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We assessed the effects of vildagliptin, a novel dipeptidyl peptidase IV inhibitor, on postprandial lipid and lipoprotein metabolism in patients with type 2 diabetes. This was a single-centre, randomised, double-blind study in drug-naive patients with type 2 diabetes. Patients received vildagliptin (50 mg twice daily, n=15) or placebo (n=16) for 4 weeks. Triglyceride, cholesterol, lipoprotein, glucose, insulin, glucagon and glucagon-like peptide-1 (GLP-1) responses to a fat-rich mixed meal were determined for 8 h postprandially before and after 4 weeks of treatment. Relative to placebo, 4 weeks of treatment with vildagliptin decreased the AUC(0-8h) for total trigyceride by 22+/-11% (p=0.037), the incremental AUC(0-8h) (IAUC(0-8h)) for total triglyceride by 85+/-47% (p=0.065), the AUC(0-8h) for chylomicron triglyceride by 65+/-19% (p=0.001) and the IAUC(0-8h) for chylomicron triglyceride by 91+/-28% (p=0.002). This was associated with a decrease in chylomicron apolipoprotein B-48 (AUC(0-8h), -1.0+/-0.5 mg l(-1) h, p=0.037) and chylomicron cholesterol (AUC(0-8h), -0.14+/-0.07 mmol l(-1) h, p=0.046). Consistent with previous studies, 4 weeks of treatment with vildagliptin also increased intact GLP-1, suppressed inappropriate glucagon secretion, decreased fasting and postprandial glucose, and decreased HbA(1c) from a baseline of 6.7% (change, -0.4+/-0.1%, p<0.001), all relative to placebo. Treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal. The mechanisms underlying the effects of this dipeptidyl peptidase IV inhibitor on postprandial lipid metabolism remain to be explored.

The nucleos(t)ide reverse transcriptase inhibitors, emtricitabine and tenofovir disoproxil fumarate (tenofovir DF), and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, are now available as a fixed-dose single-tablet regimen (emtricitabine/rilpivirine/tenofovir DF; Complera ® , Eviplera ® ) for the treatment of adults infected with HIV-1. In treatment-naïve adults, once-daily emtricitabine/rilpivirine/tenofovir DF was noninferior to once-daily emtricitabine/efavirenz/tenofovir DF with regard to establishing virological suppression over 96 weeks of therapy in a randomized, open-label, phase IIIb study (STaR). These data confirmed the findings of a pooled subset analysis of two earlier 96-week, double-blind, phase III trials (ECHO and THRIVE) in which treatment-naïve adults received either rilpivirine or efavirenz in combination with emtricitabine/tenofovir DF. However, the virological benefit of emtricitabine/rilpivirine/tenofovir DF in this setting appeared limited in patients with low CD4+ cell counts or high viral loads at baseline. In 48-week phase IIIb (SPIRIT) and IIb (Study 111) trials in treatment-experienced patients already virologically suppressed with a single- or multiple-tablet antiretroviral regimen and without prior virological failure, switching to once-daily emtricitabine/rilpivirine/tenofovir DF maintained virological suppression and was noninferior to remaining on a more complex multiple-tablet regimen in this regard. Emtricitabine/rilpivirine/tenofovir DF is generally well tolerated and appears to have a more favourable tolerability profile than emtricitabine/efavirenz/tenofovir DF. Thus, emtricitabine/rilpivirine/tenofovir DF is a welcome addition to the other single-tablet regimens currently available for the treatment of HIV-1 infection, providing a convenient and effective option for some adults who are treatment-naïve, as well as those who are already virologically suppressed on their current treatment regimen and wish to switch because of intolerance or to simplify their regimen.

Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using dual electrocatalysis. Using this strategy, we leverage electrochemistry to seamlessly combine two canonical radical reactions—cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation—to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidants. We also harness electrochemistry’s unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis uncovers the origin of enantio-induction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions to direct the enantio-determining C–CN bond formation. This work demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry.A general method for the enantioselective hydrocyanation of alkenes has been a long-standing synthetic challenge. Now, using a dual electrocatalytic approach that combines two synergistic redox catalytic cycles, a wide variety of chiral nitriles can be synthesized from conjugated alkenes in high enantioselectivity.

