Palladium-Catalyzed Enantioselective Intramolecular Heck Dearomative Annulation of Indoles with N-Tosylhydrazones.

An elegant Pd(dba)2-catalyzed enantioselective Heck dearomative annulation of indoles and N-tosylhydrazones for the straightforward assembly of structurally diverse optically active indoline scaffolds containing the quaternary carbon centers at the C2 position has been developed. The tandem protocol, which utilized a Pd(dba)2/BINOL-based phosphoramidite ligand as the catalytic system, proceeded smoothly through successive oxidative addition, intramolecular carbon palladation, migratory insertion, and ß-elimination sequences, leading to the chiral indoline derivatives in moderate to excellent yields, with excellent enantioselectivities and diastereoselectivities. In addition, the synthetic practicability of the catalytic system was underlined by a scaled-up experiment and the late-stage derivatization of the products, thus highlighting the potential applications in synthetic chemistry, medicinal chemistry, and material science.

Lewis Acid Catalyzed [4 + 2] Annulation of Propargylic Alcohols with 2-Vinylanilines.

An elegant Lewis acid catalyzed, protection-free, and straightforward synthetic strategy for the assembly of a series of sophisticated polycyclic quinoline skeletons employing propargylic alcohols and 2-vinylanilines as the substrates in the presence of Yb(OTf)3 (10 mol %) and AgOTf (10 mol %) in tetrahydrofuran has been described. This annulation protocol, which proceeds through a sequential Meyer-Schuster rearrangement/nucleophilic substitution/deprotonation sequence, provides a versatile, practical, and atom-economical approach for accessing quinoline derivatives in moderate-to-good yields.

New synthetic approaches toward OCF3-containing compounds.

Fluorinated organic compounds are an important class of organic molecules and play a key role in both academic and industrial communities due to the unique nature of fluorine. Among the fluorine-containing functional groups, the OCF3 group is of vital importance because of its favorable physicochemical properties, so it frequently acts as the pivotal skeletal motif in a broad spectrum of pharmaceutical molecules, agrochemicals, natural products, and materials. Over the past few decades, a wider range of strategies for the efficient, versatile, and practical synthesis of trifluoromethoxylated compounds have been the focus of a number of research initiatives. These synthesis approaches are especially fascinating in the context of the design of agrochemicals and new drugs as established pathways for installing the OCF3 moiety. In this review, the state of the art of the synthesis of OCF3-containing compounds is summarized. It can be segmented into six categories: (1) de novo formation of the OCF3 group; (2) construction of trifluoromethoxylated compounds via trifluoromethylation of the corresponding alcohol or phenol; (3) construction of trifluoromethoxylated compounds via installing the entire OCF3 group straightaway onto a complex molecule; (4) visible-light-induced trifluoromethoxylation; (5) transition metal-catalyzed trifluoromethoxylation; and (6) construction of the trifluoromethoxylated compounds via rearrangement reactions.

Flexible open conformation of the AP-3 complex explains its role in cargo recruitment at the Golgi.

Vesicle formation at endomembranes requires the selective concentration of cargo by coat proteins. Conserved adapter protein complexes at the Golgi (AP-3), the endosome (AP-1), or the plasma membrane (AP-2) with their conserved core domain and flexible ear domains mediate this function. These complexes also rely on the small GTPase Arf1 and/or specific phosphoinositides for membrane binding. The structural details that influence these processes, however, are still poorly understood. Here we present cryo-EM structures of the full-length stable 300 kDa yeast AP-3 complex. The structures reveal that AP-3 adopts an open conformation in solution, comparable to the membrane-bound conformations of AP-1 or AP-2. This open conformation appears to be far more flexible than AP-1 or AP-2, resulting in compact, intermediate, and stretched subconformations. Mass spectrometrical analysis of the cross-linked AP-3 complex further indicates that the ear domains are flexibly attached to the surface of the complex. Using biochemical reconstitution assays, we also show that efficient AP-3 recruitment to the membrane depends primarily on cargo binding. Once bound to cargo, AP-3 clustered and immobilized cargo molecules, as revealed by single-molecule imaging on polymer-supported membranes. We conclude that its flexible open state may enable AP-3 to bind and collect cargo at the Golgi and could thus allow coordinated vesicle formation at the trans-Golgi upon Arf1 activation.

