Novel TDP1 Inhibitors: Disubstituted Thiazolidine-2,4-Diones Containing Monoterpene Moieties.

International journal of molecular sciences 2023 Feb 14

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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.

Citation

Dmitry I Ivankin, Tatyana E Kornienko, Marina A Mikhailova, Nadezhda S Dyrkheeva, Alexandra L Zakharenko, Chigozie Achara, Jóhannes Reynisson, Victor M Golyshev, Olga A Luzina, Konstantin P Volcho, Nariman F Salakhutdinov, Olga I Lavrik. Novel TDP1 Inhibitors: Disubstituted Thiazolidine-2,4-Diones Containing Monoterpene Moieties. International journal of molecular sciences. 2023 Feb 14;24(4)