Helvetica Chimica Acta最新文献

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.

Type 2 diabetes mellitus is a metabolic dreadful disease caused by an uncontrolled glucose level in the bloodstream, particularly high after a meal. Inhibitors of glucosidases, involved in the digestion of carbohydrates, can regulate this post-prandial increase in glucose concentration. The traditional drugs act as competitive inhibitors of both pancreatic α-amylase and α-glucosidases and this unselective inhibition is behind severe gastrointestinal side effects related to the concomitant inhibition of α-amylase. We described herein some perglycosylated cyclodextrins as efficient and selective inhibitors of α-glucosidase with low micromolar IC₅₀ (3.64-7.98 μM) compared to the acarbose (IC₅₀ 212 μM), clinically used for patients suffering from type 2 diabetes. On the other hand, they do not inhibit α-amylase (IC₅₀>500 μM). Structure/activity relationship rationalization suggests multiple interactions between the described inhibitors and α-glucosidase, which support the existence of both active site and allosteric interactions.

Building upon a previously established (2+3)-cycloaddition strategy, a series of N,N-dialkylated aminocyclopentanes was synthesized using a partially protected eno-furanose as the starting point. The resulting N-methylisoxazolidine was subsequently transformed into the corresponding aminocyclopentane, which was further N-alkylated, yielding a collection of compounds with potential as inhibitors and pharmacological chaperones of β-d-glucocerebrosidase. A comprehensive screening involving a range of biologically relevant glycosidases unveiled that these compounds exhibit remarkable potency and selectivity as inhibitors of human lysosomal β-d-glucocerebrosidase. However, none of these compounds exhibit significant activity enhancement of Morbus Gaucher related p.N409S/p.L483P mutant β-d-glucocerebrosidase.

Two glass lined reactors in a launch platform facility operated by Syngenta have been damaged during the crystallization of an organic compound due to electrostatic discharges. The goal of this work was to design and commission a novel setup to measure charges and currents generated by this slurry in a laboratory-scale reactor. An improved and more sophisticated setup was then proposed for possible implementation in Syngenta's own laboratories. With this novel setup, the electrostatic charging of stirred suspensions involving nonconductive solvents could be accurately measured in the context of a case study that involved the suspension that led to liner damages in the production facilities of Syngenta.

The generation of benzylic radicals through hydrogen atom abstraction (HAT) has been a recent research focus and various C(sp³)−H bond functionalization protocols have been developed relying on this elementary step. We report herein copper- and iron-catalyzed C(sp³)−H benzylic azidation reactions using mCPBA and NFSI as oxidant, respectively, and TMSN₃ as azide source. The reaction is thought to be initiated via intermolecular abstraction of benzylic hydrogen by the in situ generated heteroatom-centered radicals. The Fe(OTf)₃-catalyzed azidation protocol displays good chemoselectivity as it takes place preferentially at the secondary and tertiary benzylic C(sp³)−H bonds over the primary benzylic and tertiary aliphatic carbons. Efforts on the development of catalytic enantioselective processes are also documented.