Catalytic Asymmetric Transfer Hydrogenation of Acylboronates: BMIDA as the Privileged Directing Group.

Developing a general, highly efficient, and enantioselective catalytic method for the synthesis of chiral alcohols is still a formidable challenge. We report in this article the asymmetric transfer hydrogenation (ATH) of N-methyliminodiacetyl (MIDA) acylboronates as a general substrate-independent entry to enantioenriched secondary alcohols. ATH of acyl-MIDA-boronates with (het)aryl, alkyl, alkynyl, alkenyl, and carbonyl substituents delivers a variety of enantioenriched α-boryl alcohols. The latter are used in a range of stereospecific transformations based on the boron moiety, enabling the synthesis of carbinols with two closely related α-substituents, which cannot be obtained with high enantioselectivities using direct asymmetric hydrogenation methods, such as the (R)-cloperastine intermediate. Computational studies illustrate that the BMIDA group is a privileged enantioselectivity-directing group in Noyori-Ikariya ATH compared to the conventionally used aryl and alkynyl groups due to the favorable CH-O attractive electrostatic interaction between the η6-arene-CH of the catalyst and the σ-bonded oxygen atoms in BMIDA. The work expands the domain of conventional ATH and shows its huge potential in addressing challenges in symmetric synthesis.

Narrow Bandgap Schottky Heterojunction Sonosensitizer with High Electron-Hole Separation Boosted Sonodynamic Therapy in Bladder Cancer.

Sonodynamic therapy (SDT) is applied to bladder cancer (BC) given its advantages of high depth of tissue penetration and nontoxicity due to the unique anatomical location of the bladder near the abdominal surface. However, low electron-hole separation efficiency and wide bandgap of sonosensitizers limit the effectiveness of SDT. This study aims to develop a TiO2-Ru-PEG Schottky heterojunction sonosensitizer with high electron-hole separation and narrow bandgap for SDT in BC. Density functional theory (DFT) calculations and experiments collectively demonstrate that the bandgap of TiO2-Ru-PEG is reduced due to the Schottky heterojunction with the characteristic of crystalline-amorphous interface formed by the deposition of ruthenium (Ru) within the shell layer of TiO2. Thanks to the enhancement of oxygen adsorption and the efficient separation of electron-hole pairs, TiO2-Ru-PEG promotes the generation of reactive oxygen species (ROS) under ultrasound (US) irradiation, resulting in cell cycle arrest and apoptosis of bladder tumor cells. The in vivo results prove that TiO2-Ru-PEG boosted the subcutaneous and orthotopic bladder tumor models while exhibiting good safety. This study adopts the ruthenium complex for optimizing sonosensitizers, contributing to the progress of SDT improvement strategies and presenting a paradigm for BC therapy.

Asymmetric Transfer Hydrogenation of Cyclobutenediones.

Four-membered carbocycles are fundamental substructures in bioactive molecules and approved drugs and serve as irreplaceable building blocks in organic synthesis. However, developing efficient protocols furnishing diversified four-membered ring compounds in a highly regio-, diastereo-, and enantioselective fashion remains challenging but very desirable. Here, we report the unprecedented asymmetric transfer hydrogenation of cyclobutenediones. The reaction can selectively afford three types of four-membered products in high yields with high stereoselectivities, and the highly functionalized products enable a series of further transformations to form more diversified four-membered compounds. Asymmetric synthesis of di-, tri-, and tetrasubstituted bioactive molecules has also been achieved. Systematic mechanistic studies and theoretical calculations have revealed the origin of the regioselectivity, the key hydrogenation transition state models, and the sequence of the double and triple hydrogenation processes. The work provides a new choice for the catalytic asymmetric synthesis of cyclobutanes and related structures and demonstrates the robustness of asymmetric transfer hydrogenation in the accurate selectivity control of highly functionalized substrates.

Copper-Catalyzed Umpolung Reactivity of Propargylic Carbonates in the Presence of Diboronates: One Stone Four Birds.

Allylation and propargylation are two powerful synthetic strategies for making new substances that have been of significant importance in chemistry, medicine, and material fields. Conventional tactics employ various preformed allylation and propargylation reagents. In this study, a conceptually novel copper-catalyzed and B2pin2-mediated Umpolung reactivity of propargylic carbonates has been achieved for the first time, realizing both allylation and propargylation of aldehydes and ketones without additional reductants. Three types of allylation products and one type of propargylation product are generated efficiently, and all allylation products are formed with syn-configurations predominantly. The choice of ligands plays a vital role in modulating the Umpolung modes. The synthetic applications have been demonstrated in a myriad of further transformations including natural product synthesis, and systematic mechanistic studies have been conducted to reveal detailed insights into the Umpolung processes.

