Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma
| Autor: | Wesam Ali, Sabrina Garbo, Annamária Kincses, Márta Nové, Gabriella Spengler, Elisabetta Di Bello, Ewelina Honkisz-Orzechowska, Tadeusz Karcz, Ewa Szymańska, Ewa Żesławska, Małgorzata Starek, Monika Dąbrowska, Wojciech Nitek, Katarzyna Kucwaj-Brysz, Patryk Pyka, Rossella Fioravanti, Claus Jacob, Cecilia Battistelli, Clemens Zwergel, Jadwiga Handzlik |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
03.03. Egészségtudományok Lymphoma Triazines Organic Chemistry Antineoplastic Agents 03.01. Általános orvostudomány General Medicine Sulfides Drug Resistance Multiple Neoplasm Proteins Mice Pharmaceutical Preparations Drug Resistance Neoplasm Cell Line Tumor Drug Discovery Animals Humans ATP Binding Cassette Transporter Subfamily G Member 2 |
| Popis: | Lymphomas are still difficult to treat even with modern therapies as, among others, multidrug resistance (MDR) is often counteracting a successful cancer therapy. P-gp/ABC-transporters are well-known for their crucial role in the main tumour MDR mechanism, eliminating drugs and cytotoxic substances from the cancer cell by efflux, and their modulators are promising for innovative therapy, but none has been approved in the pharmaceutical market yet. Herein, we have designed, synthesised and analysed 30 novel seleno- and thioether 1,3,5-triazine derivatives conducting comprehensive studies to evaluate their potential application in human JURKAT lymphoma cells. Among the new compounds, four (11, 12, 13 and 23) were much more effective than the reference inhibitor verapamil, being potent ABCB1 inhibitors already at 2 μM, while 5 and 15 showed very potent ABCB1 inhibitory activity only at 20 μM. Results of P-gp ATPase assays, supported with docking studies, indicated the competitive substrate mode of modulating action for 15, while ABCB1, ABCC1 and ABCG2 genes expression induction by 15 with q-PCR was confirmed. All compounds were evaluated for their cytotoxic and antiproliferative properties in both sensitive (PAR) and resistant (MDR) mouse T-lymphoma cell lines, and compound 15, also considering its promising ABCB1 inhibition properties, was revealed to be the best compound in terms of its cytotoxic effect (IC |
| Databáze: | OpenAIRE |
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