Validating Eaton's hypothesis: cubane as a benzene bioisostere

Chalmers, Benjamin A., Xing, Hui, Houston, Sevan, Clark, Charlotte, Ghassabian, Sussan, Kuo, Andy, Cao, Benjamin, Reitsma, Andrea, Murray, Cody-Ellen P., Stok, Jeanette E., Boyle, Glen M., Pierce, Carly J., Littler, Stuart W., Winkler, David A., Bernhardt, Paul V., Pasay, Cielo, De Voss, James J., McCarthy, James, Parsons, Peter G., Walter, Gimme H., Smith, Maree T., Cooper, Helen M., Nilsson, Susan K., Tsanaktsidis, John, Savage, G. Paul and Williams, Craig M. (2016) Validating Eaton's hypothesis: cubane as a benzene bioisostere. Angewandte Chemie (International Edition), 55 11: 3580-3585. doi:10.1002/anie.201510675


Author Chalmers, Benjamin A.
Xing, Hui
Houston, Sevan
Clark, Charlotte
Ghassabian, Sussan
Kuo, Andy
Cao, Benjamin
Reitsma, Andrea
Murray, Cody-Ellen P.
Stok, Jeanette E.
Boyle, Glen M.
Pierce, Carly J.
Littler, Stuart W.
Winkler, David A.
Bernhardt, Paul V.
Pasay, Cielo
De Voss, James J.
McCarthy, James
Parsons, Peter G.
Walter, Gimme H.
Smith, Maree T.
Cooper, Helen M.
Nilsson, Susan K.
Tsanaktsidis, John
Savage, G. Paul
Williams, Craig M.
Title Validating Eaton's hypothesis: cubane as a benzene bioisostere
Journal name Angewandte Chemie (International Edition)   Check publisher's open access policy
ISSN 1521-3773
1433-7851
Publication date 2016-02-05
Year available 2016
Sub-type Article (original research)
DOI 10.1002/anie.201510675
Open Access Status Not Open Access
Volume 55
Issue 11
Start page 3580
End page 3585
Total pages 6
Place of publication Wiley
Publisher Weinheim, Germany
Collection year 2017
Language eng
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.
Keyword Agrochemicals
Bioisosteres
Cubane
Pharmaceuticals
Structure-activity relationships
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Fri, 12 Feb 2016, 14:45:49 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences