2-{5-[(Z,2Z)-2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl -3-methylbutanoic acid as a potential anti-breast cancer molecule
| Autor: | Kamila Buzun, Agnieszka Gornowicz, Roman Lesyk, Anna Kryshchyshyn-Dylevych, Andrzej Gzella, Robert Czarnomysy, Gniewomir Latacz, Agnieszka Olejarz-Maciej, Jadwiga Handzlik, Krzysztof Bielawski, Anna Bielawska |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Inorganic Chemistry
Organic Chemistry General Medicine 4-thiazolidinones breast cancer apoptosis autophagy anticancer agents chemotherapy topoisomerase inhibitor etoposide 3-MA ADME-Tox parameters Physical and Theoretical Chemistry Molecular Biology Spectroscopy Catalysis Computer Science Applications |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 8; Pages: 4091 |
| Popis: | It was established that the synthesis of hybrid molecules containing a thiazolidinone and a (2Z)-2-chloro-3-(4-nitrophenyl)prop-2-ene structural fragments is an effective approach for the design of potential anticancer agents. Given the results of the previous SAR-analysis, the aim of the study was to synthesize a novel 4-thiazolidinone derivative Les-3331 and investigate its molecular mechanism of action in MCF-7 and MDA-MB-231 breast cancer cells. The cytotoxic properties and antiproliferative potential of Les-3331 were determined. The effect of the tested compound on apoptosis induction and mitochondrial membrane potential was checked by flow cytometry. ELISA was used to determine caspase-8 and caspase-9, LC3A, LC3B, Beclin-1, and topoisomerase II concentration. Additionally, PAMPA, in silico or in vitro prediction of metabolism, CYP3A4/2D6 inhibition, and an Ames test were performed. Les-3331 possesses high cytotoxic and antiproliferative activity in MCF-7 and MDA-MB-231 breast cancer cells. Its molecular mechanism of action is associated with apoptosis induction, decreased mitochondrial membrane potential, and increased caspase-9 and caspase-8 concentrations. Les-3331 decreased LC3A, LC3B, and Beclin-1 concentration in tested cell lines. Topoisomerase II concentration was also lowered. The most probable metabolic pathways and no DDIs risk of Les-3331 were confirmed in in vitro assays. Our studies confirmed that a novel 4-thiazolidinone derivative represents promising anti-breast cancer activity. |
| Databáze: | OpenAIRE |
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