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

Article https://doi.org/10.1038/s41467-023-41298-3 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring Received: 13 January 2023 Accepted: 30 August 2023 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. 1234567890():,; 1234567890():,; Check for updates Vadym V. Levterov1, Yaroslav Panasiuk1, Kateryna Sahun1, Oleksandr Stashkevych1, Valentyn Badlo1, Oleh Shablykin1,2, Iryna Sadkova1, Lina Bortnichuk1, Oleksii Klymenko-Ulianov1, Yuliia Holota1, Leonid Lachmann3, Petro Borysko1, Kateryna Horbatok1, Iryna Bodenchuk1, Yuliia Bas4, Dmytro Dudenko1 & Pavel K. Mykhailiuk 1 The phenyl ring is a basic structural element in chemistry. It is one of the most common structural motifs in natural products1 and bioactive compounds2,3. Moreover, more than five hundred drugs contain a fragment of para-substituted phenyl ring (Fig. 1a, b)4, including the well-known to everyone Paracetamol. However, organic compounds with more than two phenyl rings often suffer from poor solubility5–7. In 2012, however, Stepan and colleagues showed that a replacement of the central phenyl ring in a γ-secretase inhibitor with the bicyclo[1.1.1]pentane improved its physicochemical properties and retained bioactivity8–11. Later, analogous replacements were undertaken with cubane12–19, and bicyclo[2.2.2]octane (Fig. 1a, b)20–22. Therefore, during the past decade, these scaffolds proved to be useful in drug discovery, medicinal chemistry, and supramolecular chemistry23–31. Replacement of the ortho- and meta-substituted phenyl rings in bioactive compounds with saturated bioisosteres was also recently achieved26–31. Recent studies, however, showed that all three bioisosteres had drawbacks. In bicyclo[1.1.1]pentane, the most popular among them today32–40, the distance between two bridgehead carbon atoms (C-C) is 1.8 Å, which is ca. 35% shorter than that in the parasubstituted phenyl ring (2.8 Å). Bicyclo[2.2.2]octane has a closer C-C distance (2.6 Å), but higher lipophilicity41. Cubane, in turn, was recently demonstrated to be unstable under contact with transition metals42,43, under mechanochemical treatment or heating44. In this work, we have rationally designed, synthesized, and characterized the new bioisostere of the phenyl ring – 2-oxabicyclo[2.2.2] octane (Fig. 1c). Interestingly, 2-oxabicyclo[2.2.2]octane core has been known in the literature, but not in the context of phenyl bioisostere. Chemists used it as a starting material in organic synthesis;45,46 and in medicinal chemistry47–49 as an analog of 4-aminopiperidine50–53 or cyclohexane54,55. Also, 2-oxabicyclo[2.2.2]octane containing molecules exhibited a broad range of biological activities: estrogen receptor-beta 1 Enamine Ltd., Winston Churchill street 78, 02094 Kyiv, Ukraine. 2V. P. Kukhar IBOPC of the NASciences of Ukraine, Academician Kukhar Str. 1, 02094 Kyiv, Ukraine. 3Bienta, Winston Churchill street 78, 02094 Kyiv, Ukraine. 4Taras Shevchenko National University of Kyiv, Chemistry Department, Volodymyrska e-mail: 64, 01601 Kyiv, Ukraine. Nature Communications | (2023)14:5608 1 Article a https://doi.org/10.1038/s41467-023-41298-3 c >500 drugs o o d = 1.8 A d = 2.6 A too short too lipophilic New bioisostere Bioisosteres o (2012) para-Benzene b o d = 2.9 A Bicyclo[1.1.1]pentane Bicyclo[2.2.2]octane d = 2.6 A F(sp3) Cubane [+O] o d = 2.7 A This work 2012 >3000 patents o Cl N N O O N S O N Me N O NH N H2N Pfizer 2012 JMC 2012, 3414 d Ph O EtO2C N N H O N H O Me Me Singh, Fukuda (2014) NH Merck 2016 WO2016/89833 N N N H distance lipophilicity stable conformationally rigid metabolically stable non-chiral collinear vectors N O N o often unstable NH CF3 O CO2Me MeO2C Presidio Pharm. 2014 BMCL 2014, 5731 NHBoc CO2Et 8% total yield O O 2 N N NMe Me 1 Harrison (2019) 6 steps Michael addition Br Me N H 15 steps alkylation MeO2C Pfizer 2016 CMC 2016, 31 Br 40% total yield MeO2C limited to Ar-substituents 4 O 3 Fig. 1 | The para-substituted phenyl ring and its saturated bioisosteres. a The para-substituted phenyl ring is a part of >500 drugs and agrochemicals. Bicyclo[1.1.1]pentanes, bicyclo[2.2.2]octanes, and cubane as saturated bioisosteres of the para-substituted phenyl ring. b Bioactive derivatives of bicyclo[1.1.1]pentanes, bicyclo[2.2.2]octanes, and cubane are described in >3000 patents. c Aim of this work: replacement of the para-substituted phenyl ring in bioactive compounds with 2-oxabicyclo[2.2.2]heptane. d Previous syntheses of 2-oxabicyclo[2.2.2]heptane by Singh, Fukuda (2014)50 and Harrison (2019)54. agonists47, myeloperoxidase inhibitors48, antibacterial agents49–53, DGAT1 Inhibitors54, and RORγt agonists55. analogous conditions the expected product 6 was not formed (Table 1, entry 1). We repeated the reaction several times varying the time and the temperature, however, with the same negative outcome (Table 1, entries 2-4). The addition of the iodine molecule to the double C=C bond did take place, but the cyclization failed to occur. Subsequently, we realized that in contrast to the already conformationally preorganized small cyclobutane, the larger and more flexible cyclohexane ring should adopt the highly energetic boat Results Design In the design of the improved phenyl bioisostere, we first needed to keep the advantages of the previously used cores: their conformational rigidity, metabolic stability, non-chirality, and collinearity of vectors (φ = 180°). At the same time, we needed to address their drawbacks: C-C distance, and lipophilicity. Considering the possible saturated structures (for the details of the design, please, see Supplementary Iinformation, page 5, Supplementary Fig. 1.), we decided to select the bicyclo[2.2.2]octane scaffold, because of its appropriate C-C distance, and decorate it with an oxygen atom. In particular, replacing one carbon atom with oxygen would give 2-oxabicyclo[2.2.2]octane with similar geometry and reduced lipophilicity ( (...truncated)