A sustainable and green route to access diverse functionalized ketones via dehydrogenative–dehydrative cross‐coupling of primary and secondary alcohols is demonstrated. This borrowing hydrogen ...approach employing a pincer N‐heterocyclic carbene Mn complex displays high activity and selectivity. A variety of primary and secondary alcohols are well tolerant and result in satisfactory isolated yields. Mechanistic studies suggest that this reaction proceeds via a direct outer‐sphere mechanism and the dehydrogenation of the secondary alcohol substrates plays a vital role in the rate‐limiting step.
Borrowing hydrogen: A sustainable and green route to access diverse functionalized ketones via dehydrogenative–dehydrative cross‐coupling of primary and secondary alcohols is demonstrated. This borrowing‐hydrogen approach employing a pincer N‐heterocyclic carbene Mn complex displays high activity and selectivity. Mechanistic studies suggest that this reaction proceeds via a direct outer‐sphere mechanism and the dehydrogenation of the secondary alcohol substrates plays a vital role in the rate‐limiting step.
The implementation of non‐noble metals mediated chemistry is a major goal in homogeneous catalysis. Borrowing hydrogen/hydrogen autotransfer (BH/HA) reaction, as a straightforward and sustainable ...synthetic method, has attracted considerable attention in the development of non‐noble metal catalysts. Herein, we report a tungsten‐catalyzed N‐alkylation reaction of anilines with primary alcohols via BH/HA. This phosphine‐free W(phen)(CO)4 (phen=1,10‐phenthroline) system was demonstrated as a practical and easily accessible in‐situ catalysis for a broad range of amines and alcohols (up to 49 examples, including 16 previously undisclosed products). Notably, this tungsten system can tolerate numerous functional groups, especially the challenging substrates with sterically hindered substituents, or heteroatoms. Mechanistic insights based on experimental and computational studies are also provided.
The art of Borrowers: Borrowing hydrogen is one of the most powerful acceptorless dehydrogenative transformations with sustainable feedstocks because of its atomic economy, use of sustainable resources, avoidance of toxic reagents, and no formation of waste byproducts. Traditional catalysts are mainly based on noble metals. Herein, the first example of a tungsten‐catalyzed N‐alkylation of amines with alcohols via borrowing hydrogen. This phosphine‐free approach is simple and tolerate a large number of functional groups.
A new class of large‐but‐flexible Pd‐BIAN‐NHC catalysts (BIAN=acenaphthoimidazolylidene, NHC=N‐heterocyclic carbene) has been rationally designed to enable the challenging Buchwald‐Hartwig amination ...of coordinating heterocycles. This robust class of BIAN‐NHC catalysts permits cross‐coupling under practical aerobic conditions of a variety of heterocycles with aryl, alkyl, and heteroarylamines, including historically challenging oxazoles and thiazoles as well as electron‐deficient heterocycles containing multiple heteroatoms with BIAN‐INon (N,N′‐bis(2,6‐di(4‐heptyl)phenyl)‐7H‐acenaphtho1,2‐dimidazol‐8‐ylidene) as the most effective ligand. Studies on the ligand structure and electronic properties of the carbene center are reported. The study should facilitate the discovery of even more active catalyst systems based on the unique BIAN‐NHC scaffold.
Large‐but‐flexible palladium precatalysts have been rationally designed to enable the challenging Buchwald‐Hartwig amination of coordinating heterocycles. This robust new class of precatalysts permits cross‐coupling of a variety of heterocycles with aryl, alkyl and heteroarylamines, including historically challenging oxazoles and thiazoles as well as electron‐deficient heterocycles containing multiple heteroatoms, under practical aerobic conditions. Studies on the ligand structure and electronic properties of the carbene center are also reported.
