Iodoetherification as a strategy towards sp3-rich scaffolds for drug discovery.

Functionalised tetrahydropyran and spirooxepane scaffolds were prepared utilising an iodoetherification strategy and elaborated to demonstrate their potential use in library synthesis. The iodoetherification products could be readily transformed to the corresponding azides that could be further functionalised via copper-catalysed azide-alkyne cycloaddition or reduction to the amine. The lead-likeness and three-dimensionality of the scaffolds were examined and compared to commercial libraries.

Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity.

Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free-Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.