Carbonylative Cyclization of 2-Iodofluorobenzenes and 2-Aminophenols with Recyclable Palladium-Complexed Dendrimers on SBA-15: One-Pot Synthesis of Dibenzoxazepinones.

A novel, efficient, and practical route to dibenzoxazepinones has been developed through a one-pot heterogeneous palladium-catalyzed aminocarbonylation/aromatic nucleophilic substitution (SNAr) sequence starting from readily available 2-iodofluorobenzenes and 2-aminophenols. The carbonylative cyclization reaction proceeds smoothly in dimethyl sulfoxide (DMSO) at 120 °C with 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as the base by using a polyamidoamine (PAMAM)-dendronized SBA-15-supported bidentate phosphine-palladium complex [G(1)-2P-Pd(OAc)2-SBA-15] as the catalyst under 10 bar of CO, yielding a wide variety of dibenzo[b,e][1,4]oxazepin-11(5H)-one derivatives in good to excellent yields. Moreover, this new heterogenized dendritic palladium catalyst has competitive advantages in that it can be facilely recovered by simple filtration in air and recycled more than eight times without any significant loss of activity. The broad substrate scope, high functional group tolerance, and excellent palladium catalyst recyclability of the reaction make this approach a general, efficient, and economical method for the construction of valuable dibenzoxazepinone derivatives.

Copper(II)-catalyzed cascade Csp2-P/C-C bond formation to construct benzo[d]thiazol-2-ylphosphonates.

A novel, copper(II)-catalyzed cascade Csp2-P/C-C bond formation in o-haloaryl isothiocyanates with organophosphorus esters has been developed under mild conditions. A series of benzo[d]thiazol-2-ylphosphonates were synthesized in moderate to good yields. Different from the traditional method of obtaining these scaffolds with radical reactions, the method proposed allows accessing them via ionic reactions and has the advantages of easy access to raw materials and simple operation. Finally, we carried out a gram-scale experiment to further demonstrate the scalability of this strategy in the efficient synthesis of benzo[d]thiazol-2-ylphosphonates.

Regio- and Diastereoselective Construction of Functionalized Benzo[b]oxepines and Benzo[b]azepines via Recyclable Gold(I)-Catalyzed Cyclizations.

The heterogeneous gold-catalyzed cyclization of (o-alkynyl)phenoxy- or N-(o-alkynylphenyl)tolylsulfonamidoacrylates with alcohols has been developed by using an MCM-41-anchored diphenylphosphine-Au(I) complex [MCM-41-Ph2P-AuNTf2] as the catalyst under mild reaction conditions, yielding diverse functionalized benzo[b]oxepines or benzo[b]azepines with good to high yields and excellent diastereoselectivity. This heterogenized gold(I) catalyst exhibits a comparable activity to homogeneous Ph3PAuNTf2 and can be facilely recovered by a simple filtration of the reaction solution and reused more than seven times with almost a consistent catalytic efficiency.

[Optimization of formulation of paclitaxel nanosuspension encapsulated by erythrocyte membrane based on Box-Behnken method].

In view of the longevity and innate immune escape of red blood cells, this study designed the red blood cell membrane-coated paclitaxel nanosuspension [RBC-(PTX)NS] and investigated its physicochemical properties and antitumor effect in vitro. Paclitaxel nanosuspension [(PTX)NS] was prepared by ultrasonic precipitation and then RBC-(PTX)NS by ultrasonic coating. The formulation of(PTX)NS was optimized with Box-Behnken method and indexes of particle diameter, zeta potential, and stability. The morphology, particle diameter, stability, in vitro dissolution, and antitumor effect of(PTX)NS and RBC-(PTX)NS were characterized. The results showed that the particle diameter and zeta potential were(129.38±0.92) nm and(-22.41±0.48) mV, respectively, for the optimized(PTX)NS, while(142.5±0.68) nm and(-29.85±0.53) mV, respectively, for RBC-(PTX)NS. Under the transmission electron microscope,(PTX)NS was spherical and RBC-(PTX)NS had obvious core-shell structure. RBC-(PTX)NS remained stable for 5 days at 4 ℃. The in vitro dissolution test demonstrated that the cumulative release rate of RBC-(PTX)NS reached 79% within 20 min, which was significantly higher than that(25%) of(PTX)NS(P<0.05). As evidenced by MTT assay, RBC-(PTX)NS highly inhibited the proliferation of HepG2 cells in a dose-dependent manner. The cell membrane-coated nano-preparation preparation method is simple and reproducible. It improves the solubility of PTX and endows RBC-(PTX)NS with higher stability and stronger cytotoxicity. Thus, it is a new method for the delivery of PTX via nanocrystallization.

