TBAI-Catalysed Formal [4+4]-Cycloaddition: Easy Access to Oxa-Bridged Eight-Membered Heterocycles.

TBAI-catalysed [4+4]-cyclization reaction of anthranils with hydrazones to deliver oxa-bridged eight-membered heterocycles in accepted yields was developed. Preliminary mechanistic studies indicated that the reaction involved the in situ generation of vinyldiazenes from readily available hydrazones followed by an aza-Michael addition of the anthranil substrates onto the vinyldiazenes and subsequent annulation. This transformation involved the formation of two new C-N bonds and C-O bond in one pot, overcoming the synthetic limitations of anthranils in organic chemistry. This strategy benefits from high efficiency and atomic economy with mild reaction conditions.

MiR-302c-5p affects the stemness and cisplatin resistance of nasopharyngeal carcinoma cells by regulating HSP90AA1.

Nasopharyngeal carcinoma (NPC) is one of the most frequent malignant tumors diagnosed in China. Cisplatin is one of the most commonly used anticancer drugs containing platinum in combined chemotherapy. The molecular mechanism of NPC is still largely unknown, and we aim to spare no effort to elucidate it. Normal human nasopharyngeal epithelial cells and NPC cell lines were cultured. The expression levels of miR-302c-5p and HSP90AA1 were detected with quantitative real-time PCR. Western blotting was used to analyze levels of the HSP90AA1, protein kinase B (AKT), p-AKT, CD44 and SOX2 proteins. The interaction between miR-302c-5p and HSP90AA1 was detected using a luciferase reporter assay. The bicinchoninic acid assay was used to observe cisplatin resistance in NPC cells. Our records confirmed that the expression of miR-302c-5p was substantially reduced and HSP90AA1 was increased in NPC cells. Additionally, miR-302c-5p inhibited cisplatin resistance and the traits of stem cells in NPC. A luciferase assay confirmed that miR-302c-5p is bound to HSP90AA1. Overexpression of HSP90AA1 may reverse the effects of overexpressed miR-302c-5p and inhibit cisplatin resistance and stem cell traits of NPC. This study investigated whether miR-302c-5p inhibited the AKT pathway by regulating HSP90AA1 expression and altered the resistance of NPC cells to cisplatin and the traits of tumor stem cells, which has not yet been reported.

Copper-Catalyzed Bifunctionalization/Annulation of Unactivated Alkene with Alkyl Bromides.

ß-Lactam is a ubiquitous scaffold in bioactive compounds and pharmaceuticals. Herein, we disclose a streamlined method for the construction of ß-lactams starting from unactivated alkenes and alkyl bromides via a Cu-catalyzed inter-/intramolecular carboamidation. This reaction proceeded smoothly under mild reaction conditions and exhibited a broad substrate scope and various functional groups. This protocol is not only compatible with 1, 2, and 3° alkyl bromides but also suitable for α-bromo nitrile as well as various benzyl bromides. The mechanism exploration indicated that sequential radical addition/reductive elimination was involved.

Thiol-promoted intermolecular cyclization to synthesize 1,2,4-oxadiazoles including tioxazafen under transition metal-free conditions.

A simple and efficient one-pot intermolecular annulation reaction for the synthesis of 1,2,4-oxadiazoles from amidoximes and benzyl thiols has been developed, in which benzyl thiols act as not only reactants but also organo-catalysts. The control experiments proved that thiol substrates could facilitate the dehydroaromatization step. High yield, functional group diversity and transition metal-free, extra oxidant-free, and mild conditions are the important practical features. Moreover, this protocol provides an effective alternative method for the synthesis of a commercially available broad-spectrum nematicide, tioxazafen.

EIF4A3-induced circFIP1L1 represses miR-1253 and promotes radiosensitivity of nasopharyngeal carcinoma.

