Functionalized Tri- and Tetraphosphine Ligands as a General Approach for Controlled Implantation of Phosphorus Donors with a High Local Density in Immobilized Molecular Catalysts

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

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

Highly Functionalized Ferrocenes

International audienceFerrocene is unique among organometallic compounds, and serves notably as a versatile platform towards the production of ligands useful to promote transition metals chemistry. A general limiting aspect of the synthesis of ferrocene derivatives is the efficient access to sophisticated highly functionalized polysubstituted ferrocenes, i. e. bearing four or more substituents replacing hydrogen atoms on the cyclopentadienyl rings. These ferrocene derivatives can bear various functional or/and structuring spectator substituents. Their preparation involves synthetic difficulties resulting from the need of multiple functionalizations coexisting altogether, and satisfying functional group compatibility and high selectivity issues. In the last decades, our group initially designed highly functionalized polyphosphines and hybrid ligands (1,1',3,3'-tetrafunctionalized Fc) using dialkylated 1,1'-tert-butylferrocene as a scaffold, which opened the way to various new classes of hybrid compounds. Some of these original ferrocenes were used as ligands, promoting metal catalysed C–C and C–X bond formation (X = O, S, N, etc.). Thus, highly functionalized ferrocenes, which include notably (P,P,P,P)-, (P,P,N,N)-, (P,P,P')-, (P,P,B)-, (P,B)- and (N,B)-compounds were developed in which the heteroatoms coexist in a close proximity on a common ferrocene platform with a controlled conformation. The present review details the concepts attached to the synthesis of these highly functionalized ferrocene species, and illustrates their main features and applications related to organometallic chemistry directed towards organic synthesis by metal catalysis