Applications of oxetanes in drug discovery and medicinal chemistry.

The compact and versatile oxetane motifs have gained significant attention in drug discovery and medicinal chemistry campaigns. This review presents an overview of the diverse applications of oxetanes in clinical and preclinical drug candidates targeting various human diseases, including cancer, viral infections, autoimmune disorders, neurodegenerative conditions, metabolic disorders, and others. Special attention is given to biologically active oxetane-containing compounds and their disease-related targets, such as kinases, epigenetic and non-epigenetic enzymes, and receptors. The review also details the effect of the oxetane motif on important properties, including aqueous solubility, lipophilicity, pKa, P-glycoprotein (P-gp) efflux, metabolic stability, conformational preferences, toxicity profiles (e.g., cytochrome P450 (CYP) suppression and human ether-a-go-go related gene (hERG) inhibition), pharmacokinetic (PK) properties, potency, and target selectivity. We anticipate that this work will provide valuable insights that can drive future discoveries of novel bioactive oxetane-containing small molecules, enabling their effective application in combating a wide range of human diseases.

Jet-Cooled Phosphorescence Excitation Spectrum of the T1(n,π*) ← S0 Transition of 4H-Pyran-4-one.

The 4H-pyran-4-one (4PN) molecule is a cyclic conjugated enone with spectroscopically accessible singlet and triplet (n,π*)excited states. Vibronic spectra of 4PN provide a stringent test of electronic-structure calculations, through comparison of predicted vs measured vibrational frequencies in the excited state. We report here the T1(n,π*) ← S0 phosphorescence excitation spectrum of 4PN, recorded under the cooling conditions of a supersonic free-jet expansion. The jet cooling has eliminated congestion appearing in previous room-temperature measurements of the T1 ← S0 band system and has enabled us to determine precise fundamental frequencies for seven vibrational modes of the molecule in its T1(n,π*) state. We have also analyzed the rotational contour of the 000 band, obtaining experimental values for spin-spin and spin-rotation constants of the T1(n,π*) state. We used the experimental results to test predictions from two commonly used computational methods, equation-of-motion excitation energies with dynamical correlation incorporated at the level of coupled cluster singles doubles (EOM-EE-CCSD) and time-dependent density functional theory (TDDFT). We find that each method predicts harmonic frequencies within a few percent of observed fundamentals, for in-plane vibrational modes. However, for out-of-plane modes, each method has specific liabilities that result in frequency errors on the order of 20-30%. The calculations have helped to identify a perturbation from the T2(π,π*) state that leads to unexpected features observed in the T1(n,π*) ← S0 origin band rotational contour.