Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, ul. Tamka 12, 91403, Łódź, Poland.
Cytometry Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, 90236, Łódź, Poland.
Chemistry. 2021 Apr 7;27(20):6254-6262. doi: 10.1002/chem.202005133. Epub 2021 Mar 5.
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 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.
我们合成了两个系列的依托泊苷的偕二茂铁基和偕钌基类似物，带有 1,2,3-三唑基或氨基烷基连接体，并评估了它们的细胞毒性、对细胞周期的影响、诱导微管蛋白聚合的能力以及抑制拓扑异构酶 II 活性。我们发现，用金属茂基取代依托泊苷的糖部分会导致金属有机缀合物表现出不同的抗增殖活性。生物学研究表明，两个偕二茂铁基烷基氨基缀合物比依托泊苷更具活性，对 SW620、依托泊苷耐药的 SW620E 和氨甲喋呤耐药的 SW620M 癌细胞系的 IC 值均为亚微摩尔或低微摩尔。此外，最简单的偕二茂铁基甲基氨基缀合物对微管蛋白聚合和拓扑异构酶 II 活性具有双重抑制作用，而其他研究的化合物仅影响拓扑异构酶 II 活性。
