Monoterpene substituted thiazolidin-4-ones as novel TDP1 inhibitors: Synthesis, biological evaluation and docking.

Autor: Ivankin DI; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia., Dyrkheeva NS; Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Science, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia., Zakharenko AL; Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Science, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia., Ilina ES; Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Science, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia., Zarkov TO; Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Science, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia., Reynisson J; School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire ST5 5BG, UK., Luzina OA; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia., Volcho KP; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia. Electronic address: volcho@nioch.nsc.ru., Salakhutdinov NF; N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 9, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia., Lavrik OI; Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Science, 8, Akademika Lavrentieva Ave., 630090 Novosibirsk, Russia.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Oct 01; Vol. 73, pp. 128909. Date of Electronic Publication: 2022 Jul 27.
DOI: 10.1016/j.bmcl.2022.128909
Abstrakt: Tyrosyl-DNA phosphodiesterase 1(TDP1) is a promising target for a new therapy in oncological disease as an adjunct to topoisomerase 1 (TOP1) drugs. In this paper, novel thiazolidin-4-one derivatives with a benzyl and monoterpene substituents were synthesized. Compounds with a monoterpene fragment attached via a phenyloxy linker were active against TDP1 with IC 50 values in the 1 ÷ 3 μM range, while direct attachment of monoterpene moiety to the thiazolidin-4-one fragment had no activity. Molecular modelling predicted two plausible binding modes of the active compounds both effectively blocking access to the catalytic site of TDP. At non-toxic concentrations the active ligands potentiated the efficacy of the TOP1 poison topotecan in human cervical cancer HeLa cells, but not in non-cancerous HEK293A cells.
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Databáze: MEDLINE
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