AURA: Accelerating drug discovery with accuracy, utility, and rank-order assessment for data-driven decision making.

Biopharmaceutical companies generate a wealth of data, ranging from in silico physicochemical properties and machine learning models to both low and high-throughput in vitro assays and in vivo studies. To effectively harnesses this extensive data, we introduce a statistical methodology facilitated by Accuracy, Utility, and Rank Order Assessment (AURA), which combines basic statistical analyses with dynamic data visualizations to evaluate endpoint effectiveness in predicting intestinal absorption. We demonstrated that various physicochemical properties uniquely influence intestinal absorption on a project-specific basis, considering factors like intestinal efflux, passive permeability, and clearance.

Photo-Brook rearrangement of acyl silanes as a strategy for photoaffinity probe design.

Photoaffinity labeling (PAL) is a powerful tool for the identification of non-covalent small molecule-protein interactions that are critical to drug discovery and medicinal chemistry, but this approach is limited to only a small subset of robust photocrosslinkers. The identification of new photoreactive motifs capable of covalent target capture is therefore highly desirable. Herein, we report the design, synthesis, and evaluation of a new class of PAL warheads based on the UV-triggered 1,2-photo-Brook rearrangement of acyl silanes, which hitherto have not been explored for PAL workflows.

Construction of Complex Cyclobutane Building Blocks by Photosensitized [2 + 2] Cycloaddition of Vinyl Boronate Esters.

Cyclobutyl moieties in drug molecules are rare, and in general, they are minimally substituted and stereochemically simple. Methods to assemble structurally complex cyclobutane building blocks suitable for rapid diversification are thus highly desirable. We report herein a photosensitized [2 + 2] cycloaddition with vinyl boronate esters affording straightforward access to complex, densely functionalized cyclobutane scaffolds.

Spin-Selective Generation of Triplet Nitrenes: Olefin Aziridination through Visible-Light Photosensitization of Azidoformates.

Azidoformates are interesting potential nitrene precursors, but their direct photochemical activation can result in competitive formation of aziridination and allylic amination products. Herein, we show that visible-light-activated transition-metal complexes can be triplet sensitizers that selectively produce aziridines through the spin-selective photogeneration of triplet nitrenes from azidoformates. This approach enables the aziridination of a wide range of alkenes and the formal oxyamination of enol ethers using the alkene as the limiting reagent.