Catalytic glycosylation for minimally protected donors and acceptors.

Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.

Efficacy and safety of perioperative application of ketamine on postoperative depression: A meta-analysis of randomized controlled studies.

Ketamine, a commonly used general anesthetic, can produce rapid and sustained antidepressant effect. However, the efficacy and safety of the perioperative application of ketamine on postoperative depression remains uncertain. We performed a meta-analysis to determine the effect of perioperative intravenous administration of ketamine on postoperative depression. Randomized controlled trials comparing ketamine with placebo in patients were included. Primary outcome was postoperative depression scores. Secondary outcomes included postoperative visual analog scale (VAS) scores for pain and adverse effects associated with ketamine. Fifteen studies with 1697 patients receiving ketamine and 1462 controls were enrolled. Compared with the controls, the ketamine group showed a reduction in postoperative depression scores, by a standardized mean difference (SMD) of -0.97, 95% confidence interval [CI, -1.27, -0.66], P < 0.001, I2 = 72% on postoperative day (POD) 1; SMD-0.65, 95% CI [-1.12, -0.17], P < 0.001, I2 = 94% on POD 3; SMD-0.30, 95% CI [-0.45, -0.14], P < 0.001, I2 = 0% on POD 7; and SMD-0.25, 95% CI [-0.38, -0.11], P < 0.001, I2 = 59% over the long term. Ketamine reduced VAS pain scores on POD 1 (SMD-0.93, 95% CI [-1.58, -0.29], P = 0.005, I2 = 97%), but no significant difference was found between the two groups on PODs 3 and 7 or over the long term. However, ketamine administration distinctly increased the risk of adverse effects, including nausea and vomiting (risk ratio [RR] 1.40, 95% CI [1.12, 1.75], P = 0.003, I2 = 30%), headache (RR 2.47, 95% CI [1.41, 4.32], P = 0.002, I2 = 19%), hallucination (RR 15.35, 95% CI [6.24, 37.34], P < 0.001, I2 = 89%), and dizziness (RR 3.48, 95% CI [2.68, 4.50], P < 0.001, I2 = 89%) compared with the controls. In conclusion, perioperative application of ketamine reduces postoperative depression and pain scores with increased risk of adverse effects.

Melatonin Delays Arthritis Inflammation and Reduces Cartilage Matrix Degradation through the SIRT1-Mediated NF-κB/Nrf2/TGF-ß/BMPs Pathway.

Cartilage, a flexible and smooth connective tissue that envelops the surfaces of synovial joints, relies on chondrocytes for extracellular matrix (ECM) production and the maintenance of its structural and functional integrity. Melatonin (MT), renowned for its anti-inflammatory and antioxidant properties, holds the potential to modulate cartilage regeneration and degradation. Therefore, the present study was devoted to elucidating the mechanism of MT on chondrocytes. The in vivo experiment consisted of three groups: Sham (only the skin tissue was incised), Model (using the anterior cruciate ligament transection (ACLT) method), and MT (30 mg/kg), with sample extraction following 12 weeks of administration. Pathological alterations in articular cartilage, synovium, and subchondral bone were evaluated using Safranin O-fast green staining. Immunohistochemistry (ICH) analysis was employed to assess the expression of matrix degradation-related markers. The levels of serum cytokines were quantified via Enzyme-linked immunosorbent assay (ELISA) assays. In in vitro experiments, primary chondrocytes were divided into Control, Model, MT, negative control, and inhibitor groups. Western blotting (WB) and Quantitative RT-PCR (q-PCR) were used to detect Silent information regulator transcript-1 (SIRT1)/Nuclear factor kappa-B (NF-κB)/Nuclear factor erythroid-2-related factor 2 (Nrf2)/Transforming growth factor-beta (TGF-ß)/Bone morphogenetic proteins (BMPs)-related indicators. Immunofluorescence (IF) analysis was employed to examine the status of type II collagen (COL2A1), SIRT1, phosphorylated NF-κB p65 (p-p65), and phosphorylated mothers against decapentaplegic homolog 2 (p-Smad2). In vivo results revealed that the MT group exhibited a relatively smooth cartilage surface, modest chondrocyte loss, mild synovial hyperplasia, and increased subchondral bone thickness. ICH results showed that MT downregulated the expression of components related to matrix degradation. ELISA results showed that MT reduced serum inflammatory cytokine levels. In vitro experiments confirmed that MT upregulated the expression of SIRT1/Nrf2/TGF-ß/BMPs while inhibiting the NF-κB pathway and matrix degradation-related components. The introduction of the SIRT1 inhibitor Selisistat (EX527) reversed the effects of MT. Together, these findings suggest that MT has the potential to ameliorate inflammation, inhibit the release of matrix-degrading enzymes, and improve the cartilage condition. This study provides a new theoretical basis for understanding the role of MT in decelerating cartilage degradation and promoting chondrocyte repair in in vivo and in vitro cultured chondrocytes.

