title: Deciphering the activation sequence of ferrociphenol anticancer drug candidates.
abstract: 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.
authors.affiliation: UMR CNRS 8640 PASTEUR Ecole Normale Supérieure, Département de Chimie & Université Pierre et Marie Curie, 24 rue Lhomond, 75231 Paris Cedex 05, France.
authors.forename: Pierluca
authors.initials: P
authors.lastname: Messina
authors.forename: Eric
authors.initials: E
authors.lastname: Labbé
authors.forename: Olivier
authors.initials: O
authors.lastname: Buriez
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hillard
authors.forename: Anne
authors.initials: A
authors.lastname: Vessières
authors.forename: Didier
authors.initials: D
authors.lastname: Hamels
authors.forename: Siden
authors.initials: S
authors.lastname: Top
authors.forename: Gérard
authors.initials: G
authors.lastname: Jaouen
authors.forename: Yves Michel
authors.initials: YM
authors.lastname: Frapart
authors.forename: Daniel
authors.initials: D
authors.lastname: Mansuy
authors.forename: Christian
authors.initials: C
authors.lastname: Amatore
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005296:Ferrous Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D045563:Indolequinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D045563:Indolequinones; C533771:ferrociphenol; D013629:Tamoxifen; C068040:quinone methide