Electrochemical Trifluoromethylation/Bicyclization of N-Cyanamide Alkenes: Synthesis of Bicyclic Amidine Derivatives.

An anodically oxidizing trifluoromethylation cascade of N-cyanamide alkene bearing two electronically differentiated olefin moieties was reported, in which various N-unsaturated acyl cyanamide alkenes and CF3SO2Na acting as readily available starting materials furnished nonaromatic fused azaheterobicyclic compounds in a highly efficient and sustainable manner. The broad substrate scope, facile scalability, and sustainability enabled this electrochemical process to be an appealing complement for trifluoromethylated cyclic amidines.

Construction of Functionalized α-Imino Ketones via Pd-Catalyzed C-H Addition to Nitriles/Aerobic Oxidation Sequences.

Pd(II)-catalyzed addition of sp2 C-H to nitrile/aerobic oxidation sequences for the preparation of functionalized α-imino ketones is described in which readily available heteroarenes and O-acyl cyanohydrins were employed. Various functionalized targeted molecules can be prepared in good yields with high atom and step economy. Moreover, a broad substrate scope and the ready manipulation and availability of the reaction partners enable this protocol to be appealing to explore the chemical space of the construction of functionalized α-imino ketones with high efficiency.

Machine learning for differentiation of lipid-poor adrenal adenoma and subclinical pheochromocytoma based on multiphase CT imaging radiomics.

BACKGROUND: There is a paucity of research investigating the application of machine learning techniques for distinguishing between lipid-poor adrenal adenoma (LPA) and subclinical pheochromocytoma (sPHEO) based on radiomic features extracted from non-contrast and dynamic contrast-enhanced computed tomography (CT) scans of the abdomen. METHODS: We conducted a retrospective analysis of multiphase spiral CT scans, including non-contrast, arterial, venous, and delayed phases, as well as thin- and thick-thickness images from 134 patients with surgically and pathologically confirmed. A total of 52 patients with LPA and 44 patients with sPHEO were randomly assigned to training/testing sets in a 7:3 ratio. Additionally, a validation set was comprised of 22 LPA cases and 16 sPHEO cases from two other hospitals. We used 3D Slicer and PyRadiomics to segment tumors and extract radiomic features, respectively. We then applied T-test and least absolute shrinkage and selection operator (LASSO) to select features. Six binary classifiers, including K-nearest neighbor (KNN), logistic regression (LR), decision tree (DT), random forest (RF), support vector machine (SVM), and multi-layer perceptron (MLP), were employed to differentiate LPA from sPHEO. Receiver operating characteristic (ROC) curves and area under the curve (AUC) values were compared using DeLong's method. RESULTS: All six classifiers showed good diagnostic performance for each phase and slice thickness, as well as for the entire CT data, with AUC values ranging from 0.706 to 1. Non-contrast CT densities of LPA were significantly lower than those of sPHEO (P < 0.001). However, using the optimal threshold for non-contrast CT density, sensitivity was only 0.743, specificity 0.744, and AUC 0.828. Delayed phase CT density yielded a sensitivity of 0.971, specificity of 0.641, and AUC of 0.814. In radiomics, AUC values for the testing set using non-contrast CT images were: KNN 0.919, LR 0.979, DT 0.835, RF 0.967, SVM 0.979, and MLP 0.981. In the validation set, AUC values were: KNN 0.891, LR 0.974, DT 0.891, RF 0.964, SVM 0.949, and MLP 0.979. CONCLUSIONS: The machine learning model based on CT radiomics can accurately differentiate LPA from sPHEO, even using non-contrast CT data alone, making contrast-enhanced CT unnecessary for diagnosing LPA and sPHEO.

Diastereo- and Enantioselective Synthesis of Functionalized Dihydropyrans via an Organocatalytic Claisen Rearrangement/Oxa-Michael Addition Tandem Sequence.

A straightforward diastereo- and enantioselective Claisen rearrangement/oxa-Michael addition tandem sequence with a cinchona squaramide catalyst was described, which afforded a practical and atom-economical approach to access a range of valuable dihydropyrans in good to excellent yields with excellent stereoselectivities. The organo-bifunctional catalyst played a key role in enhancing stereoselectivity in this asymmetric tandem sequence. Moreover, the asymmetric catalytic sequential processes of the hydroalkoxylation/Claisen rearrangement/cyclization sequence and Claisen rearrangement/aza-Michael addition tandem sequence have also been afforded good yields and moderate stereoselectivities.

A tyrosine, histidine-selective bifunctional cross-linker for protein structure analysis.

Chemical cross-linking mass spectrometry (XL-MS) significantly contributes to the analysis of protein structures and the elucidation of protein-protein interactions. Currently available cross-linkers mainly target N-terminus, lysine, glutamate, aspartate, and cysteine residues in protein. Herein, a bifunctional cross-linker, named [4,4'-(disulfanediylbis(ethane-2,1-diyl)) bis(1-methyl-1,2,4-triazolidine-3,5-dione)] (DBMT) has been designed and characterized aiming to extremely expand the application of XL-MS approach. DBMT is capable of selectively targeting tyrosine residue in protein via an electrochemical click reaction, and/or targeting histidine residue in protein in the presence of 1O2 generated under photocatalytic reaction. A novel cross-linking strategy based on this cross-linker has been developed and demonstrated using model proteins, which provides a complementary XL-MS tool analyzing protein structure, protein complexes, protein-protein interactions, and even protein dynamics.

