Pursuing our exploration on anticancer activity of organometallic tamoxifen derivatives, we have synthesized a series of hybrid complexes resulting from the substitution of ferrocifen (FcTAM) side chain with SAHA, a histone-deacetylase inhibitor (HDACi) used in the treatment of certain lymphomas. From FcTAM-SAHA hybrid, five types of modifications have been performed. They are [1] modification of the hydroxamic acid function (CONHOH) with a primary amide (CONH2) and a carboxylic acid (COOH), [2] variation of the side chain length, [3] with or without an aromatic substituent, [4] substitution of the metallocene and [5] substitution of the ferrocenyl unit with a phenyl group. The antiproliferative effects of the new complexes have been studied on two breast cancer cell lines, MDA-MB-231 (hormone-independent and triple-negative cell line) and MCF-7 (hormone-dependent cell line). A synergistic effect of the toxicity was observed in series FcTAM-SAHA on both cell lines. Surprisingly, no increase in toxicity was observed in the phenolic (FcOHTAM-SAHA-type) and in ferrocenophane (FnTAM-SAHA-type) hybrids. This observation suggests that the redox properties of the molecules are not expressed in the same way for precursors and hybrid compounds. In general, the hydroxamic acids and primary amides are more cytotoxic than carboxylic acids and these effects are not influenced by the length of the side chain. Finally, we found that the ferrocenic compounds are always more cytotoxic than their organic analogs. This difference highlights the importance of the presence of the ferrocenic moiety associated with its unique redox properties.