Copper-Catalysed Rearrangement of Cyclic Ethynylethylene Carbonates: Synthetic Applications and Mechanistic Studies.

Transition-metal-catalysed reactions of cyclic ethynylethylene carbonates have been intensively studied because of their robustness in new bond formation and diversified molecule construction. Known reaction modes usually involve a substitution step occurring at either the propargylic or terminal alkyne positions. Here, we report an unprecedented reaction pattern in which cyclic ethynylethylene carbonates first undergo a rearrangement to release allenal intermediates, which subsequently react with diverse nucleophiles to furnish synthetically useful allylic and propargylic allenols, phosphorus ylides, and cyclopropylidene ketones through an addition process rather than a substitution pathway. The products enable various further transformations, and mechanistic studies and theoretical calculations reveal that the reaction does not proceed via a semipinacol type [1,2]-hydride shift, but through base-mediated deprotonation as the key step to induce the rearrangement.

Dynamic Kinetic Resolution of ß-Substituted α-Diketones via Asymmetric Transfer Hydrogenation.

Developing innovative dynamic kinetic resolution (DKR) modes and achieving the highly regio- and enantioselective semihydrogenation of unsymmetrical α-diketones are two formidable challenges in the field of contemporary asymmetric (transfer) hydrogenation. In this work, we report the highly regio- and stereoselective asymmetric semi-transfer hydrogenation of unsymmetrical α-diketones through a unique DKR mode, which features the reduction of the carbonyl group distal from the labile stereocenter, while the proximal carbonyl remains untouched. Moreover, the protocol affords a variety of enantioenriched acyclic ketones with α-hydroxy-α'-C(sp2)-functional groups, which represent a new product class that has not been furnished in known arts. The utilities of the products have been demonstrated in a series of further transformations including the rapid synthesis of drug molecules. Density functional theory calculations and plenty of control experiments have also been conducted to gain more mechanistic insights into the highly selective semihydrogenation.

Oxa-Nazarov Cyclization-Michael Addition Sequence for the Rapid Construction of Dihydrofuranones.

The Nazarov cyclization has been established as a powerful tool in constructing cyclopentenone skeletons. In sharp contrast, oxa-Nazarov cyclization that affords dihydrofuranones, a new type of product, has been less explored. In this work, we report the I2-catalyzed oxa-Nazarov cyclization-Michael addition cascade between vinyl α-diketones and enones. The protocol allows access to a range of functionalized dihydrofuranones with good to high yields, and diverse further transformations on the products have been achieved. Furthermore, the mechanistic studies reveal that the 1,2-hydride shift occurs simultaneously during the dihydrofuranone formation.

Traditional Chinese medicine active ingredients-based selenium nanoparticles regulate antioxidant selenoproteins for spinal cord injury treatment.

BACKGROUND: As Traditional Chinese Medicine (TCM) drugs, Huangqi and Danshen are always applied in combination for spinal cord injury (SCI) treatment based on the compatibility theory of TCM. Astragalus Polysaccharidesis (APS) and Tanshinone IIA (TSIIA) are the main active ingredients of Huangqi and Danshen, and they both possess neuroprotective effects through antioxidant activities. However, low solubility and poor bioavailability have greatly limited their application. In recent years, selenium nanoparticles (SeNPs) have drawn enormous attention as potential delivery carrier for antioxidant drugs. RESULTS: In this study, TCM active ingredients-based SeNPs surface decorated with APS and loaded with TSIIA (TSIIA@SeNPs-APS) were successfully synthesized under the guidance of the compatibility theory of TCM. Such design improved the bioavailability of APS and TSIIA with the benefits of high stability, efficient delivery and highly therapeutic efficacy for SCI treatment illustrated by an improvement of the antioxidant protective effects of APS and TSIIA. The in vivo experiments indicated that TSIIA@SeNPs-APS displayed high efficiency of cellular uptake and long retention time in PC12 cells. Furthermore, TSIIA@SeNPs-APS had a satisfactory protective effect against oxidative stress-induced cytotoxicity in PC12 cells by inhibiting excessive reactive oxygen species (ROS) production, so as to alleviate mitochondrial dysfunction to reduce cell apoptosis and S phase cell cycle arrest, and finally promote cell survival. The in vivo experiments indicated that TSIIA@SeNPs-APS can protect spinal cord neurons of SCI rats by enhancing GSH-Px activity and decreasing MDA content, which was possibly via the metabolism of TSIIA@SeNPs-APS to SeCys2 and regulating antioxidant selenoproteins to resist oxidative stress-induced damage. CONCLUSIONS: TSIIA@SeNPs-APS exhibited promising therapeutic effects in the anti-oxidation therapy of SCI, which paved the way for developing the synergistic effect of TCM active ingredients by nanotechnology to improve the efficacy as well as establishing novel treatments for oxidative stress-related diseases associated with Se metabolism and selenoproteins regulation.

