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Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere.
Benjamin A Chalmers1, Hui Xing1, Sevan Houston1
1School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia.
Angewandte Chemie (International Ed. in English)
|February 6, 2016
Summary
Cubane, a unique hydrocarbon scaffold, shows promise as a benzene bioisostere in drug discovery. Derivatives of cubane demonstrated comparable or enhanced bioactivity, potentially revitalizing existing drug candidates.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Drug Discovery
Background:
- Pharmaceutical and agrochemical industries face pressure for innovation to meet global demand.
- Classical hydrocarbon scaffolds are vital in developing new molecules.
- The cubane molecule, a Platonic solid, has been proposed as a potential benzene bioisostere.
Purpose of the Study:
- To validate the hypothesis that cubane can serve as a benzene bioisostere.
- To explore the bioactivity of cubane derivatives in place of benzene in existing drugs and agrochemicals.
Main Methods:
- Synthesis of cubane derivatives for five known bioactive molecules (clinical or agrochemical).
- Comparative bioactivity assessment of cubane analogues against their original benzene counterparts.
Main Results:
- Two cubane analogues exhibited increased bioactivity compared to their benzene counterparts.
- Two cubane analogues displayed bioactivity equal to their benzene counterparts.
- One cubane analogue demonstrated partial efficacy.
Conclusions:
- The study validates cubane's potential as a benzene bioisostere.
- Replacing benzene with cubane in bioactive molecules could revitalize lead candidates.
- This approach may expedite the identification of new drug and agrochemical candidates.
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