Evidence for Targeting Thioredoxin Reductases with Ferrocenyl Quinone Methides. A Possible Molecular Basis for the Antiproliferative Effect of Hydroxyferrocifens on Cancer Cells

Abstract

Many anticancer compounds are strong inhibitors of thioredoxin reductases (TrxRs), selenoenzymes involved in cellular redox regulation. This study examined the effect of two hydroxyferrocifens (1, FcOH; 2, FcOHTAM) and of their corresponding quinone methides (QMs), 1-QM, and 2-QM, on these enzymes. In vitro, both QMs were more potent TrxR inhibitors (IC50 ≈ 2.5 μM) than the hydroxyferrocifens (IC50 ≈ 15 μM). This inhibition was due to a Michael addition of the penultimate selenocysteine residue of TrxRs to the QMs. In Jurkat cancer cells, both 2 and 2-QM inhibited TrxRs in the same proportion, leading to accumulation of oxidized forms of thioredoxin, while 1 and 1-QM were scarcely effective. This difference of behavior was ascribed to the competitive conversion of 1-QM to an inactive indene in protic medium. This set of experiments confirms for the first time the role played by ferrocenyl quinone methides on several biological targets and gives a molecular basis for these effects. It also highlights differences in the mechanisms of action of 1 and 2 in cancer cells.

Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

“…This may be related to a stabilization associated with the oxygen-donating mesomeric effect. A difference in the inhibition of TrxR activity has also been found in the ferrocifen series after incubation with Jurkat cells [32]. As here, the inhibition is more marked for the tamoxifen-like complex than for the phenolic, but it is not correlated with the antiproliferative effect of the complexes [32].…”

“…In addition, the UV-VIS spectra of 1* and 2*, the species obtained by treatment of 1 and 2 with HRP/H 2 O 2 , do not correspond to those of their quinone methides (Fig. 2) as it was the case in the ferrocifen series [32]. This result should also be viewed from the perspective of the recent observation that the electrochemical oxidation of 1 corresponds, in the presence of a base, to a 2-electron transfer but does not lead to the corresponding QM [26].…”

“…The recent study of thioredoxin reductases as possible targets of the ferrocifens has allowed new perspectives concerning their mechanism of action [32]. In the present paper, we examine the biological effects of two osmocifens, namely the monophenolic and the tamoxifen-like complexes 1 and 2, their oxidized derivatives obtained after enzymatic oxidation, and their corresponding quinone methides obtained by chemical oxidation (Chart 1).…”

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

“…[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. Substitution of the hydroxy chain of 4 by an amido chain gives access to 12, the most cytotoxic complex of the series.…”

Gold(I) NHC-based homo- and heterobimetallic complexes: synthesis, characterization and evaluation as potential anticancer agents

“…Thus, inhibition of TrxR by metal compounds has been shown to occur at the nanomolar to low micromolar level and this often correlates with their antiproliferative effects in vitro. The mechanism of inhibition essentially involves metal binding to the Sec residue at the TrxR C-terminus [36]. Two isoforms, a cytosolic (TrxR1) and a mitochondrial (TrxR2), are found in cells [37,38].…”