Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides

Abstract

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.

Atypical Lone Pair–π Interaction with Quinone Methides in a Series of Imido‐Ferrociphenol Anticancer Drug Candidates

“…[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. [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. [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.…”

“…[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.…”

Selective cytotoxicity of arene tricarbonylchromium towards tumour cell lines

“…The complexes of Fe [20][21][22][23], Ru [24][25][26], Os [27,28] and Ag [29] have been found to be very active against cancer cells. Arene tricarbonylchromium group, for which the oxidation state of chromium is zero, has been attached to biological substances such as β-estradiol molecule to produce complexes that have been mainly studied for their capacity to act as a probe for the detection of biological substances by infrared spectroscopy [30].…”

Electrochemical transformations and evaluation of antioxidant activity of some Schiff bases containing ferrocenyl and (thio‐)phenol, catechol fragments

“…Ferrocifens are family of compounds with redox motif [ferrocene‐ene‐phenol] which can be selectively activated in cancer cells. Ferrocifens are considered as pro‐drugs which activate during the oxidation of ferrocenyl fragment . The oxidized forms of these compounds can operate via different mechanisms of cytotoxic action including apoptosis and senescence induction, ROS generation, forming quinomethide structures …”