The synthesis and chemical oxidation profile of a new generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular, the hydroxypropyl derivative HO(CH2 )3 C(Fc)=C(C6 H4 OH)2 (3 b) exhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA-MB-231 TNBC, with IC50 values of 0.07 and 0.11 μM, respectively. Chemical oxidation of 3 b yielded an unprecedented tetrahydrofuran-substituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH3 CH2 -C(Fc)=C(C6 H4 OH)2 merely formed a vinyl QM. The ferrocenyl group in 3 b plays a key role, not only as an intramolecular reversible redox "antenna", but also as a stabilized carbenium ion "modulator". The presence of the oxygen heterocycle in 3 b-QM enhances its stability and leads to a unique chemical oxidation profile, thus revealing crucial clues for deciphering its mechanism of action in vivo.

Ferrociphenols,especially those possessing aheterocycle at the terminus of an aliphatic chain, displays trong anticancer activity through an ovel redox mechanismt hat generates active metabolites such as quinone methides (QMs). X-ray crystallography and UV/Vis spectroscopyreveal that the specific lone pair (lp)-p interaction between acarbonyl group of the imide and the quinone motif of the QM plays an important role in the exceptional cytotoxic behaviour of their imido-ferrociphenol precursors.T his intramolecular lp-p interaction markedly enhanced the stability of the QMs and lowered the pK a values of the corresponding phenol/phenolate couples.Asthe first example of such anon-covalent interaction that stabilizes QMs remotely,itn ot only expands the scope of the lp-p interaction in supramolecular chemistry,b ut also represents an ew mode of stabilization of aQ M. This unprecedented application of lp-p interactions in imidoferrociphenol anticancer drug candidates maya lso have great potential in drug discovery and organocatalyst design.With the goal of circumventing the drawbacks [1] associated with the widely used coordination complexes of Pt 2+ , transition-metal bioorganometallic chemistry has gradually come to the fore. [2] Antitumor agents based on iron, an abundant and inexpensive metal, occupy ap rivileged position, and mostly feature ferrocene,acompact, stable,n ontoxic metallocene showing reversible redox properties. [3] We have investigated the possible use of ferrocenes in oncology in the so-called ferrocifen family (Figure 1a), such as compounds 1 and 2,w hose IC 50 values against triple-negative breast cancer (TNBC) cell lines (MDA-MB-231) are 0.6 and 0.5 mm,r espectively.T hese singular entities possess ar edox motif of the ferrocenyl-ene-phenol type,g iving rise to reactive oxygen species (ROS) in cancer cells.T he initial reversible oxidation of the ferrocenyl antenna permits electronic delocalization, leading selectively to electrophilic quinone methides (QMs,see below), which induce senescence and/or apoptosis,d epending on the particular parameters. [3a] Functionalization of the alkyl chain of 1 by attaching aterminal hydroxy substituent [4] or aheterocyclic group, [5] as in 3 or 4,resulted in extremely low IC 50 values (0.035 mm)on TNBC MDA-MB-231 cells;m oreover,f or the epithelial ovarian cancer cell line A2780 and the cisplatin-resistant species A2780cisR, the IC 50 values were 0.035 and 0.049 mm, respectively.T he first metabolite obtained either in the chemical (Ag + )o re nzymatic oxidation of 1 in cancer cells is the quinone methide 1-QM (Figure 1a), which can react in a1 ,8-Michael addition with selective nucleophiles in the cancer cells. [6] Them echanism of action of 4 may follow asimilar pathway to that of 1.Thelone pair-p (lp-p)interaction, depicted schematically in Figure 1b,r efers to the stabilizing association between al one pair of electrons and the face of a p system. First invoked in 1995 for the stabilization of Z-DNA, [7] it is now widely recognised as anew supramolecul...