Chemoproteomics-Enabled Identification of 4-Oxo-ß-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9.

Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-ß-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date.

Palladium-catalyzed incorporation of atmospheric CO2: efficient synthesis of functionalized oxazolidinones.

Methods to incorporate atmospheric CO2 into organic molecules are on demand. Here we present two Pd-catalyzed multicomponent reactions that provide functionalized oxazolidinones from propargylamines, aryl halides and CO2 as starting materials. These transformations, devoid of high CO2 pressures, represent a streamlined stereocontrolled synthesis of previously inaccessible versions of these useful heterocycles in an atom-economic manner, as up to four new single bonds are formed in a single synthetic operation.