BACKGROUND: Radiation is currently used to be a mainstay of salvage therapy for nasopharyngeal carcinoma (NPC), however, development of radioresistance largely limits the radiation efficacy. Circular RNAs (circRNAs) have been shown to affect NPC progression, but its role in radioresistance remain unclear. METHODS: The circular structure of circFIP1L1(circ_0069740) was verified by RNA-sequencing, RT-PCR based on gDNA or cDNA, RNase R treatment, and actinomycin D treatment. Cellular localization of circFIP1L1 and miR-1253 was detected by nucleoplasmic separation and/or fluorescence in situ hybridization. Expression of non-coding RNAs and mRNAs was detected by qRT-PCR, protein expression was detected by Western blot. Functionally, EdU, CCK-8, and colony formation experiments were employed to assess cell proliferation, flow cytometry was adopted to estimate cell cycle and apoptosis. Xenograft tumor growth was performed to detect the role of circFIP1L1 in vivo. Mechanistically, we examined the interplay between miR-1253 and circFIP1L1 or EIF4A3 through dual-luciferase reporter assay. The potential regulatory impacts of EIF4A3 on circFIP1L1 or PTEN was examined by RNA immunoprecipitation and RNA pull-down assays. RESULTS: CircFIP1L1 overexpression and miR-1253 knockdown repressed NPC cell proliferation, facilitated NPC cell apoptosis, and enhanced NPC radiosensitivity. Mechanistically, circFIP1L1 was revealed to repress miR-1253 by binding to it, and EIF4A3 is a target gene of miR-1253. CircFIP1L1 regulated NPC proliferation, apoptosis, and radiosensitivity through miR-1253/EIF4A3. Moreover, we found that EIF4A3 bound to FIP1L1 mRNA transcript and induced circFIP1L1 formation, and thus stabilizing PTEN mRNA. CONCLUSION: Our findings suggested that EIF4A3-induced circFIP1L1 repressed NPC cell proliferation, facilitated NPC cell apoptosis, and enhanced NPC radiosensitivity by miR-1253.

Ruthenium-Catalyzed ortho-C-H Hydroxyfluoroalkylation of Arenes with Fluorinated Alcohols.

A facile and mild Ru(II)-catalyzed ortho-C-H hydroxyfluoroalkylation of arenes with cheap and easily accessible fluorinated alcohols has been developed in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO). The readily available fluorinated alcohols were used as hydroxyfluoroalkylation reagents to form various α-aryl-α-trifluoromethyl alcohols. The present work provides a new method for the introduction of hydroxyfluoroalkyl groups into arenes.

Copper-promoted difunctionalization of unactivated alkenes with silanes.

An efficient copper-catalyzed cascade difunctionalization of N-allyl anilines toward the synthesis of silylated indolines using commercially available silanes has been reported. This strategy provides a new avenue for the synthesis of a diverse array of indolines in reasonable yields. Preliminary mechanistic investigations indicate that the reaction probably proceeds via a radical pathway with unactivated alkenes as radical acceptors and simple silanes as radical precursors. This protocol is distinguished by its atom economy, broad substrate scope and readily available starting materials.

Metal-free alkylation of quinoxalinones with aryl alkyl ketones.

The first metal-free method for alkylation of quinoxalinones using cheap and stable aryl alkyl ketones as nucleophilic alkylation reagents is reported. This strategy greatly broadens the application channels of aryl alkyl ketones through carbon-carbon bond activation. In addition, the protocol has the advantages of simple operation, broad substrate scope, and good functional group tolerance.

[4 + 2] cycloaddition reactions of ß-naphtha-1-thioquinones generated from 2-naphthols and DAST.

An original and facile method for the generation of ß-naphtha-1-thioquinones using DAST and 2-naphthols has been developed. A series of dehydro-2-naphthol-1-sulphides or naphtha-oxathiane derivatives were synthesized by in situ Diels-Alder cycloaddition reactions of ß-naphtha-1-thioquinone with itself or various alkenes.

A simple approach to C3-ethoxycarbonylmethylation of thiophenes/furans with diethyl bromomalonate.

