Chemistry and bioactivity of ferrocenyl quinone methides

The antiproliferative behaviour of the ferrocifens, derived by replacing a phenyl substituent in tamoxifen by ferrocenyl, and also in their diphenol counterparts, against both ER+ and ER- breast cancers may be attributed to two key factors: the redox-mediated formation of reactive oxygen species (ROS), and the formation of ferrocenyl quinone methides (Fc-QMs) that react with nucleophilic thiols, and also inhibit the ability of thioredoxin reductase to function, thereby weakening the cell’s defence towards ROS. Metabolites arising from the reactions of these Fc-QMs are generated from a variety of novel reactions and molecular rearrangements. These include the formation of dihydrofurans and pyrans, spirobonded tetrahydrofurans, and ferrocenyl migrations, all arising in a stepwise manner via the intermediacy of ferrocenyl-stabilized quinone methide cations. X-ray crystal structures of Fc-QMs bearing alkyl-imido substituents reveal the existence of novel lone pair-π* interactions that enhance their stabilities and lifetimes and allow a rationalisation of their effectiveness against a wide range of tumours.