Nickel/Copper Cooperative Catalysis Decarbonylative Heteroarylation of Aryl Anhydrides with Benzoxazoles via C-O/C-H Coupling.

A new strategy for the synthesis of 2-arylbenzoxazole derivatives via nickel-/copper-catalyzed decarbonylative heteroarylation of aryl anhydrides via C-O/C-H coupling has been developed. The reaction is promoted by a user-friendly, inexpensive, and air- and moisture-stable Ni precatalyst. A variety of 2-arylbenzoxazole derivatives have been successfully synthesized and have good functional group tolerance in this process, which afforded products in moderate-to-excellent yields.

RIPK1 inhibition contributes to lysosomal membrane stabilization in ischemic astrocytes via a lysosomal Hsp70.1B-dependent mechanism.

Receptor-interacting protein kinase 1 (RIPK1) contributes to necroptosis. Our previous study showed that pharmacological or genetic inhibition of RIPK1 protects against ischemic stroke-induced astrocyte injury. In this study, we investigated the molecular mechanisms underlying RIPK1-mediated astrocyte injury in vitro and in vivo. Primary cultured astrocytes were transfected with lentiviruses and then subjected to oxygen and glucose deprivation (OGD). In a rat model of permanent middle cerebral artery occlusion (pMCAO), lentiviruses carrying shRNA targeting RIPK1 or shRNA targeting heat shock protein 70.1B (Hsp70.1B) were injected into the lateral ventricles 5 days before pMCAO was established. We showed that RIPK1 knockdown protected against OGD-induced astrocyte damage, blocked the OGD-mediated increase in lysosomal membrane permeability in astrocytes, and inhibited the pMCAO-induced increase in astrocyte lysosome numbers in the ischemic cerebral cortex; these results suggested that RIPK1 contributed to the lysosomal injury in ischemic astrocytes. We revealed that RIPK1 knockdown upregulated the protein levels of Hsp70.1B and increased the colocalization of Lamp1 and Hsp70.1B in ischemic astrocytes. Hsp70.1B knockdown exacerbated pMCAO-induced brain injury, decreased lysosomal membrane integrity and blocked the protective effects of the RIPK1-specific inhibitor necrostatin-1 on lysosomal membranes. On the other hand, RIPK1 knockdown further exacerbated the pMCAO- or OGD-induced decreases in the levels of Hsp90 and the binding of Hsp90 to heat shock transcription factor-1 (Hsf1) in the cytoplasm, and RIPK1 knockdown promoted the nuclear translocation of Hsf1 in ischemic astrocytes, resulting in increased Hsp70.1B mRNA expression. These results suggest that inhibition of RIPK1 protects ischemic astrocytes by stabilizing lysosomal membranes via the upregulation of lysosomal Hsp70.1B; the mechanism underlying these effects involves decreased Hsp90 protein levels, increased Hsf1 nuclear translocation and increased Hsp70.1B mRNA expression.

Valproic Acid Inhibits Glial Scar Formation after Ischemic Stroke.

INTRODUCTION: Cerebral ischemia induces reactive proliferation of astrocytes (astrogliosis) and glial scar formation. As a physical and biochemical barrier, the glial scar not only hinders spontaneous axonal regeneration and neuronal repair but also deteriorates the neuroinflammation in the recovery phase of ischemic stroke. OBJECTIVES: Previous studies have shown the neuroprotective effects of the valproic acid (2-n-propylpentanoic acid, VPA) against ischemic stroke, but its effects on the ischemia-induced formation of astrogliosis and glial scar are still unknown. As targeting astrogliosis has become a therapeutic strategy for ischemic stroke, this study was designed to determine whether VPA can inhibit the ischemic stroke-induced glial scar formation and to explore its molecular mechanisms. METHODS: Glial scar formation was induced by an ischemia-reperfusion (I/R) model in vivo and an oxygen and glucose deprivation (OGD)-reoxygenation (OGD/Re) model in vitro. Animals were treated with an intraperitoneal injection of VPA (250 mg/kg/day) for 28 days, and the ischemic stroke-related behaviors were assessed. RESULTS: Four weeks of VPA treatment could markedly reduce the brain atrophy volume and improve the behavioral deficits in rats' I/R injury model. The results showed that VPA administrated upon reperfusion or 1 day post-reperfusion could also decrease the expression of the glial scar makers such as glial fibrillary acidic protein, neurocan, and phosphacan in the peri-infarct region after I/R. Consistent with the in vivo data, VPA treatment showed a protective effect against OGD/Re-induced astrocytic cell death in the in vitro model and also decreased the expression of GFAP, neurocan, and phosphacan. Further studies revealed that VPA significantly upregulated the expression of acetylated histone 3, acetylated histone 4, and heat-shock protein 70.1B in the OGD/Re-induced glial scar formation model. CONCLUSION: VPA produces neuroprotective effects and inhibits the glial scar formation during the recovery period of ischemic stroke via inhibition of histone deacetylase and induction of Hsp70.1B.

