Bromide-mediated, C2-selective, and oxygenative alkylation of pyridinium salts using alkenes and molecular oxygen.

Herein, we report a bromide-mediated, C2-selective, and oxygenative alkylation of pyridinium salts using alkenes and O2 for the synthesis of important ß-2-pyridyl ketones. Notably, a quaternary carbon center was successfully installed at the C2-position of pyridine and the resulting C2-substituents were highly functionalized. The intermediary cycloadduct was isolated and further transformed into the desired product, which indicated that this three-component reaction underwent a reaction cascade including dearomative cycloaddition and rearomative ring-opening oxygenation. Finally, the bromide-mediated mechanism was discussed and active Br(I) species were proposed to be generated in situ and promote the rearomative ring-opening oxygenation by halogen bond-assisted electron transfer.

Multi-parameter ultrasonography-based predictive model for breast cancer diagnosis.

Objectives: To develop, validate, and evaluate a predictive model for breast cancer diagnosis using conventional ultrasonography (US), shear wave elastography (SWE), and contrast-enhanced US (CEUS). Materials and methods: This retrospective study included 674 patients with 674 breast lesions. The data, a main and an independent datasets, were divided into three cohorts. Cohort 1 (80% of the main dataset; n = 448) was analyzed by logistic regression analysis to identify risk factors and establish the predictive model. The area under the receiver operating characteristic curve (AUC) was analyzed in Cohort 2 (20% of the main dataset; n = 119) to validate and in Cohort 3 (the independent dataset; n = 107) to evaluate the predictive model. Results: Multivariable regression analysis revealed nine independent breast cancer risk factors, including age > 40 years; ill-defined margin, heterogeneity, rich blood flow, and abnormal axillary lymph nodes on US; enhanced area enlargement, contrast agent retention, and irregular shape on CEUS; mean SWE higher than the cutoff value (P < 0.05 for all). The diagnostic performance of the model was good, with AUC values of 0.847, 0.857, and 0.774 for Cohorts 1, 2, and 3, respectively. The model increased the diagnostic specificity (from 31% to 81.3% and 7.3% to 73.1% in cohorts 2 and 3, respectively) without a significant loss in sensitivity (from 100.0% to 90.1% and 100.0% to 81.8% in cohorts 2 and 3, respectively). Conclusion: The multi-parameter US-based model showed good performance in breast cancer diagnosis, improving specificity without a significant loss in sensitivity. Using the model could reduce unnecessary biopsies and guide clinical diagnosis and treatment.

The association between conventional ultrasound and contrast-enhanced ultrasound appearances and pathological features in small breast cancer.

OBJECTIVE: To investigate the association between ultrasound appearances and pathological features in small breast cancer. MATERIALS AND METHODS: A total of 186 small breast cancers in 186 patients were analyzed in this retrospective study from January 2015 to December 2019 according to pathological results. Forty-seven cases of axillary lymph node metastasis were found. All patients underwent radical axillary surgery following conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) examinations. The association between ultrasound appearances and pathological features was analyzed using univariate distributions and multivariate analysis. Then, a logistic regression model was established using the pathological diagnosis of lymph node metastasis and biochemical indicators as the dependent variable and the ultrasound appearances as independent variables. RESULTS: In small breast cancer, risk factors of axillary lymph node metastasis were crab claw-like enhancement on CEUS and abnormal axillary lymph nodes on US. The logistic regression model was established as follows: (axillary lymph node metastasis) = 1.100×(crab claw-like enhancement of CEUS) + 2.749×(abnormal axillary lymph nodes of US) -5.790. In addition, irregular shape on CEUS and posterior echo attenuation on US were risk factors for both positive estrogen receptor and progesterone receptor expression, whereas calcification on US was a risk factor for positive Her-2 expression. A specific relationship could be found using the following logistic models: (positive ER expression) = 1.367×(irregular shape of CEUS) + 1.441×(posterior echo attenuation of US) -5.668; (positive PR expression) = 1.265×(irregular shape of CEUS) + 1.136×(posterior echo attenuation of US) -4.320; (positive Her-2 expression) = 1.658×(calcification of US) -0.896. CONCLUSION: Logistic models were established to provide significant value for the prediction of pre-operative lymph node metastasis and positive biochemical indicators, which may guide clinical treatment.

Deconstructive di-functionalization of unstrained, benzo cyclic amines by C-N bond cleavage using a recyclable tungsten catalyst.