A facile and general method for synthesis of antibiotic-free protein-based hydrogel: Wound dressing for the eradication of drug-resistant bacteria and biofilms.

Antibacterial protein hydrogels are receiving increasing attention in the aspect of bacteria-infected-wound healing. However, bacterial drug resistance and biofilm infections lead to hard healing of wounds, thus the construction of biological agents that can overcome these issues is essential. Here, a simple and universal method to construct antibiotic-free protein hydrogel with excellent biocompatibility and superior antibacterial activity against drug-resistant bacteria and biofilms was developed. The green industrial microbicide tetrakis (hydroxymethyl) phosphonium sulfate (THPS) as cross-linking agent can be quickly cross-linked with model protein bovine serum albumin (BSA) to form antibacterial hydrogel through simple mixing without any other initiators, subsequently promoting drug-resistance bacteria-infected wound healing. This simple gelatinization strategy allows at least ten different proteins to form hydrogels (e.g. BSA, human serum albumin (HSA), egg albumin, chymotrypsin, trypsin, lysozyme, transferrin, myohemoglobin, hemoglobin, and phycocyanin) under the same conditions, showing prominent universality. Furthermore, drug-resistance bacteria and biofilm could be efficiently destroyed by the representative BSA hydrogel (B-Hydrogel) with antibacterial activity, overcoming biofilm-induced bacterial resistance. The in vivo study demonstrated that the B-Hydrogel as wound dressing can promote reepithelization to accelerate the healing of methicillin-resistant staphylococcus aureus (MRSA)-infected skin wounds without inducing significant side-effect. This readily accessible antibiotic-free protein-based hydrogel not only opens an avenue to provide a facile, feasible and general gelation strategy, but also exhibits promising application in hospital and community MRSA disinfection and treatment.

Uptake, transport, and metabolism of selenium and its protective effects against toxic metals in plants: a review.

Selenium (Se) is an essential trace element of fundamental importance to humans, animals, and plants. However, the uptake, transport, and metabolic processes of Se and its underlying mechanisms in plants have not been well characterized. Here, we review our current understanding of the adsorption and assimilation of Se in plants. First, we discussed the conversion of Se from inorganic Se into organic forms, the mechanisms underlying the formation of seleno-amino acids, and the detoxification of Se. We then discussed the ways in which Se protects plants against toxic metal ions in the environment, such as by alleviating oxidative stress, regulating the activity of antioxidant enzymes, sequestering metal ions, and preventing metal ion uptake and accumulation. Generally, this review will aid future research examining the molecular mechanisms underlying the antagonistic relationships between Se and toxic metals in plants.

Access to enantioenriched compounds bearing challenging tetrasubstituted stereocenters via kinetic resolution of auxiliary adjacent alcohols.

Contemporary asymmetric catalysis faces huge challenges when prochiral substrates bear electronically and sterically unbiased substituents and when substrates show low reactivities. One of the inherent limitations of chiral catalysts and ligands is their incapability in recognizing prochiral substrates bearing similar groups. This has rendered many enantiopure substances bearing several similar substituents inaccessible. Here we report the rationale, scope, and applications of the strategy of kinetic resolution of auxiliary adjacent alcohols (KRA*) that can be used to solve the above troubles. Using this method, a large variety of optically enriched tertiary alcohols, epoxides, esters, ketones, hydroxy ketones, epoxy ketones, ß-ketoesters, and tetrasubstituted methane analogs with two, three, and four spatially and electronically similar groups can be readily obtained (totally 96 examples). At the current stage, the strategy serves as the optimal solution that can complement the inability caused by direct asymmetric catalysis in getting chiral molecules with challenging fully substituted stereocenters.

