Synthesis and in vitro Biological Evaluation of Ferrocenyl Side‐Chain‐Functionalized Paclitaxel Derivatives. (2nd November 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: ChemMedChem. Volume 12:Number 22(2017)
• Page Start: 1882
• Page End: 1892
• Publication Date: 2017-11-02
• Subjects: ABCB1 -- anticancer agents -- ferrocenyl taxanes -- reactive oxygen species -- tubulin polymerization; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700576
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Fortified with iron : Two series of ferrocenyl‐decorated paclitaxels were synthesized, and their anticancer properties were studied. The cytotoxic activity of these compounds depends strongly on the position of the ferrocenyl group, with N ‐benzoyl‐substituted compounds6 a –d being the most active. Substitution of a 3′‐phenyl group with a ferrocenyl moiety (in13 b and13 c ) leads to compounds that are able to overcome multidrug resistance, as they are virtually unrecognized by ABCB1.