Deciphering the Activation Sequence of Ferrociphenol Anticancer Drug Candidates

Authors

  • Pierluca Messina,

    1. UMR CNRS 8640 “PASTEUR” Ecole Normale Supérieure, Département de Chimie & Université Pierre et Marie Curie, 24 rue Lhomond, 75231 Paris Cedex 05 (France)
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  • Prof. Eric Labbé,

    Corresponding author
    1. UMR CNRS 8640 “PASTEUR” Ecole Normale Supérieure, Département de Chimie & Université Pierre et Marie Curie, 24 rue Lhomond, 75231 Paris Cedex 05 (France)
    • UMR CNRS 8640 “PASTEUR” Ecole Normale Supérieure, Département de Chimie & Université Pierre et Marie Curie, 24 rue Lhomond, 75231 Paris Cedex 05 (France)
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  • Dr. Olivier Buriez,

    1. UMR CNRS 8640 “PASTEUR” Ecole Normale Supérieure, Département de Chimie & Université Pierre et Marie Curie, 24 rue Lhomond, 75231 Paris Cedex 05 (France)
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  • Dr. Elizabeth A. Hillard,

    1. UMR CNRS 7223, Laboratoire Charles Friedel, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05 (France)
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  • Dr. Anne Vessières,

    1. UMR CNRS 7223, Laboratoire Charles Friedel, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05 (France)
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  • Didier Hamels,

    1. UMR CNRS 7223, Laboratoire Charles Friedel, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05 (France)
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  • Dr. Siden Top,

    1. UMR CNRS 7223, Laboratoire Charles Friedel, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05 (France)
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  • Prof. Gérard Jaouen,

    1. UMR CNRS 7223, Laboratoire Charles Friedel, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05 (France)
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  • Dr. Yves Michel Frapart,

    1. UMR CNRS 8601, Laboratoire de Chimie et Biochimie Pharmacologique et Toxicologique, Université Paris Descartes, 45 rue des Saints Pères, 75270 Paris (France)
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  • Prof.Dr. Daniel Mansuy,

    1. UMR CNRS 8601, Laboratoire de Chimie et Biochimie Pharmacologique et Toxicologique, Université Paris Descartes, 45 rue des Saints Pères, 75270 Paris (France)
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  • Prof. Dr. Christian Amatore

    Corresponding author
    1. UMR CNRS 8640 “PASTEUR” Ecole Normale Supérieure, Département de Chimie & Université Pierre et Marie Curie, 24 rue Lhomond, 75231 Paris Cedex 05 (France)
    • UMR CNRS 8640 “PASTEUR” Ecole Normale Supérieure, Département de Chimie & Université Pierre et Marie Curie, 24 rue Lhomond, 75231 Paris Cedex 05 (France)
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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.

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