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Synthesis and biological evaluation of a series of flavone derivatives as potential radioligands for imaging the multidrug resistance-associated protein 1 (ABCC1/MRP1)
Authors:Mavel Sylvie  Dikic Branko  Palakas Somchit  Emond Patrick  Greguric Ivan  de Gracia Adrienne Gomez  Mattner Filomena  Garrigos Manuel  Guilloteau Denis  Katsifis Andrew
Institution:1. Université François Rabelais, Faculté de Pharmacie, Lab. de Biophysique Médicale et Pharmaceutique, INSERM U619, 31 av. Monge, 37200 Tours, France;2. ANSTO, Radiopharmaceuticals Research Institute, New Illawarra Road Lucas Heights, NSW 2234, Australia;3. Unité de Recherche Associée 2096 (CNRS), Service de Biophysique des Fonctions Membranaires (DBJC, CEA), CEA-Saclay, 91191 Gif-sur-Yvette cedex, France;3. EA 6306 Innovation Moléculaire et Thérapeutique, Université François Rabelais, UFR des Sciences et Techniques, UFR de Pharmacie, 37200 Tours, France;5. Centre d''Etudes des Pathologies Respiratoires INSERM UMR 1100, Université François Rabelais, UFR de Médecine, 37032 Tours Cedex 1, France,;4. Groupe de Recherche en Hypertension Pulmonaire, CRIUCPQ, Québec, Québec G1V 4G5, Canada;1. Bio-Organic Chemistry Laboratory, Department of Chemistry, Siksha Bhavana, Visva-Bharati (Central University), Santiniketan 731 235, West Bengal, India;2. Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India;1. School of Pharmacy, University of Reading, Whiteknights, RG6 6AD Berkshire, UK;2. Institute of Cardiovascular and Metabolic Research, School of Biological Sciences, University of Reading, Whiteknights, RG6 6AD Berkshire, UK;1. China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, Key Lab of Industrial Fermentation Microbiology, Tianjin Key Lab of Industrial Microbiology, Sino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China;2. State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 211198, PR China;3. College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Tianjin Normal University, Tianjin, 300387, PR China;4. College of Food Engineering and Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China;5. 382 Longvalley Lane, DeKalb, IL 80115, USA;1. China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 200120, China;2. Division of Mathematics and Science, University of South Carolina Salkehatchie, Walterboro, SC 29488, United States;3. China National Pharmaceutical Industry Information Center, 1320 West Beijing Road, Shanghai 200040, China;1. Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic;2. Department of Biophysics, Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science, Palacký University, t?. 17 listopadu 12, 771 46 Olomouc, Czech Republic;3. INSERM UMR 850, Univ. Limoges, School of Pharmacy, 2 rue du Docteur Marcland, 87025 Limoges, France;4. Institute of Microbiology, Laboratory of Biotransformation, Czech Academy of Sciences, Vídeňská 1083, 142 20 Prague, Czech Republic;5. J. Heyrovský Institute of Physical Chemistry, Czech Academy of Sciences, Dolej?kova 3, 182 23 Prague 8, Czech Republic;6. Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11158 Belgrade, Serbia;7. Department of Physical Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, t?. 17 listopadu 12, 771 46 Olomouc, Czech Republic
Abstract:Multidrug resistance (MDR) is one of the major problems affecting the treatment of cancer. In vivo visualization and quantification of MDR proteins would be of great value to better select the therapeutic strategy. Six flavone-based compounds were synthesized and evaluated for their cytotoxic activity and MDR-reversing capacity using hMRP1 or hMDR1 overexpressing cell lines for in vitro assays. All the flavone derivatives were highly selective for hMRP1-expressing cell lines. These derivatives each used at 4muM (a non-cytotoxic concentration) enhance significantly the sensitivity of hMRP1-mediated MDR cell line toward doxorubicin toxicity. Their MDR-reversing capacity suggests that, in particular, the 4'-fluoroalkyloxy and 4'-iodo apigenin derivatives are potential new radiopharmaceuticals to visualize in vivo MRP1-mediated MDR phenomenon by PET or SPECT.
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