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Established maximum levels for the mycotoxin zearalenone (ZEN) in edible oil require monitoring by reliable analytical methods. Therefore, an automated SPE-HPLC online system based on dynamic covalent hydrazine chemistry has been developed. The SPE step comprises a reversible hydrazone formation by ZEN and a hydrazine moiety covalently attached to a solid phase. Seven hydrazine materials with different properties regarding the resin backbone, pore size, particle size, specific surface area, and loading have been evaluated. As a result, a hydrazine-functionalized silica gel was chosen. The final automated online method was validated and applied to the analysis of three maize germ oil samples including a provisionally certified reference material. Important performance criteria for the recovery (70–120 %) and precision (RSD r <25 %) as set by the Commission Regulation EC 401/2006 were fulfilled: The mean recovery was 78 % and RSD r did not exceed 8 %. The results of the SPE-HPLC online method were further compared to results obtained by liquid–liquid extraction with stable isotope dilution analysis LC-MS/MS and found to be in good agreement. The developed SPE-HPLC online system with fluorescence detection allows a reliable, accurate, and sensitive quantification (limit of quantification, 30 μg/kg) of ZEN in edible oils while significantly reducing the workload. To our knowledge, this is the first report on an automated SPE-HPLC method based on a covalent SPE approach. Graphical Abstract SPE-HPLC online method for automatic analysis of the mycotoxin zearalenone in edible oils.

Transition-metal catalyzed couplings of aryl halides or arenes with aryl organometallics, as well as direct reductive coupling of two aryl halides, are the predominant methods to synthesize biaryls. However, stoichiometric amounts of metals are inevitably utilized in these reactions, either in the pre-generation of organometallic reagents or acting as reductant in situ, thus producing quantitative metal waste. Herein, we demonstrate that this longstanding challenge can be overcome with N H as a metal surrogate. The fundamental innovation of this strategy is that N and H are generated as side products, which readily escape from the system after the reaction. The success of both homo- and cross-coupling of various aryl electrophiles bearing a wide range of functional groups manifests the powerfulness and versatility of this strategy. Furthermore, both homo- and cross-couplings of a series of alkaloids, amino acids and steroids exemplify application of this protocol in the functionalization of biologically active molecules.

Carbon–hydrogen (C–H) and carbon–carbon (C–C) bonds are the main constituents of organic matter. Recent advances in C–H functionalization technology have vastly expanded our toolbox for organic synthesis 1 . By contrast, C–C activation methods that enable editing of the molecular skeleton remain limited 2 – 7 . Several methods have been proposed for catalytic C–C activation, particularly with ketone substrates, that are typically promoted by using either ring-strain release as a thermodynamic driving force 4 , 6 or directing groups 5 , 7 to control the reaction outcome. Although effective, these strategies require substrates that contain highly strained ketones or a preinstalled directing group, or are limited to more specialist substrate classes 5 . Here we report a general C–C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone and transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules. Aromatization-driven C–C bond activation through iridium/phosphine catalysis enables deacylative transformations in various ketone substrates.

Triacsins are an intriguing class of specialized metabolites possessing a conserved N -hydroxytriazene moiety not found in any other known natural products. Triacsins are notable as potent acyl-CoA synthetase inhibitors in lipid metabolism, yet their biosynthesis has remained elusive. Through extensive mutagenesis and biochemical studies, we here report all enzymes required to construct and install the N -hydroxytriazene pharmacophore of triacsins. Two distinct ATP-dependent enzymes were revealed to catalyze the two consecutive N–N bond formation reactions, including a glycine-utilizing, hydrazine-forming enzyme (Tri28) and a nitrite-utilizing, N -nitrosating enzyme (Tri17). This study paves the way for future mechanistic interrogation and biocatalytic application of enzymes for N–N bond formation. During the biosynthesis of triacsin, the two N–N bond formation reactions necessary to create the unique N -hydroxytriazene moiety are catalyzed by a glycine-utilizing hydrazine-forming enzyme and a nitrite-utilizing N-nitrosating enzyme.

Fosfazinomycin and kinamycin are natural products that contain nitrogen–nitrogen (N–N) bonds but that are otherwise structurally unrelated. Despite their considerable structural differences, their biosynthetic gene clusters share a set of genes predicted to facilitate N–N bond formation. In this study, we show that for both compounds, one of the nitrogen atoms in the N–N bond originates from nitrous acid. Furthermore, we show that for both compounds, an acetylhydrazine biosynthetic synthon is generated first and then funneled via a glutamyl carrier into the respective biosynthetic pathways. Therefore, unlike other pathways to N–N bond-containing natural products wherein the N–N bond is formed directly on a biosynthetic intermediate, during the biosyntheses of fosfazinomycin, kinamycin, and related compounds, the N–N bond is made in an independent pathway that forms a branch of a convergent route to structurally complex natural products. The natural products fosfazinomycin A and kinamycin D are structurally distinct except for a nitrogen-nitrogen (N-N) bond. Here, the authors show that fosfazinomycin and kinamycin share a common pathway for N-N bond formation that is different from pathways found for other natural products.

Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12–cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts. Chemical profiling in hyponeddylated cells coupled with multi-omics target deconvolution led to the identification of molecular glue degraders of cyclin K that function by inducing proximity between the CRL adaptor DDB1 and a CDK12–cyclin K complex.

Ladderane lipids are unique to anaerobic ammonium-oxidizing (anammox) bacteria and are enriched in the membrane of the anammoxosome, an organelle thought to compartmentalize the anammox process, which involves the toxic intermediate hydrazine (N₂H₄). Due to the slow growth rate of anammox bacteria and difficulty of isolating pure ladderane lipids, experimental evidence of the biological function of ladderanes is lacking. We have synthesized two natural and one unnatural ladderane phosphatidylcholine lipids and compared their thermotropic properties in self-assembled bilayers to distinguish between [3]- and [5]-ladderane function. We developed a hydrazine transmembrane diffusion assay using a water-soluble derivative of a hydrazine sensor and determined that ladderane membranes are as permeable to hydrazine as straight-chain lipid bilayers. However, pH equilibration across ladderane membranes occurs 5–10 times more slowly than across straight-chain lipid membranes. Langmuir monolayer analysis and the rates of fluorescence recovery after photobleaching suggest that dense ladderane packing may preclude formation of proton/hydroxide-conducting water wires. These data support the hypothesis that ladderanes prevent the breakdown of the proton motive force rather than blocking hydrazine transmembrane diffusion in anammox bacteria.

Azides are energy-rich compounds with diverse representation in a broad range of scientific disciplines, including material science, synthetic chemistry, pharmaceutical science and chemical biology. Despite ubiquitous usage of the azido group, the underlying biosynthetic pathways for its formation remain largely unknown. Here we report the characterization of an enzymatic route for de novo azide construction. We demonstrate that Tri17, a promiscuous ATP- and nitrite-dependent enzyme, catalyses organic azide synthesis through sequential N -nitrosation and dehydration of aryl hydrazines. Through biochemical, structural and computational analyses, we further propose a plausible molecular mechanism for azide synthesis that sets the stage for future biocatalytic applications and biosynthetic pathway engineering. Despite widespread use of azides across material science and various areas across chemistry, the underlying biosynthetic pathways for its formation have so far been unknown. Now, a promiscuous ATP-utilizing enzyme, Tri17, capable of synthesizing various azide molecules has been identified. Biochemical, structural and computational analyses support a potential molecular mechanism for azide formation by Tri17.

The synthesis of transition metal–dinitrogen complexes and the stoichiometric transformation of their coordinated dinitrogen into ammonia and hydrazine have been the subject of considerable research, with a view to achieving nitrogen fixation under ambient conditions. Since a single example in 2003, no examples have been reported of the catalytic conversion of dinitrogen into ammonia under ambient conditions. The dimolybdenum–dinitrogen complex bearing PNP pincer ligands was found to work as an effective catalyst for the formation of ammonia from dinitrogen, with 23 equiv. of ammonia being produced with the catalyst (12 equiv. of ammonia are produced based on the molybdenum atom of the catalyst). This is another successful example of the catalytic and direct conversion of dinitrogen into ammonia under ambient reaction conditions. We believe that the results described in this Article provide valuable information with which to develop a more effective nitrogen-fixation system under mild reaction conditions. Nitrogen fixing is an extremely energy-consuming industrial process so there is much effort underway to develop better catalytic methods. Now, a dimolybdenum–dinitrogen complex bearing a PNP pincer ligand has been found to work as an effective catalyst for the formation of ammonia from dinitrogen.

It has been established that pyrazolines and their analogs are pharmacologically active scaffolds. The pyrazoline moiety is present in several marketed molecules with a wide range of uses, which has established its importance in pharmaceutical and agricultural sectors, as well as in industry. Due to its broad-spectrum utility, scientists are continuously captivated by pyrazolines and their derivatives to study their chemistry. Pyrazolines or their analogs can be prepared by several synthesis strategies, and the focus will always be on new greener and more economical ways for their synthesis. Among these methods, chalcones, hydrazines, diazo compounds, and hydrazones are most commonly applied under different reaction conditions for the synthesis of pyrazoline and its analogs. However, there is scope for other molecules such as Huisgen zwitterions, different metal catalysts, and nitrile imine to be used as starting reagents. The present article consists of recently reported synthetic protocols, pharmacological activities, and the structure–activity relationship of pyrazoline and its derivatives, which will be very useful to researchers.