Hypoxic-ischemic brain damage (HIBD) is a leading cause of death and disability in neonatal or perinatal all over the world, seriously affecting children, families and society. Unfortunately, only ...few satisfactory therapeutic strategies have been developed. It has been demonstrated that Echinacoside (ECH), the major active component of
Cistanches Herba
, exerts many beneficial effects, including antioxidative, anti-apoptosis, and neuroprotective in the traditional medical practice in China. Previous research has demonstrated that ECH plays a protective effect on ischemic brain injury. This study aimed to investigate whether ECH provides neuroprotection against HIBD in neonatal rats. We subjected 120 seven-day-old Sprague–Dawley rats to cerebral hypoxia–ischemia (HI) and randomly divided into the following groups: sham group, HI group and ECH (40, 80 and 160 mg/kg, intraperitoneal) post-administration group. After 48 h of HI, 2,3,5-Triphenyltetrazolium chloride, Hematoxylin-Eosin and Nissl staining were conducted to evaluate the extent of brain damage. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, total antioxidant capacity (T-AOC), and malondialdehyde (MDA) production were assessed to determine the antioxidant capacity of ECH. TUNEL staining and Western blot analysis was performed to respectively estimate the extent of brain cell apoptosis and the expression level of the apoptosis-related proteins caspase-3, Bax, and Bcl-2. Results showed that ECH remarkably reduced the brain infarct volume and ameliorated the histopathological damage to neurons. ECH post-administration helped recovering the antioxidant enzyme activities and decreasing the MDA production. Furthermore, ECH treatment suppressed neuronal apoptosis in the rats with HIBD was by reduced TUNEL-positive neurons, the caspase-3 levels and increased the Bcl-2/Bax ratio. These results suggested that ECH treatment was beneficial to reducing neuronal damage by attenuating oxidative stress and apoptosis in the brain under HIBD.
To achieve efficient palladium-catalyzed cross-coupling reaction under mild reaction conditions with the flexible steric bulk strategy, a series of Pd-PEPPSI (PEPPSI: pyridine-enhanced precatalyst ...preparation, stabilization, and initiation) complexes C1–C6 were synthesized and characterized, in which unsymmetric flexible steric bulk was introduced on the N-aryl of ancenaphthyl skeleton. These well-defined palladium complexes were found to be excellent precatalysts for Buchwald–Hartwig amination of aryl chlorides with amines in air. The electronic effect of the Pd-PEPPSI complexes and the effect of ancillary pyridine ligands were evaluated, among which complex C3 exhibited the most efficiency. It was demonstrated that the cross-coupling products were obtained in excellent yields in the presence of 0.5–0.1 mol % palladium loading. A wide range of aryl- and heteroaryl chlorides as well as various amines were compatible. The oxidative addition of aryl chlorides is revealed to be the rate-determining step in the catalytic cycle. The catalytic activity can be enhanced by introducing electron-donating groups to the Pd-PEPPSI complexes. This type of Pd-PEPPSI precatalyst showed the most efficiency reported to date for the challenging C–N cross-coupling reactions requiring no anhydrous and inert atmosphere protections, suggesting flexible steric bulk as a promising catalyst design strategy.
A highly efficient and practical protocol has been developed for the synthesis of 5-(hetero)arylated thiazole derivatives via an N-heterocyclic carbene palladium (Pd-NHC) complex catalyzed direct C-H ...arylation reaction. Utilization of this methodology, the arylation of substituted thiazoles with (hetero)aryl bromides efficiently proceeded at low catalyst loading (0.1–0.05 mol%) and under aerobic conditions. A variety of (hetero)aryl bromides, even some strongly deactivated or highly congested (hetero)aryl bromides, with a broad range of functional groups were compatible under the optimal reaction conditions. In all cases, the target products were afforded in moderate to quantitative yields.
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•This work is for better understanding of catalyst design for direct C-H arylation.•Reactions efficiently proceeded under aerobic conditions with low catalyst loading.•Good yields were achieved in most cases.
With the goal of achieving highly efficient palladium-catalyzed cross-coupling reactions under mild reaction conditions, the Pd-PEPPSI complexes C1 and C2 bearing 1,2-di(tert-butyl)acenaphthyl ...(DtBu-An) backbones were synthesized and characterized, and their use in Suzuki–Miyaura cross-coupling was investigated. The effects of catalyst structure and reaction conditions on the cross-coupling efficiency were evaluated in detail. The significant differences in catalytic activity compared with classical PEPPSI-IPr and PEPPSI-IPrAn precatalysts are discussed, where the axial sterics on the backbone play an important role. At low palladium loadings of 0.05–0.1 mol % and upon the addition of the relatively weak base K3PO4, the palladium complex C1 was found to be highly efficient for the coupling of (hetero)aryl chlorides with arylboronic acids under aerobic conditions, affording the corresponding biaryls in excellent yields.
•Vanillin promotes early neurofunctional development on neonatal rats following hypoxic-ischemic brain damage.•Vanillin ameliorates brain infarct volume, brain edema and histomorphological damage ...after HIBD in neonatal rats.•Vanillin alleviates neonatal HIBD possibly by attenuating oxidative damage and preserving BBB integrity.•Vanillin might be a promising neuroprotective candidate for neonatal hypoxic-ischemic encephalopathy.
