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

摘要

The ferrocenyl compound 2-ferrocenyl-1,1-bis( 4-hydroxyphenyl)-but-1-ene(3), is very cytotoxic against breast cancer cells ( IC50 = 0.44 mu M 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 a ( RBAs = 0.9 - 9.6%) and beta ( 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 mu M. 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.