Synthesis and Biological Activity of Ferrocenyl and Ruthenocenyl Analogues of Etoposide: Discovery of a Novel Dual Inhibitor of Topoisomerase II Activity and Tubulin Polymerization |
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Authors: | Karolina Chrabąszcz Dr Andrzej Błauż Martyna Gruchała Marcin Wachulec Dr Błażej Rychlik Prof Damian Plażuk |
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Institution: | 1. Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, ul. Tamka 12, 91403 Łódź, Poland;2. Cytometry Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, 90236 Łódź, Poland |
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Abstract: | Two series of the ferrocenyl and ruthenocenyl analogues of etoposide bearing 1,2,3-triazolyl or aminoalkyl linker were synthesized and evaluated for their cytotoxic properties, influence on the cell cycle, ability to induce tubulin polymerization, and inhibition of topoisomerase II activity. We found that the replacement of the etoposide carbohydrate moiety with a metallocenyl group led to organometallic conjugates exhibiting differentiated antiproliferative activity. Biological studies demonstrated that two ferrocenylalkylamino conjugates were notably more active than etoposide, with submicromolar or low-micromolar IC50 values towards SW620, etoposide-resistant SW620E, and methotrexate-resistant SW620M cancer cell lines. Moreover, the simplest ferrocenylmethylamino conjugate exerted dual inhibitory action against tubulin polymerization and topoisomerase II activity while other studied compounds affected only topoisomerase II activity. |
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Keywords: | cancer cytotoxicity dual inhibitors metallocenes drug discovery |
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