Hybrid membrane-coated nanosuspensions for multi-modal anti-glioma therapy via drug and antigen delivery.

BACKGROUND: Glioma is one of the deadliest human cancers. Although many therapeutic strategies for glioma have been explored, these strategies are seldom used in the clinic. The challenges facing the treatment of glioma not only involve the development of chemotherapeutic drugs and immunotherapeutic agents, but also the lack of a powerful platform that could deliver these two moieties to the targeted sites. Herein, we developed chemoimmunotherapy delivery vehicles based on C6 cell membranes and DC membranes to create hybrid membrane-coated DTX nanosuspensions (DNS-[C6&DC]m). RESULTS: Results demonstrated successful hybrid membrane fusion and nanosuspension functionalization, and DNS-[C6&DC]m could be used for different modes of anti-glioma therapy. For drug delivery, membrane coating could be applied to target the source cancer cells via a homotypic-targeting mechanism of the C6 cell membrane. For cancer immunotherapy, biomimetic nanosuspension enabled an immune response based on the professional antigen-presenting characteristic of the dendritic cell membrane (DCm), which carry the full array of cancer cell membrane antigens and facilitate the uptake of membrane-bound tumor antigens for efficient presentation and downstream immune n. CONCLUSION: DNS-[C6&DC]m is a multifunctional biomimetic nano-drug delivery system with the potential to treat gliomas through tumor-targeted drug delivery combined with immunotherapy, thereby presenting a promising approach that may be utilized for multiple modes of cancer therapy.

Cancer Cell Membrane-Coated Nanosuspensions for Enhanced Chemotherapeutic Treatment of Glioma.

Effective intracerebral delivery is key for glioma treatment. However, the drug delivery system within the brain is largely limited by its own adverse physical and chemical properties, low targeting efficiency, the blood-brain barrier and the blood-brain tumor barrier. Herein, we developed a simple, safe and efficient biomimetic nanosuspension. The C6 cell membrane (CCM) was utilized to camouflaged the 10-hydroxycamptothecin nanosuspension (HCPT-NS) in order to obtain HCPT-NS/CCM. Through the use of immune escape and homotypic binding of the cancer cell membrane, HCPT-NS/CCM was able to penetrate the blood-brain barrier and target tumors. The HCPT-NS is only comprised of drugs, as well as a small amount of stabilizers that are characterized by a simple preparation method and high drug loading. Similarly, the HCPT-NS/CCM is able to achieve targeted treatment of glioma without any ligand modification, which leads it to be stable and efficient. Cellular uptake and in vivo imaging experiments demonstrated that HCPT-NS/CCM is able to effectively cross the blood-brain barrier and was concentrated at the glioma site due to the natural homing pathway. Our results reveal that the glioma cancer cell membrane is able to promote drug transport into the brain and enter the tumor via a homologous targeting mechanism.

Recyclable Heterogeneous Palladium-Catalyzed Cyclocarbonylation of 2-Iodoanilines with Acyl Chlorides in the Biomass-Derived Solvent 2-Methyltetrahydrofuran.

A highly efficient, green palladium-catalyzed cyclocarbonylation of 2-iodoanilines with acyl chlorides has been developed that proceeds smoothly in a biomass-derived solvent 2-methyltetrahydrofuran with N,N-diisopropylethylamine as base at 100 °C under 20 bar of carbon monoxide using an 2-aminoethylamino-modified MCM-41-anchored palladium acetate complex [2N-MCM-41-Pd(OAc)2] as a heterogeneous catalyst, yielding a wide variety of 2-substituted 4H-3,1-benzoxazin-4-one derivatives in good to excellent yields. This supported palladium catalyst could be facilely obtained by a two-step procedure from easily available starting materials and readily recovered via a simple filtration process and recycled at least 8 times without any apparent decrease in catalytic efficiency. The developed methodology not only avoids the use of toxic solvents such as tetrahydrofuran and dimethylformamide but also solves the basic problem of expensive palladium catalyst recovery and reuse and prevents effectively palladium contamination of the desired product.