Visible-Light-Induced Oxyalkylation of 1,2,4-Triazine-3,5(2H, 4H)-diones with Ethers via Oxidative Cross-Dehydrogenative Coupling.

An efficient and convenient method to synthesize 6-oxyalkylated 1,2,4-triazine-3,5(2H, 4H)-diones has been developed via visible-light-induced cross-dehydrogenative coupling reaction between 1,2,4-triazine-3,5(2H, 4H)-diones and ethers with a wide range of functional group tolerance. The present transformation employs the cheap and low-toxic 2-tert-butylanthraquinone as a metal-free photocatalyst and air as a green oxidant at room temperature. Moreover, this reaction can also be driven by sunlight as a clean energy resource. The synthetic utility of this method is further demonstrated by gram-scale reaction and application in the preparation of key intermediates of bioactive molecules.

Primary Amination of Ar2P(O)-H with (NH4)2CO3 as an Ammonia Source under Simple and Mild Conditions and Its Extension to the Construction of Various P-N or P-O Bonds.

A facile and efficient method for the synthesis of primary phosphinamides from Ar2P(O)-H reagents with stable and readily available ammonium carbonate as an ammonia source is disclosed herein for the first time. This ethyl bromoacetate-mediated primary amination proceeds smoothly under mild and simple conditions, without any metal catalyst or oxidant. Moreover, this method is also appropriate for the reaction of Ar2P(O)-H with a variety of amines, alcohols, and phenols to construct P-N or P-O bonds, with features of handy operation, good functional group tolerance, and broad substrate scope.

Palladium-Catalyzed Intramolecular Heck Dearomative Alkenylation of Indoles with N-Tosylhydrazones.

An elegant Pd-catalyzed intramolecular Heck dearomative alkenylation of aryl iodides with functionalized N-tosylhydrazones proceeded through a sequential dearomative carbopalladation, migratory insertion, and ß-hydride elimination in the presence of Pd(CF3COO)2 (10 mol %), PPh3 (30 mol %), and Cs2CO3 (2.0 equiv) in 1,4-dioxane (2.0 mL) at 120 °C for 14 h under an argon atmosphere. This cascade cycloaddition protocol provided a reliable and versatile approach to a sequence of structurally diverse indolines in moderate to good yields with good functional group compatibility. In addition, the synthetic robustness of the methodology is highlighted by a scaled-up experiment and derivatization of products via epoxidation and reduction reactions.

DEPP Deficiency Contributes to Browning of White Adipose Tissue.

Decidual protein induced by progesterone (DEPP) was originally identified as a modulator in the process of decidualization in the endometrium. Here, we define that DEPP is involved in adipose tissue thermogenesis, which contributes to metabolic regulation. Knockdown of DEPP suppressed adipocyte differentiation and lipid accumulation in 3T3-L1 cells, induced expression of brown adipose tissue (BAT) markers in primary brown adipocyte and induced mouse embryonic fibroblasts (MEFs) differentiation to brown adipocytes. Moreover, DEPP deficiency in mice induced white adipocyte browning and enhanced BAT activity. Cold exposure stimulated more browning of white adipose tissue (WAT) and maintained higher body temperature in DEPP knockout mice compared to that in wild-type control mice. DEPP deficiency also protected mice against high-fat-diet-induced insulin resistance. Mechanistic studies demonstrated that DEPP competitively binds SIRT1, inhibiting the interaction between peroxisome proliferator-activated receptor gamma (PPARγ) and Sirtuin 1 (SIRT1). Collectively, these findings suggest that DEPP plays a crucial role in orchestrating thermogenesis through regulating adipocyte programs and thus might be a potential target for the treatment of metabolic disorders.

Visible-Light-Induced C(sp2)-C(sp3) Cross-Dehydrogenative-Coupling Reaction of N-Heterocycles with N-Alkyl-N-methylanilines under Mild Conditions.

Disclosed herein is a cross-dehydrogenative-coupling reaction of N-heterocycles including 1,2,4-triazine-3,5(2H, 4H)-diones and quinoxaline-2(1H)-ones with N-methylanilines to form C(sp2)-C(sp3) under visible-light illumination and ambient air at room temperature. In this process, easily available Ru(bpy)3Cl2·6H2O serves as the catalyst, and air acts as the green oxidant. This method features high atom economy, environmental friendliness, and convenient operation and provides an efficient and practical access to aminomethyl-substituted N-heterocycles with extensive functional group compatibility in 40-86% yields.

Palladium-Catalyzed Asymmetric Intramolecular Dearomative Heck Annulation of Aryl Halides to Furnish Indolines.

An unprecedented Pd-catalyzed asymmetric intramolecular cascade cyclization of aryl halides with readily available arylboronic acids proceeds through a Heck-type dearomative cyclization terminated with arylation in the presence of Pd2(dba)3 (10 mol %), Cu2O (5 mol %), and Cs2CO3 (2.0 equiv) in 1,2-dichloroethane (1.0 mL) at 100 °C for 15 h in air using BINOL-based phosphoramidite as the chiral ligand. This dearomative Heck protocol, which tolerates a broad variety of functional groups, is amenable to the generation of optically active indoline derivatives bearing all-carbon quaternary stereogenic centers in one step in moderate to excellent yields, with excellent diastereoselectivities (>20:1) and enantioselectivities (up to >99% ee). It is worth mentioning that no decrease in the enantiopurity of the indoline derivatives was observed during the synthetic transformations of the products.

A 2-step algorithm combining glutamate dehydrogenase and nucleic acid amplification tests for the detection of Clostridioides difficile in stool specimens.

The optimized diagnosis algorithm of Clostridioides difficile infection (CDI) is worldwide concerns. The purpose of this study was to assess the toxigenic C. difficile test performance and propose an optimal laboratory workflow for the diagnosis of CDI in mild virulent epidemic areas. Diarrhea samples collected from patients were analyzed by glutamate dehydrogenase (GDH), toxin AB (CDAB), and nucleic acid amplification test (NAAT). We assessed the performance of GDH, the GDH-CDAB algorithm, and the GDH-NAAT algorithm using toxigenic culture (TC) as a reference method. In this study, 186 diarrhea samples were collected. The numbers of TC-positive and TC-negative samples were 39 and 147, respectively. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa of the GDH assay were 100%, 80.3%, 57.4%, 100%, and 0.63; of the GDH-CDAB algorithm were 48.7%, 97.3%, 82.6%, 87.7%, and 0.54; and of the GDH-NAAT algorithm were 74.4%, 100%, 100%, 93.6%, and 0.82, respectively. The GDH-NAAT algorithm has great concordance with TC in detecting toxigenic C. difficile (kappa = 0.82), while the sensitivity of the GDH-CDAB algorithm was too low to meet the demand of CDI diagnosis clinically. GDH-NAAT algorithm is recommended for the detection of toxigenic C. difficile with high specificity, increased sensitivity, and cost-effective.

Genetic Variation on TNF/LTA and TNFRSF1A Genes is Associated with Outcomes of Hepatitis C Virus Infection.

Hepatitis C virus (HCV) infections are a serious global-scaled public health problem. Tumor necrosis factor (TNF)/lymphotoxin alpha (LTA) has been found to play a crucial role in relation to the outcomes of HCV infection after it binds to TNF receptor superfamily member 1A (TNFRSF1A). Thus, we investigated whether or not the TNF/LTA gene cluster and TNFRSF1A gene polymorphisms were associated with the outcomes of HCV infection. 1103 control participants without HCV infection, 497 patients with spontaneous clearance of HCV infection, and 713 patients with persistent HCV infection were enrolled. Rs2229094, rs1041981, rs1799964, and rs767455 were genotyped using the ABI TaqMan allelic discrimination assay. After adjusting for age, gender, and after determining a high-risk population, we used logistic regression analyses for which results indicated that the rs767455-C allele was associated with a reduced risk of HCV infection compared to respective results for the wild-type T allele (dominant model: adjusted OR = 0.74, 95% CI = 0.60-0.92, P = .006; additive model: adjusted OR = 0.76, 95% CI = 0.62-0.91, P = .004). Results also indicated that the rs1041981-A allele was associated with a decreased risk of persistent HCV infection compared to respective results for the wild-type C allele (additive model: adjusted OR = 0.81, 95% CI = 0.68-0.96, P = .017). Genetic polymorphisms in the LTA and TNFRSF1A genes were found to have been potentially important in relation to the susceptibility and chronicity of HCV infection among Chinese Han population.

