0587162 - ÚMG 2025 RIV GB eng J - Journal Article
Řehulka, J. - Jurášek, M. - Dráber, Pavel - Ivanová, A. - Gurská, S. - Ječmenová, K. - Mokshyna, Olena - Hajdúch, M. - Polishchuk, P. - Drašar, P. B. - Džubák, P.
Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation.
Journal of Enzyme Inhibition and Medicinal Chemistry. Roč. 39, č. 1 (2024), s. 2367139. ISSN 1475-6366. E-ISSN 1475-6374
R&D Projects: GA MŠMT LM2023052; GA MŠMT(CZ) LM2023053; GA MŠMT LX22NPO5102
Institutional support: RVO:68378050 ; RVO:61388963
Keywords : estradiol dimers * EDs variants * structural modification
OECD category: Biochemistry and molecular biology
Impact factor: 5.6, year: 2023 ; AIS: 0.722, rok: 2023
Method of publishing: Open access
Result website:
https://www.tandfonline.com/doi/full/10.1080/14756366.2024.2367139DOI: https://doi.org/10.1080/14756366.2024.2367139

Estradiol dimers (EDs) possess significant anticancer activity by targeting tubulin dynamics. In this study, we synthesised 12 EDs variants via copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction, focusing on structural modifications within the aromatic bridge connecting two estradiol moieties. In vitro testing of these EDs revealed a marked improvement in selectivity towards cancerous cells, particularly for ED1-8. The most active compounds, ED3 (IC50=0.38muM in CCRF-CEM) and ED5 (IC50=0.71muM in CCRF-CEM) demonstrated cytotoxic effects superior to 2-methoxyestradiol (IC50=1.61muM in CCRF-CEM) and exhibited anti-angiogenic properties in an endothelial cell tube-formation model. Cell-based experiments and in vitro assays revealed that EDs interfere with mitotic spindle assembly. Additionally, we proposed an in silico model illustrating the probable binding modes of ED3 and ED5, suggesting that dimers with a simple linker and a single substituent on the aromatic central ring possess enhanced characteristics compared to more complex dimers.
Permanent Link: https://hdl.handle.net/11104/0354427