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The medicinal chemistry of ferrocene and its derivatives

Nature Reviews Chemistry volume 1, Article number: 0066 (2017) Cite this article

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Abstract

Ferrocene derivatives have attracted significant interest as anticancer, antibacterial, antifungal and antiparasitic drug candidates. Discovered in the 1990s, the two most prominent derivatives, ferroquine and ferrocifen, have since been studied extensively for the treatment of malaria and cancer, respectively. The ferrocenyl moiety in these two compounds participates in important metal-specific modes of action that contribute to the overall therapeutic efficacy of the molecules. Although ferroquine is currently in phase II clinical trials and ferrocifen is in preclinical evaluation, no other ferrocene derivative — in fact, no other non-radioactive organometallic compound of any kind — has advanced into clinical trials. This Perspective delineates strategies for the systematic incorporation of ferrocenyl groups into known drugs or drug candidates, with a view to finding new drug leads. In addition, we provide a critical evaluation of the difficulties associated with obtaining the clinical approval that would enable ferrocene-containing molecules to transition from being synthetic curiosities to effective drugs.

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Figure 1: Ferrocene derivatives.
Figure 2: Ferrocene derivatives in medicinal applications.
Figure 3: Redox chemistry of hydroxyferrocifen.
Figure 4: The roles of ferrocenyl groups in biologically active compounds.
Figure 5: The ferrocenyl group as a bioisostere.
Figure 6: Organometallic moieties bind strongly to enzyme hydrophobic pockets and cause inhibition.
Figure 7: Heterometallic complexes for multi-modal targeting.
Figure 8: The number of reports published each year describing the biological activity of organometallic compounds, including ferrocene and ruthenocene.

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Acknowledgements

This work was financially supported by the Swiss National Science Foundation (Professorship Nos PP00P2_133568 and PP00P2_157545 to G.G.), the University of Zurich (G.G.) and the UBS Promedica Stiftung (M.P. and G.G.). This work has also received support under the Investissements d’Avenir programme launched by the French Government and implemented by the L’Agence Nationale de la Recherche (ANR-10-IDEX-0001-02 PSL, G.G.). The authors thank G. Jaouen and C. Biot for insight into the development of ferrocifens and ferroquine, and B. Spingler and P. Ung for useful feedback on this manuscript.

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  1. Malay Patra is at the Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.,

    Malay Patra

  2. Gilles Gasser is at the Chimie ParisTech, PSL Research University, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France.,

    Gilles Gasser

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Patra, M., Gasser, G. The medicinal chemistry of ferrocene and its derivatives. Nat Rev Chem 1, 0066 (2017). https://doi.org/10.1038/s41570-017-0066

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