New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties |
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| Institution: | 1. N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation;2. Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russian Federation;3. School of Chemical Sciences, University of Auckland, New Zealand;4. Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russian Federation;1. Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Avenue, Tampa, FL 33620, USA;2. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 E Fowler Ave, Tampa, FL, USA;1. Department of Orthopedics, Heilongjiang Province Hospital, Harbin 150036, Heilongjiang Province, China;2. Department of Orthopedics, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China;3. Department of Orthopedics, Traditional Chinese Medicine Hospital of Harbin, Harbin 150000, Heilongjiang Province, China;4. Department of Orthopedics, Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China;1. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People’s Republic of China;2. Jiangsu Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing 210000, People’s Republic of China;1. Enzymologie Moléculaire et Fonctionnelle, UR4, Université Pierre et Marie Curie – Sorbonne Universités (UPMC), case courrier 256, 7, quai St Bernard, 75252 Paris Cedex 05, France;2. Molécules Thérapeutiques in silico (MTi), Université Paris-Diderot, Inserm UMR-S, 973 Lamarck Building, 35 rue Hélène Brion, 75205 Paris Cedex 13, France;3. INSERM U781, Université Paris Descartes – Sorbonne Paris Cité, Institut Imagine, Necker Hospital, 149 rue de Sèvres, France;4. Department of Genetics, Necker Hospital, 149 rue de Sèvres, 75743 Paris Cedex 15, France;1. Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, NY 11794, United States;2. Department of Microbiology and Immunology, State University of New York at Buffalo, Buffalo, NY 14214, United States;3. Department of Basic Sciences, Touro University—California, Mare Island, Vallejo, CA 94592, United States;4. Department of Pharmaceutical Chemistry, University of California San Francisco, CA 94143, United States;5. Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794, United States;6. Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, United States |
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| Abstract: | A number of derivatives of 7-hydroxycoumarins containing aromatic or monoterpene substituents at hydroxy-group were synthesized based on a hit compound from a virtual screen. The ability of these compounds to inhibit tyrosyl-DNA phosphodiesterase I (Tdp 1), important target for anti-cancer therapy, was studied for the first time. It was found that the 7-hydroxycoumarin derivatives with monoterpene pinene moiety are effective inhibitors of Tdp 1 with the most active derivative (+)-25c with IC50 value of 0.675 μM. This compound has low cytotoxicity (CC50 >100 μM) when tested against human cancer cells which is crucial for presupposed application in combination with clinically established anticancer drugs. The ability of the new compounds to enhance the cytotoxicity of camptothecin, an established topoisomerase 1 poison, was demonstrated. |
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| Keywords: | Tyrosyl-DNA Phosphodiesterase I inhibitor Coumarin Monoterpene Molecular modeling |
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