Selective Hydrogen Isotope Exchange Catalysed by Simple Alkali-Metal Bases in DMSO.

Isotope Exchange processes are becoming the preferred way to prepare isotopically labelled molecules, avoiding the redesign of multistep synthetic protocols. In the case of deuterium incorporation, the most used strategy has employed transition metals, that offer high reactivity under mild reaction conditions. Despite their success, the trade-off is that these metals are precious, and often exhibit high toxicity.

HEX17(Neumifil): An intranasal respiratory biotherapeutic with broad-acting antiviral activity.

Broad-acting antiviral strategies to prevent respiratory tract infections are urgently required. Emerging or re-emerging viral diseases caused by new or genetic variants of viruses such as influenza viruses (IFVs), respiratory syncytial viruses (RSVs), human rhinoviruses (HRVs), parainfluenza viruses (PIVs) or coronaviruses (CoVs), pose a severe threat to human health, particularly in the very young or old, or in those with pre-existing respiratory conditions such as asthma or chronic obstructive pulmonary disease (COPD). Although vaccines remain a key component in controlling and preventing viral infections, they are unable to provide broad-spectrum protection against recurring seasonal infections or newly emerging threats.

Alkene Isomerisation Catalysed by a Superbasic Sodium Amide.

Typically catalysed by transition metals, alkene isomerisation is a powerful methodology for preparation of internal olefins. In contrast, the use of more earth abundant main group reagents is limited to activated substrates, requiring high temperatures and excess stoichiometric amounts. Opening a new avenue for progressing this field, here we report applications of bulky sodium amide NaTMP (TMP=2,2,6,6-tetramethylpiperidide) when partnered with tridentate Lewis donor PMDETA (N,N,N',N'',N''-pentamethyldiethylenetriamine) in catalytic alkene isomerisation of terminal olefins under mild reaction conditions.

Uncovering the Untapped Potential of the Use of Sodium Amides for Regioselective Arene Functionalisation.

Alkali-metal amides have become key reagents in synthetic chemistry, with special focus in deprotonation reactions. Despite the higher reactivity found in the heavier sodium and potassium amides, their insolubility and low stability has favoured the use of the more soluble  lithium analogues, converting them into the most used non-nucleophilic bases. Studying the coordination effects of Lewis donor molecules such as tridentate amine PMDETA (N,N,N',N'',N''-pentamethyldiethylenetriamine) in combination with the sodium amide NaTMP (TMP = 2,2',6,6'-tetramethylpiperidide), we have been able to unlock the use of these reagents for the functionalisation of arenes, i.

New Frontiers in Organosodium Chemistry as Sustainable Alternatives to Organolithium Reagents.

With their highly reactive respective C-Na and N-Na bonds, organosodium and sodium amide reagents could be viewed as obvious replacements or even superior reagents to the popular, widely utilised organolithiums. However, they have seen very limited applications in synthesis due mainly to poor solubility in common solvents and their limited stability. That notwithstanding in recent years there has been a surge of interest in bringing these sustainable metal reagents into the forefront of organometallics in synthesis.

Sodium mediated deprotonative borylation of arenes using sterically demanding B(CHSiMe): unlocking polybasic behaviour and competing lateral borane sodiation.

The deprotonative metalation of organic molecules has become a convenient route to prepare functionalised aromatic substrates. Amongst the different metallating reagents available, sodium bases have recently emerged as a more sustainable and powerful alternative to their lithium analogues. Here we report the study of the sterically demanding electrophilic trap B(CHSiMe) for the deprotonative borylation of arenes using NaTMP (TMP = 2,2,6,6-tetramethylpiperidide) in combination with tridentate Lewis donor PMDETA (PMDETA = ,,','',''-pentamethyldiethylenetriamine).

Highly Reactive Hydrocarbon Soluble Alkylsodium Reagents for Benzylic Aroylation of Toluenes using Weinreb Amides.

Deaggregating the alkyl sodium NaCH SiMe with polydentate nitrogen ligands enables the preparation and characterisation of new, hydrocarbon soluble chelated alkylsodium reagents. Equipped with significantly enhanced metalating power over their organolithium counterparts, these systems can promote controlled sodiation of weakly acidic benzylic C-H bonds from a series of toluene derivatives under mild stoichiometric conditions. This has been demonstrated through the benzylic aroylation of toluenes with Weinreb amides, that delivers a wide range of 2-arylacetophenones in good to excellent yields.

Perdeuteration of Arenes via Hydrogen Isotope Exchange Catalyzed by the Superbasic Sodium Amide Donor Species NaTMP·PMDETA.

Hydrogen isotope exchange (HIE) has become one of the most studied methods to prepare deuterated molecules, with the primary focus recently on metal-catalyzed C-H activation with transition metals. Here we report the use of a simple sodium amide, NaTMP (TMP = 2,2,6,6-tetramethylpiperidide), combined with tridentate Lewis donor PMDETA (,,',″,″-pentamethyldiethylenetriamine), which is able to catalytically promote the HIE of a series nonactivated arenes under mild reaction conditions using CD as the deuterium source. Establishing the potential of NaTMP for the deuteration of aromatic molecules, several nonactivated substrates such as naphthalene, diphenylacetylene, and stilbene could be deuterated under mild reaction conditions without the need of transition metals.

