Discovery of the first non-planar flavonoid that can strongly inhibit xanthine oxidase: protoapigenone 1′-O-propargyl ether |
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| Authors: | Attila Hunyadi Ana Martins Balazs Danko Da-Wei Chuang Patrick Trouillas Fang-Rong Chang Yang-Chang Wu George Falkay |
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| Institution: | 1. Institute of Pharmacognosy, University of Szeged, Eötvös u. 6, Szeged 6720, Hungary;2. Department of Medical Microbiology and Immunobiology, University of Szeged, Dóm tér 9, Szeged 6720, Hungary;3. Unidade de Parasitologia e Microbiologia Médica, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Junqueira 100, Lisbon 1349-008, Portugal;4. Graduate Institute of Natural Products, Kaohsiung Medical University, Shih-Chuan 1st Rd. 100, Kaohsiung 80708, Taiwan, ROC;5. Laboratoire de Chimie des Substances Naturelles EA-1069, Faculté de Pharmacie, Université de Limoges, 2 rue du Docteur Marcland, Limoges CEDEX 87000, France;6. Service de Chimie des Matériaux Nouveaux, Université de Mons—UMONS, Place du Parc 20, Mons 7000, Belgium;g Regional Center of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University, 17. listopadu 1192/12, Olomouc 77146 , Czech Republic;h Cancer Center, Kaohsiung Medical University Hospital, Shih-Chuan 1st Rd. 100, Kaohsiung 80708, Taiwan, ROC;i R&D Center of Chinese Herbal Medicines & New Drugs, College of Pharmacy, Kaohsiung Medical University, Shih-Chuan 1st Rd. 100, Kaohsiung 80708, Taiwan, ROC;j School of Pharmacy, College of Pharmacy, China Medical University Hospital, China Medical University, Hsueh-Shih Rd. 91, Taichung 404, Taiwan, ROC;k Natural Medicinal Products Research Center, Center for Molecular Medicine, China Medical University Hospital, China Medical University, Hsueh-Shih Rd. 91, Taichung 404, Taiwan, ROC;l Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6, Szeged 6720, Hungary |
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| Abstract: | Xanthine oxidase (XO) is a key enzyme in purine metabolism with an important role in various pathologies. Several flavonoids have been reported for their capacity to inhibit this enzyme, and, for these compounds, the ability to adopt a planar 3D structure has been accepted as fundamental prerequisite for such activity. Here we report the in vitro investigation of a series of non-planar protoflavone derivatives as XO inhibitors, among which protoapigenone 1′-O-propargyl ether was found to be an efficient competitive inhibitor of the enzyme with an IC50 value of 3.61 μM, significantly (p <0.001) stronger than the anti-gout drug allopurinol (IC50 = 8.72 μM). Methoxy substitution at C-7, however, resulted in complete loss of activity. In silico docking supported the observed structure–activity relationships, based on which a ‘planar structure’ itself can no longer be considered as a criterion for flavonoid-type inhibitors of XO. |
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| Keywords: | Xanthine oxidase inhibitor Flavonoid Protoflavone Protoapigenone Structure&ndash activity relationships Docking study |
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