title: 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 (), is very cytotoxic against breast cancer cells (IC(50) = 0.44 microM 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 (), 2-ferrocenyl-1-(3-hydroxyphenyl)-1-(4-hydroxyphenyl)-but-1-ene (), 1,2-di-ferrocenyl-1-(4-hydroxyphenyl)-but-1-ene (), and 1,2-di-ferrocenyl-1-(3-hydroxyphenyl)-but-1-ene ()] 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 () and ()]. We also report the synthesis and characterization of the diphenyl analogue, 2-ferrocenyl-1,1-diphenyl-but-1-ene (). This structure-activity relationship study was motivated by our hypothesis that the cytotoxicity of 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 alpha (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 IC(50) values against the MDA-MB-231 cell line ranging from 0.44-3.5 microM. 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.
authors.affiliation: Laboratoire de Chimie et Biochimie des Complexes Moléculaires, UMR CNRS 7576, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231, Paris, Cedex 05, France.
authors.forename: Elizabeth Anne
authors.initials: EA
authors.lastname: Hillard
authors.forename: Pascal
authors.initials: P
authors.lastname: Pigeon
authors.forename: Anne
authors.initials: A
authors.lastname: Vessières
authors.forename: Christian
authors.initials: C
authors.lastname: Amatore
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004583:Electrons; D005296:Ferrous Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D000075163:Metallocenes; D010636:Phenols / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D000075163:Metallocenes; D010636:Phenols; C004998:ferrocene