Synthesis and Biological Activity of Ferrocenyl and Ruthenocenyl Analogues of Etoposide: Discovery of a Novel Dual Inhibitor of Topoisomerase II Activity and Tubulin Polymerization
Karolina Chrabąszcz, Andrzej Błauż, Martyna Gruchała, Marcin Wachulec, Błażej Rychlik, Damian Plażuk
Abstract
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 IC 50 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.