We recently described glutathione peroxidase 4 (GPX4) as a promising target for killing therapy-resistant cancer cells via ferroptosis. The onset of therapy resistance by multiple types of treatment results in a stable cell state marked by high levels of polyunsaturated lipids and an acquired dependency on GPX4. Unfortunately, all existing inhibitors of GPX4 act covalently via a reactive alkyl chloride moiety that confers poor selectivity and pharmacokinetic properties. Here, we report our discovery that masked nitrile-oxide electrophiles, which have not been explored previously as covalent cellular probes, undergo remarkable chemical transformations in cells and provide an effective strategy for selective targeting of GPX4. The new GPX4-inhibiting compounds we describe exhibit unexpected proteome-wide selectivity and, in some instances, vastly improved physiochemical and pharmacokinetic properties compared to existing chloroacetamide-based GPX4 inhibitors. These features make them superior tool compounds for biological interrogation of ferroptosis and constitute starting points for development of improved inhibitors of GPX4. Nitrile-oxide electrophiles were identified as covalent inhibitors of GPX4 that exhibit increased selectivity and reduced off-target effects relative to chloroacetamide-based inhibitors.

Amide bond formation is one of the most important reactions in both chemistry and biology 1 – 4 , but there is currently no chemical method of achieving α-peptide ligation in water that tolerates all of the 20 proteinogenic amino acids at the peptide ligation site. The universal genetic code establishes that the biological role of peptides predates life’s last universal common ancestor and that peptides played an essential part in the origins of life 5 – 9 . The essential role of sulfur in the citric acid cycle, non-ribosomal peptide synthesis and polyketide biosynthesis point towards thioester-dependent peptide ligations preceding RNA-dependent protein synthesis during the evolution of life 5 , 9 – 13 . However, a robust mechanism for aminoacyl thioester formation has not been demonstrated 13 . Here we report a chemoselective, high-yielding α-aminonitrile ligation that exploits only prebiotically plausible molecules—hydrogen sulfide, thioacetate 12 , 14 and ferricyanide 12 , 14 – 17 or cyanoacetylene 8 , 14 —to yield α-peptides in water. The ligation is extremely selective for α-aminonitrile coupling and tolerates all of the 20 proteinogenic amino acid residues. Two essential features enable peptide ligation in water: the reactivity and p K aH of α-aminonitriles makes them compatible with ligation at neutral pH and N -acylation stabilizes the peptide product and activates the peptide precursor to (biomimetic) N-to-C peptide ligation. Our model unites prebiotic aminonitrile synthesis and biological α-peptides, suggesting that short N -acyl peptide nitriles were plausible substrates during early evolution. Prebiotic peptide formation is achieved through chemoselective, high-yielding ligation of α-aminonitriles in water, showing selectivity for α-peptide coupling and tolerance of all proteinogenic amino acid residues.

Covalent organic frameworks are a family of crystalline porous materials with promising applications. Although active research on the design and synthesis of covalent organic frameworks has been ongoing for almost a decade, the mechanisms of formation of covalent organic frameworks crystallites remain poorly understood. Here we report the synthesis of a hollow spherical covalent organic framework with mesoporous walls in a single-step template-free method. A detailed time-dependent study of hollow sphere formation reveals that an inside-out Ostwald ripening process is responsible for the hollow sphere formation. The synthesized covalent organic framework hollow spheres are highly porous (surface area ∼1,500 m 2 g −1 ), crystalline and chemically stable, due to the presence of strong intramolecular hydrogen bonding. These mesoporous hollow sphere covalent organic frameworks are used for a trypsin immobilization study, which shows an uptake of 15.5 μmol g −1 of trypsin. Hollow, spherical nano/microstructures are potentially useful for energy and drug delivery applications. Here, the authors show that these structures can be fabricated from covalent organic frameworks, and exploit their chemical stability and mesoporous structures for enzyme encapsulation.

Rapid synthesis of complex molecules via selective functionalization of unactivated carbon–hydrogen bonds is here made easier with the use of removable ‘templates’ that enable the activation of distal bonds. An innovative route to carbon–hydrogen-bond activation The functionalization of unactivated carbon-hydrogen (C–H) single bonds is an efficient and rapid method for the generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity of C–H activation in target molecules possessing multiple inequivalent C–H bonds. These authors report a class of easily removable 'templates' that direct the activation of distal meta-C–H bonds (more than ten bonds away) of a tethered arene. The innovative structures that are generated through this method are extremely hard to access by traditional methods and may provide different avenues for the development of innovative C–H activation reactions. Functionalization of unactivated carbon–hydrogen (C–H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C–H bonds are present in the target molecule. The usual approach is to use σ -chelating directing groups, which lead to ortho -selectivity through the formation of a conformationally rigid six- or seven-membered cyclic pre-transition state 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . Despite the broad utility of this approach, proximity-driven reactivity prevents the activation of remote C–H bonds. Here we report a class of easily removable nitrile-containing templates that direct the activation of distal meta -C–H bonds (more than ten bonds away) of a tethered arene. We attribute this new mode of C–H activation to a weak ‘end-on’ interaction 15 between the linear nitrile group and the metal centre. The ‘end-on’ coordination geometry relieves the strain of the cyclophane-like pre-transition state of the meta -C–H activation event. In addition, this template overrides the intrinsic electronic and steric biases as well as ortho -directing effects with two broadly useful classes of arene substrates (toluene derivatives and hydrocinnamic acids).