XANES/EPR Evidence of the Oxidation of Nickel(II) Quinolinylpropioamide and Its Application in Csp3 -H Functionalization.

An in situ generated oxidation species of nickel quinolinylpropioamide intermediate was produced. Characterization by X-ray absorption near edge structure (XANES) and EPR provides complementary insights into this oxidized nickel species. With aliphatic amides and isocyanides as substrates, a nickel-catalyzed facile synthesis of structurally diverse five-membered lactams could be achieved.

Synthesis of thiazolo[2,3-b]quinazoline derivatives via base-promoted cascade bicyclization of o-alkenylphenyl isothiocyanates with propargylamines.

A highly efficient cascade bicyclization reaction of o-alkenylphenyl isothiocyanates with propargylamines has been developed, which affords a series of thiazolo[2,3-b]quinazolines in good to excellent yields by using K2CO3 as a base in MeCN at 80 °C. This method is transition-metal-free and operationally simple with broad functional group tolerance. Mechanistically, 6-exo-trig hydroamination followed by 5-exo-dig hydrothiolation was involved in this transformation.

A silver(i)-catalyzed cascade bicyclization strategy for synthesis of 5H-benzo[d]tetrazolo[5,1-b][1,3]thiazines.

A simple and efficient protocol for silver(i)-catalyzed tandem reaction of o-alkynylphenyl isothiocyanates with sodium azide has been developed, affording a series of 5H-benzo[d]tetrazolo[5,1-b][1,3]thiazines in moderate to good yields. In this transformation, a [3 + 2] cycloaddition reaction mechanism was involved and two new rings were formed in one pot.

Copper-catalyzed tandem aryl-halogen hydroxylation and CH2Cl2-based N,O-acetalization toward the synthesis of 2,3-dihydrobenzoxazinones.

The concise synthesis of 2,3-dihydro-4H-benzo[e][1,3]oxazin-4-ones has been accomplished by copper-catalyzed tandem reactions of o-halobenzamides, LiOH and dichloromethane. The aryl-halogen bond hydroxylation and subsequent N,O-acetalization on CH2Cl2 are enabled under catalytic conditions which allows the generation of C(sp2)-O, C(sp3)-O and C(sp3)-N bonds to give the target products.

Phosphine-Free, Heterogeneous Palladium-Catalyzed Atom-Efficient Carbonylative Cross-Coupling of Triarylbismuths with Aryl Iodides: Synthesis of Biaryl Ketones.

A novel and highly efficient heterogeneous palladium-catalyzed carbonylative cross-coupling of aryl iodides with triarylbismuths has been developed that proceeds smoothly at atmospheric CO pressure and provides a general and powerful tool for the preparation of various valuable biaryl ketones with high atom economy, good to excellent yield, and recyclability of the catalyst. The reaction is the first example of Pd-catalyzed carbonylative cross-coupling for the construction of biaryl ketones using triarylbismuths as substrates.

C-H bond halogenation catalyzed or mediated by copper: an overview.

Carbon-halogen (C-X) bonds are amongst the most fundamental groups in organic synthesis, they are frequently and widely employed in the synthesis of numerous organic products. The generation of a C-X bond, therefore, constitutes an issue of universal interest. Herein, the research advances on the copper-catalyzed and mediated C-X (X = F, Cl, Br, I) bond formation via direct C-H bond transformation is reviewed.

Synthesis of indolyl imidazole derivatives via base-promoted tandem reaction of N-[2-(1-alkynyl)phenyl]carbodiimides with isocyanides.

An efficient route to indolyl imidazole derivatives has been developed through a base-promoted tandem reaction of N-[2-(1-alkynyl)phenyl]carbodiimides with isocyanides in DMSO at 40 °C. The present tandem process allows the assembly of a variety of indolyl imidazole derivatives in moderate to good yields.

Targeted Ferroptosis-Immunotherapy Synergy: Enhanced Antiglioma Efficacy with Hybrid Nanovesicles Comprising NK Cell-Derived Exosomes and RSL3-Loaded Liposomes.

