title: Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere.
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.
authors: School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia.
authors: Benjamin A
authors: http://orcid.org/0000-0001-8490-0628
authors: BA
authors: Chalmers
authors: School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia.
authors: Hui
authors: H
authors: Xing
authors: School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia.
authors: Sevan
authors: S
authors: Houston
authors: Queensland Brain Institute, UQ, Australia.
authors: Charlotte
authors: C
authors: Clark
authors: Centre for Integrated Preclinical Drug Development, UQ, Australia.
authors: Sussan
authors: http://orcid.org/0000-0003-2832-9038
authors: S
authors: Ghassabian
authors: Centre for Integrated Preclinical Drug Development, UQ, Australia.
authors: Andy
authors: http://orcid.org/0000-0001-6395-3114
authors: A
authors: Kuo
authors: CISRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168, Victoria (VIC, Australia.|Australian Regenerative Medicine Institute, Monash University (MU), Melbourne, 3168, VIC, Australia.
authors: Benjamin
authors: http://orcid.org/0000-0002-3024-3893
authors: B
authors: Cao
authors: CISRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168, Victoria (VIC, Australia.|Australian Regenerative Medicine Institute, Monash University (MU), Melbourne, 3168, VIC, Australia.
authors: Andrea
authors: A
authors: Reitsma
authors: School of Biological Sciences, UQ, Australia.
authors: Cody-Ellen P
authors: CE
authors: Murray
authors: School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia.
authors: Jeanette E
authors: JE
authors: Stok
authors: QIMR Berghofer Medical Research Institute, PO Royal Brisbane Hospital, Brisbane, 4029, QLD, Australia.
authors: Glen M
authors: GM
authors: Boyle
authors: QIMR Berghofer Medical Research Institute, PO Royal Brisbane Hospital, Brisbane, 4029, QLD, Australia.
authors: Carly J
authors: CJ
authors: Pierce
authors: CISRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168, Victoria (VIC, Australia.
authors: Stuart W
authors: http://orcid.org/0000-0002-6243-7334
authors: SW
authors: Littler
authors: CISRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168, Victoria (VIC, Australia.|Monash Institute of Pharmaceutical Sciences, Parkville, 3052, MU, Australia.
authors: David A
authors: http://orcid.org/0000-0002-7301-6076
authors: DA
authors: Winkler
authors: School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia.
authors: Paul V
authors: PV
authors: Bernhardt
authors: QIMR Berghofer Medical Research Institute, PO Royal Brisbane Hospital, Brisbane, 4029, QLD, Australia.
authors: Cielo
authors: C
authors: Pasay
authors: School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia.
authors: James J
authors: JJ
authors: De Voss
authors: QIMR Berghofer Medical Research Institute, PO Royal Brisbane Hospital, Brisbane, 4029, QLD, Australia.|Australian Centre for International and Tropical Health, UQ, Australia.
authors: James
authors: J
authors: McCarthy
authors: QIMR Berghofer Medical Research Institute, PO Royal Brisbane Hospital, Brisbane, 4029, QLD, Australia.
authors: Peter G
authors: http://orcid.org/0000-0002-0473-3346
authors: PG
authors: Parsons
authors: School of Biological Sciences, UQ, Australia.
authors: Gimme H
authors: http://orcid.org/0000-0003-1025-7101
authors: GH
authors: Walter
authors: Centre for Integrated Preclinical Drug Development, UQ, Australia.
authors: Maree T
authors: http://orcid.org/0000-0003-2281-3734
authors: MT
authors: Smith
authors: Queensland Brain Institute, UQ, Australia.
authors: Helen M
authors: HM
authors: Cooper
authors: CISRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168, Victoria (VIC, Australia.|Australian Regenerative Medicine Institute, Monash University (MU), Melbourne, 3168, VIC, Australia.
authors: Susan K
authors: http://orcid.org/0000-0002-7926-7335
authors: SK
authors: Nilsson
authors: CISRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168, Victoria (VIC, Australia. John.Tsanaktsidis@csiro.au.
authors: John
authors: http://orcid.org/0000-0002-4704-1382
authors: J
authors: Tsanaktsidis
authors: CISRO Manufacturing, Ian Wark Laboratory, Melbourne, 3168, Victoria (VIC, Australia. Paul.Savage@csiro.au.
authors: G Paul
authors: http://orcid.org/0000-0001-7805-8630
authors: GP
authors: Savage
authors: School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia. c.williams3@uq.edu.au.
authors: Craig M
authors: http://orcid.org/0000-0002-3834-7398
authors: CM
authors: Williams
mesh_terms: D000368:Aged; D000818:Animals; D001554:Benzene / Q000737:chemistry*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
chemical_list: D001554:Benzene
keywords: agrochemicals; bioisosteres; cubane; pharmaceuticals; structure-activity relationships