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The synthesis of purine/triazole 6'-isonucleosides and of glucuronic acid/glucuronamide-derived N-glycosylsulfonohydrazides through efficient and stereo- or regioselective methodologies is described. Their structures were envisaged to mimic nucleosides, sugar phosphates, or nucleotides, and were expected to provide potential inhibitors of therapeutically relevant enzymes, the active sites of which could potentially bind their structural fragments or functional groups. Such enzymes include cholinesterases, carbonic anhydrase II (CA-II) and cyclin-dependent kinase 2 (CDK-2). A (triazolyl)methyl amide-linked disaccharide nucleoside, based on a new prospective structural framework for analogues of nucleoside diphosphate sugars, was synthesized. The synthetic strategies employed unprotected or partially protected carbohydrate derivatives as precursors, including ribose, glucuronic acid, glucuronolactone, and glycopyranosides and relied on stereoselective N-glycosylation, regioselective Mitsunobu coupling and 'click chemistry' approaches. Some 6'-isonucleosides and triazole-containing glycoderivatives displayed moderate selective acetylcholinesterase inhibitory activities. The best inhibitor was an aminomethyltriazole 6'-isonucleoside with a Ki value of 11.9 μM. N-Glucuronylsulfonohydrazide showed good inhibition of CA-II (Ki = 9.5 μM). Molecular docking of the most active compounds into the effected enzymes showed interactions with key amino acid residues for substrate recognition. In addition, the tested compounds did not show toxicity to normal cells. [ABSTRACT FROM AUTHOR]

Humanneutrophil elastase (HNE) is an attractive target for treating chronicand acute inflammatory lung diseases. An optimization campaign ofthe kojic acid scaffold to develop new potent HNE inhibitors is reported. O3-Pivaloyl derivatives were shown to be themost potent inhibitors with IC5ovalues down to 80 nM.These compounds presented excellent selectivity and cytotoxicity profileswith suitable ligand efficiency. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors. [Copyright &y& Elsevier]

Abstract: Acid zeolites as catalysts offer unique achievements in the carbohydrate field allowing regio- and stereocontrolled reactions, mainly related to their shape-selective properties. Moreover, these materials are environmentally safe and easy to handle, contributing to clean and sustainable procedures in carbohydrate transformations. The scope of this review is to summarize the most significant applications of these heterogeneous catalysts in carbohydrate chemistry, notably in mediating key transformations such as glycosylation, sugar protection and deprotection, hydrolysis and dehydration, highlighting the exciting results that the use of zeolites may provide. [Copyright &y& Elsevier]

Graphical abstract Highlights • Derivatives of ursolic and oleanolic acid were prepared and tested in Ellman's assays. • Several compounds acted as good inhibitors for acetyl- or butyrylcholinesterase. • 2-Methyl-3-oxo-methyl-ursolate 18 acted as a mixed type inhibitor for AChE. • Ursolic acid derived hydroxy-propinyl 10 was a competitive inhibitor for BChE. • This compound was twice as active as standard galantamine hydrobromide. Abstract Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer's disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman's assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined. As a result, several compounds were shown as good inhibitors for acetylcholinesterase and butyrylcholinesterase even in a micromolar range. An ursolic acid derived hydroxyl-propinyl derivative 10 was a competitive inhibitor for butyrylcholinesterase with an inhibition constant of K i = 4.29 μM, and therefore being twice as active as gold standard galantamine hydrobromide. The best inhibitor for acetylcholinesterase, however, was 2-methyl-3-oxo-methyl-ursoloate (18), acting as a mixed-type inhibitor showing K i = 1.72 µM and K i ′ = 1.28 μM, respectively. [ABSTRACT FROM AUTHOR]

Review: 112 refs. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity‐based protein profiling (ABPP)‐mediated discovery of 4‐oxo‐β‐lactams as potent, non‐substrate‐like nanomolar DPP8/9 inhibitors. X‐ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2′ (eS2′) subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure‐guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date. [ABSTRACT FROM AUTHOR]

Die Dipeptidylpeptidasen 8 und 9 (DPP8/9) sind aufgrund ihrer wichtigen Rolle in biologischen Prozessen wie der Immunität und Tumorgenese in den letzten Jahren in den Fokus der Wirkstoffforschung gerückt. Der individuelle Beitrag der jeweiligen Protease innerhalb dieser Prozesse ist bisher jedoch meistens noch unbekannt. Die Untersuchung ihrer individuellen Funktion kann dabei von der Verfügbarkeit Protease‐selektiver und chemisch‐diverser Hemmstoffe profitieren. In dieser Arbeit stellen wir die durch Anwendung von Aktivitäts‐basiertem Protein‐Profiling (ABPP) entdeckten 4‐Oxo‐β‐lactame als potente, nicht‐Substrat‐abgeleitete, nanomolare DPP8/9‐Inhibitoren vor. Röntgenkristallographische Untersuchungen von Liganden‐DPP‐Komplexen offenbarten dabei unterschiedliche Ligandenbindungsmodi für DPP8 und DPP9, einschließlich einer neuartigen Adressierung einer erweiterten S2′ (eS2′)‐Bindetasche in DPP8. Zusätzliche Assays bestätigten ihre Hemmwirkung sowohl auf biochemischer als auch auf zellulärer Ebene. Zusammenfassend führte unser kombinierter Ansatz aus chemischer Proteomik und strukturbasiertem Design somit zu der Entwicklung neuartiger DPP8/9‐Inhibitoren mit einem alternativem molekularen Hemmmechanismus und einem bisher nicht erreichten Selektivitätsindex. [ABSTRACT FROM AUTHOR]