With H2WO4 as the catalyst and H2O2 as the oxidant, we herein report a deconstructive difunctionalization of the C-N bond in unstrained, benzo cyclic amines to generate an ester group and nitro group simultaneously. The preliminary mechanistic studies suggested that the corresponding hydroxamic acid is the key intermediate for this transformation. Importantly, with the utilization of this transformation, we achieved an interesting approach for the ring contraction of quinoline to indole, an example of scaffold hopping in a hetero-aromatic system.

Direct Evidence for the Origin of Bis-Gold Intermediates: Probing Gold Catalysis with Mass Spectrometry.

Gold-catalyzed alkyne hydration was studied by using in situ reacting mass spectrometry (MS) technology. By monitoring the reaction process in solution under different conditions (regular and very diluted catalyst concentrations, different pH values) and examining the reaction occurrence in the early reaction stage (1-2 ms after mixing) with MS, we collected a series of experimental evidence to support that the bis-gold complex is a potential key reaction intermediate. Furthermore, both experimental and computational studies confirmed that the σ,π-bis-gold complexes are not active intermediates toward nucleophilic addition. Instead, formation of geminally diaurated complex C is crucial for this catalytic process.

Visible-Light-Induced Carbo-2-pyridylation of Electron-Deficient Alkenes with Pyridinium Salts.

A simple and practical visible-light-induced carbo-2-pyridylation of electron-deficient alkenes with readily available N-benzoylmethylpyridinium bromides is reported. More than 40 examples are presented and proceed in greater than 80 % yield (on average) with excellent regio- and diastereoselectivities.

TGF-ß1 and TIMP1 double directional rAAV targeted by UTMD in atherosclerotic vulnerable plaque.

In the present study, we determined whether ultrasound-targeted microbubble destruction (UTMD) combined with dual targeting of transforming growth factor (TGF)-ß1 and tissue inhibitors of metalloproteinase (TIMP) 1 recombinant adeno-associated virus (rAAV) can stabilize atherosclerotic vulnerable plaques. First, we used rabbit model to detect the TGF-ß1/TIMP1 virus therapy result. H&E staining was used to evaluate the tissues. The protein levels of TGF-ß1 and TIMP1 were detected in rabbit models. The THP-1 cells were induced into macrophages, and transfected with TGF-ß1 and TIMP1 rAAV under optimized UTMD. The expression of TGF-ß1 and TIMP1 was measured by RT-PCR and western blotting. We found that the apoptotic rates were induced when compared to the control group. The rAAV virus group showed a significant decrease in the p-ERT and p-AKT expression. These data support the hypothesis that TGF-ß1 and TIMP1 are crucial in the regulation of atherosclerotic plaques.

Palladium-Catalyzed Aminomethylamination and Aromatization of Aminoalkenes with Aminals via C-N Bond Activation.

Thanks to the facile imine-enamine tautomerization, the ß,γ-unsaturated hydrazones have been successfully utilized as surrogates of aminodienes for realizing the Pd-catalyzed tandem aminomethylamination/aromatization reaction with aminals via C-N bond activation. This direct and operationally simple protocol provides a fundamentally novel strategy to synthesize aromatic heterocycles from alkenes in the absence of external oxidant and base. Mechanistic studies suggested that aminal not only functioned as an aminomethyl source but also acted as formal oxidant and inner base to promote the aromatization.

Ligand-controlled gold-catalyzed cycloisomerization of 1,n-enyne esters toward synthesis of dihydronaphthalene.

We describe herein a gold-catalyzed rearrangement of propargyl esters followed by allene-ene cyclization to afford substituted bicyclic [4.4.0] dihydronaphthalene compounds. This method is also applied to vinylethers and vinylamines of 1,7-enyne esters to form dihydroquinoline and dihydrobenzopyran structures. The basis of this transformation is the ligand-controlled preferential activation of the alkene over the allene, affording the desired aromatic bicyclic structures in moderate to excellent yields.

Correlation between blood circulation grading and angiogenesis using ultrasonic contrast of rabbit VX2 hepatic carcinoma.

