Synthesis of substituted 5[H]phenanthridin-6-ones as potent poly(ADP-ribose)polymerase-1 (PARP1) inhibitors |
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| Affiliation: | 1. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic;2. Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic;3. Department of Cybernetics and Biomedical Engineering, Faculty of Electrical Engineering and Computer Science, VSB-Technical University of Ostrava, 17. Listopadu 15, 708 33 Ostrava-Poruba, Czech Republic;4. Department of Epidemiology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic;5. Department of Surgical Studies, Faculty of Medicine, University of Ostrava, Syllabova 19, 700 30 Ostrava, Czech Republic;6. Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic;7. Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic;8. Departement de Toxicologie et Risque Chimique, Institut de Recherche Biomédicale des Armées, BP73, F-91223 Brétigny-sur-Orge, France;1. Medicinal Chemistry Laboratory, Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan;2. Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan;3. Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Tamura-cho, Nagahama 526-0829, Japan;1. Department of Chemistry, Villanova University, Villanova, PA 19085, United States;2. Department of Chemistry, Temple University, Philadelphia, PA 19122, United States;1. Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada;2. Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada;3. Boehringer Ingelhein Pharmaceuticals Inc., 175 Briar Ridge Road, Ridgefield, CT 06877, United States;1. Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;2. Department of Chemistry, College of Science & Arts, King Abdulaziz University, P.O. Box 344, Rabigh 21911, Saudi Arabia;3. Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt;4. Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India;5. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;6. Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt |
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| Abstract: | 1-, 2-, 3-, 4-, 8-, or 10-Substituted 5(H)phenanthridin-6-ones were synthesized and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC50 values (compound 1b, 10 nM) but also desirable water solubility characteristics. These properties, which are superior to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds allows SAR analysis of favored substituents and substituted positions on 5(H)phenanthridin-6-one ring. |
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