Synthesis and Biological Activity of Ferrocenyl and Ruthenocenyl Analogues of Etoposide: Discovery of a Novel Dual Inhibitor of Topoisomerase II Activity and Tubulin Polymerization

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.

Design, Synthesis, and Evaluation of Biological Activity of Ferrocene‐Ispinesib Hybrids: Impact of a Ferrocenyl Group on the Antiproliferative and Kinesin Spindle Protein Inhibitory Activity

“…Using a two‐step approach described previously, [19] we evaluated the antiproliferative activity of both the ( R )‐ and ( S )‐ enantiomers at a fixed concentration, i. e., equal to the IC 50 value for ispinesib ( R )‐ 1 and ( S )‐ 1 for the respective cell lines (Figure 2).…”

“…[18] The presence of an organometallic group in podophyllotoxin aminoconjugates was responsible for revealing dual inhibitory properties affecting both tubulin polymerization and topoisomerase II activity. [19] Furthermore, replacing a phenyl group in cytotoxic plinabulin with a ferrocenyl moiety led to compounds capable of circumventing multidrug resistance caused by overexpression of ABCB1 and ABCG2 proteins. [20] We have shown that conjugating a ferrocenyl substituent to monastrol resulted in higher antiproliferative and KSP inhibitory activity.…”

“…Moreover, in the case of ferrocenyl analogues of paclitaxel, a significantly increased ability to induce tubulin polymerization was observed compared to the parent compound [18] . The presence of an organometallic group in podophyllotoxin aminoconjugates was responsible for revealing dual inhibitory properties affecting both tubulin polymerization and topoisomerase II activity [19] . Furthermore, replacing a phenyl group in cytotoxic plinabulin with a ferrocenyl moiety led to compounds capable of circumventing multidrug resistance caused by overexpression of ABCB1 and ABCG2 proteins [20] .…”

Ferrocenyl Azoles: Versatile N‐Containing Heterocycles and their Anticancer Activities

“…The triazoles 457 , 459 – 461 did not inhibit the tubulin polymerization and the cell cycle phase distribution in SW620 and SW620E cells [99a] . The etoposide triazole 464 , have shown less cytotoxicity (IC 50 : SW620=2.40 μM, SW620E: 87.2 μM and SW620M: 4.13 μM) than the parent drug, etoposide 454 ( IC 50 : SW620=1.39 μM, SW620E: 50.6 μM and SW620 M: 14.1 μM) [99b] . The triazoles 462 – 464 , have decreased the population of SW620 cells in the G0/G1 phase and increased their fraction in the G2/M and subG1 phases.…”

Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib – impact of the organometallic group on the antimitotic activity

“…The presence of an organometallic moiety may also increase the ability of the compound to generate reactive oxygen species (ROS), which are detrimental to the cell, 40,41 or lead to highly active anticancer agents with a multimodal mechanism of activity. [42][43][44][45][46] We and others have recently demonstrated that Rh and Ir half-sandwich complexes derived from 2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one exhibit a higher KSP inhibitory activity than the ligand itself 47 while the Ru half sandwich complexes derived from monastrol showed low activity. 48 Also, conjugating a ferrocenyl moiety with monastrol positively impacted the cytotoxicity and KSP inhibitory activity.…”