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 Sadkova, Lina Bortnichuk, Oleksii Klymenko-Ulianov, Yuliia Holota, Leonid Lachmann, Petro Borysko, Kateryna Horbatok, Iryna Bodenchuk, Yuliia Bas, Dmytro Dudenko and Pavel K. Mykhailiuk ()
Additional contact information
Vadym V. Levterov: Enamine Ltd.
Yaroslav Panasiuk: Enamine Ltd.
Kateryna Sahun: Enamine Ltd.
Oleksandr Stashkevych: Enamine Ltd.
Valentyn Badlo: Enamine Ltd.
Oleh Shablykin: Enamine Ltd.
Iryna Sadkova: Enamine Ltd.
Lina Bortnichuk: Enamine Ltd.
Oleksii Klymenko-Ulianov: Enamine Ltd.
Yuliia Holota: Enamine Ltd.
Leonid Lachmann: Bienta
Petro Borysko: Enamine Ltd.
Kateryna Horbatok: Enamine Ltd.
Iryna Bodenchuk: Enamine Ltd.
Yuliia Bas: Taras Shevchenko National University of Kyiv, Chemistry Department
Dmytro Dudenko: Enamine Ltd.
Pavel K. Mykhailiuk: Enamine Ltd.

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41298-3

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