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

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. The phenyl ring is a basic structural element in chemistry. Here, the authors show the design, synthesis, and validation of 2-oxabicyclo[2.2.2]octane as a new saturated bioisostere with improved physicochemical properties

Automated summary

This study presents the design and synthesis of a new saturated bioisostere, 2-oxabicyclo[2.2.2]octane, with improved physicochemical properties. By analyzing the advantages and disadvantages of previously used bioisosteres, the authors developed a key synthesis step using iodocyclization. The incorporation of 2-oxabicyclo[2.2.2]octane into Imatinib and Vorinostat drugs led to improved properties or the creation of a new drug analog. This research expands the options for saturated bioisosteres in drug discovery projects.