Direct Stannylation and Silylation of Arylmethanols by Palladium Catalysis.

A direct transformation of non-preactivated benzyl alcohols to benzyl stannanes and benzyl silanes was realized through Pd-catalyzed C(sp3)-O activation process. By using versatile tin and silicon sources, these reactions exhibit a broad substrate scope and a high efficiency under mild conditions, affording functionalized benzyl and allylic stannanes and benzylsilanes with high yields. The successful implementation of gram-scale stannylation/silylation as well as the one-pot Stille coupling reaction demonstrates the potential application of this method in organic synthesis. Both experimental and theoretical investigations reveal the mechanistic details of this reaction.

Recent Development of Aryl Diazonium Chemistry for the Derivatization of Aromatic Compounds.

Aryl diazonium salts are versatile building blocks in organic synthesis. In light of the ever-increasing importance of aryl diazonium salts spanning most disciplines of the chemical sciences, we review the recent development of aryl diazonium chemistry over the past seven years (2013-2020). Special emphasis is put on various new transformations involving the generation of radical intermediates via thermal, photochemical, and electrochemical means. Recent advances in the development of transition metal-catalyzed reactions using aryl diazonium salts are also reviewed. Together, these newly developed transformations significantly expand the synthetic chemist's repertoire of aromatic carbon-carbon and carbon-heteroatom bond forming methods using aryl diazonium precursors, providing powerful tools for the synthesis and modification of complex molecular scaffolds.

Risk of esketamine anesthesia on the emergence delirium in preschool children after minor surgery: a prospective observational clinical study.

Emergence delirium (ED) is a common mental complication during recovery from anesthesia. However, studies on the effects of esketamine, an intravenous anesthetic for pediatrics, on ED are still lacking. This study aimed to investigate the effects of a single-dose of esketamine during anesthesia induction on ED after minor surgery in preschool children. A total of 230 children (aged 2-7 years) completed the study. The exposed group (0.46 mg kg-1: average dose of esketamine) was associated with an increased incidence of ED and a higher maximum Pediatric Anesthesia Emergence Delirium score than the non-exposed group. The length of post-anesthesia care unit stay was longer in the exposed group than the non-exposed group. In contrast, extubation time, face, legs, activity, cry, and consolability (FLACC) scores, and the proportions of rescue analgesics were comparable between the two groups. Furthermore, five factors, including preoperative anxiety scores, sevoflurane and propofol compared with sevoflurane alone for anesthesia maintenance, dezocine for postoperative analgesia, FLACC scores, and esketamine exposure, were associated with ED. In conclusion, a near-anesthetic single-dose of esketamine for anesthesia induction may increase the incidence of ED in preschool children after minor surgery. The use of esketamine in preschool children for minor surgery should be noticed during clinical practice.

Transition Metal Free Stannylation of Alkyl Halides: The Rapid Synthesis of Alkyltrimethylstannanes.

A transition metal free stannylation reaction of alkyl bromides and iodides with hexamethyldistannane has been developed. This protocol is operationally convenient and features a rapid reaction and good functional group tolerance. A wide range of functionalized primary and secondary alkyl and benzyl trimethyl stannanes are prepared in moderate to excellent yields. The success of the gram-scale procedure and tandem Stille coupling reaction has allowed this protocol to demonstrate potential for application in organic synthesis. Both experimental and theoretical studies reveal the mechanistic details of this stannylation reaction.

The anticancer activity of carbazole alkaloids.