Nickel-Catalyzed Selective Decarbonylation of α-Amino Acid Thioester: Aminomethylation of Mercaptans.

The nickel-catalyzed aminomethylation of mercaptans has been disclosed that offers efficient and expedient access to synthesize α-aminosulfides. The intramolecular fragment coupling shows excellent chemoselectivity. This transformation shows good functional-group compatibility, tolerates a wide range of electron-withdrawing, electron-neutral, and electron-donating substituents in this process, and can serve as a powerful synthetic tool for the synthesis of α-aminosulfides at a gram scale. Thus, the newly developed methodology enables a facile route for C-S bond formation in a straightforward fashion.

Synthesis of Biaryls via Decarbonylative Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Aryl Anhydrides.

Transition metal-catalyzed cross-couplings have been widely employed in the synthesis of many important molecules in synthetic chemistry for the construction of diverse C-C bonds. Conventional cross-coupling reactions require active electrophilic coupling partners, such as organohalides or sulfonates, which are not environmentally friendly enough. Herein, we disclose the first nickel-catalyzed Suzuki-Miyaura cross-coupling of aryl anhydrides and arylboronic acids for the synthesis of biaryls in a decarbonylation manner. The reaction tolerates a wide range of electron-withdrawing, electron-neutral, and electron-donating substituents in this process.

Forging C-S Bonds through Nickel-Catalyzed Aryl Anhydrides with Thiophenols: Decarbonylation or Decarbonylation Accompanied by Decarboxylation.

A nickel-catalyzed decarbonylation or decarbonylation accompanied by decarboxylation cross-coupling reaction of aryl anhydrides with thiophenols as coupling partners was disclosed. This method is promoted by a commercially available, moisture-stable, and inexpensive nickel(II) precatalyst. The process can tolerate a variety of functional groups using ubiquitous aryl anhydrides as cross-coupling precursors to produce thioethers in moderate to excellent yields.

One-Pot Synthesis of N-Imidoyl-(1 H)-indoles via Palladium-Catalyzed Oxidative Insertion Domino Reaction with Isocyanide and Arylboronic Acid.

Efficient one-pot synthesis of N-imidoyl-(1 H)-indoles has been described, which is achieved by the palladium-catalyzed oxidative insertion of 2-(phenylethynyl)aniline, arylboronic acid, and isonitrile. This method provides a new way to synthesize N-imidoyl-(1 H)-indoles, which has a wide substrate scope, good functional group tolerance, and mild reaction condition.

CID1067700, a late endosome GTPase Rab7 receptor antagonist, attenuates brain atrophy, improves neurologic deficits and inhibits reactive astrogliosis in rat ischemic stroke.

