Click 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 moiet...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2367139 |
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| author | Jiří Řehulka Michal Jurášek Pavel Dráber Aleksandra Ivanová Soňa Gurská Kateřina Ječmeňová Olena Mokshyna Marián Hajdúch Pavel Polishchuk Pavel B. Drašar Petr Džubák |
| author_facet | Jiří Řehulka Michal Jurášek Pavel Dráber Aleksandra Ivanová Soňa Gurská Kateřina Ječmeňová Olena Mokshyna Marián Hajdúch Pavel Polishchuk Pavel B. Drašar Petr Džubák |
| author_sort | Jiří Řehulka |
| collection | DOAJ |
| description | 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 = 0.38 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 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. |
| format | Article |
| id | doaj-art-c6ffcd1be2c54765a90525facd8c6a33 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-c6ffcd1be2c54765a90525facd8c6a332025-08-20T02:35:33ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2367139Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluationJiří Řehulka0Michal Jurášek1Pavel Dráber2Aleksandra Ivanová3Soňa Gurská4Kateřina Ječmeňová5Olena Mokshyna6Marián Hajdúch7Pavel Polishchuk8Pavel B. Drašar9Petr Džubák10Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech RepublicDepartment of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Praha 6, Czech RepublicDepartment of Biology of Cytoskeleton, Institute of Molecular Genetics of the Czech Academy of Sciences, Praha 4, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech RepublicDepartment of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Praha 6, Czech RepublicInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Olomouc, Czech RepublicEstradiol 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 = 0.38 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 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.https://www.tandfonline.com/doi/10.1080/14756366.2024.2367139Estradioldimertubulincancer cellin silico |
| spellingShingle | Jiří Řehulka Michal Jurášek Pavel Dráber Aleksandra Ivanová Soňa Gurská Kateřina Ječmeňová Olena Mokshyna Marián Hajdúch Pavel Polishchuk Pavel B. Drašar Petr Džubák Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation Journal of Enzyme Inhibition and Medicinal Chemistry Estradiol dimer tubulin cancer cell in silico |
| title | Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation |
| title_full | Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation |
| title_fullStr | Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation |
| title_full_unstemmed | Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation |
| title_short | Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation |
| title_sort | click estradiol dimers with novel aromatic bridging units synthesis and anticancer evaluation |
| topic | Estradiol dimer tubulin cancer cell in silico |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2367139 |
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