Synthesis and antiproliferative activity of hydroxyferrocifen hybrids against triple-negative breast cancer cells

We have recently shown that the combination of chemical motifs of vorinostat (SAHA) and ferrocifen (FcTAM) in the single FcTAM–SAHA hybrid produced beneficial effects in terms of antiproliferative activity of both agents against cancer cells. Since hydroxylation of FcTAM to form hydroxyferrocifen (FcOHTAM) improves the biological response, we explore in this work the anticancer effects of a new family of hybrid phenolic compounds bearing some molecular features of FcOHTAM, OHTAM and SAHA. Results concerning their cytotoxicity on both triple-negative MDA-MB-231 and hormone-dependent MCF-7 breast cancer cells are reported here. Organometallic compounds showed better antiproliferative activities than organic analogs. For instance, FcOHTAM–SAHA (IC50 = 1.5 μM) was around seven times more active than OHTAM–SAHA (IC50 = 10.9 μM) against MCF-7 cells. In the case of triple-negative MDA-MB-231 cells, the IC50 values for ferrocene compounds are in the range of 1.3–4.5 μM and those for organic derivatives are 5.2–34.5 μM. Studies concerning the isomerization and redox behaviors of these compounds are also presented. Despite the potential of FcOHTAM–SAHA to exhibit ex cellulo redox activation, it seems that this feature is not completely expressed in cellulo. This surprising behavior is related to the driving effect of the side chain to direct the new constructs to different targets.