OBJECTIVE: To build the rabbit model of VX2 hepatic carcinoma, examine the tumor body using the ultrasonic contrast and study the correlation between the blood circulation grading and angiogenesis. METHODS: The VX2 tumor strain was prepared in the lateral muscle of the hind legs of 40 male New Zealand rabbits (which were purchased from Nanjing Senbao Biotech Co., Ltd.). The tumor block was embedded in the center of left liver lobe directly to build the rabbit model of VX2 hepatic carcinoma. The ultrasonic contrast was performed 14 d after implanting the tumor body. The semi-quantitative classification (0-IV level) was taken according to the blood flow of tumor vessel. Animals were executed using the air embolism method. The liver was separated to extract RNA and total protein respectively. The real-time PCR and western blotting method were employed to detect the expression of angiogenesis-related factors of VEGF, bFGF and TNF-α, while the ultrasonic contrast to detect the correlation with blood circulation grading. The Pearson product moment correlation coefficient was used to measure the linear relationship between these two variables and analyze the correlation between the blood circulation grading and angiogenesis using the ultrasonic contrast. RESULTS: Thirty-three rabbits had the successful model of VX2 hepatic carcinoma. The blood circulation grading by ultrasonic contrast was: 2 cases at level 0 (6.60%), 5 cases at level I (16.7%), 12 cases at level II (40.0%), 6 cases at level III (20.0%) (local dense or clustered blood flow) and 5 cases at level IV (16.7%). The results showed that there was positive correlation between three angiogenesis-related factors and the blood circulation grading. The correlation coefficient between three angiogenesis-related factors and the blood circulation grading was over 0.9, which indicated the relatively high correlation. CONCLUSIONS: The ultrasound blood circulation grading for the hepatic carcinoma can clearly reflect the changes of blood vessel, which will be of critical significance for the early diagnosis of hepatic carcinoma and clinical evaluation of angiogenesis indicators.

Transition-metal catalysed C-N bond activation.

Transition-metal catalysed C-N bond activation has attracted much attention and become one of the most promising bond disconnection and formation strategies that encompass a broad spectrum of applications in many reactions. In this tutorial review, efficient strategies for catalytic cleavage of C(sp)-N, C(sp(2))-N and C(sp(3))-N bonds and their applications in new C-C and C-N bond formation reactions are summarized.

Triazole-gold promoted intermolecular propargyl alcohol addition to alkyne: the reaction cascade toward substituted allenes.

Gold-catalyzed intermolecular propargyl alcohol addition to alkyne was achieved. The reaction of propargyl alcohol with a typical gold catalyst gave the hydration product almost exclusively. The triazole gold catalyst (TA-Au) successfully prevented the hydration, giving the vinyl ether followed by a 3,3-rearrangement. Synthetically useful substituted allenes were formed with high efficiency, substrate tolerability and chemoselectivity. Also, more than 95% chirality transfer from propargyl alcohol to allene was obtained.

Splitting a Substrate into Three Parts: Gold-Catalyzed Nitrogenation of Alkynes by C-C and C≡C Bond Cleavage.

A gold-catalyzed nitrogenation of alkynes for the synthesis of carbamides and amino tetrazoles through C-C and C≡C bond cleavages is described. A diverse set of functionalized carbamide and amino tetrazole derivatives were selectively constructed under mild conditions. The chemoselectivity can be easily switched by the selection of the acid additives. The reaction is characterized by its broad substrate scope, direct construction of high value products, easy operation under air, and mild conditions at room temperature. This chemistry provides a way to transform alkynes by splitting the substrate into three parts.

Gold Catalyzed Synthesis of Substituted Furan by Intermolecular Cascade Reaction of Propargyl Alcohol and Alkyne.

Using a combination of triazole-gold (TA-Au) and copper catalysts, the substituted furan was achieved in one pot through a three-step reaction cascade. The reaction tolerates a large substrate scope with simple starting materials. The desired di-, tri-, and tetrasubstituted furans were prepared in good to excellent yields.

Digital human modeling and its applications: Review and future prospects.

OBJECTIVE: The digital human modeling combines information technology with bioscience, applied to analog study from DNA molecule and protein to cell and tissue, as well as organ. It has been widely implemented in various fields such as aviation, national defense, film and television, sports and medical treatment. This paper sorts relative research achievements and progress in recent years and summarizes issues and challenges of research work. The purpose of this paper is to provide references for the development of Digital Human Modeling. METHODS: Basing on the development plans proposed by Federation of American Scientists (FAS) and current theories, we sorted academic achievements and relative references since the beginning of the digital human concept until 2014 into four aspects, which were named as Visible Human, Virtual Physical Human, Virtual Physiological Human, and Intelligent Virtual Human. We collected information of data acquisition, data analysis and dataset establishment for Visible Human. We outlined the Virtual Physical Human references in four physical categories, including radiation, ultrasonic, electrics, and mechanics. For Virtual Physiological Human, relative researches related to the physiological and biochemical changes of human body were categorized in four aspects as gene molecules, cells, and organs. Relative researches of Virtual Brain Human were mainly concentrated on virtual human brain and virtual human control. RESULTS: According to the differences in investigations and applications requirements of Digital Human in all aspects, we classified, analyzed and concluded extensive preference data. The overall plan of Digital Human, as well as technical routes, work plans, present states, goals, results and application value in each stage of research was summarized. We discussed the technical issues existing in each aspect of Digital Human, along with the urgent key technologies including data collection, data processing, and modeling. CONCLUSION: Analyzing the core technologies and the general technical schemes in the field of Digital Human, this paper summarizes the technical solutions, research results and technical problems of major researchers. The future prospects of Digital Human are reviewed.