Chemotherapy is the first choice for the majority of cancers, but severe side effects and drug resistance restrict the actual clinical efficacy. Carbazole alkaloids, mainly from the Rutaceae family, possess favorable donor ability, good planarity, rich photophysical properties, and excellent biocompatibility. Carbazole alkaloids could not only intercalate in DNA but could also inhibit telomerase and topoisomerase and regulate protein phosphorylation. Hence, carbazole alkaloids are useful in providing lead hits/candidates for the development of novel anticancer agents. This review summarizes the research progress made regarding the anticancer properties of carbazole alkaloids, covering articles published from January 2010 to June 2021.

Downregulation of the NLRP3/Caspse-1 Pathway Ameliorates Ketamine-Induced Liver Injury and Inflammation in Developing Rats.

Ketamine is an anesthetic drug that is widely used in human and veterinary medicine. In the developmental stage, long-term exposure to ketamine may cause serious side effects. MCC950 and VX765 play protective roles in many disease models by regulating the NLRP3/Caspase-1 pathway. This study aims to explore the potential protective effect of MCC950 and VX765 on ketamine-induced liver injury in neonatal rats and clarify its underlying mechanism. After administration of MCC950 and VX765 in a ketamine-induced liver injury rat model, liver function and inflammatory factors were determined, and immunohistochemistry and western blotting were performed. We found that ketamine caused liver injury in 7-day-old SD rats, decreased liver function indexes, and increased inflammation. MCC950 and VX765 effectively alleviated liver damage and inflammation, and downregulated the expression of proteins such as NLRP3, Caspase-1, and GSDMD-N. In summary, these results indicated that MCC950 and VX765 could have potential protective effects on ketamine-induced liver injury through inhibiting the NLRP3/Caspase-1 pathway.

A Library of Rare Earth Oxide Ultrathin Nanowires with Polymer-Like Behaviors.

Ultrathin nanowires (NWs) have always attracted the attention of researchers due to their unique properties, but their facile synthesis is still a great challenge. Herein we developed a general method for the synthesis of rare earth (RE) oxide ultrathin NWs at atmospheric pressure and low temperature (50 °C). The formation mechanism of ultrathin NWs lies in two aspects: thermodynamic advantage of one dimensional (1D) growth at low temperature, and supplement of effective monomers. As an extension, fifteen kinds of RE oxide ultrathin NWs were synthesized through this strategy, and they all exhibited polymer-like behaviors. Meanwhile, the high viscosity, organic gel, wet- and electro-spinning of Ce-Mo-O NWs were studied in detail, demonstrating the similarity of ultrathin inorganic NWs to polymers. In addition, the Ce-Mo-O ultrathin NWs were used as photocatalysts for toluene oxidation and showed excellent performance with toluene conversion ratio of 83.8 %, suggesting their potential application in organic photocatalysis.

Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats.

BACKGROUND: Multiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various neurological diseases. However, the role of NLRP3/caspase-1 axis-related pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain. METHODS: To evaluate whether ketamine caused NLRP3/caspase1-dependent pyroptosis, flow cytometry analysis, western blotting, ELISA test, histopathological analysis, Morris water maze (MWM) test, cell viability assay, and lactate dehydrogenase release (LDH) assay were carried out on PC12 cells, HAPI cells, and 7-day-old rats. In addition, the NLRP3 inhibitor MCC950 or the caspase-1 inhibitor VX-765 was used to investigate the role of the NLRP3/caspase-1 axis in ketamine-induced neurotoxicity and cognitive dysfunction. RESULTS: Our findings demonstrated that ketamine exposure caused cell damage and increased the levels of pyroptosis in PC12 cells, HAPI cells, and the hippocampus of neonatal rats. After continuous exposure to ketamine, targeting NLRP3 and caspase-1 with MCC950 or VX765 improved pyroptosis, reduced neuropathological damages, and alleviated cognitive dysfunction. CONCLUSION: NLRP3/Caspase-1 axis-dependent pyroptosis is involved in ketamine-induced neuroinflammation and cognitive dysfunction, and it provides a promising strategy to treat ketamine-related neurotoxicity.

Metal-Free Trifluoromethylthiolation of Arylazo Sulfones.

A visible-light-driven protocol for the synthesis of aryl trifluoromethyl thioethers under photocatalyst- and metal-free conditions has been pursued. The procedure exploits the peculiar properties of arylazo sulfones (having electron-rich or electron-poor substituents on the (hetero)aromatic ring) as photochemical precursors of aryl radicals and S-trifluoromethyl arylsulfonothioates as easy-to-handle trifluoromethylthiolating agents.

