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)3C(Fc)=C(C6H4OH)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 CH3CH2‐C(Fc)=C(C6H4OH)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.

Heterogeneity of Response to Iron-Based Metallodrugs in Glioblastoma Is Associated with Differences in Chemical Structures and Driven by FAS Expression Dynamics and Transcriptomic Subtypes

“…Ferrocifens were prepared as described in the following publications: P15 [ 14 ], P5 [ 57 ], P85 [ 58 ], P41 [ 59 ], P53 [ 60 ], P722 [ 34 ]. Stock solutions (10 −3 M) of ferrocifens were prepared in DMSO.…”

A Novel Organometallic Rhenium Salt: DNA-Binding and Cytotoxicity Studies on Pancreatic, Breast and Lymphoma Cancers

“…Cytotoxicity of a few metal complexes against numerous pancreatic cancer cell lines are also known [40][41][42]. rhenium [18][19][20][21][22][23][24][25]44] and ferrocifen complexes [45][46][47].…”

A New Series of Succinimido-ferrociphenols and Related Heterocyclic Species Induce Strong Antiproliferative Effects, Especially against Ovarian Cancer Cells Resistant to Cisplatin

“…20 It was also superior to the tetrahydrofuran-substituted 2a-QM (t½ in acetone ~30 h), resulting from the oxidation of 2a. 26 These preliminary results have been obtained by oxidation using rat liver microsomes (containing cytochrome P450, to be published).…”

“…In all the early modifications of 1 the ethyl entity was left untouched and, when chains were modified, this occurred mostly on the phenol side. 13 It is only recently that we have begun to consider modification of the alkyl chain by attaching an OH group to the end, and we have obtained particularly low IC 50 values (IC 50 = 0.11 µM) with 2a on triple negative breast cancer cell lines (MDA-MB-231); 26 moreover, the bioactivity of their metabolites, all of which have been identified, was also evaluated. [27][28] Meanwhile a number of recent research projects have focused on biologically-oriented ferrocene compounds substituted by heterocyclic skeletons, including for example nucleobases, sugars or flavonoids.…”