Side‐Chain Effects on the 1‐(Bis‐aryl‐methylidene)‐[3]ferrocenophane Skeleton: Antiproliferative Activity against TNBC Cancer Cells and Comparison with the Acyclic Ferrocifen Series

As part of our ongoing study of the toxicity of compounds derived from 1,1‐bis(4‐hydroxyphenyl)‐2‐ferrocenylbut‐1‐ene, we have recently shown that closely analogous [3]ferrocenophane complexes have an in vitro toxicity level substantially higher than that of their ferrocene counterparts, particularly in the case of mono‐ and diphenol complexes. In this study we have examined whether the presence of a dimethylamino chain, analogous to the chain in hydroxytamoxifen, is capable of producing in the ferrocenophane series the same antiestrogenic effect observed for OH‐Tam and Fc‐OH‐Tam. To this end, we have synthesized and characterized new complexes bearing various side‐chains [O(CH 2 ) 3 NMe 2 , O(CH 2 ) 3 piperidine, O(CH 2 ) 3 pyrrolidine, NHCO(CH 2 ) 2 NMe 2 ] and studied the biochemical properties of those complexes possessing appropriate solubility. The results revealed that the new complexes of [3]ferrocenophane have very strong antiproliferative effects; one of the compounds bearing an NHCO(CH 2 ) 2 NMe 2 chain has an IC 50 value of 0.05 ± 0.02 µ m for MDA‐MB‐231 breast cancer cells. All the complexes showed affinity for the estradiol receptor. At the low (nanomolar range) concentrations at which the estrogenic/antiestrogenic effect is expressed in these molecules, the presence of an amino‐substituted side‐chain does not induce in the [3]ferrocenophane series the antiestrogenic effect observed with OH‐Tam and Fc‐OH‐Tam. However, this effect has been found for the complex with a slightly longer chain [O(CH 2 ) 4 NMe 2 ].