Ferrocenyl Paclitaxel and Docetaxel Derivatives: Impact of an Organometallic Moiety on the Mode of Action of Taxanes

Abstract

A series of ferrocenyl analogues and derivatives of paclitaxel and docetaxel were synthesised and assayed for their antiproliferative/cytotoxic effects, impact on the cell cycle distribution and ability to induce tubulin polymerisation. The replacement of the 3'-N-benzoyl group of paclitaxel with a ferrocenoyl moiety, in particular, led to formation of an analogue that was at least one order of magnitude more potent in terms of antiproliferative activity than the parent compound (IC50 values of 0.11 versus 1.11 μm, respectively), but still preserved the classical taxane mode of action, that is, microtubule stabilisation leading to mitotic arrest. Molecular docking studies revealed an unexpected binding pocket in the tubulin structure for the ferrocenoyl group introduced in the paclitaxel backbone.

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

“…In general, the N ‐benzoyl‐substituted compounds were the most active against all the cell lines studied. This indicates the impact of a single substitution of the N ‐benzoyl group with a ferrocenoyl moiety, as earlier demonstrated in other cases . Additionally, it became apparent that the spatial positioning of the ferrocenyl group at the side chain of paclitaxel impacts the biological properties as m ‐substituted 6 c was more active than p ‐substituted 6 d .…”

“…All other compounds were much weaker polymerization promotors unable to induce tubulin polymerization even at high concentrations. Earlier studies suggested that the higher cytotoxic activity of compound 6 a relative to 1 is based on its higher potency to promote tubulin polymerization …”

“…Chemicals and solvents (HPLC grade) were purchased from Sigma–Aldrich and used as received. Compound 6 a was synthesized as described previously . 1D ( 1 H, 13 C{ 1 H} and 13 C DEPT 135) and 2D ( 1 H– 1 H COSY, 1 H– 13 C HSQC, 1 H– 13 C HMBC) NMR spectra were recorded on a Bruker ARX 600 MHz (spectrometer frequency 600.3 MHz for 1 H and 150.9 MHz for 13 C).…”

“…(3 R ,4 S )‐ N ‐(2‐Ferrocenylbenzoyl)‐3‐triethylsilyloxy‐4‐phenylazetidin‐2‐one ( 3 b ) was prepared in 67 % yield (640 mg) following a published procedure starting from 800 mg (2.6 mmol) of 2‐ferrocenylbenzoic acid ( 2 b ), 1.05 g (8.28 mmol) of oxalyl chloride, 470 mg (1.69 mmol) of (3 R ,4 S )‐3‐triethylsilyloxy‐4‐phenylazetidin‐2‐one and 607 mg (6.0 mmol) of triethylamine. The crude product was purified on silica using n ‐hexane/ethyl acetate (4:1).…”

“…We have previously reported that the incorporation of a ferrocenoyl moiety instead of an N ‐benzoyl group in a side chain of paclitaxel significantly increased its cytotoxicity and ability to induce tubulin polymerization and, consequently, apoptosis . Based on these promising results, the influence of the ferrocenyl moiety on the biological properties of paclitaxel was studied here in detail.…”