Computer-aided search for 5-arylideneimidazolone anticancer agents able to overcome ABCB1-based multidrug resistance
| Autor: | Małgorzata Starek, Monika Dąbrowska, Gabriella Spengler, Gniewomir Latacz, Jadwiga Handzlik, Katarzyna Kucwaj-Brysz, Aneta Kaczor, Nikoletta Szemerédi |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
ATP Binding Cassette Transporter
Subfamily B Cell Survival In silico Tariquidar Antineoplastic Agents 01 natural sciences Biochemistry Rhodamine 123 Mice Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Drug Discovery Tumor Cells Cultured medicine Animals General Pharmacology Toxicology and Pharmaceutics Cytotoxicity Cell Proliferation Pharmacology Dose-Response Relationship Drug 010405 organic chemistry Organic Chemistry Imidazoles Drug Resistance Multiple 0104 chemical sciences Multiple drug resistance 010404 medicinal & biomolecular chemistry chemistry Drug Resistance Neoplasm Cancer cell Lipophilicity Computer-Aided Design Molecular Medicine Drug Screening Assays Antitumor Pharmacophore medicine.drug |
| Popis: | ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5-arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug-resistant (MDR) ABCB1-overexpressing T-lymphoma cancer cells using cytotoxicity assays. The ABCB1-modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp-Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP-TLC). Pharmacophore-based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents (p-fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T-lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1-modulating action; in particular, two 5-benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar. |
| Databáze: | OpenAIRE |
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