A mild and efficient visible-light-induced radical method was developed to produce C3-malonated five-membered heterocycles using 2-substituted thiophenes/furans and diethyl bromomalonate as the starting materials. Various 2-substituted (benzo)thiophenes/furans were suitable for the C3-ethoxycarbonylmethylation. The free radical mechanism was proposed based on the results of control experiments, cyclic voltammetry experiments and luminescence quenching experiments. We suggested that the heteroleptic halogen-bridged iridium(III) dimers might play an important role in this system.

Directing group migration strategy in transition-metal-catalysed direct C-H functionalization.

Very recently, directing group (DG) migration has emerged as a practical strategy for transition-metal-catalysed direct C-H activation, resulting in a highly atom-economical process and enabling the reusage of DG. Therefore, great progress has been made in developing multitasking DGs. In this tutorial review, we present the rapid advances of this novel strategy by analyzing and comparing the different types of migratable DGs (including N-O, N-C, N-N or O-C bond cleavage to trigger DG migration). The related mechanisms, as well as synthetic applications, are also mentioned.

Silver(I) Promoted the C4-H Bond Phosphonation of 1-Naphthylamine Derivatives with H-Phosphonates.

A simple and efficient protocol for silver-promoted direct C-H phosphonation of 1-naphthylamine derivatives with H-phosphonates was described. This reaction proceeded smoothly for 1-naphthylamine derivatives at the C4 site, providing a facile and efficient route to 4-phosphonated 1-naphthylamine derivatives. This phosphonation could tolerate a diverse type of functional groups at the pyridinyl and naphthyl moieties. Further functionalization of the phosphonated product was also explored at the C2 and C8 sites, such as fluoridation, methylation, methoxylation, and amination. In addition, DFT studies of the reaction intermediate showed that the most electrophilic reactive site is at the C4 site in the naphthyl ring.

Merging Photoredox Catalysis with Transition Metal Catalysis: Direct C4-H Sulfamidation of 1-Naphthylamine Derivatives.

A mild and efficient protocol for the copper(I)-catalyzed C4-H sulfamidation of 1-naphthylamine derivatives with diphenylsulfonimide (NHSI) was explored at room temperature, affording the desire produces in moderate to good yields. The control experiments indicated that this visible-light-promoted reaction might proceed via a single-electron-transfer process. In addition, preliminary DFT studies for the intermediates in the catalytic cycle were also explored, indicating that the C4 site in the naphthyl ring is the most likely electrophilic reactive site and providing some exact basis for the plausible mechanism.

Visible-Light-Induced Direct Csp2-H Radical Trifluoroethylation of Coumarins with 1,1,1-Trifluoro-2-iodoethane (CF3CH2I).

Herein, we developed the first visible-light-induced direct Csp2-H radical 2,2,2-trifluoroethylation of coumarins with commercially available and cheap reagent CF3CH2I at room temperature. This transformation proceeded smoothly under mild conditions and showed excellent functional group compatibility. The synthetic value of the protocol was also demonstrated by the successful functionalization of several pharmaceuticals.

DPYSL2 as potential diagnostic and prognostic biomarker linked to immune infiltration in lung adenocarcinoma.