Triptolide suppresses the growth and metastasis of non-small cell lung cancer by inhibiting ß-catenin-mediated epithelial-mesenchymal transition.

Non-small cell lung cancer (NSCLC) is characterized by a high incidence of metastasis and poor survival. As epithelial-mesenchymal transition (EMT) is well recognized as a major factor initiating tumor metastasis, developing EMT inhibitor could be a feasible treatment for metastatic NSCLC. Recent studies show that triptolide isolated from Tripterygium wilfordii Hook F attenuated the migration and invasion of breast cancer, colon carcinoma, and ovarian cancer cells, and EMT played important roles in this process. In the present study we investigated the effect of triptolide on the migration and invasion of NSCLC cell lines. We showed that triptolide (0.5, 1.0, 2.0 nM) concentration-dependently inhibited the migration and invasion of NCI-H1299 cells. Triptolide treatment concentration-dependently suppressed EMT in NCI-H1299 cells, evidenced by significantly elevated E-cadherin expression and reduced expression of ZEB1, vimentin, and slug. Furthermore, triptolide treatment suppressed ß-catenin expression in NCI-H1299 and NCI-H460 cells, overexpression of ß-catenin antagonized triptolide-caused inhibition on EMT, whereas knockout of ß-catenin enhanced the inhibitory effect of triptolide on EMT. Administration of triptolide (0.75, 1.5 mg/kg per day, ip, every 2 days) for 18 days in NCI-H1299 xenograft mice dose-dependently suppressed the tumor growth, restrained EMT, and decreased lung metastasis, as evidence by significantly decreased expression of mesenchymal markers, increased expression of epithelial markers as well as reduced number of pulmonary lung metastatic foci. These results demonstrate that triptolide suppresses NSCLC metastasis by targeting EMT via reducing ß-catenin expression. Our study implies that triptolide may be developed as a potential agent for the therapy of NSCLC metastasis.

Dyedauxiliary Groups, an Emerging Approach in Organic Chemistry. The Case of Arylazo Sulfones.

The number of research papers that report photocatalyst-free protocols is currently increasing. Among the different approaches proposed, the conversion of a strong C-X bond of a stable substrate into a photolabile reactive moiety has been recently proposed. In this Synopsis, we introduce the so-dubbed dyedauxiliary group strategy by focusing on arylazo sulfones that are bench stable and visible-light responsive derivatives of anilines that have been exploited as precursors of a wide range of intermediates, including carbon-centered radicals as well as aryl cations.

Renaissance of Sandmeyer-Type Reactions: Conversion of Aromatic C-N Bonds into C-X Bonds (X = B, Sn, P, or CF3).

The Sandmeyer reaction represents an important organic transformation that converts an arylamine to an aryl halide using Cu(I) halide via a diazonium salt intermediate. The reaction was first reported by Sandmeyer in 1884, and a number of named reactions closely related to it have been developed and widely applied in organic synthesis throughout the 20th century. These include the Pschorr reaction for the synthesis of biaryl tricycles, the Gomberg-Bachmann reaction for biaryl formations, the Balz-Schiemann reaction for C-F bond formations, and the Meerwein reaction for arylation of α,ß-unsaturated carbonyl compounds. However, all these reactions were discovered before 1940. In 1977, Doyle and co-workers reported an organic phase diazotization process, and Kikukawa and Matsuda used aryldiazonium salts in transition metal-catalyzed cross-coupling reactions. However, completely new processes involving diazonium salts have been seldom reported since then, although aryldiazonium salts are widely utilized in modern organic synthesis. In the past few years, diazonium salt chemistry has been revisited and become a fast-growing research topic. Several novel transformations based on diazonium salts have been developed and have been practiced in organic synthesis. In 2010, we reported a direct conversion of arylamines to pinacol boronates through the reaction of in situ generated aryl diazonium salts with B2pin2. This new strategy is under metal-free conditions and thus completely avoids contamination by transition metals in the boron products. From readily available arylamines various functionalized arylboronates, some of which are difficult to access by other methods, can be easily obtained with this reaction. Mechanistic investigations indicate the reaction likely follows a radical mechanism, which is similar to traditional Sandmeyer-type reactions. Subsequently, modified reaction conditions for this transformation appeared in the literature, which include light-induced reactions, aqueous-phase diazotization methods, and reactions with aryltriazenes as the arene diazonium salt surrogates. In addition to the borylation, we have also demonstrated the corresponding stannylation and phosphorylation of arylamines with similar Sandmeyer-type approaches. The stannylation of arylamines was achieved by the reaction of in situ generated diazonium salts with a distannane reagent, while phosphorylation is the reaction of arylamines with trimethyl phosphite in the presence of tert-butyl nitrite (t-BuONO). With the sequential borylation and stannylation approaches, the aromatic compounds bearing two amino groups are easily converted into trimethylstannyl arylboronates, which can be further used in consecutive Stille and Suzuki-Miyaura cross-couplings. Finally, direct conversion of the amino group of arylamines to the trifluoromethyl group has been developed through aryl diazonium salts almost simultaneously by several groups. These reactions represent a novel strategy to achieve trifluoromethylation of aromatic compounds. These developments show the revivification of this age-old chemistry, and this Account will summarize the Sandmeyer reaction-related transformations that have been developed since 2010.

