biostudies-literatureRehulka JNational Institute for Cancer ResearchCZ-OPENSCREENEATRIS-CZMinistry of Education, Youth and Sports of the Czech Republic through the e-INFRA CZEXCELESUCT Prague2367139https://www.ebi.ac.uk/biostudies/studies/S-EPMC467089biostudies-literatureUnknown39(1)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. <i>In vitro</i> testing of these EDs revealed a marked improvement in selectivity towards cancerous cells, particularly for ED1-8. The most active compounds, ED3 (IC₅₀ = 0.38 μM in CCRF-CEM) and ED5 (IC₅₀ = 0.71 μM in CCRF-CEM) demonstrated cytotoxic effects superior to 2-methoxyestradiol (IC₅₀ = 1.61 μM in CCRF-CEM) and exhibited anti-angiogenic properties in an endothelial cell tube-formation model. Cell-based experiments and <i>in vitro</i> assays revealed that EDs interfere with mitotic spindle assembly. Additionally, we proposed an <i>in silico</i> 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.Journal of enzyme inhibition and medicinal chemistryClick estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation.PMC467089A1_FPBT_2023_00390254LX22NPO5102LM2023052LM2023053IGA_LF_2024_038Ivanova AGurska SPolishchuk PRehulka JDrasar PBDraber PDzubak PJecmenova KHajduch MJurasek MMokshyna OfalseClick estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation.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. <i>In vitro</i> testing of these EDs revealed a marked improvement in selectivity towards cancerous cells, particularly for ED1-8. The most active compounds, ED3 (IC₅₀ = 0.38 μM in CCRF-CEM) and ED5 (IC₅₀ = 0.71 μM in CCRF-CEM) demonstrated cytotoxic effects superior to 2-methoxyestradiol (IC₅₀ = 1.61 μM in CCRF-CEM) and exhibited anti-angiogenic properties in an endothelial cell tube-formation model. Cell-based experiments and <i>in vitro</i> assays revealed that EDs interfere with mitotic spindle assembly. Additionally, we proposed an <i>in silico</i> 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.2024-01-01T00:00:00Z2024 Dec2026-04-29T12:12:19.215Z2025-04-06T17:10:50.957ZS-EPMC4670893890414910.1080/14756366.2024.2367139