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

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.

SUBMITTER: Ivankin DI

PROVIDER: S-EPMC9964680 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Ivankin Dmitry I DI Kornienko Tatyana E TE Mikhailova Marina A MA Dyrkheeva Nadezhda S NS Zakharenko Alexandra L AL Achara Chigozie C Reynisson Jóhannes J Golyshev Victor M VM Luzina Olga A OA Volcho Konstantin P KP Salakhutdinov Nariman F NF Lavrik Olga I OI

International journal of molecular sciences 20230214 4

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 ...[more]

PMID: 36835244

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Project description:ObjectivesThe aim was the synthesis of novel substituted 5-[morpholino(phenyl)methyl]-thiazolidine-2,4-diones and screening for their in vivo hypoglycemic activity and in vitro anti-inflammatory activity, as well as molecular docking studies to find out active potential lead molecules.Materials and methodsSubstituted aromatic aldehydes, thiazolidine-2,4-dione, and morpholine on Mannich reaction gave the title compounds. They were characterized by physical and spectral methods. In vivo hypoglycemic activity was examined in alloxan induced Wistar albino rats by tail tipping method. In vitro anti-inflammatory activity was tested by human red blood cell (HRBC) membrane stabilization and protein denaturation. Using AutoDock, molecular docking studies were carried out to find out the best fit ligands.ResultsSeries of substituted 5-[morpholino(phenyl)methyl]-thiazolidine-2,4-diones were synthesized and chemically they were confirmed by spectral techniques. Acute toxic studies of in vivo hypoglycemic activity results revealed that compounds 4c, 4h, and 4n exhibited good activity at 35 mg/kg body weight. Chronic toxic study results indicated that compounds 4h and 4n exhibited good activity at 70 mg/kg body weight. Anti-inflammatory activity results indicated the highest inhibition was shown by compounds 4k and 4f at 500 μg/mL in HRBC membrane stabilization. In protein denaturation, the highest inhibition was shown by compound 4k at 500 μg/mL. In molecular docking studies, compounds 4h and 4n exhibited higher binding affinity at PPARγ receptor protein and compound 4k exhibited higher binding affinity at COX-1 and COX-2 actives sites.ConclusionMicrowave irradiation produced high yield in short reaction times. The presence of electron releasing groups at the para position of the phenyl ring may give the ability to produce hypoglycemic activity and the presence of electron withdrawing groups at the para position of the phenyl ring causes anti-inflammatory activity. The results showed that some compounds exhibited good hypoglycemic and anti-inflammatory activities. Compounds 4h and 4n exhibited higher binding affinity at PPARγ receptor protein and compound 4k exhibited higher binding affinity at COX isoenzymes' active sites in molecular docking studies.

Dataset Information

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

Publications

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

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