BACKGROUND: Dihydropyrimidinase like 2 (DPYSL2) has been linked to tumor metastasis. However, the function of DPSY2L in lung adenocarcinoma (LUAD) is yet to be explored. METHODS: Herein, we assessed DPYSL2 expression in various tumor types via online databases such as Oncomine and Tumor Immune Estimation Resource (TIMER). Further, we verified the low protein and mRNA expressions of DPYSL2 in LUAD via the ULCAN, The TCGA and GEPIA databases. We applied the ROC curve to examine the role of DPYSL2 in diagnosis. The prognostic significance of DPYSL2 was established through the Kaplan-Meier plotter and the Cox analyses (univariate and multivariate). TIMER was used to explore DPYSL2 expression and its connection to immune infiltrated cells. Through Gene Set Enrichment Analysis, the possible mechanism of DPYSL2 in LUAD was investigated. RESULTS: In this study, database analysis revealed lower DPYSL2 expression in LUAD than in normal tissues. The ROC curve suggested that expression of DPYSL2 had high diagnostic efficiency in LUAD. The DPYSL2 expression had an association with the survival time of LUAD patients in the Kaplan-Meier plotter and the Cox analyses. The results from TIMER depicted a markedly positive correlation of DPYSL2 expression with immune cells infiltrated in LUAD, such as macrophages, dendritic cells, CD4+ T cells, and neutrophils. Additionally, many gene markers for the immune system had similar positive correlations in the TIMER analysis. In Gene Set Enrichment Analysis, six immune-related signaling pathways were associated with DPYSL2. CONCLUSIONS: In summary, DPYSL2 is a novel biomarker with diagnostic and prognostic potential for LUAD as well as an immunotherapy target. HIGHLIGHTS: 1. Expression of DPYSL2 was considerably lower in LUAD than in normal tissues. 2. Investigation of multiple databases showed a high diagnostic value of DPYSL2 in LUAD. 3. DPYSL2 can independently predict the LUAD outcomes. 4. Immune-related mechanisms may be potential ways for DPYSL2 to play a role in LUAD.

Copper(II)-Catalyzed Direct Amination of 1-Naphthylamines at the C8 Site.

A new and simple protocol for C8-H amination of 1-naphthylamine derivatives was developed using copper salt and di-tert-butyl peroxide (DTBP) as the catalyst and oxidant, respectively. This reaction proceeded smoothly under the additive and solvent-free conditions. In addition, this amination showed excellent regioselectivity and could tolerate various functional groups.

"One-Pot" Synthesis of γ-Pyrones from Aromatic Ketones/Heteroarenes and Carboxylic Acids.

Despite the various attractive properties of γ-pyrones, there are still some deficiencies in their synthetic approaches such as lower atom economy, multistep processes, and prefunctionalization of the reagents. In this work, an efficient and simple (CF3CO)2O/CF3SO3H-mediated "one-pot" approach was realized to produce γ-pyrones by applying aromatic ketones/heteroarenes and carboxylic acids as the starting materials. The target products were isolated in moderate to excellent yields. The reaction mechanism was studied by density functional theory calculational methods. The results of experimental and theoretical investigations not only helped us explain the reason of high selectivity formation of ß-diketones but also proved that 1,3,5-ketones might be important intermediates for the cyclization to afford γ-pyrones.

Palladium-catalyzed C8-H alkoxycarbonylation of 1-naphthylamines with alkyl chloroformates.

A simple and efficient protocol for palladium-catalyzed C8-H alkoxycarbonylation of 1-naphthylamine derivatives with alkyl chloroformates has been developed, exhibiting broad functional group tolerance, high regioselectivity, and oxidant-free conditions. Furthermore, the reaction features its ease of further functionalization and transformation. For example, the concise synthesis of one BET bromodomain inhibitor was accomplished via benz[cd]indol-2(1H)-one after multistep transformations from the obtained alkoxycarbonylation product. In addition, the control experiments suggest that the reaction might involve a radical process and the C-H bond cleavage might not be involved in the rate-determining step.

A Cu2O/TBAB-promoted approach to synthesize heteroaromatic 2-amines via one-pot cyclization of aryl isothiocyanates with ortho-substituted amines in water.

An efficient approach to synthesize heteroaromatic 2-amines from one-pot desulfurization/dehydrogenative cyclization of aryl isothiocyanates with ortho-substituted amines in water was developed. This approach tolerated a wide range of functional groups on the aromatic ring, providing a practical and environment-friendly process to synthesize heteroaromatic 2-amines in moderate to excellent yields. A plausible mechanism was proposed and the role of TBAB and Cu2O in the present strategy was suggested with the help of ESI mass spectrometry.

External oxidant-free alkylation of quinoline and pyridine derivatives.

A novel and efficient method for the generation of alkyl radicals and the alkylation of quinoline and pyridine derivatives under mild conditions has been developed. This strategy allows the direct alkylation of heteroaromatics in the absence of an external oxidant. A preliminary mechanistic study suggests that the present reaction probably proceeds via an intermolecular HAT process.