Factor H-Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy.

Background: C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H-related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear.

Methods: Using and assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain.

Results from two-year rodent oral carcinogenicity studies of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine is a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence. To assess its carcinogenic potential, cizolirtine was administered by oral route once daily for up to 104 weeks to CD-1 mice at doses of 40, 90, or 200 mg/kg/day, and to Han Wistar rats at doses of 40, 90 or 200 mg/kg/day to males and 40, 110 or 160 mg/kg/day to females. There were treatment-related neoplastic findings both in mice and rats.

Enhancing Metalating Efficiency of the Sodium Amide NaTMP in Arene Borylation Applications.

Though LiTMP (TMP=2,2',6,6'-tetramethylpiperidide) is a commonly used amide, surprisingly the heavier NaTMP has hardly been utilised. Here, by mixing NaTMP with tridentate donor PMDETA (N,N,N',N'',N''-pentamethyldiethylenetriamine), we provide structural, and mechanistic insights into the sodiation of non-activated arenes (e.g.

Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease.

Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 () knockout mice. Floxed JNK1/2 () and animals were sacrificed at different time points during progression of liver disease.

Nickel-Catalyzed Reductive Carboxylation and Amidation Reactions.

The ubiquity and importance of carboxylic acids and amides in peptides, pharmaceuticals, agrochemicals, and synthetic materials has challenged chemists to design catalytic carboxylation and amidation protocols. They represent a powerful alternative to canonical oxidation of alcohols and aldehydes, hydrolysis of nitriles, transamidation reactions, or condensation techniques for the synthesis of these functional groups. Among various scenarios, the recent years have witnessed considerable advances in Ni-catalyzed reductive carboxylation and amidation reactions utilizing carbon dioxide and isocyanate counterparts.

Twenty six-week repeat dose oral rat toxicity study of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine, a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence, was orally administered for 26-weeks to rats at dosages of 20, 60 and 200 mg/kg/day. Clinical signs were limited to post-dosing salivation and brown staining on head and muzzle. There were slight decreases in bodyweight gain and slight increases in water consumption among cizolirtine-treated animals.

Assessment of the Genotoxic Potential of Cizolirtine a Substance-P and Calcitonin Gene-Related Peptide Release Modulator.

The analysis of the genotoxic potential of cizolirtine, a compound being developed as a drug for analgesia and for urinary incontinence, was carried out using a battery of and assays as recommended in the guidelines for medicinal products. Negative results were obtained in an Ames test (up to 5000 µg/plate), in a Mouse Lymphoma assay (up to 2000 µg/ml) and in a single dose mouse bone marrow micronucleus assay (up to 300 mg/kg). In a human lymphocyte chromosome aberration assay, a slight statistical increase in the frequency of cells with chromosome aberrations including gaps was reported for the concentrations of 200 and 1600 μg/ml at the 24-h sampling time.

The role of complement in IgA nephropathy.

IgA nephropathy (IgAN) is common and often progresses to end stage renal disease. IgAN encompasses a wide range of histology and clinical features. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition.

Transition-Metal-Catalyzed Carboxylation Reactions with Carbon Dioxide.

Driven by the inherent synthetic potential of CO as an abundant, inexpensive and renewable C chemical feedstock, the recent years have witnessed renewed interest in devising catalytic CO fixations into organic matter. Although the formation of C-C bonds via catalytic CO fixation remained rather limited for a long period of time, a close look into the recent literature data indicates that catalytic carboxylation reactions have entered a new era of exponential growth, evolving into a mature discipline that allows for streamlining the synthesis of carboxylic acids, building blocks of utmost relevance in industrial endeavors. These strategies have generally proven broadly applicability and convenient to perform.

Ni-Catalyzed Site-Selective Dicarboxylation of 1,3-Dienes with CO.

A site-selective catalytic incorporation of multiple CO molecules into 1,3-dienes en route to adipic acids is described. This protocol is characterized by its mild conditions, excellent chemo- and regioselectivity and ease of execution under CO (1 atm), including the use of bulk butadiene and/or isoprene feedstocks.

Complete functional characterization of disease-associated genetic variants in the complement factor H gene.

Genetic analyses in atypical hemolytic uremic syndrome (aHUS) and C3-glomerulopathy (C3G) patients have provided an excellent understanding of the genetic component of the disease and informed genotype-phenotype correlations supporting an individualized approach to patient management and treatment. In this context, a correct categorization of the disease-associated gene variants is critical to avoid detrimental consequences for patients and their relatives. Here we describe a comprehensive procedure to measure levels and functional activity of complement regulator factor H (FH) encoded by CFH, the commonest genetic factor associated with aHUS and C3G, and present the results of the analysis of 28 uncharacterized, disease-associated, FH variants.

Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis.

von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases.