Enzymatic oxidation of ansa-ferrocifen leads to strong and selective thioredoxin reductase inhibition in vitro

Abstract

This paper reports the inhibitory effect on the cytosolic thioredoxin reductase (TrxR1) in vitro by the ansa-ferrocifen derivative (ansa-FcdiOH, 1). We found that 1 decreased only slightly enzyme activity (IC=8μM), while 1*, the species generated by enzymatic oxidation by the HRP (horseradish peroxidase)/HO mixture, strongly inhibited TrxR1 (IC=0.15μM). At the same concentrations, neither 1 nor 1* had effect on glutathione reductase (GR). The most potent TrxR1 inhibitor did not appear to be the corresponding quinone methide as it was the case for ferrocifens of the acyclic series, or the stabilized carbocation as in the osmocifen series, but rather the quinone methide radical. This hypothesis was confirmed by ab-initio calculations of the species generated by oxidation of 1 and by EPR spectroscopy. BIAM (biotin-conjugated iodoacetamide) assay showed that 1* targeted both cysteine and selenocysteine of the C-terminal redox center of TrxR1.

Small Structural Differences between Two Ferrocenyl Diphenols Determine Large Discrepancies of Reactivity and Biological Effects

“…If the experiment was performed at pH 6.8, we observed the presence of the two bands (Figure S1, lower panel). This behaviour is reminiscent of that previously observed for the ansa‐ferrociphenol derivative 5 , which lets us conclude that enzymatic oxidation of 1 affords the corresponding QM in the anionic phenolate form 8 A at pH 8.1, the neutral phenolic form 8 B at pH 5.0 (Scheme ), or as a mixture of 8 A and 8 B at the intermediate pH 6.8.…”

Side‐Chain Effects on the 1‐(Bis‐aryl‐methylidene)‐[3]ferrocenophane Skeleton: Antiproliferative Activity against TNBC Cancer Cells and Comparison with the Acyclic Ferrocifen Series

“…The mechanistic particularity of 4, the most studied complex in the ferrocenophane series, has recently been disclosed and is associated with an active radical intermediate. [24] All the complexes in the series retain an affinity for the estrogen receptor, with only those of the acyclic ferrocenyl series expressing an antiestrogenic effect analogous to that of OHTam on hormone-dependent MCF-7 cells. This effect is not found in their analogues in the ferrocenophane series except for 14.…”

“…We recently showed that the enzymatic oxidation of 4, the most studied complex in the ferrocenophane series, leads to the formation of a transient short-lived species attributed to a quinone methide radical. [24] In contrast, the enzymatic oxidation of the ferrocenyl complexes 2 and 3 leads to the formation of quinone methides. [25] The reactivity of a quinone methide radical is expected to be higher than that of a quinone methide and could explain the higher cytotoxicity of the ferrocenophane complexes.…”

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 …”