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 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.

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) and Harrison (2019).

Fig. 2. Scalable synthesis of 2-oxabicyclo[2.2.2]octane 6.

The synthesis started from the commercially available ketone 7. Iodide 6 was obtained on a 135 g scale in one run.

Fig. 3. Synthesis of 2-oxabicyclo[2.2.2]octanes and 2-azabicyclo[2.2.2]octanes.

a Synthesis of 2-oxabicyclo[2.2.2]octanes with three exit vectors (for products 10–29, ethyl ester analog of alkene 8 was used). b Synthesis of 2-oxabicyclo[2.2.2]octanes with one and two exit vectors. X-ray crystal structure of compound 30b (carbon – white, oxygen – red, iodine - violet). Hydrogen atoms are omitted for clarity. c Iodocyclization of alkenes 34, 36, and 38. d, Synthesis of 2-azabicyclo[2.2.2]octane 43.

Fig. 4. Synthesis of functionalized 2-oxabicyclo[2.2.2]octanes for medicinal chemistry.

X-ray crystal structure of compounds 57, 67, and 69 (carbon – white, oxygen – red, nitrogen – blue, iodine - violet). Hydrogen and chlorine atoms are omitted for clarity.

Fig. 5. Сrystallographic analysis of 2-oxabicyclo[2.2.2]octanes.

a Definition of distances r, d and angles φ₁, φ₂ (2-oxabicyclo[2.2.2]octane core is shown as example). b Geometric parameters r, d and φ₁, φ₂ for para-substituted phenyl ring (Imatinib drug), its known saturated bioisosteres 80–82 and the new saturated bioisosteres 30, 69. aData is taken from ref. . bData is taken from ref. . cData is taken from ref. . dData is taken from ref. . Two individual molecules of Imatinib (A and B) are present in the crystal lattice.

Fig. 6. Experimental pKa values of carboxylic acids 47, 54, 83, and 84.

Data is obtained by the titration method. Para-methyl benzoic acid (83) is used as a reference.

Fig. 7. Replacement of the para-phenyl ring with saturated bioisosteres in anticancer drug Imatinib.

Solubility: experimental kinetic solubility in phosphate-buffered saline, pH 7.4 (µM). clogP: calculated lipophilicity. logD (7.4): experimental distribution coefficient in n-octanol/phosphate-buffered saline, pH 7.4. Reliable logD measured were obtained within a range of 1.0–4.5. CL_int clearance intrinsic: experimental metabolic stability in human liver microsomes (µl/min/mg). t_1/2 (min) experimental half-time of a metabolic decomposition.

Fig. 8. Replacement of the phenyl ring with saturated bioisosteres in anticancer drug Vorinostat (SAHA).

a Synthesis of compound 88 – a saturated analog of Vorinostat. Reaction conditions: a) Cl(O)C(CH₂)₆CO₂Me, NEt₃, CH₂Cl₂, rt, 2 h. b) NaOH, MeOH, reflux, 30 min. c) NH₂OH•HCl, DMF, CDI, rt, 30 min. b Structure of Vorinostat (SAHA), and its saturated analog 89.

Fig. 9. Anticancer activity of Vorinostat (SAHA) and its saturated analogs 88, 89.

Types of HepG2 cell death (% of total cells) after treatment with Vorinostat and compounds 88, 89 (1 μM, 5 μM, and 50 μM) for 48 h. Red: necrotic cell death. Green: early apoptotic cell death. The data were presented as mean ± SEM (n = 3, independent wells for every of which approx. 2000 visualized cells were analyzed).* - indicates P < 0.05, ** - indicates P < 0.01, *** - P < 0.001 compared with the non-treated group in a two-tailed unpaired t-test with Welch correction on each row of data.