2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring
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 d...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41298-3 |
| _version_ | 1797558513648533504 |
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| author | 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 Pavel K. Mykhailiuk |
| author_facet | 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 Pavel K. Mykhailiuk |
| author_sort | Vadym V. Levterov |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:31:27Z |
| format | Article |
| id | doaj.art-40ae1c7eff7f48309d4252061fceaf57 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:31:27Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-40ae1c7eff7f48309d4252061fceaf572023-11-20T09:59:25ZengNature PortfolioNature Communications2041-17232023-10-0114111010.1038/s41467-023-41298-32-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ringVadym V. Levterov0Yaroslav Panasiuk1Kateryna Sahun2Oleksandr Stashkevych3Valentyn Badlo4Oleh Shablykin5Iryna Sadkova6Lina Bortnichuk7Oleksii Klymenko-Ulianov8Yuliia Holota9Leonid Lachmann10Petro Borysko11Kateryna Horbatok12Iryna Bodenchuk13Yuliia Bas14Dmytro Dudenko15Pavel K. Mykhailiuk16Enamine Ltd.Enamine Ltd.Enamine Ltd.Enamine Ltd.Enamine Ltd.Enamine Ltd.Enamine Ltd.Enamine Ltd.Enamine Ltd.Enamine Ltd.BientaEnamine Ltd.Enamine Ltd.Enamine Ltd.Taras Shevchenko National University of Kyiv, Chemistry DepartmentEnamine Ltd.Enamine Ltd.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.https://doi.org/10.1038/s41467-023-41298-3 |
| spellingShingle | 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 Pavel K. Mykhailiuk 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring Nature Communications |
| title | 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring |
| title_full | 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring |
| title_fullStr | 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring |
| title_full_unstemmed | 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring |
| title_short | 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring |
| title_sort | 2 oxabicyclo 2 2 2 octane as a new bioisostere of the phenyl ring |
| url | https://doi.org/10.1038/s41467-023-41298-3 |
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