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

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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 LTB4 production 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 PGE2 production presented IC50 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 PGE2 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.

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Acknowledgements

Sincere thanks are expressed to Faculdade de Farmácia da Universidade do Porto, Universidade de Aveiro, Instituto Politécnico de Bragança, Fundação para a Ciência e a Tecnologia (FCT, Portugal), Ministério da Educação e Ciência, European Union, FEDER, PT 2020, QREN, and COMPETE funding UCIBIO, REQUIMTE [(PT2020 UID/MULTI/04378/2013 - POCI/01/0145/FEDER/007728), (NORTE-01-0145-FEDER-000024), and (PTDC/QEQ-QAN/1742/2014 – POCI-01-0145-FEDER-016530)] and QOPNA (FCT UID/QUI/00062/2013) Research Units and also to the Portuguese National NMR Network (RNRMN). We gratefully acknowledge Graça Porto and the nursing staff of the Centro Hospitalar do Porto - Hospital de Santo António blood bank for the collaboration in the recruitment of blood donors involved in the present work.

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Authors and Affiliations

  1. School of Agriculture, Polytechnic Institute of Bragança, Campus de Santa Apolónia, 5300-253, Bragança, Portugal

    Clementina M. M. Santos

  2. Department of Chemistry & QOPNA, University of Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal

    Clementina M. M. Santos & Artur M. S. Silva

  3. 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

    Daniela Ribeiro & Eduarda Fernandes

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  1. Clementina M. M. Santos
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Correspondence to Clementina M. M. Santos or Eduarda Fernandes.

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Santos, C.M.M., Ribeiro, D., Silva, A.M.S. et al. 2,3-Diarylxanthones as Potential Inhibitors of Arachidonic Acid Metabolic Pathways. Inflammation 40, 956–964 (2017). https://doi.org/10.1007/s10753-017-0540-6

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