Novel TDP1 Inhibitors: Disubstituted Thiazolidine-2,4-Diones Containing Monoterpene Moieties
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Published:2023-02-14
Issue:4
Volume:24
Page:3834
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Ivankin Dmitry I.1, Kornienko Tatyana E.2, Mikhailova Marina A.3, Dyrkheeva Nadezhda S.2ORCID, Zakharenko Alexandra L.2, Achara Chigozie4, Reynisson Jóhannes4ORCID, Golyshev Victor M.2ORCID, Luzina Olga A.1ORCID, Volcho Konstantin P.1ORCID, Salakhutdinov Nariman F.13, Lavrik Olga I.23ORCID
Affiliation:
1. N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia 2. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Science, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia 3. Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia 4. School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Newcastle-under-Lyme, Staffordshire ST5 5BC, UK
Abstract
Tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy; the use of TDP1 inhibitors with a topoisomerase 1 poison such as topotecan is a potential combination therapy. In this work, a novel series of 3,5-disubstituted thiazolidine-2,4-diones was synthesized and tested against TDP1. The screening revealed some active compounds with IC50 values less than 5 μM. Interestingly, compounds 20d and 21d were the most active, with IC50 values in the submicromolar concentration range. None of the compounds showed cytotoxicity against HCT-116 (colon carcinoma) and MRC-5 (human lung fibroblasts) cell lines in the 1–100 μM concentration range. Finally, this class of compounds did not sensitize cancer cells to the cytotoxic effect of topotecan.
Funder
Russian Science Foundation
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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