Neonatal hypoxic-ischemic brain damage (HIBD) is a leading cause of death and perpetual neurological dysfunction in neonates. Vanillin (Van), a natural phenolic compound with neuroprotective properties, exerts neuroprotection on a gerbil model of global ischemia by inhibiting oxidative damage. This study aimed to explore the potential neuroprotective roles of Van in neonatal rats suffering from hypoxic-ischemic (HI). An HI model of 7-day-old SD rats was induced by left carotid artery ligation followed by exposure to 8% oxygen (balanced with nitrogen) for 2.5 h at 37 °C. At 48 h after intraperitoneal injection with Van (20, 40, and 80 mg/kg) or saline, neurobehavioral function, cerebral infract volume, brain water content, and histomorphological changes were performed to evaluate brain injury. Transmission electron microscopy and immunoglobulin G (IgG) staining were conducted to evaluate the integrity of the blood-brain barrier (BBB). The levels of oxidative stress and tight junction proteins, as well as the activities of matrix metalloproteinases (MMPs), were also determined in the ipsilateral hemisphere. Results showed that Van post-treatment significantly ameliorated early neurobehavioral deficits, decreased infarct volume and brain edema, as well as attenuated histopathologic injury and IgG extravasation. Furthermore, Van markedly increased the activities of endogenous antioxidant enzymes and decreased malondialdehyde content. Meanwhile, the activation of MMP-2 and MMP-9 induced by HI was partially blocked by Van. Finally, Van obviously increased the expression of ZO-1, Occludin, and Claudin-5 compared with the HI group. Collectively, Van can provide neuroprotective effects against neonatal HIBD possibly by attenuating oxidative damage and preserving BBB integrity.
Neuronal apoptosis is a major pathological process associated with neurological dysfunction in neonates after hypoxic–ischemic brain damage (HIBD). Our previous study demonstrated that oxymatrine ...(OMT) exerts potential neuroprotective effects on neonatal rats subjected to hypoxic–ischemic insult. However, the underlying molecular mechanism remains unclear. In this study, we investigated the effects of OMT-mediated neuroprotection on neonatal HIBD by attempting to determine its effect on the Wnt/β-catenin signaling pathway and explored the underlying mechanism. Both 7-day-old rat pups and primary hippocampus neurons were used to establish the HIBD and oxygen-glucose deprivation (OGD) injury models, respectively. Our results demonstrated that OMT treatment significantly increased cerebral blood flow and reduced S100B concentration, infarct volume, and neuronal apoptosis in neonatal rats. In vitro, OMT markedly increased cell viability and MMP level and decreased DNA damage. Moreover, OMT improved the mRNA and protein levels of Wnt1 and β-catenin, inhibited the expression of DKK1 and GSK-3β, enhanced the nuclear transfer of β-catenin, and promoted the binding activity of β-catenin with Tcf-4; however, it downregulated the expression of cleaved caspase-3 and cleaved caspase-9. Notably, the introduction of XAV-939 (a Wnt/β-catenin signaling inhibitor) reversed the positive effects of OMT both in vivo and in vitro. Collectively, our findings demonstrated that OMT exerted a neuroprotective effect on neonatal HIBD by inhibiting neuronal apoptosis, which was partly via the activation of the Wnt/β-catenin signaling pathway.
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•OMT treatment alleviated the brain injury in neonatal rats suffering from HI insult.•OMT effectively reversed the apoptosis of hippocampus neurons following OGD injury.•OMT exerted neuroprotection on neonatal HIBD by inhibiting neuronal apoptosis.•Activation of the Wnt/β-Catenin pathway mediated the anti-apoptotic effect of OMT.
Neuropathic pain is a refractory disease that occurs across the world and pharmacotherapy has limited efficacy and/or safety. This disease imposes a significant burden on both the somatic and mental ...health of patients; indeed, some patients have referred to neuropathic pain as being 'worse than death'. The pharmacological agents that are used to treat neuropathic pain at present can produce mild effects in certain patients, and induce many adverse reactions, such as sedation, dizziness, vomiting, and peripheral oedema. Therefore, there is an urgent need to discover novel drugs that are safer and more effective. Natural compounds from medical plants have become potential sources of analgesics, and evidence has shown that glycosides alleviated neuropathic pain via regulating oxidative stress, transcriptional regulation, ion channels, membrane receptors and so on. In this review, we summarize the epidemiology of neuropathic pain and the existing therapeutic drugs used for disease prevention and treatment. We also demonstrate how glycosides exhibit an antinociceptive effect on neuropathic pain in laboratory research and describe the antinociceptive mechanisms involved to facilitate the discovery of new drugs to improve the quality of life of patients experiencing neuropathic pain.
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