N-Heterocyclic Carbene-Catalyzed Asymmetric Synthesis of Cyclopentenones.

N-Heterocyclic carbene-catalyzed asymmetric construction of cyclopentenones using enals and α-diketones is achieved, furnishing a series of highly functionalized cyclopentenones in a highly diastereo- and enantioselective manner. The protocol tolerates substrates with both aromatic and aliphatic groups, and further transformations of the products delivered a range of value-added molecules.

Induction of ferroptosis in human nasopharyngeal cancer cells by cucurbitacin B: molecular mechanism and therapeutic potential.

Cucurbitacin B (CuB) is a widely available triterpenoid molecule that exhibits various biological activities. Previous studies on the anti-tumour mechanism of CuB have mostly focused on cell apoptosis, and research on the ferroptosis-inducing effect has rarely been reported. Herein, we first discovered the excellent cytotoxicity of CuB towards human nasopharyngeal carcinoma cells and elucidated its potential ferroptosis-inducing mechanisms. Morphology alterations of mitochondrial ultrastructure, as observed via transmission electron microscopy, showed that CuB-treated cells undergo ferroptosis. CuB caused intracellular accumulation of iron ions and depletion of glutathione. Detailed molecular mechanism investigation confirmed that CuB both induced widespread lipid peroxidation and downregulated the expression of GPX4, ultimately initiating a multipronged mechanism of ferroptosis. Furthermore, CuB exhibited anti-tumour effects in vitro by inhibiting cellular microtubule polymerization, arresting cell cycle and suppressing migration and invasion. Finally, CuB significantly inhibited tumour progression without causing obvious side effects in vivo. Altogether, our study highlighted the therapeutic potential of CuB as a ferroptosis-inducing agent for nasopharyngeal cancer, and it provided valuable insights for developing effective anti-tumour agents with novel molecular mechanisms derived from natural products.

Ti(OiPr)4-Facilitated Formal Deoxygenative Annulation of Alkynyl 1,2-Diketones for the Synthesis of Highly Functionalized Furans.

A unique deoxygenative cyclodimerization of alkynyl 1,2-diketones facilitated by Ti(OiPr)4 is achieved, affording a series of highly functionalized furan products. An unusual C-C bond and C═O bond cleavage of the substrates is observed, and Ti(OiPr)4 plays triplicate roles in the reaction. Furthermore, the products show uncommon fluorescent emission in the solid state, indicating the potential practical applications of this work.

Bone mesenchymal stem cell-derived extracellular vesicles promote the repair of intervertebral disc degeneration by transferring microRNA-199a.

Extracellular vesicles (EVs) secreted by bone marrow mesenchymal stem cells (BMSCs) protect intervertebral disc degeneration (IDD) by regulating nucleus pulposus cell (NPC) apoptosis. But the mechanism of BMSCs-EVs-microRNA (miR)-199a in IDD remains unclear. In this study, after the acquisition and identification of BMSCs and BMSCs-EVs, IDD mouse model was established and treated with BMSCs-EVs. The pathological changes of NPCs, positive expression of MMP-2, MMP-6 and TIMP1, and the senescence and apoptosis of NPCs were evaluated. Microarray analysis was employed to analyze the differentially expressed miRs and genes after EV treatment. NPCs were treated with EVs/miR-199a/TGF-ß agonist SRI-011381. The positive expression of col II and Aggrecan was assessed. The target gene and downstream pathway of miR-199a were analyzed. In vivo experiment, after BMSCs-EV treatment, MMP-2, MMP-6, TIMP1 and TUNEL-positive cells in IDD mice were decreased, and miR-199a was increased. In vitro experiments, the expression of col Ⅱ and Aggrecan, SA-ß gal positive cells and apoptosis rate of NPCs were decreased after EV intervention. The protective effect of BMSCs-EVs on NPCs was impaired by reducing miR-199a carried by EVs. miR-199a could target GREM1 to inactivate the TGF-ß pathway. miR-199a carried by BMSCs-EVs promotes IDD repair by targeting GREM1 and downregulating the TGF-ß pathway. Our work confers a promising therapeutic strategy for IDD.

