Autotaxin (ATX) is a secreted phosphodiesterase that hydrolyzes the abundant phospholipid lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in inflammation, fibrosis, and tumor progression, rendering ATX an attractive drug target. We recently described a boronic acid-based inhibitor of ATX, named HA155 (1). Here, we report the design of new inhibitors based on the crystal structure of ATX in complex with inhibitor 1. Furthermore, we describe the syntheses and activities of these new inhibitors, whose potencies can be explained by structural data. To understand the difference in activity between two different isomers with nanomolar potencies, we performed molecular docking experiments. Intriguingly, molecular docking suggested a remarkable binding pose for one of the isomers, which differs from the original binding pose of inhibitor 1 for ATX, opening further options for inhibitor design.

E=MCR2! The introduction of orthogonal functional groups in multicomponent reactions (MCRs) with unique solvent and functional‐group compatibility enables their combination with other multicomponent reactions in one pot. The resulting novel 5‐ and 6CRs and an unprecedented 8CR afford very complex products in up to 80 % yields (see picture), with up to nine new bond formations and eleven diversity points in a single reaction.

E=MCR2! Orthogonale funktionelle Gruppen mit einzigartiger Kompatibilität mit Lösungsmitteln und anderen funktionellen Gruppen ermöglichen die Kombination mehrerer Mehrkomponenten‐Reaktionen in Eintopfprozessen. Die entsprechenden 5‐ und 6CRs sowie eine neuartige 8CR liefern in einer einzigen Reaktion und in bis zu 80 % Ausbeute sehr komplexe Produkte mit bis zu neun neuen Bindungen und elf Diversitätspunkten (siehe Bild).

Every year three million people die as a result of bacterial infections, and this number may further increase due to resistance to current antibiotics. These antibiotics target almost all essential bacterial processes, leaving only a few new targets for manipulation. The host proteome has many more potential targets for manipulation in order to control bacterial infection, as exemplified by the observation that inhibiting the host kinase Akt supports the elimination of different intracellular bacteria including Salmonella and M. tuberculosis. If host kinases are involved in the control of bacterial infections, phosphatases could be as well. Here we present an integrated small interference RNA and small molecule screen to identify host phosphatase-inhibitor combinations that control bacterial infection. We define host phosphatases inhibiting intracellular growth of Salmonella and identify corresponding inhibitors for the dual specificity phosphatases DUSP11 and 27. Pathway analysis places many kinases and phosphatases controlling bacterial infection in an integrated pathway centered around Akt. This network controls host cell metabolism, survival, and growth and bacterial survival and reflect a natural host cell response to bacterial infection. Inhibiting two enzyme classes with opposite activities–kinases and phosphatases–may be a new strategy to overcome infections by antibiotic-resistant bacteria.

Objectives: Sugars in tobacco products enhance the taste and smoke characteristics of the blend. Sugars are often added to processed tobacco, particularly air-cured Burley tobacco leaves that contain virtually no sugars. The most commonly used sugars were systematically added to Burley tobacco to study the effect on aldehyde emissions in mainstream smoke. Methods: Two levels of sucrose, glucose, and fructose were added to Burley tobacco. Formaldehyde, acetaldehyde, acetone, acrolein, crotonaldehyde, propionaldehyde, and butanal in mainstream smoke were sampled on Carboxen 572 cartridges and determined by HPLC-DAD. Results: The addition of sugars to Burley tobacco resulted in an increase of the aldehydes acetaldehyde, acrolein, crotonaldehyde, propionaldehyde, and butanal in the mainstream tobacco smoke. This increase is specific, as much lower increases in tar, nicotine, and carbon monoxide levels were observed. The observed aldehyde level increases ranged from 5% to 40%. The increase was higher after the addition of fructose compared to sucrose and glucose. Conclusions: Sugars added to Burley tobacco increase the emissions of aldehydes, an important class of toxicants in tobacco smoke. Limiting sugars levels in processed tobacco may be an effective approach in tobacco product regulation to reduce the attractiveness of smoking, and the toxicants levels in cigarette smoke.