Functionalized ferrocenes: The role of the para substituent on the phenoxy pendant group

•The para substituent on ferrocene esters influences the anti-proliferative activity.•1H-pyrrol-1-yl substituent yields highly active species in cancerous and normal cells.•Docking studies between the ferrocene esters and ERα investigated.•4-Bromophenyl ferrocenecarboxylate has good anti-proliferative activity on MCF-7.

Six ferrocenecarboxylates with phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl as pendant groups were synthesized and fully characterized by spectroscopic, electrochemical and X-ray diffraction methods. The anti-proliferative activity of these complexes were investigated in hormone dependent MCF-7 breast cancer and MCF-10A normal breast cell lines, to determine the role of the para substituent on the phenoxy pendant group. The 4-fluorophenyl ferrocenecarboxylate is inactive in both cell lines while 4-(1H-pyrrol-1-yl)phenyl ferrocenecarboxylate is highly cytotoxic in both cell lines. 4-chlorophenyl and 4-bromophenyl ferrocenecarboxylates have moderate to good anti-proliferative activity in MCF-7 and low anti-proliferative activity on normal breast cell line, MCF-10A whereas the 4-iodophenyl analog is highly toxic on normal breast cell line. The phenyl ferrocenecarboxylate has proliferative effects on MCF-7 and is inactive in MCF-10A. Docking studies between the complexes and the alpha-estrogen receptor (ERα) were performed to search for key interactions which may explain the anti-proliferative activity of 4-bromophenyl ferrocenecarboxylate. Docking studies suggest the anti-proliferative activity of these ferrocenecarboxylates is attributed to the cytotoxic effects of the ferrocene group and not to anti-estrogenic effects.

Graphical abstract4-Bromophenyl and 4-iodophenyl ferrocenecarboxylates have the same type of interactions inside the estradiol binding pocket but their anti-proliferative properties are different. The anti-proliferative activity of 4-bromophenyl ferrocenecarboxylate is attributed to the redox behavior of ferrocene and not to anti-estrogenic effects.Figure optionsDownload full-size imageDownload as PowerPoint slide