Oxidative Sequence of a Ruthenocene-Based Anticancer Drug Candidate in a Basic Environment

The complete oxidation sequence of ruthenociphenol ( 1 ), an organometallic ruthenocene-based analogue of ferrocifens, a promising anticancer drug series, has been investigated by cyclic voltammetry. As for the unsubstituted ruthenocene, the oxidation of 1 produced the corresponding species 1 +, which engaged in a reversible dimerization reaction. The highest reversibility occurred in dichloromethane (DCM), a low-donor solvent, with the weakly coordinating supporting electrolyte anion B(C 6 F 5 ) 4 . Under these conditions, the addition of pyridine triggered a chemical sequence through which the hydroxyl group of electrogenerated 1 + was ultimately converted into the phenoxy radical 2 . Unlike analogue ferrocifen derivatives, 2 did not undergo a further electrochemical oxidation but engaged in coupling with 1 + . The slow deprotonation of the resulting species appeared to be the key step leading to the quinone methide 3 after sluggish electron transfer. Again, in contrast with the ferrocifen series, 3 was not the final and stable complex of this oxidation sequence. It was indeed shown that the quinone methide spontaneously underwent a further oxidative evolution under our conditions. This led to a five-membered-ring closure and regeneration of the phenolic species 4, which could be further oxidized irreversibly, leading presumably to the new quinone methide 6 . Such distinct behavior in comparison to ferrocene analogues may explain the different cytotoxic activities observed against hormone-independent breast cancer cells for ruthenocifens and ferrocifens.