Nitriles are uncommon in nature and are typically constructed from oximes through the oxidative decarboxylation of amino acid substrates or from the derivatization of carboxylic acids. Here we report a third nitrile biosynthesis strategy featuring the cyanobacterial nitrile synthase AetD. During the biosynthesis of the eagle-killing neurotoxin, aetokthonotoxin, AetD transforms the 2-aminopropionate portion of 5,7-dibromo- l -tryptophan to a nitrile. Employing a combination of structural, biochemical and biophysical techniques, we characterized AetD as a non-haem diiron enzyme that belongs to the emerging haem-oxygenase-like dimetal oxidase superfamily. High-resolution crystal structures of AetD together with the identification of catalytically relevant products provide mechanistic insights into how AetD affords this unique transformation, which we propose proceeds via an aziridine intermediate. Our work presents a unique template for nitrile biogenesis and portrays a substrate binding and metallocofactor assembly mechanism that may be shared among other haem-oxygenase-like dimetal oxidase enzymes. Nitrile-containing molecules and their biosynthetic enzymes are uncommon in nature. Now, a nitrile-forming diiron enzyme involved in the biosynthesis of aetokthonotoxin—the ‘eagle-killing’ neurotoxin—has been characterized using biochemical, structural and biophysical methods. High-resolution protein crystal structures together with the identification of catalytically relevant tryptophan-based products provide mechanistic insights into this unusual nitrile-forming reaction.

Electrocatalytic reduction of water to molecular hydrogen via the hydrogen evolution reaction may provide a sustainable energy supply for the future, but its commercial application is hampered by the use of precious platinum catalysts. All alternatives to platinum thus far are based on nonprecious metals, and, to our knowledge, there is no report about a catalyst for electrocatalytic hydrogen evolution beyond metals. Here we couple graphitic-carbon nitride with nitrogen-doped graphene to produce a metal-free hybrid catalyst, which shows an unexpected hydrogen evolution reaction activity with comparable overpotential and Tafel slope to some of well-developed metallic catalysts. Experimental observations in combination with density functional theory calculations reveal that its unusual electrocatalytic properties originate from an intrinsic chemical and electronic coupling that synergistically promotes the proton adsorption and reduction kinetics. Electrocatalytic reduction of water is a very important process for developing energy solutions. Here, the authors report a graphitic-carbon nitride/nitrogen-doped graphene composite material capable of efficiently evolving hydrogen, and experimentally and computationally probe the origin of this behaviour.

A method is described for selectively activating remote C–H bonds in heterocycles by using a catalytic template that binds by reversible coordination instead of a covalent linkage, removing the need for specific functional groups on which to attach the template. C–H activation using a reversible template One way to reduce the number of steps in a chemical synthesis is to use C–H activation, in which reactions are directed to specific carbons without needing to have a functional group attached to that carbon. But organic molecules contain many C–H bonds so, to ensure that only one is activated, directing protocols with removable templates have been developed. Jin-Quan Yu and colleagues expand on this idea to enable remote C–H activation of 3-phenylpyridines using a directing template that is temporarily attached through reversible metal–ligand bonds. This methodology means that C–H activation of more remote bonds can be achieved, and the number of steps can be reduced, because the reversibility of the attachment means that the template does not need to be attached and removed in separate steps. In chemical syntheses, the activation of carbon–hydrogen (C–H) bonds converts them directly into carbon–carbon or carbon–heteroatom bonds without requiring any prior functionalization. C–H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C–H bond in a substrate can be activated by using a ‘directing’ (usually a functional) group to obtain the desired product selectively 1 , 2 , 3 , 4 , 5 . The applicability of such a C–H activation reaction can be severely curtailed by the distance of the C–H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations 6 , 7 , 8 , 9 , 10 , 11 , 12 . In one such approach, an understanding of the distal and geometric relationships between the functional groups and C–H bonds of a substrate has been exploited to achieve meta -selective C–H activation by using a covalently attached, U-shaped template 13 , 14 , 15 , 16 , 17 . However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C–H bonds. Using this strategy, we demonstrate remote, site-selective C–H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.