title: 2,3-Diarylxanthones as Potential Inhibitors of Arachidonic Acid Metabolic Pathways.
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 anti-inflammatory 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 B4(LTB4) formation in human neutrophils and inhibition of COX-1- and COX-2-catalyzed prostaglandin E2(PGE2) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB4production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC50∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE2production presented IC50values 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 PGE2catalyzed 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.
authors.affiliation: School of Agriculture, Polytechnic Institute of Bragança, Campus de Santa Apolónia, 5300-253, Bragança, Portugal. clems@ipb.pt.|Department of Chemistry & QOPNA, University of Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal. clems@ipb.pt.
authors.forename: Clementina M M
authors.initials: CMM
authors.lastname: Santos
authors.affiliation: UCIBIO, REQUIMTE, Applied Chemistry Laboratory, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ribeiro
authors.affiliation: Department of Chemistry & QOPNA, University of Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal.
authors.forename: Artur M S
authors.initials: AMS
authors.lastname: Silva
authors.affiliation: UCIBIO, REQUIMTE, Applied Chemistry Laboratory, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal. egracas@ff.up.pt.
authors.forename: Eduarda
authors.initials: E
authors.lastname: Fernandes
mesh_terms: D001094:Arachidonate 5-Lipoxygenase; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016859:Lipoxygenase Inhibitors; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D009504:Neutrophils / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D044004:Xanthones; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
keywords: 5-LOX; COX-1; COX-2; human neutrophils; human whole-blood assay; xanthones