Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides

Abstract The synthesis and chemical oxidation profile of a new generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular, the hydroxypropyl derivative HO(CH 2 ) 3 C(Fc)=C(C 6 H 4 OH) 2 ( 3 b ) exhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA‐MB‐231 TNBC, with IC 50 values of 0.07 and 0.11 μ M , respectively. Chemical oxidation of 3 b yielded an unprecedented tetrahydrofuran‐substituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH 3 CH 2 ‐C(Fc)=C(C 6 H 4 OH) 2 merely formed a vinyl QM. The ferrocenyl group in 3 b plays a key role, not only as an intramolecular reversible redox “antenna”, but also as a stabilized carbenium ion “modulator”. The presence of the oxygen heterocycle in 3 b‐QM enhances its stability and leads to a unique chemical oxidation profile, thus revealing crucial clues for deciphering its mechanism of action in vivo.