Silver Trifluoromethanesulfonate-Catalyzed Annulation of Propargylic Alcohols with 3-Methyleneisoindolin-1-one.

A silver-catalyzed formal [3 + 3] annulation of 3-methyleneisoindolin-1-one with alkynol for the synthesis of 1,5-dihydroindolizin-3(2H)-one derivatives is disclosed. The protocol allows practical synthesis of N-heterocyclic scaffolds with a broad scope of functional groups and could be efficiently scaled up to gram scale, which incarnates a potential application of this methodology. In addition, a range of chlorine anion substitution of alkenes can be constructed by adjusting the structure of the alkynol substrates with the use of TMSCl.

Synthesis of 1,6-Dihydropyridine-3-carbonitrile Derivatives via Lewis Acid-Catalyzed Annulation of Propargylic Alcohols with (E)-3-Amino-3-phenylacrylonitriles.

A novel Lewis acid-catalyzed, highly efficient, practical, and atom-economical protocol for the synthesis of functionalized 1,2-dihydropyridine-3-carbonitrile derivatives in the presence of Bi(OTf)3 (10 mol %) in tetrahydrofuran (2.0 mL) at 80 °C for 8 h in air is described, starting from readily accessed propargylic alcohols and (E)-3-amino-3-phenylacrylonitriles. This cycloaddition protocol, which is scalable and proceeds under mild conditions, is amenable to the gram-scale construction of valuable 1,2-dihydropyridine-3-carbonitriles. Furthermore, the good functional group compatibility and broad scope of this strategy were demonstrated by a broad range of propargylic alcohols and (E)-3-amino-3-phenylacrylonitriles, with yields ranging from 34 to 96%.

RNA interference targeting CD147 inhibits metastasis and invasion of human breast cancer MCF-7 cells by downregulating MMP-9/VEGF expression.

Breast cancer is one of the most common malignancies. It is necessary to identify new markers for predicting tumor progression and therapeutic molecular targets. It has been reported that CD147 is one of the most commonly expressed proteins in primary tumors and in metastatic cells. In this study, we investigated the role of CD147 in human breast cancer metastasis and invasion, and examined its underlying molecular mechanisms. Immunohistochemistry results revealed high expression of CD147 in human breast tumor tissues, which was positively correlated with the malignancy of breast cancer. MCF-7 cells were transfected with CD147 siRNA eukaryotic expression vector, which resulted in significant knockdown of CD147. We found that CD147 siRNA dramatically inhibited cell proliferation, metastasis, and invasion. Furthermore, our results demonstrated that CD147 siRNA inhibited the synthesis of matrix metalloproteinase 9 (MMP-9) but had no significant effect on matrix metalloproteinase 2 (MMP-2). In addition, CD147 siRNA significantly inhibited the production of vascular endothelial growth factor (VEGF). Taken together, these data indicate that CD147 promotes breast cancer cell proliferation, metastasis, and invasion by modulating MMP-9 and VEGF expression. Thus, CD147 may be used as an important indicator for the judgment of malignant behavior of breast cancer, and may be a potential novel target for breast cancer therapy.

Lewis Acid Catalyzed Dehydrogenative Coupling of Tertiary Propargylic Alcohols with Quinoline N-Oxides.

An unprecedented Lewis acid catalyzed, high-efficiency synthesis of valuable 2-(quinolin-2-yl)prop-2-en-1-ones via dehydrogenative coupling of propargylic alkynols with quinoline N-oxides is described. This protocol, which tolerates a broad range of functional groups, provides a straightforward pathway to the products 2-(quinolin-2-yl)prop-2-en-1-one scaffolds in satisfactory yields. The conversion could be scaled up to gram scale efficiently, which underlines a latent application of this methodology.

