2,3-Diarylxanthones as Potential Inhibitors of Arachidonic Acid Metabolic Pathways

Abstract

Abstract-In response to an inflammatory stimulus, arachidonic acid (AA), the main polyunsaturated fatty acid present in the phospholipid layer of cell membranes, is released and metabolized to a series of eicosanoids. These bioactive lipid mediators of inflammation arise physiologically through the action of the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenases (constitutive COX-1 and inducible COX-2). It is believed that dual inhibition of 5-LOX and COXs may have a higher beneficial impact in the treatment of inflammatory disorders rather than the inhibition of each enzyme. With this demand for new dual-acting antiinflammatory agents, a range of 2,3-diarylxanthones were tested through their ability to interact in the AA metabolism. In vitro anti-inflammatory activity was evaluated through the inhibition of 5-LOX-catalyzed leukotriene B 4 (LTB 4 ) formation in human neutrophils and inhibition of COX-1-and COX-2-catalyzed prostaglandin E 2 (PGE 2 ) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB 4 production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC 50 ∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE 2 production presented IC 50 values from 1 to 7 μM, exhibiting a structural feature with at least one non-substituted aryl group. All the studied arylxanthones were ineffective to prevent the formation of PGE 2 catalyzed by COX-2, up to the maximum concentration of 100 μM. The ability of the tested 2,3-diarylxanthones to interact with both 5-LOX and COX-1 pathways constitutes an important step in the research of novel dual-acting anti-inflammatory drugs.

Arachidonic Acid Metabolism and Kidney Inflammation

“…A more exciting result was that licofelone inhibited IL-18-induced mesangial cell proliferation, and the results indicated that licofelone might be effective for the treatment of glomerulonephritis in children [201]. 2,3-diarylxanthones, dual inhibitors of COX and 5-LOX, are capable of preventing the production of LTB 4 in human neutrophils as well as decreasing PGE 2 production in human whole blood in a concentration-dependent manner [235]. According to the current results, the effect of lox-related drugs in regulating inflammation is still in the experimental study stage.…”

Justicia secunda Leaf Aqueous Fraction Suppressed NF-κB, TNF-α, IL-6, and COX-2 in Arthritic Rat

“…This indicates that the mechanistic action of JSALF could be connected to the prevention of leukotriene and prostaglandins production through lipoxygenase and cyclooxygenase pathways since the sensitivity of arachidonic acid to LOX are more than that of COX enzyme [45,46]. Two-fold inhibitors of both LOX and COX enzymes such as diclofenac and 2,3-diarylxanthones can prevent the production of leukotriene B 4 (LTB 4 ) as well as Prostaglandin E 2 (PGE 2 ) [49,50]. LTB 4 mediates leukocytes activation in inflammation whereas PGE 2 produces the five manifestations of inflammation which include fever, swelling, redness, immobility, and pain.…”

Raging the War Against Inflammation With Natural Products

“…However, it has been reported that numerous external and internal factor have the tenacity to activate the phospholipase A 2 (PLA 2 ). This activation cleaves the membrane bound AA from the phospholipids and makes it available for three major inflammatory pathways including cytochrome P-450 monooxygenase (Capdevila et al, 2000 ; De Montellano, 2005 ), lipoxygenase (Piomelli et al, 1987 ), and cyclooxygenase pathway (Kuehl and Egan, 1980 ; Santos et al, 2017 ).…”