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

AbstractThe ferrocenyl diphenol complexes 1,1‐bis(4′‐hydroxyphenyl)‐2‐ferrocenyl‐but‐1‐ene (1) and 1,2‐bis(4′‐hydroxyphenyl)‐1‐ferrocenyl‐but‐1‐ene [(Z)‐2], which differ by the relative position of the two phenolic substituents, display dramatically different antiproliferative activities on cancer cells (1is far more cytotoxic than2). In this study, our goal was to discover the origin of this difference by comparing their reactivity and biological behaviour. In terms of common behaviour, we found that1and2are both efficient inhibitors of thioredoxin reductase (TrxR) in vitro after oxidation by a horseradish peroxidase/H2O2system. However, as1is only a moderate inhibitor of TrxR in MDA‐MB‐231 cells, TrxR is probably not the major target responsible for the cytotoxicity of1. In terms of differences, we noted that1induced a significant redox imbalance characterised by lipid peroxidation and thiol oxidation, and a moderate decrease of the mitochondrial membrane potential in breast cancer cells, whereas2has almost no effect. These results underline the importance of thetransconfiguration in the ferrocenyl–double bond–phenol motif, which is present in1but iscisin (Z)‐2.

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