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- Title
2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring.
- Authors
Levterov, Vadym V.; Panasiuk, Yaroslav; Sahun, Kateryna; Stashkevych, Oleksandr; Badlo, Valentyn; Shablykin, Oleh; Sadkova, Iryna; Bortnichuk, Lina; Klymenko-Ulianov, Oleksii; Holota, Yuliia; Lachmann, Leonid; Borysko, Petro; Horbatok, Kateryna; Bodenchuk, Iryna; Bas, Yuliia; Dudenko, Dmytro; Mykhailiuk, Pavel K.
- 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. 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
- Subjects
DRUG discovery; PENTANE; BIOISOSTERES; IMATINIB; LIPOPHILICITY
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41298-3