Dissecting Room

The Nobel Chronicles

Organometallic quinone methides (OM-QMs) have unique chemical and biological properties compared to their purely organic counterparts, but their originality has not previously been delineated in review form. These phenomena are particularly evident when they are incorporated into a judiciously chosen substrate, in this specific case the ferrocifens, bioorganometallic modifications of hydroxytamoxifen, the antiestrogen of reference. The newly created architecture reveals an embedded ferrocenyl-ene-phenol motif that is key to the formation of metallocene quinone methides by reversible oxidation, either chemically, electrochemically or enzymatically, whereby the sandwich unit functions as a redox antenna. In cancer cells, the QMs are primary metabolites that behave as selective electrophiles that undergo Michael additions with thiols or selenols of key proteins crucial to maintaining redox balance, thus generating a disruption of cell metabolism. Within this class of metallocene complexes, the ferrocifens are the most cytotoxic of the iron, ruthenium, osmium triad against a wide range of cancer cells, while osmium allows the complexes to be used as an imaging probe. We describe here the syntheses and structures of ferrocifen derivatives carrying substituted alkyl, imido or hydroxyalkyl chains that allow access to new types of biologically effective quinone methides. The potential of OM-QMs in chemistry and biology is thus demonstrated in its diversity.