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Biofilms of pathogenic bacteria are responsible for persistent infections in humans, therefore investigations of biofilm formation and treatment strategies are required. The gram-negative enterobacterium Escherichia (E.) coli is the most common pathogen causing chronic or recurring urinary tract infections. Metabolomics approaches targeted the bacterium to investigate specific metabolic patterns of biofilms and regulatory influences on biofilm formation. In this study, we aimed to investigate the metabolome of biofilms formed by the multidrug-resistant extended-spectrum beta-lactamase-producing (ESBL) E. coli PBIO729. For this purpose, a protocol for fast sampling of the macrocolony biofilms and efficient extraction of metabolites was optimized. Validation of an LC-MS/MS method confirmed its usability for the analysis of nucleotides and other phosphorylated metabolites. A GC-MS approach was used to monitor nutrient uptake from the medium in addition to the analysis of amino acid content and metabolites of glycolysis and TCA cycle in E. coli biofilms.

In this communication, a straighforward asymmetric synthesis of spiro-indoline-pyrazolone compounds is described. This methodology consists in a formal [4+1] cycloaddition reaction of 4-bromopyrazolones and aza-ortho-quinone methides generated in situ catalyzed by a bisquinine-derived squaramide in CHCl₃ under basic conditions. A variety of chiral spirocyclic compounds bearing a pyrazolone and an indoline moieties were obtained in moderate to good yields (up to 68 %) and moderate to excellent enantioselectivities (up to 93 % ee).

It is often said that pnictogen-bonding catalysis, and σ-hole catalysis in general, would not work in aqueous systems because the solvent would interfere as an overcompetitive pnictogen-bond acceptor. In this study, we show that the transfer of pnictogen-bonding catalysis from hydrophobic solvents to aqueous systems is possible by replacing only hydrophobic with hydrophilic substrates, without changing catalyst or reaction. This differs from conventional covalent Lewis acid catalysts, which are instantaneously destroyed by ligand exchange. With their water-proof substituents in place of exchangeable ligands, pnictogen-bonding catalysts, the supramolecular counterpart of Lewis acid catalysts, are evinced to catalyze transfer hydrogenation of quinolines in neutral aqueous systems. To secure these results, we introduce a water-soluble fluorogenic substrate that releases a coumarin upon the reduction of quinolines instead of activated quinolidiniums, and stiborane catalysts with deepened σ holes. They demonstrate that pnictogen-bonding catalysts can operate in higher-order architectures for supramolecular systems catalysis under biologically relevant conditions, and provide an operational assay for high-throughput catalyst screening by fluorescence imaging, in situ under relevant aqueous conditions.

Alkylation of N-substituted imidazoles ImR’ (R’=2,4,6-trimethylphenyl, 2,6-diisopropylphenyl, 1-adamantyl) with Mn(I) methylenephosphonium complexes [Cp(CO)₂Mn(η²-P,C-R₂P=C(H)Ph)](BF₄) (PR₂=PPh₂, PCy₂, trans-PC(H)PhCH₂CH₂C (H)Ph) followed by photochemical demetallation afforded a series of bidentate NHC-phosphine ligand precursors [R₂PC(H)PhImR’](BF₄) in moderate to good yield. The same strategy was successfully applied to N-functionalized imidazoles ImL (L=2-pyridyl, CH₂SMe, CH₂ImMe) to afford selectively NHC core pincer pre-ligands featuring phosphine/thioether, phosphine/NHC and phosphine/pyridine side arms. For PCy₂ derivatives, free NHCs in both bidentate and pincer series generated by deprotonation of the corresponding cationic precursors were shown to be persistent at room temperature.

The evolution of the synthesis of a benzothiophene-2-yl-boronic acid - a key building block for the anti-cancer agent Rogaratinib - is reported from multi-gram scale to industrialization. The pitfalls and learnings during process development are outlined, describing the optimization of the initial research synthesis route, investigation of an alternative approach based on a palladium-catalyzed Newman-Kwart rearrangement and finally changing the synthetic strategy from thiophene-construction to benzene-ring formation. Although the initial route was utilized to deliver material on kg-scale, the requirements for market-supply triggered the decision to pursue a new synthetic route. Catalyst costs, high purity-requirements, and not the least technical practicality caused the change to a synthesis with indeed higher step-count. However, this could be mitigated by repeated application of a telescoping approach. The free boronic acid was finally selected and manufactured as a stable isolated intermediate after challenges like proto-deboronation and trimerization to boroxine upon drying could be solved by an optimized crystallization procedure.

Chemistry/science is fun because you learn something new every day. Breakthrough ideas come to me when I discuss my chemistry with other scientists or when hearing/reading about exciting science from other research areas. My favorite drink is coffee, black, no sugar. Lots.

The RFamide family of peptides represents an important class of GPCR ligand neuropeptides covering a wide range of biological functions. While many analogues of the highly conserved C-terminal RFamide motif within this peptide class have been synthesized and their functional significance elucidated, additional exploration of the structure activity relationship is of value. We have developed a novel linker for solid phase peptide synthesis (SPPS) which is able to anchor amine functionalised compounds for further elaboration. The acid labile benzofuranone based amine (ALBA) linker (5-(3-aminopropylcarbamoyl)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]benzoic acid) is compatible with Fmoc based SPPS and has two cleavage modes. As a proof of concept, the ALBA linker was used to successfully synthesise a novel analogue of Kisspeptin 10, the natural ligand for GPCR54, whereby the natural RFamide motif was replaced with an RFamine. Biological evaluation of the amine-containing analogue revealed that the group is not compatible with receptor activation.

Nanoparticles, especially gold nanoparticles (GNPs) have emerged as promising tools for biomedical applications due to their unique properties and ability to be functionalized. However, quantitative analysis of biomolecules conjugated to nanoparticles remains a challenge. Here we report a method to conjugate a synthetic hybrid-type N-glycan to GNPs and quantitatively analyze the glycan content. The glycan was first conjugated to N-hydroxysuccinimide (NHS)-ester activated GNPs and confirmed qualitatively by Fourier-transform infrared spectroscopy and flow cytometry. The glycan conjugated-GNPs were then treated with neuraminidase to release terminal sialic acid from the glycan, which was labeled with 1,2-diamino-4,5-methylenedioxybenzene and quantitatively analyzed by Ultraperformance Liquid Chromatography (UPLC). The amount of the sialic acid released was equivalent to the glycan content on GNPs. This method enabled a precise quantification of glycans conjugated to gold nanoparticles and should facilitate its biomedical applications, including studies of multivalent receptor-glycan interaction, cell targeting and sorting, and immunization. Overall, this work provides an effective approach to synthesize and characterize nanoparticles conjugates.

This perspective is an essay that tries to comprehend and reflect Andrea Vasella's work on the active sites of enzymes such as glycoside hydrolases.