Carbonic anhydrase II, belonging to one of the most important enzyme groups of the human body, is a well-studied isozyme from the family of the carbonic anhydrases. Since it is involved in several physiological processes, it has been a pharmaceutical target for many years. In this study we synthesized a number of sulfamates derived from pentacyclic methyl triterpenoates, and we demonstrate their potential as carbonic anhydrase II inhibitors using the well-established photometric 4-nitrophenyl acetate assay. Inhibition constants, as an indicator of their inhibition strength, were in the micromolar range; one compound ( 10 , methyl (3β) 3-(aminosulfonyloxy)-oleanoate) showed a K i value as low as 0.3 μM. This K i value is comparable to that of acetazolamide which is a potent carbonic anhydrase inhibitor and a drug for the treatment of glaucoma. [ABSTRACT FROM AUTHOR]

Cover Picture: Chemoproteomics-Enabled Identification of 4-Oxo- -Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9 (Angew. Keywords: Activity-Based Protein Profiling; Dipeptidyl Peptidases 8/9; 4-Oxo- -Lactams; Proteomics; X-Ray Diffraction EN Activity-Based Protein Profiling Dipeptidyl Peptidases 8/9 4-Oxo- -Lactams Proteomics X-Ray Diffraction 1 1 1 11/16/22 20221121 NES 221121 B A lone 4-oxo- I i -lactam molecule b moves towards the catalytic site of an illuminated dipeptidyl peptidase 8 (DPP8) in a vast universe of chemical space. The 4-oxo- I i -lactams, identified by a chemoproteomics platform as DPP8/9 inhibitors, may hold the key to the highly sought DPP8/9 selectivity via an unprecedented DPP8-specific mechanism, as demonstrated through X-ray diffraction by Markus Kaiser, Rui Moreira et al. in their Research Article (e202210498). [Extracted from the article]

Die Erzielung einer DPP8/9-Selektivität ist nach wie vor eine Herausforderung für die chemische Biologie. Die 4-Oxo- -lactame, die mithilfe einer Chemoproteomics-Plattform als DPP8/9-Inhibitoren identifiziert wurden, könnten der Schlüssel zur gesuchten DPP8/9-Selektivität über einen präzedenzlosen DPP8-spezifischen Mechanismus sein, wie Markus Kaiser, Rui Moreira et al. in ihrem Forschungsartikel (e202210498) mittels Röntgenbeugung demonstrieren. Keywords: 4-Oxo- -lactame; Aktivitäts-basiertes Protein Profiling (ABPP); Dipeptidylpeptidasen 8/9; Proteomics; Röntgenstrukturanalyse DE 4-Oxo- -lactame Aktivitäts-basiertes Protein Profiling (ABPP) Dipeptidylpeptidasen 8/9 Proteomics Röntgenstrukturanalyse 1 1 1 11/16/22 20221121 NES 221121 B Ein einsames 4-Oxo b - B I i -lactam-Molekül b bewegt sich in Richtung des katalytischen Zentrums einer Dipeptidylpeptidase 8 (DPP8) in einem Universum an chemischem Raum. [Extracted from the article]

Abstract: Submillimolar concentrations of cytotoxic bile acids (BAs) induce cell death via apoptosis. On the other hand, several cytoprotective BAs were shown to prevent apoptosis in the same concentration range. Still, the mechanisms by which BAs trigger these opposite signaling effects remain unclear. This study was aimed to determine if cytotoxic and cytoprotective BAs, at physiologically active concentrations, are able to modulate the biophysical properties of lipid membranes, potentially translating into changes in the apoptotic threshold of cells. Binding of BAs to membranes was assessed through the variation of fluorescence parameters of suitable derivatized BAs. These derivatives partitioned with higher affinity to liquid disordered than to the cholesterol-enriched liquid ordered domains. Unlabeled BAs were also shown to have a superficial location upon interaction with the lipid membrane. Additionally, the interaction of cytotoxic BAs with membranes resulted in membrane expansion, as concluded from FRET data. Moreover, it was shown that cytotoxic BAs were able to significantly disrupt the ordering of the membrane by cholesterol at physiologically active concentrations of the BA, an effect not associated with cholesterol removal. On the other hand, cytoprotective bile acids had no effect on membrane properties. It was concluded that, given the observed effects on membrane rigidity, the apoptotic activity of cytotoxic BAs could be potentially associated with changes in plasma membrane organization (e.g. modulation of lipid domains) or with an increase in mitochondrial membrane affinity for apoptotic proteins. [Copyright &y& Elsevier]

Abstract: We report herein the first regioselective synthesis of β-galactofuranosides by Fischer glycosidation of GalNAc with methanol catalyzed by HY, HZSM-5 and HBEA acid zeolites. The zeolite HY (Si/Al ratio 3.1) was the most efficient catalyst, leading to the highest yield of methyl β-galactofuranoside, isolated as its acetylated or isopropylidene derivatives, indicating that with large pore zeolites, the reaction efficiency depends upon the concentration of the zeolite acid sites and its hydrophilicity. However, the best regioselectivity for β-galactofuranoside versus β-galactopyranoside was obtained with the medium pore zeolite HZSM-5, which also led to the lowest starting material conversion, suggesting that both the zeolite pore size and topology are determinant for the obtained results. Furthermore, these acid zeolites proved to be efficient catalysts to transform 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-d-arabino-hex-1-enitol (6) (3,4,6-tri-O-benzyl-d-glucal) exclusively in the 2,3-unsaturated-O- and -S-α-d-glycosides by Ferrier rearrangement, in moderate yield. For this reaction, the number of acid sites was the key factor for the reaction yield, being HY (Si/Al ratio 3.1) also the most effective zeolite. [Copyright &y& Elsevier]

The article presents diagrammatic representation of aromatic carbon rings which shows activity of heterocycles against human neutrophile elastase based on a boron promoted one-pot assembly reaction.