The influence of phenolic hydroxy substitution on the electron transfer and anti-cancer properties of compounds based on the 2-ferrocenyl-1-phenyl-but-1-ene motif

Abstract

The ferrocenyl compound 2-ferrocenyl-1,1-bis(4-hydroxyphenyl)-but-1-ene (3), is very cytotoxic against breast cancer cells (IC₅₀ = 0.44 µM against MDA-MB-231). We now report the synthesis of a new series of para- and meta- substituted mono- and di- ferrocenyl phenols [2-ferrocenyl-1-(3-hydroxyphenyl)-1-phenyl-but-1-ene (6), 2-ferrocenyl-1-(3-hydroxyphenyl)-1-(4-hydroxyphenyl)-but-1-ene (7), 1,2-di-ferrocenyl-1-(4-hydroxyphenyl)-but-1-ene (8), and 1,2-di-ferrocenyl-1-(3-hydroxyphenyl)-but-1-ene (9)] and their electrochemical and biochemical properties, especially in comparison to the previously reported “standard” compounds [2-ferrocenyl-1-(4-hydroxyphenyl)-1-phenyl-but-1-ene (2) and (3)]. We also report the synthesis and characterization of the diphenyl analogue, 2-ferrocenyl-1,1-diphenyl-but-1-ene (5). This structure–activity relationship study was motivated by our hypothesis that the cytotoxicity of 3 is related to its ability to form a quinone methide structure after two in situ 1-electron oxidations, a process which requires the presence of at least one p-phenol. The mono-ferrocenyl compounds (including those previously reported) are reasonably well recognized by the oestrogen receptors α (RBAs = 0.9–9.6%) and β (RBAs = 0.28–16.3%), although the bulkier di-ferrocenyl compounds show very little affinity. In vitro, the cytotoxic effects of the phenolic complexes are related to the positioning of the hydroxyl group (para- superior to meta-), and to the number of ferrocenyl groups (one superior to two), with IC₅₀ values against the MDA-MB-231 cell line ranging from 0.44–3.5 µM. On the hormone-dependent breast cancer cell line MCF-7, the observed effect seems to be the result of two components, one cytotoxic (antiproliferative) and one estrogenic (proliferative). Electrochemical studies show that only the compounds with a p-phenol engage in proton-coupled intramolecular electron transfer.