2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring
Vadym V. Levterov, Yaroslav Panasiuk, Kateryna Sahun, Oleksandr Stashkevych, Valentyn Badlo, Oleh Shablykin, Iryna V. Sadkova, Lina Bortnichuk, Oleksii Klymenko‐Ulianov, Yuliia Holota, Leonid Lachmann, Petro Borysko, Kateryna Horbatok, Iryna Bodenchuk, Yuliia Bas, Dmytro Dudenko, Pavel K. Mykhailiuk
Abstract
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.