Ambient benzotriazole ring opening through intermolecular radical addition to vinyltriazole.

Radical addition to vinyltriazole was developed as a new approach to achieve 1,2,3-triazole ring opening under mild conditions. Through reagent control, excellent chemoselectivity was achieved, giving either nitrile under basic conditions or quinoxaline under neutral conditions. Reactivities made this method an attractive new reaction mode.

Ultrasound contrast-enhanced imaging and in vitro antitumor effect of paclitaxel-poly(lactic-co-glycolic acid)-monomethoxypoly (ethylene glycol) nanocapsules with ultrasound-targeted microbubble destruction.

A combination of diagnostic and therapeutic ultrasound (US) techniques may be able to provide the basis of specific therapeutic protocols, particularly for the treatment of tumors. Nanotechnology may aid the progression towards the use of US for tumor diagnosis and targeted therapy. The current study investigated in vivo and in vitro US contrast imaging using nanocapsules (NCs), and also US and US­targeted microbubble destruction (UTMD) therapy using drug­loaded NCs for pancreatic cancer in vitro. In the current study, the NCs were made from the polymer nanomaterial poly(lactic­co­glycolic acid)­monomethoxypoly(ethylene glycol) (PLGA­mPEG), encapsulated with paclitaxel (PTX), to create PTX­PLGA­mPEG NCs. The PTX­PLGA­mPEG NCs were used as a US contrast agent (UCA), which produced satisfactory US contrast­enhanced images in vitro and in vivo of the rabbit kidneys, with good contrast compared with lesions in the peripheral regions. However, clear contrast­enhanced images were not obtained using PTX­PLGA­mPEG NCs as a UCA, when imaging the superficial pancreatic tumors of nude mice in vivo. Subsequently, fluorescence and flow cytometry were used to measure the NC uptake rate of pancreatic tumor cells under various US or UTMD conditions. An MTT assay was used to evaluate the efficiency of PTX and PTX­PLGA­mPEG NCs in killing tumor cells following 24 or 48 h of US or UTMD therapy, compared with controls. The specific US or UTMD conditions had been previously demonstrated to be optimal through repeated testing, to determine the conditions by which cells were not impaired and the efficiency of uptake of nanoparticles was highest. The current study demonstrated high cellular uptake rates of PLGA­mPEG NCs and high tumor cell mortality with PTX­PLGA­mPEG NCs under US or UTMD optimal conditions. It was concluded that the use of NCs in US­mediated imaging and antitumor therapy may provide a novel application for US.

Chemoselective carbophilic addition of α-diazoesters through ligand-controlled gold catalysis.

The chemoselective addition of arenes and 1,3-diketones to α-aryldiazoesters was achieved through ligand-controlled gold catalysis. Unlike a dirhodium catalyst (which promotes C(sp3)-H insertion and cyclopropanation) and a copper catalyst (which catalyzes O-H and N-H insertions), the gold catalyst with an electron-deficient phosphite as the ancillary ligand exclusively gave the carbophilic addition product, thus representing a new and efficient approach to form "carbophilic carbocations", which selectively react with carbon nucleophiles.

Ceric ammonium nitrate (CAN) catalyzed modification of ketones via two C-C bond cleavages with the retention of the oxo-group.

A simple ceric ammonium nitrate (CAN) catalyzed functionalization of ketones through double C-C bond cleavage strategy has been disclosed. This reaction provides a mild, practical method toward carbamoyl azides, which are versatile intermediates and building blocks in organic synthesis. Based on relevant mechanistic studies, a unique and plausible C-C bond and N-O bond cleavage process is proposed, where the oxyamination intermediate plays an important role in this reaction.

Asymmetric synthesis of substituted NH-piperidines from chiral amines.

Previously, we reported an efficient asymmetric synthesis of substituted piperidines through an exocyclic chirality induced nitroalkene/amine/enone (NAE) condensation reaction. An effective protecting group strategy was developed herein to achieve enantiopure piperidines (yields up to 92%) with complete chirality retention (ee > 95%). A simple derivatization of the obtained piperidines gave thiourea catalysts, indicating the strong potential of this method for producing new amine-based dual functional organocatalysts for future development.