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

Plażuk, Damian; Wieczorek, Anna; Ciszewski, Wojciech M.; Kowalczyk, Karolina; Błauż, Andrzej; Pawlędzio, Sylwia; Makal, Anna; Eurtivong, Chatchakorn; Arabshahi, Homayon J.; Reynisson, Jóhannes; Hartinger, Christian G.; Rychlik, Błażej

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.

Citation

Plażuk, D., Wieczorek, A., Ciszewski, W. M., Kowalczyk, K., Błauż, A., Pawlędzio, S., …Rychlik, B. (2017). Synthesis and in vitro Biological Evaluation of Ferrocenyl Side-Chain-Functionalized Paclitaxel Derivatives. ChemMedChem, 12(22), 1882-1892. https://doi.org/10.1002/cmdc.201700576

• Journal Article Type: Article
• Acceptance Date: Sep 21, 2017
• Online Publication Date: Sep 21, 2017
• Publication Date: Nov 22, 2017
• Deposit Date: Jun 13, 2023
• Journal: ChemMedChem
• Print ISSN: 1860-7179
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 22
• Pages: 1882-1892
• DOI: https://doi.org/10.1002/cmdc.201700576
• Keywords: Organic Chemistry; General Pharmacology, Toxicology and Pharmaceutics; Molecular Medicine; Drug Discovery; Biochemistry; Pharmacology