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Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in
Wesam Ali1, Sabrina Garbo2, Annamária Kincses3
1Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, 30-688, Kraków, Poland; Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany.
Abstract:
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 (IC50: 16.73 μM) as well as concerning the antiproliferative effect (IC50: 5.35 μM) in MDR cells. Regarding the mechanistic studies looking at the cell cycle, the thioether 15 and selenium derivatives 26 and 29 were significantly effective in the regulation of cell cycle-related genes alone or in co-treatment with doxorubicin counteracting Cyclin D1 and E1 expression and increasing p53 and p21 levels, shedding first light on their mechanism of action. In summary, we explored the chemical space of seleno- and thioether 1,3,5-triazine derivatives with interesting activity against lymphoma. Especially compound 15 is worthy of being studied deeper to evaluate its precise mode of action further as well it can be improved regarding its potency and drug-likeness.
Insights
Novel seleno- and thioether 1,3,5-triazine derivatives show potential against multidrug resistance (MDR) in lymphoma. Compound 15 effectively inhibits ABCB1 transporters and exhibits significant cytotoxic and antiproliferative effects in resistant lymphoma cells.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Lymphomas remain challenging to treat due to multidrug resistance (MDR).
- P-glycoprotein (P-gp/ABCB1) is a key transporter in tumor MDR, mediating drug efflux.
- Modulators of P-gp are sought for innovative cancer therapies, but none are approved.
Purpose of the Study:
- To design, synthesize, and evaluate novel seleno- and thioether 1,3,5-triazine derivatives for activity against human JURKAT lymphoma cells.
- To investigate the potential of these compounds as modulators of P-gp/ABCB1.
- To assess their cytotoxic and antiproliferative effects in drug-sensitive and drug-resistant lymphoma cell lines.
Main Methods:
- Synthesis and structural analysis of 30 novel seleno- and thioether 1,3,5-triazine derivatives.
- In vitro evaluation of ABCB1 inhibitory activity using P-gp ATPase assays.
- Docking studies to elucidate the mode of action.
- Quantitative PCR (qPCR) to assess gene expression changes (ABCB1, ABCC1, ABCG2).
- Cytotoxicity and antiproliferative assays (IC50 determination) in sensitive and MDR lymphoma cell lines.
- Cell cycle analysis and assessment of cell cycle-related gene expression.
Main Results:
- Four derivatives (11, 12, 13, 23) showed potent ABCB1 inhibition at 2 μM; compounds 5 and 15 were potent at 20 μM.
- Compound 15 demonstrated competitive substrate inhibition of P-gp ATPase activity and induced ABCB1, ABCC1, and ABCG2 gene expression.
- Compound 15 exhibited the best cytotoxic (IC50: 16.73 μM) and antiproliferative (IC50: 5.35 μM) effects in MDR cells.
- Compounds 15, 26, and 29 modulated cell cycle-related genes, counteracting Cyclin D1/E1 and increasing p53/p21 levels, particularly in combination with doxorubicin.
Conclusions:
- Seleno- and thioether 1,3,5-triazine derivatives represent a promising chemical class for targeting lymphoma.
- Compound 15 shows significant potential as an ABCB1 inhibitor and anti-lymphoma agent.
- Further studies are warranted to optimize compound 15 for potency and drug-likeness and to fully elucidate its mechanism of action.
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