Increasing evidence suggests that Ras-related in brain 7 (Rab7), an endosome-localized small GTPase contributes to cerebral ischemic brain injury. In the present study, we investigated the role of Rab7 in ischemic stroke-induced formation of astrogliosis and glial scar. Rats were subjected to transient middle cerebral artery occlusion (tMCAO); the rats were injected with the Rab7 receptor antagonist CID1067700 (CID). Primary astrocytes were subjected to an oxygen and glucose deprivation and reoxygenation (OGD/Re) procedure; CID was added to the cell culture media. We found that Rab7 was significantly elevated over time in both the in vivo and in vitro astrocytic injury models, and administration of CID significantly down-regulated the glial scar markers such as glial fibillary acidic protein (GFAP), neurocan and phosphacan. Moreover, administration of CID significantly attenuated the brain atrophy and improved neurologic deficits in tMCAO rats, and protected astrocytes against OGD/Re-induced injury. Further, CID downregulated the protein levels of Lamp1 and active cathepsin B in astrocytes after OGD/Re or tMCAO injury; CID inhibited the co-localization of cathepsin B and Rab7, Lamp1 and Rab7; CID decreased OGD/Re-induced increase in lysosomal membrane permeability and blocked OGD/Re-induced release of cathepsin B from the lysosome into the cytoplasm in astrocytes. Taken together, these results suggest that Rab7 is involved in ischemic stroke-induced formation of astrogliosis and glial scar. CID administration attenuates brain atrophy and improves neurologic deficits and inhibits astrogliosis and glial scar formation after ischemic stroke via reducing the activation and release of cathepsin B from the lysosome into the cytoplasm.

Coordination of Autophagy and Other Cellular Activities.

Conventionally, autophagy (=self-eating) is thought to be a catabolic cellular process that is responsible for regulating cell homeostasis. However, the newly evidence have expanded the range of the impact of autophagy in biology. Autophagy interplays with endocytosis through shared factors such as phosphatidylinositol 3 kinase complex (PI(3)K complex), autophagy associated gene (Atg), and lysosome. Autophagy and phagocytosis orchestrate in maintaining homeostasis, in MHC class II antigen processing, in the removal of pathogens, in cell death, immunity, and inflammation. There are numerous cross talks of autophagy with biosynthetic processes such as conventional and unconventional secretion of biologically active cargo and trafficking of integral membrane proteins, as well as the exosome secretion. There are also links between autophagy and trafficking events from plasma membrane, including lateral plasma membrane proteins connexins, cell connections, and ciliogenesis.

Cu-Mediated Stereoselective [4+2] Annulation between N-Hydroxybenzimidoyl Cyanide and Norbornene.

A Cu-mediated stereoselective [4+2] annulation between N-hydroxybenzimidoyl cyanides and norbornene (NBE) has been developed for the synthesis of 4 H-1,2-oxazin-4-ones. The reaction proceeds through sequentially forming C-O/C-C bonds. The advantage of this reaction includes high stereoselectivity, excellent yields, as well as simple and mild reaction conditions. A total of 26 examples are presented along with some control experiments.

Palladium-Catalyzed Oxidative Three-Component Coupling of Anthranilamides with Isocyanides and Arylboronic Acids: Access to 2,3-Disubstituted Quinazolinones.

A novel palladium-catalyzed oxidative three-component coupling of easily accessible N-substituted anthranilamides with isocyanides and arylboronic acids is achieved. This protocol offers an alternative approach toward 2,3-disubstituted quinazolinones with a wide substrate scope and good functional group tolerance.

Palladium-catalyzed carbonylative synthesis of isocoumarins and phthalides by using phenyl formate as a carbon monoxide source.

A simple and efficient palladium-catalyzed intramolecular carbonylative synthesis of isocoumarins and phthalides from the easily available starting materials by employing phenyl formate as a CO surrogate has been achieved. The approach affords target compounds in good to excellent yields with the advantages of lower toxicity, milder conditions, easy operation and wide functional group tolerance.

Palladium-catalyzed oxidative coupling of arylboronic acid with isocyanide to form aromatic carboxylic acids.

A valuable palladium-catalyzed oxidative coupling of aryl- and alkenyl borides with isocyanide for the synthesis of corresponding carboxylic acids has been developed. With wide substrate scopes and good functional group tolerance, this reaction offers corresponding carboxylic acids in moderate to excellent yields.

Palladium-Catalyzed Synthesis of α-Iminonitriles from Aryl Halides via Isocyanide Double Insertion Reaction.

An efficient one-pot synthesis of α-iminonitriles from readily available aryl halides via palladium-catalyzed double isocyanide insertion and elimination has been developed, without using various hypertoxic cyanides and excess oxidants. Furthermore, the utility of this reaction was demonstrated by the rapid total synthesis of quinoxaline and the reaction of functional groups exchanged with aryl halides.

