choline pathway (see fig. 19.4). The fatty acid at the sn-2 position, which is usually unsaturated, is hydrolyzed by phospholi-pase A2, and the lysophosphatidylcholine is reacylated with palmitoyl-CoA. This modification permits alteration of the properties of the phospholipid without resynthesis of the entire molecule, a strategy called remodeling. Deacylation-reacylation of phosphatidylcholine occurs in other tissues and provides an important route for alteration of the fatty acid substituents at both the sn-1 and sn-2 positions. For example, fatty acids at the sn-2 position can be replaced by arachidonic acid, which is stored there until needed for eicosanoid biosynthesis, as we discuss later in this chapter. 

FIGURE 15-2 Eicosanoid biosynthesis. PG = prostaglandin TX = thromboxane LT = leukotriene. 

WL Smith. Eicosanoid biosynthesis and mechanism of action. Am J Physiol 263 F181-F191, 1992. 

Ziboh, V.A., Essential fatty acids/eicosanoid biosynthesis in the skin biological significance, Proc. Soc. Exp. Biol. Med., 1, 1994. 

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. 

Selley ML, Ardlie NG. 1986. Lipid peroxides and eicosanoid biosynthesis in platelets. Int Congr Ser -Excerpta Med 696 477-480. 

Arachidonic acid metabolism through eicosanoid biosynthesis is accompanied by the generation and subsequent utilization of oxygen-derived free radicals. Arachidonic acid, released from lipids as a result... 

The development of these chronic. Western-type diseases is associated with an excessive formation and function of eicosanoids derived from n-6 fatty acids. As balance can be restored to eicosanoid biosynthesis by dietary n-3 fatty acids, an effective strategy to diminish cardio-cerebrovascular mortality (in addition to several other serious disorders) may be to decrease the intake of n-6 fatty acids and replace them with n-3 fatty acids (116). Such a strategy is supported by studies that show an increased incidence of cardiovascular diseases, specifically ischemic heart disease, in Japanese whose diet has increasingly become more Westernized (113, 117). 

To advance understanding of the dynamic influence of dietary lipids, research efforts are focusing on the importance of the balance between n-6 and n-3 fatty acids in the human diet. What is emerging is recognition that these PUFAs modulate eicosanoid biosynthesis in numerous tissues and cell types, alter signal transduction, and influence gene expression (87, 118). The effect of n-6 and n-3 PUFA on CVD, cancer and bone/joint health is related to the newer discoveries of how dietary PUFA impact health. 

Malcolm KC, and Fitzpatrick FA (1992). Indirect actions fiiapsigargin in human platelets activation of eicosanoid biosynthesis and cellular signalling pathways. J. Pharm Exp. Thorap. 260 1244-1249. 

Arachidonic acid is of particular importance, being the initial compound for eicosanoid biosynthesis. Prostaglandins, prostacyclins and thromboxanes are synthesized from the eicosanoids via the cyclo-oxygenase pathway. The important mediators of inflammation — such as leukotrienes and leukotetraenes — are synthesized via the lipoxygenase pathway, (s. fig. 3.10)... 

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