Deciphering the Activation Sequence of Ferrociphenol Anticancer Drug Candidates

• Published in: Chemistry : a European journal 2012-05, Vol.18 (21), p.6581-6587
• Main Authors: Messina, Pierluca, Labbé, Eric, Buriez, Olivier, Hillard, Elizabeth A., Vessières, Anne, Hamels, Didier, Top, Siden, Jaouen, Gérard, Frapart, Yves Michel, Mansuy, Daniel, Amatore, Christian
• Format: Article
• Language: English
• Subjects: Activation; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antitumor agents; Cancer; Cations; Chemical Sciences; Cheminformatics; Chemistry; Coordination chemistry; cyclic voltammetry; Drug Screening Assays, Antitumor; Drugs; Electron Spin Resonance Spectroscopy; Female; ferrociphenols; Ferrous Compounds - chemistry; Ferrous Compounds - pharmacology; Humans; Imidazole; Indolequinones - chemical synthesis; Indolequinones - chemistry; Indolequinones - pharmacology; Medicinal Chemistry; Models, Molecular; Molecular Structure; Monitors; Organic chemistry; Oxidation; Oxidation-Reduction; Quinones; reaction mechanisms; Tamoxifen - pharmacology; Voltammetry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201103378

The complete oxidation sequence of a model for ferrociphenols, a new class of anticancer drug candidate, is reported. Cyclic voltammetry was used to monitor the formation of oxidation intermediates on different timescales, thereby allowing the electrochemical characterization of both the short‐lived and stable species obtained from the successive electron‐transfer and deprotonation steps. The electrochemical preparation of the ferrocenium intermediate enabled a stepwise voltammetric determination of the stable oxidation compounds obtained upon addition of a base as well as the electron stoichiometry observed for the overall oxidation process. A mechanism has been established from the electrochemical data, which involves a base‐promoted intramolecular electron transfer between the phenol and the ferrocenium cation. The resulting species is further oxidized then deprotonated to yield a stable quinone methide. To further characterize the transient species successively formed during the two‐electron oxidation of the ferrociphenol to its quinone methide, EPR was used to monitor the fate of the paramagnetic species generated upon addition of imidazole to the electrogenerated ferrocenium. The study revealed the passage from an iron‐centered to a carbon‐centered radical, which is then oxidized to yield the quinone methide, namely, the species that interacts with proteins and so forth under biological conditions. Model behavior: The complete oxidation sequence of a model for ferrociphenols, a new class of anticancer drug candidates, is reported (see scheme). A combination of cyclic voltammetry, EPR spectroscopy, and 1H and 13C NMR spectroscopy was used to monitor and characterize the different species along the pathway.