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Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere
Author(s) -
Chalmers Benjamin A.,
Xing Hui,
Houston Sevan,
Clark Charlotte,
Ghassabian Sussan,
Kuo Andy,
Cao Benjamin,
Reitsma Andrea,
Murray CodyEllen 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.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201510675
Subject(s) - cubane , bioisostere , benzene , molecule , chemistry , ring (chemistry) , combinatorial chemistry , stereochemistry , organic chemistry , in vitro , biochemistry , chemical synthesis
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.