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

The 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 (1 is far more cytotoxic than 2). 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 that 1 and 2 are both efficient inhibitors of thioredoxin reductase (TrxR) in vitro after oxidation by a horseradish peroxidase/H O system. However, as 1 is only a moderate inhibitor of TrxR in MDA-MB-231 cells, TrxR is probably not the major target responsible for the cytotoxicity of 1. In terms of differences, we noted that 1 induced a significant redox imbalance characterised by lipid peroxidation and thiol oxidation, and a moderate decrease of the mitochondrial membrane potential in breast cancer cells, whereas 2 has almost no effect. These results underline the importance of the trans configuration in the ferrocenyl-double bond-phenol motif, which is present in 1 but is cis in (Z)-2.