Platelet-derived microparticles induce polymorphonuclear leukocyte-mediated damage of human pulmonary microvascular endothelial cells.

BACKGROUND: Platelets (PLTs) stored at 22°C accumulate microparticles and biologic response modifiers (BRMs) that induce inflammatory reactions in transfusion recipients. However, soluble BRMs are fully diluted in the recipient's blood circulation. The mechanisms by which BRMs exert their effects have not been elucidated. The objectives of this study were to determine the effect of PLT microparticles (PMPs) on polymorphonuclear leukocyte (PMN)-mediated human pulmonary microvascular endothelial cell (HMVEC) damage and determine the role of soluble CD40 ligand (sCD40L). STUDY DESIGN AND METHODS: PMPs were isolated from apheresis PLT concentrates. We used a two-insult in vitro model of HMVEC damage to investigate the effects of PMP and sCD40L and role of apocynin, an inhibitor of PMN respiratory burst. Their priming activities were measured using hydrogen peroxide production. The expression of intercellular cell adhesion molecule-1 (ICAM-1) and integrin αM (CD11b) were also determined. RESULTS: Lipopolysaccharide (LPS)-activated HMVEC damage and PMN respiratory burst depend on the presence of PMP and the concentration of sCD40L. PMP-induced PMN-mediated HMVEC damage was significantly reduced by apocynin-treated PMNs (p < 0.05). The surface expression of ICAM-1 on HMVEC was increased by LPS stimulation. The expression of CD11b on PMNs was increased by PMP priming. Blocking ICAM-1 with a monoclonal antibody (MoAb) CD54 significantly reduced HMVEC damage (p < 0.05). The treatment of endothelial cells but not PMN with a MoAb targeting CD40 failed to prevent the HMVEC damage caused by PMPs (p > 0.05). CONCLUSION: PMPs carry a concentrated CD40L signal, promote PMN-mediated HMVEC damage, and may affect the development of transfusion-related acute lung injury.

Palladium-Catalyzed Carbonylative Annulation Reactions Using Aryl Formate as a CO Source: Synthesis of 2-Substituted Indene-1,3(2H)-dione Derivatives.

An efficient synthesis of 2-substituted indene-1,3(2H)-diones from stable and readily available 1-(2-halophenyl)-1,3-diones by employing phenyl formate as a CO source has been developed. The reaction occurred via palladium-catalyzed intramolecular carbonylative annulation using K3PO4 as a base and DMSO as a solvent at 95 °C. In this protocol, the reaction showed a broad substrate scope with good to excellent yields.

Palladium-Catalyzed Domino Synthesis of 4-Amino-3-acyl-2- naphthols via Isocyanide Chemoselective Insertion.

A novel and efficient strategy for the synthesis of sterically hindered 4-amino-3-acyl-2-naphthols through a palladium-catalyzed coupling reaction involving isocyanide chemselective insertion and domino isomerization has been developed. The methodology, which is in accordance with the principle of "atom and step economy", efficiently constructs 4-amino-3-acyl-2-naphthols in moderate to good yields.

Palladium-catalyzed one-pot synthesis of diazoles via tert-butyl isocyanide insertion.

An efficient one-pot palladium-catalyzed reaction for the synthesis of diazoles from readily available hydrazides and aryl halide via isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs diazoles in good to excellent yields with the advantages of wide functional group tolerance and operational simplicity.

Palladium-catalyzed one-pot synthesis of quinazolinones via tert-butyl isocyanide insertion.

A novel palladium-catalyzed three-component reaction for the synthesis of quinazolin-4(3H)-ones from readily available 2-aminobenzamides and aryl halides via a palladium-catalyzed isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs quinazolin-4(3H)-ones in moderate to excellent yields with the advantages of operational simplicity.

Palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides via tert-butyl isocyanide insertion.

A simple and efficient palladium-catalyzed carbonylative Sonogashira coupling via tert-butyl isocyanide insertion has been developed, which demonstrates the utility of isocyanides in intermolecular C-C bond construction. This methodology provides a novel pathway for the synthesis of alkynyl imines which can undergo simple silica gel catalyzed hydrolysis to afford alkynones. The approach is tolerant of a wide range of substrates and applicable to library synthesis.