Synthesis and in vitro Biological Evaluation of Ferrocenyl Side‐Chain‐Functionalized Paclitaxel Derivatives

Abstract

Taxanes, including paclitaxel, are widely used in cancer therapy. In an attempt to overcome some of the disadvantages entailed with taxane chemotherapy, we devised the synthesis of ferrocenyl-functionalized paclitaxel derivatives and studied their biological properties. The cytotoxic activity was measured with a panel of human cancer cell lines of various tissue origin, including multidrug-resistant lines. A structure-activity study of paclitaxel ferrocenylation revealed the N-benzoyl-ferrocenyl-substituted derivative to be the most cytotoxic. In contrast, substitution of the 3'-phenyl group of paclitaxel with a ferrocenyl moiety led to less potent antiproliferative compounds. However, these agents were able to overcome multidrug resistance, as they were virtually unrecognized by ABCB1, a major cellular exporter of taxanes. Interestingly, the redox properties of these ferrocenyl derivatives appear to play a less important role in their mode of action, as there was no correlation between intracellular redox activity and cytotoxicity/cell-cycle distribution. The antiproliferative activity of ferrocenyl taxanes strongly depends on the substitution position, and good tubulin polymerization inducers, as confirmed by molecular docking, were usually more cytotoxic, whereas compounds with stronger pro-oxidative properties exhibited lower antiproliferative activity.

Colchicine metallocenyl bioconjugates showing high antiproliferative activities against cancer cell lines

“…4f, 15 We have previously demonstrated that even though ferrocenyl paclitaxel analogues are able to stimulate intracellular reactive oxygen species (ROS) production, the redox effects are not as important for their biological activity as their ability to bind tubulin. 16 We have been intrigued, however, by the differential effects exerted by the investigated colchicine analogues on the cells of different tissue origins (see Table 1). It seems plausible that cells derived from organs that are metabolically active or continuously exposed to reactive oxygen species such as liver 17 or lungs 18 and thus producing higher amounts of glutathione and other antioxidant barrier elements are less sensitive to redox active compounds.…”

“…C 16 H 18 ORuSi requires C, 54.1; H, 5.1%; IR (KBr) ν max /cm −1 : 3237m, 3110m, 3098m, 2959s, 2900m, 2168m, 2159m, 1629vs, 1590m, 1505w, 1448vs, 1411s, 1392s, 1372vs, 1350m, 1268vs, 1249vs, 1213w, 1102s, 1083vs, 1021s, 1004vs, 894vs, 847vs, 819vs, 761s, 752s, 725s, 705m, 632s, 569m, 482s, 423m; ESI-MS calc. for C 16 3285m, 3106m, 3090s, 2945m, 2922w, 2905w, 2115m, 1683vs, 1637m, 1456vs, 1426m, 1406s, 1396s, 1477s, 1261vs, 1225m, 1187w, 1098s, 1084vs, 1041w, 1029s, 995s, 980s, 904w, 893w, 863m, 843m, 833m, 815vs, 645vs, 606vs, 544m, 530s : 3256vs, 3086s, 2948m, 2939m, 2919m, 2904m, 2869m, 2360w, 2343w, 1671vs, 1453s, 1409s, 1393m, 1379s, 1357m, 1303m, 1290w, 1524s, 1213m, 1101s, 1096m, 1050m, 1026m, 1000m, 982m, 892m, 876w, 869w, 821s, 787w, 752w, 684s, 525w, 514m, 460s, 434s, 418m; ESI-MS calc. for C 17 H 18 ORu 340.0 (M + ) found 341.0 ((M + H) + , 100%); 1 H NMR (CDCl 3 ) δ 5.10 (t, J = 1.7 Hz, 2H, Cp), 4.77 (t, J = 1.…”

Polyphenol Extract from Evening Primrose (Oenothera paradoxa) Inhibits Invasion Properties of Human Malignant Pleural Mesothelioma Cells

“…The cell cycle analysis was performed as described previously [33]. Briefly, exponentially growing cells were treated with EPE at the desired concentration for 24 h. Then, cells were harvested by trypsinization, washed twice in ice-cold PBS, and fixed in 70% ethanol.…”

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

“…The last decades have brought huge progress in the development of new metallocenyl, mainly ferrocenyl and to al esser extent ruthenocenyl, conjugates with various types of bioactive compounds. [27] Recently,w ea nd others reported the synthesis andb iological activity of ferrocenyl conjugates acting as microtubule stabilizing [28] or destabilizing [29] agents. Metallocenyl conjugates with other tubulin-binding molecules were also studied.…”