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2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring

Nat. Commun. 2023, 14 (1), 5608

DOI: 10.1038/s41467-023-41298-3

Levterov V.; Panasiuk Y.; Sahun K.; Stashkevych O.; Badlo V.; Shablykin O.; Sadkova I.; Bortnichuk L.; Klymenko-Ulianov O.; Holota Y.; Lachmann L.; Borysko P.; Horbatok K.; Bodenchuk I.; Bas Y.; Dudenko D.; Mykhailiuk P.

The phenyl ring is a basic structural element in chemistry. Here, we show the design, synthesis, and validation of its new saturated bioisostere with improved physicochemical properties − 2-oxabicyclo[2.2.2]octane. The design of the structure is based on the analysis of the advantages and disadvantages of the previously used bioisosteres: bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, and cubane. The key synthesis step is the iodocyclization of cyclohexane-containing alkenyl alcohols with molecular iodine in acetonitrile. 2-Oxabicyclo[2.2.2]octane core is incorporated into the structure of Imatinib and Vorinostat (SAHA) drugs instead of the phenyl ring. In Imatinib, such replacement leads to improvement of physicochemical properties: increased water solubility, enhanced metabolic stability, and reduced lipophilicity. In Vorinostat, such replacement results in a new bioactive analog of the drug. This study enhances the repertoire of available saturated bioisosteres of (hetero)aromatic rings for the use in drug discovery projects.