Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere

Benjamin Chalmers, Hui Xing, Sevan Houston, Charlotte Clark, Sussan Ghassabian, Andy Kuo, Benjamin Cao, Andrea Reitsma, Cody-Ellen Murray, Jeanette Stok, Glen Boyle, Carly Pierce, Stuart Littler, David Alan Winkler, Paul Bernhardt, C Pasay, James De Voss, James McCarthy, Peter Parsons, Gimme WalterMaree Smith, Helen Cooper, Susan Nilsson, John Tsanaktsidis, G Savage, C Williams

    Research output: Contribution to journalArticle

    56 Citations (Scopus)

    Abstract

    Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

    Original languageEnglish
    Pages (from-to)3580-3585
    Number of pages6
    JournalAngewandte Chemie-International Edition
    Volume55
    Issue number11
    DOIs
    Publication statusPublished - 2016

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  • Cite this

    Chalmers, B., Xing, H., Houston, S., Clark, C., Ghassabian, S., Kuo, A., Cao, B., Reitsma, A., Murray, C-E., Stok, J., Boyle, G., Pierce, C., Littler, S., Winkler, D. A., Bernhardt, P., Pasay, C., De Voss, J., McCarthy, J., Parsons, P., ... Williams, C. (2016). Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere. Angewandte Chemie-International Edition, 55(11), 3580-3585. https://doi.org/10.1002/anie.201510675