Transition-Metal-Catalyzed Cross-Couplings through Carbene Migratory Insertion.

Transition-metal-catalyzed cross-coupling reactions have been well-established as indispensable tools in modern organic synthesis. One of the major research goals in cross-coupling area is expanding the scope of the coupling partners. In the past decade, diazo compounds (or their precursors N-tosylhydrazones) have emerged as nucleophilic cross-coupling partners in C-C single bond or C═C double bond formations in transition-metal-catalyzed reactions. This type of coupling reaction involves the following general steps. First, the organometallic species is generated by various processes, including oxidative addition, transmetalation, cyclization, C-C bond cleavage, and C-H bond activation. Subsequently, the organometallic species reacts with the diazo substrate to generate metal carbene intermediate, which undergoes rapid migratory insertion to form a C-C bond. The new organometallic species generated from migratory insertion may undergo various transformations. This type of carbene-based coupling has proven to be general: various transition metals including Pd, Cu, Rh, Ni, Co, and Ir are effective catalysts; the scope of the reaction has also been extended to substrates other than diazo compounds; and various cascade processes have also been devised based on the carbene migratory insertion. This review will summarize the achievements made in this field since 2001.

Synthesis of N-arylsulfonamides through a Pd-catalyzed reduction coupling reaction of nitroarenes with sodium arylsulfinates.

A novel one-step direct reductive coupling reaction between nitroarenes and sodium arylsulfinates was realized in the presence of an inexpensive Pd/C catalyst. In this procedure, readily available nitroarenes are employed as the nitrogen sources, and sodium arylsulfinates serve as both coupling partners and reductants. The method features high efficiency by using cheap Pd/C with low catalyst loading and good functional group tolerance in the absence of any additional reductants or ligands. This facile and mild synthetic method enables the high efficiency synthesis of functionalized N-arylsulfonamides from readily available substrates.

Synthesis of Benzyltributylstannanes by the Reaction of N-Tosylhydrazones with Bu3SnH.

An efficient stannylation process with N-tosylhydrazones or directly with carbonyl compounds has been developed. A series of functionalized benzyl- and alkyltributylstannanes can be synthesized in moderate to good yields under transition-metal-free conditions. Tandem transformations involving stannylation/Stille cross-coupling reaction have been carried out without purification of the benzyltributylstannane intermediates to afford a series of diarylmethane derivatives.

Transition-Metal-Free Direct Trifluoromethylthiolation and Trifluoromethylsulfoxidation of Electron-Rich Aromatics with CF3SO2Na in the Presence of PCl3.

A new transition-metal-free route for the direct trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics with CF3SO2Na in the presence of PCl3 was developed. Notably, PCl3 was used as a reducing and chlorination reagent. The transition-metal-free protocol utilized cheap and readily available reagents and exhibited good atom economy; therefore, it will serve as an alternative and practical strategy for the trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics.

Metal-Free Aromatic Carbon-Phosphorus Bond Formation via a Sandmeyer-Type Reaction.

An efficient metal-free phosphorylation process based on a Sandmeyer-type transformation with arylamines as the starting materials is developed. The transformation proceeds smoothly at room temperature without the exclusion of moisture or air. This phosphorylation reaction tolerates a wide range of functional groups and affords the phosphorylation products in moderate to good yields, thus providing a valuable method for the formation of aromatic carbon-phosphorus bonds.