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

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.