Studies of Novel Transition-Metal-Catalyzed Oxidative Coupling Reactions

Transition-metal-catalyzed oxidative coupling reactions are important tools for the construction of carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds from simple starting materials. A series of novel and synthetically useful reactions have been developed and are herein described

Palladium-Catalyzed Decarboxylative Alkoxycarbonylation of Potassium Aryltrifluoroborates with Potassium Oxalate Monoesters

Palladium-catalyzed decarboxylative alkoxycarbonylation of potassium aryltrifluoroborates with potassium oxalate monoesters in the presence of potassium persulfate was performed under mild conditions. A number of benzoyl esters with a wide variety of substituents at different positions were efficiently synthesized with this method. Mechanism of the palladium-catalyzed decarboxylative carbonylation of aryltrifluoroborates was studied, and a radical-mediated Pd(II)/Pd(IV) catalytic cycle was proposed

Palladium-Catalyzed Site-Selective Fluorination of Unactivated C(sp3)−H Bonds

The transition-metal-catalyzed direct C–H bond fluorination is an attractive synthetic tool toward the preparation of organofluorines. While many methods exist for the direct sp3 C–H functionalization, site-selective fluorination of unactivated sp3 carbons remains a challenge. Direct, highly site-selective and diastereoselective fluorination of aliphatic amides via a palladium-catalyzed bidentate ligand-directed C–H bond functionalization process on unactivated sp3 carbons is reported. With this approach, a wide variety of β-fluorinated amino acid derivatives and aliphatic amides, important motifs in medicinal and agricultural chemistry, were prepared with palladium acetate as the catalyst and Selectfluor as the fluorine source

SHP2 phosphatase as a novel therapeutic target for melanoma treatment

Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment

Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/β-Catenin Signaling Pathway

Background/Aims: Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/β-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. Methods: The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1β)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. Results: ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/β-catenin signaling pathway, suggesting that it might serve as a Wnt/β-catenin antagonist to reduce inflammation and prevent cartilage degradation. Conclusion: In conclusion, ART alleviates IL-1β-mediated inflammatory response and OA progression by regulating the Wnt/β-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA

Studies in novel transition-metal-catalyzed oxidative coupling reactions

Transition-metal-catalyzed oxidative coupling reactions are important tools for the construction of carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds from simple starting materials. A series of novel and synthetically useful reactions have been developed and are herein described. Palladium-catalyzed chemoselective decarboxylative cross-coupling of benzoic acids with α-oxocarboxylic acids was realized via an arene sp 2 C-H functionalization process. This work represents the first example of transition-metal-catalyzed cross-coupling reactions with two acids acting in different roles. The synthetic utility of this method was confirmed by the synthesis of pitofenone, an antispasmodic used in the combined drug Spasmalgon. A highly site-selective and diastereoselective fluorination of aliphatic amides via a palladium-catalyzed bidentate ligand-directed C-H bond functionalization process on unactivated sp3 carbons was developed. A wide variety of β-fluorinated amino acid derivatives and aliphatic amides, important motifs in medicinal and agricultural chemistry, were prepared with palladium acetate as the catalyst and selectfluor as the fluorine source. The synthesis for cinnolines from N-phenylhydrazones was performed through an oxidation/cyclization sequence, representing the first copper-catalyzed coupling reaction of hydrazones through a C(sp 3)-H bond functionalization process. The method provides an environmentally friendly and atom-efficient approach to biologically active cinnoline derivatives. A novel rhodium-catalyzed imination of sulfoxides using O-(2,4-dinitrophenyl)-hydroxylamine was developed under mild conditions with good functional group tolerance. The reaction provides an efficient access to free NH-sulfoximines, an important structural unit in a variety of biologically active compounds

Palladium-Catalyzed Chemoselective Decarboxylative Ortho Acylation of Benzoic Acids with α‑Oxocarboxylic Acids

Palladium-catalyzed chemoselective decarboxylative cross coupling of benzoic acids with α-oxocarboxylic acids was realized via an arene sp² C–H functionalization process. This work represents the first example of transition-metal-catalyzed cross-coupling reactions with two acids acting in different roles. The synthetic utility of this method was confirmed by the synthesis of pitofenone, an antispasmodic used in the combined drug Spasmalgon

Copper-promoted site-selective carbonylation of sp3 and sp2 C–H bonds with nitromethane

Copper-promoted direct carbonylation of unactivated sp3 C–H and aromatic sp2 C–H bonds of amides was developed using nitromethane as a novel carbonyl source. The sp3 C–H functionalization showed high site-selectivity by favoring the C–H bonds of α-methyl groups. The sp2 C–H carbonylation featured high regioselectivity and good functional group compatibility. Kinetic isotope effect studies indicated that the sp3 C–H bond breaking step is reversible, whereas the sp2 C–H bond cleavage is an irreversible but not the rate-determining step. Control experiments showed that a nitromethyl intermediate should be involved in the present reaction

Size-Dependent Quantum Efficiency of Flip-Chip Light-Emitting Diodes at High Current Injection Conditions

Versatile applications call for InGaN-based light-emitting diodes (LEDs) to operate at ultra-high current densities with high quantum efficiency. In this work, we investigated the size-dependent effects of the electrical and optical performance of LEDs as increasing the current density up to 100 A/cm2, which demonstrated that mini-strip flip-chip LEDs were superior option to achieve better performance. In detail, at a current density of 100 A/cm2, the light output power density of these mini-strip LEDs was improved by about 6.1 W/cm2, leading to an improvement in the wall-plug efficiency by 4.23%, while the operating temperature was reduced by 11.3 °C, as compared with the large-sized LEDs. This could be attributed to the increase in the sidewall light extraction, alleviated current crowding effect, and improved heat dissipation. This work suggests an array of mini-strip LEDs would provide an option in achieving higher luminescent efficiency at ultrahigh current injection conditions for various applications