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

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

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Pages (from-to)1882-1892
Number of pages11
JournalChemMedChem
Volume12
Issue number22
DOIs
StatePublished - Nov 22 2017
Externally publishedYes

Funding

This work was supported financially by the National Science Centre Poland (NCN) based on the decision DEC-2012/05/B/ST5/ 00300. A.M. and S.P. also thank the NCN for financial support, (decision DEC-2012/04/A/ST5/00609), which enabled X-ray structural analysis of the compounds.

Keywords

  • ABCB1
  • anticancer agents
  • ferrocenyl taxanes
  • reactive oxygen species
  • tubulin polymerization

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