Biomedical Application of Reactive Oxygen Species-Responsive Nanocarriers in Cancer, Inflammation, and Neurodegenerative Diseases.

Numerous pathological conditions, including cancer, inflammatory diseases, and neurodegenerative diseases, are accompanied by overproduction of reactive oxygen species (ROS). This makes ROS vital flagging molecules in disease pathology. ROS-responsive drug delivery platforms have been developed. Nanotechnology has been broadly applied in the field of biomedicine leading to the progress of ROS-responsive nanoparticles. In this review, we focused on the production and physiological/pathophysiological impact of ROS. Particular emphasis is put on the mechanisms and effects of abnormal ROS levels on oxidative stress diseases, including cancer, inflammatory disease, and neurodegenerative diseases. Finally, we summarized the potential biomedical applications of ROS-responsive nanocarriers in these oxidative stress diseases. We provide insights that will help in the designing of new ROS-responsive nanocarriers for various applications.

Divergent Synthesis of Bicyclo[3.2.1]octenes and Cyclohexenes via Catalytic Annulations of Nazarov Reagent and Vinyl 1,2-Diketones.

Bicyclo[3.2.1]octanes and related structures are unique units that widely exist in natural products, but the rapid and stereoselective construction of this skeleton is a challenging issue. We report the stereodivergent synthesis of bicyclo[3.2.1]octenes using Nazarov reagents and alkenyl 1,2-diketones with Brønsted base catalysis under mild conditions. Both stereoisomers of the bridged products can be obtained by tuning the reaction conditions, and cyclohexene product can also be selectively formed.

Catalytic Annulation of Alkynyl 1,2-Diketone Leading to Hydroxy Spirocyclopenteneindenedione: An Organic Dye with Strong Crystallization-Induced Emission and Data Storage Application.

An unprecedented cascade annulation between alkynyl 1,2-diketones and indene-1,3-diones is achieved for the first time, leading to a series of propeller-like large conjugated compounds in ≤99% yield. The products show strong crystallization-induced emission, with the colors changing from green to red. The fluorescence of the dye can be switched on and off by external acid/alkali stimuli, which can be utilized to develop a practical technology for rewritable information storage and security ink.

Percutaneous Full-Endoscopic Lumbar Foraminoplasty and Decompression by Using a Visualization Reamer for Lumbar Lateral Recess and Foraminal Stenosis in Elderly Patients.

BACKGROUND: Percutaneous endoscopic lumbar discectomy has been widely used to treat lumbar disc herniation; its advantages are less trauma, faster recovery, lower costs, and higher percentage of patient satisfaction compared with open surgery. Treatment of lumbar spinal stenosis with percutaneous full-endoscopic surgery is still challenging, especially for elderly patients with multiple comorbidities and complex pathologic factors. The aim of this study was to introduce percutaneous full-endoscopic lumbar foraminoplasty and decompression using a visualization reamer in elderly patients with lateral recess and foraminal stenosis and evaluate efficacy and safety. METHODS: This retrospective review comprised 65 consecutive elderly patients (30 men and 35 women) with lateral recess and foraminal stenosis who underwent percutaneous full-endoscopic lumbar foraminoplasty and discectomy from January 2017 to September 2017. Visual analog scale and Oswestry Disability Index were used to evaluate pain relief and neurologic improvement. RESULTS: Mean patient age was 71.58 years (range, 65-89 years). Mean follow-up period was 16.12 months (range, 12-20 months). Mean operative time was 98.59 minutes per level (range, 55-120 minutes). Mean intraoperative perspective frequency was 3.21 times (range, 2-6 times). Mean hospital stay after the procedure was 2.18 days (range, 1-4 days). Back and leg visual analog scale and Oswestry Disability Index scores at all time points in the postoperative period were significantly lower than preoperatively (P < 0.01). At final follow-up, modified MacNab criteria were rated as follows: excellent, 47 patients (72.31%); good, 12 patients (16.92%); fair, 3 patients (4.62%); and poor, 4 patients (6.15%). Therefore, excellent or good results were obtained in 89.23% of patients. CONCLUSIONS: Percutaneous full-endoscopic lumbar foraminoplasty and discectomy using a visualization reamer is an effective and safe treatment for elderly patients with lumbar lateral recess and foraminal stenosis. It improves safety and efficiency of decompression and reduces intraoperative fluoroscopy.