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.
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.
Hillard
Elizabeth Anne
EA
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.
Pigeon
Pascal
P
Vessières
Anne
A
Amatore
Christian
C
Jaouen
Gérard
G
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
D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D000075163:Metallocenes; D010636:Phenols; C004998:ferrocene