Ferroptosis therapy and immunotherapy have been widely used in cancer treatment. However, nonselective induction of ferroptosis in tumors is prone to immunosuppression, limiting the therapeutic effect of ferroptosis cancer treatment. To address this issue, this study reports a customized hybrid nanovesicle composed of NK cell-derived extracellular versicles and RSL3-loaded liposomes (hNRVs), aiming to establish a positive cycle between ferroptosis therapy and immunotherapy. Thanks to the enhanced permeability and retention effect and the tumor homing characteristics of NK exosomes, our data indicate that hNRVs can actively accumulate in tumors and enhance cellular uptake. FASL, IFN-γ, and RSL3 are released into the tumor microenvironment, where FASL derived from NK cells effectively lyses tumor cells. RSL3 downregulates the expression of GPX4 in the tumor, leading to the accumulation of LPO and ROS, and promotes ferroptosis in tumor cells. The accumulation of IFN-γ and TNF-α stimulates the maturation of dendritic cells and effectively induces the inactivation of GPX4, promoting lipid peroxidation, making them sensitive to ferroptosis and indirectly promoting the occurrence of ferroptosis. This study highlights the role of the customized hNRV platform in enhancing the effectiveness of synergistic treatment with selective delivery of ferroptosis inducers and immune activation against glioma without causing additional side effects on healthy organs.

ROS-responsive biomimetic nanosystem camouflaged by hybrid membranes of platelet-exosomes engineered with neuronal targeting peptide for TBI therapy.

Recovery and survival following traumatic brain injury (TBI) depends on optimal amelioration of secondary injuries at lesion site. Delivering mitochondria-protecting drugs to neurons may revive damaged neurons at sites secondarily traumatized by TBI. Pioglitazone (PGZ) is a promising candidate for TBI treatment, limited by its low brain accumulation and poor targetability to neurons. Herein, we report a ROS-responsive nanosystem, camouflaged by hybrid membranes of platelets and engineered extracellular vesicles (EVs) (C3-EPm-|TKNPs|), that can be used for targeted delivery of PGZ for TBI therapy. Inspired by intrinsic ability of macrophages for inflammatory chemotaxis, engineered M2-like macrophage-derived EVs were constructed by fusing C3 peptide to EVs membrane integrator protein, Lamp2b, to confer them with ability to target neurons in inflamed lesions. Platelets provided hybridized EPm with capabilities to target hemorrhagic area caused by trauma via surface proteins. Consequently, C3-EPm-|PGZ-TKNPs| were orientedly delivered to neurons located in the traumatized hemisphere after intravenous administration, and triggered the release of PGZ from TKNPs via oxidative stress. The current work demonstrate that C3-EPm-|TKNPs| can effectively deliver PGZ to alleviate mitochondrial damage via mitoNEET for neuroprotection, further reversing behavioral deficits in TBI mice. Our findings provide proof-of-concept evidence of C3-EPm-|TKNPs|-derived nanodrugs as potential clinical approaches against neuroinflammation-related intracranial diseases.

Synthesis of Degradable Polyolefins Bearing Disulfide Units via Metathesis Copolymerization.

Disulfide bonds are dynamic covalent bonds, which are easy to cleave and reform upon chemical stimulus. Various methods including the oxidative coupling of thiols and polymerization of disulfide-containing monomers have been developed for the synthesis of poly(disulfide)s. However, installing small amounts of disulfide units in the main chain of polyolefins has received much less attention. Herein, we report a novel strategy for incorporating cleavable disulfide units into the backbone of polyolefins using commercially available diallyl disulfide (DADS) as a comonomer via metathesis copolymerization. The copolymerization of diallyl disulfide with cyclooctene occurred using the second-generation Grubbs catalyst under mild conditions, allowing for the synthesis of copolymers with adjustable disulfide content ranging from 0.7 to 8.5 mol%, and the molecular weight of the obtained copolymers ranged from 5.8 kg·mol-1 to 42.8 kg·mol-1. The resulting polyolefins with disulfide insertion retained excellent thermal processability and exhibited degradability. Treatment of the copolymer (8.5 mol% disulfide content) with tri-n-butylphosphine resulted in a significant reduction in molecular weight from 5.8 kg·mol-1 to 1.6 kg·mol-1. Successful copolymerization with diallyl disulfide provides a convenient and effective method for obtaining degradable polyolefins.

Heterogeneous gold-catalyzed Sandmeyer coupling of aryldiazonium salts with sodium bromide or thiols for constructing C-Br and C-S bonds.

