Val-boroPro (talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of mechanistic understanding, Val-boroPro has attracted significant interest as a potential anticancer agent, reaching Phase III trials in humans. Here we show that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. We demonstrate that the inhibition of two serine proteases, DPP8 and DPP9, activates the proprotein form of caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1β, but does cleave and activate gasdermin D to induce pyroptosis. Mice lacking caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identifies the first small molecule that induces pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.

4-Hydroxy-2-pyridone alkaloids have attracted attention for synthetic and biosynthetic studies due to their broad biological activities and structural diversity. Here, we elucidated the pathway and chemical logic of (−)-sambutoxin (1) biosynthesis. In particular, we uncovered the enzymatic origin of the tetrahydropyran moiety and showed that the p-hydroxyphenyl group is installed via a late-stage, P450-catalyzed oxidation of the phenylalanine-derived side chain rather than via a direct incorporation of tyrosine.

on the occasion of his receiving the Tetrahedron Young Investigator Award Both fused and bridged tetracyclic scaffolds characteristic of endiandric acid-type natural products have been prepared in just seven steps each (longest linear sequence) from Burke's commercial cis-2-bromovinylboronic acid MIDA ester. Three iterative Suzuki-Miyaura couplings using MIDA boronates, including the first such example of a Z-Z coupling, trigger an 8/6-electrocyclization cascade. The mixture of endo and exo bicycles thus formed are elaborated into tetracycles via Horner-Wadsworth-Emmons and Diels-Alder reactions. In the process, the endo and exo diastereomers interconvert to ultimately deliver the desired products.

A green organic−inorganic laboratory experiment has been developed in which students prepare a selfassembling iron cage in D 2 O at room temperature. The tetrahedral cage captures a small, neutral molecule such as cyclohexane or tetrahydrofuran. 1 H NMR analysis distinguishes captured and free guests through diagnostic chemical shifts, splitting patterns, diffusion coefficients (using DOSY), and the appearance of captured hydrophobic molecules in D 2 O even when free guests are insoluble in water. Students are invited to test their hypotheses about guest binding and to perform control and competition experiments. All of the reagents are commercial, the 23-component self-assembly is complete in 1 week at room temperature (requiring neither workup nor purification), and the product solution is intensely purple. In their laboratory reports, students effectively related organic chemistry with molecular self-assembly, supramolecular chemistry, and host−guest interactions.