Copper-Catalyzed Oxidative Cyclization of Alkynes with Sulfonylhydrazides Leading to 2-Sulfonated 9H-pyrrolo[1,2-a]indol-9-ones.

A copper-catalyzed oxidative cyclization procedure has been developed for the production of 2-sulfonated 9H-pyrrolo[1,2-a]indol-9-ones via the direct sulfonylation of N-propargyl-substituted indoles with sulfonylhydrazides and tert-butyl hydroperoxide (TBHP). This novel protocol, which tolerates a broad range of functional groups, offers a simple, efficient, and atom-economical route to a series of fluorazones in good yields under mild conditions.

Synthesis of Organophosphorus Compounds through Copper-Catalyzed Annulation Involving C-O and C-P Bond Formations.

A novel copper(II) trifluoromethanesulfonate-catalyzed, high-efficiency, and atom-economical synthesis of valuable organophosphorus compounds via cascade annulation of propargylic alcohols with diphenylphosphine oxide is described. This protocol, which has a good functional-group compatibility and insensitivity to an ambient atmosphere, provides a simple and direct pathway to the products, organophosphorus compounds, in good yields under mild conditions. The method could be efficiently scaled up to gram scale, thus highlighting a potential application of this methodology.

It Is Imperative to Establish a Pellucid Definition of Chimeric RNA and to Clear Up a Lot of Confusion in the Relevant Research.

There have been tens of thousands of RNAs deposited in different databases that contain sequences of two genes and are coined chimeric RNAs, or chimeras. However, "chimeric RNA" has never been lucidly defined, partly because "gene" itself is still ill-defined and because the means of production for many RNAs is unclear. Since the number of putative chimeras is soaring, it is imperative to establish a pellucid definition for it, in order to differentiate chimeras from regular RNAs. Otherwise, not only will chimeric RNA studies be misled but also characterization of fusion genes and unannotated genes will be hindered. We propose that only those RNAs that are formed by joining two RNA transcripts together without a fusion gene as a genomic basis should be regarded as authentic chimeras, whereas those RNAs transcribed as, and cis-spliced from, single transcripts should not be deemed as chimeras. Many RNAs containing sequences of two neighboring genes may be transcribed via a readthrough mechanism, and thus are actually RNAs of unannotated genes or RNA variants of known genes, but not chimeras. In today's chimeric RNA research, there are still several key flaws, technical constraints and understudied tasks, which are also described in this perspective essay.

Genetic variations in vitamin D receptor were associated with the outcomes of hepatitis C virus infection among Chinese population.

Vitamin D has been considered as an immune modulator, and exerted the effect through the vitamin D receptor (VDR). This study investigated the associations of single-nucleotide polymorphisms (SNPs) of VDR with the outcomes of Hepatitis C virus (HCV) infection. Three SNPs (rs2228570, rs757343 and rs739837) were genotyped by TaqMan assay among Chinese population, including 538 HCV spontaneous clearance subjects, 834 persistent infection subjects and 1030 uninfected subjects. Binary logistic analyses were used to control the effects of confounding factors. The results showed that subjects with the rs757343 A allele and rs739837 A allele had the significantly reduced risk of HCV susceptibility (all PBonferroni<0.05 in dominant/additive model). In the stratified analysis, the protection of rs757343 A allele and rs739837 A allele against HCV infection remained effective in some subgroups. In addition, patients carrying rs739837 CA genotype were less prone to develop persistent infection (PBonferroni=0.033) and such effect still work in several subgroups in the stratified analysis. Furthermore, haplotype analysis indicated that when compared with the most frequent GC haplotype, the haplotype carrying AA (odds ratio (OR)=0.66, 95% confidence interval (CI)=0.56-0.78) and GA (OR=0.64, 95% CI=0.47-0.85) suggested a protective effect. Our findings indicated that the polymorphisms of VDR are associated with the outcomes of HCV infection among Chinese population.