An efficient heterogeneous gold-catalyzed Sandmeyer coupling of aryldiazonium salts with sodium bromide or thiols for the formation of C-Br and C-S bonds has been achieved in high yields and selectivities under mild conditions by using a bis(diphenylphosphinomethyl)amino-modified mesoporous MCM-41-immobilized gold(I) chloride complex [MCM-41-2Ph2PAuCl] as the catalyst without using sacrificial oxidants. Vital to the success of this C-heteroatom coupling is the nucleophile-promoted activation of aryldiazonium salts, which can serve as an efficient oxidant for the conversion of Au(I) to Au(III) without the use of a photocatalyst or an assisting ligand. This new heterogenized gold(I) complex can be easily prepared by a simple procedure and recovered via centrifugation, and recycled more than seven times without any significant loss of its catalytic efficiency.

Critical role of VHL/BICD2/STAT1 axis in crystal-associated kidney disease.

Nephrolithiasis is highly prevalent and associated with the increased risk of kidney cancer. The tumor suppressor von Hippel-Lindau (VHL) is critical for renal cancer development, however, its role in kidney stone disease has not been fully elucidated until now. Here we reported VHL expression was upregulated in renal epithelial cells upon exposure to crystal. Utilizing Vhl+/mu mouse model, depletion of VHL exacerbated kidney inflammatory injury during nephrolithiasis. Conversely, overexpression of VHL limited crystal-induced lipid peroxidation and ferroptosis in a BICD2-depdendent manner. Mechanistically, VHL interacted with the cargo adaptor BICD2 and promoted itsd K48-linked poly-ubiquitination, consequently resulting in the proteasomal degradation of BICD2. Through promoting STAT1 nuclear translocation, BICD2 facilitated IFNγ signaling transduction and enhanced IFNγ-mediated suppression of cystine/glutamate antiporter system Xc-, eventually increasing cell sensitivity to ferroptosis. Moreover, we found that the BRAF inhibitor impaired the association of VHL with BICD2 through triggering BICD2 phosphorylation, ultimately causing severe ferroptosis and nephrotoxicity. Collectively, our results uncover the important role of VHL/BICD2/STAT1 axis in crystal kidney injury and provide a potential therapeutic target for treatment and prevention of renal inflammation and drug-induced nephrotoxicity.

Aldh1a1 and Scl25a30 in diaphragmatic dysfunction.

New methods to prevent ventilator-induced diaphragmatic dysfunction (VIDD) are urgently needed, and the cellular basis of VIDD is poorly understood. This study evaluated whether transvenous phrenic nerve stimulation (PNS) could prevent VIDD in rabbits undergoing mechanical ventilation (MV) and explored whether oxidative stress-related genes might be candidate molecular markers for VIDD. Twenty-four adult male New Zealand white rabbits were allocated to control, MV, and PNS groups (n = 8 in each group). Rabbits in the MV and PNS groups underwent MV for 24 h. Intermittent bilateral transvenous PNS was performed in rabbits in the PNS group. Transdiaphragmatic pressure was recorded using balloon catheters. The diameters and cross-sectional areas (CSAs) of types I and II diaphragmatic fibers were measured using immunohistochemistry (IHC) techniques. Genes associated with VIDD were identified by RNA sequencing (RNA-seq), differentially expressed gene (DEG) analysis, and weighted gene co-expression network analysis (WGCNA). Reverse transcription polymerase chain reaction (RT-PCR), Western blotting, and IHC analyses were carried out to verify the transcriptome profile. Pdi60Hz, Pdi80Hz, and Pdi100Hz were significantly higher in the PNS group than in the MV group at 12 and 24 h (P < 0.05 at both time points). The diameters and CSAs of types I (slow-twitch) and II (fast-twitch) fibers were significantly larger in the PNS group than in the MV group (P < 0.05). RNA-seq, RT-PCR, Western blotting, and IHC experiments identified two candidate genes associated with VIDD: Aldh1a1 and Scl25a30. The MV group had significantly higher mRNA and protein expressions of Aldh1a1/ALDH1A1 and significantly lower mRNA and protein expressions of Scl25a30/SCL25A30 than the control or PNS groups (P < 0.05). We have identified two candidate genes involved in the prevention of VIDD by transvenous PNS. These two key genes may provide a theoretical basis for targeted therapy against VIDD.