Multicomponent Cyclization with an Inorganic Sulfur Dioxide Surrogate: Straightforward Construction of Difluorinated Benzosultams.

A straightforward three-component transformation for the preparation of functionalized benzosultams under TM-free and mild reaction conditions was described, in which easy-to-handle Na2S2O5, available bromodifluoroalkyl reagent, and N-(2-haloaryl) cyanamide were employed. Na2S2O5 was essential to the generation of difluoroalkyl radical, SO2 fixation, and cyclization, which enabled efficient construction of target products in a sustainable manner. A broad substrate scope and modular feature made this protocol attractive for exploring the chemical space of the construction of cyclic sulfonamides.

Organocatalytic Allylic Alkylation of α-(Alkylideneamino)nitriles and Its Application in the Preparation of Multisubstituted 1-Pyrrolines.

A synthetic approach for the construction of functionalized diverse 1-pyrrolines incorporating ß-quaternary carbon centers under mild reaction conditions has been reported, in which α-allyl α-(alkylideneamino)nitriles generated from a Lewis base-catalyzed allylic alkylation reaction engaged in a Lewis base-mediated tandem intramolecular cyclization to deliver the targeted molecules in a catalytically atom-economic fashion.

Radical Alkene-Trifluoromethylation-Triggered Nitrile Insertion/Remote Functionalization Relay Processes: Diverse Synthesis of Trifluoromethylated Azaheterocycles Enabled by Copper Catalysis.

A copper-catalyzed alkene-trifluoromethylation-triggered nitrile insertion/remote functionalization relay process has been achieved, in which "interrupted" remote 1,n-difunctionalizations of alkenes with nitrile insertion can deliver iminyl radical intermediates instead of C-based radicals, followed by subsequent 1,n-HAT to furnish corresponding remote functionalization. This relay protocol enables a straightforward approach to streamline the assembly of structurally diverse trifluoromethylated azaheterocycles.

Copper-Catalyzed Difluoroalkylation of Alkene/Nitrile Insertion/Cyclization Tandem Sequences: Construction of Difluorinated Bicyclic Amidines.

A copper-catalyzed difluoroalkylation of an alkene/nitrile insertion/cyclization tandem sequence of N-cyanamide alkene was described, which provided a convenient synthetic approach for accessing difluorinated bicyclic amidines bearing imine moieties in a sustainable fashion. This protocol is characterized by high yields, a broad substrate scope, and good functional group compatibility. In addition, the desired product can be readily converted into other valuable functionalized fluorinated aza-heterocycles.

Personalized and Self-Management: Systematic Search and Evaluation Quality Factors and User Preference of Drug Reference Apps in Taiwan.

BACKGROUND: Drug reference apps promote self-management and improve the efficiency and quality of work for physicians, nurses, pharmacists, and patients. This study aimed to describe a systematic and stepwise process to identify drug reference apps in Taiwan, assess the quality of these apps, and analyze the influential factors for user ratings. METHODS: A two-step algorithm (KESS) consisting of keyword growing and systematic search was proposed. Seven independent reviewers were trained to evaluate these apps using Mobile App Rating Scale (MARS). A logistic regression model was fitted and average marginal effects (AME) were calculated to identify the effects of factors for higher user ratings. RESULTS: A total of 23 drug reference apps in Taiwan were identified and analyzed. Generally, these drug reference apps were evaluated as acceptable quality with an average MARS score of 3.23. Higher user engagement, more functionality, better aesthetics, and more information associated with higher user ratings. Navigation is the most influential factor on higher user ratings (AME: 13.15%) followed by performance (AME: 11.03%), visual appeal (AME: 10.87%), credibility (AME: 10.67%), and quantity of information (AME: 10.42%). CONCLUSIONS: User experience and information clearly affect user ratings of drug reference apps. Five key factors should be considered when designing drug reference apps.

Discovery and Optimization of Highly Potent and Selective AT2R Antagonists to Relieve Peripheral Neuropathic Pain.

The angiotensin II type 2 receptor (AT2R) has attracted much attention as a potential target for the relief of neuropathic pain, which represents an area of unmet clinical need. A series of 1,2,3,4-tetrahydroisoquinolines with a benzoxazole side-chain were discovered as potent AT2R antagonists. Rational optimization resulted in compound 15, which demonstrated both excellent antagonistic activity against AT2R in vitro and analgesic efficacy in a rat chronic constriction injury model. Its favorable physicochemical properties and oral bioavailability make it a promising therapeutic candidate for neuropathic pain.

α-Iminol Rearrangement Triggered by Pd-Catalyzed C-H Addition to Nitriles Sequences: Synthesis of Functionalized α-Amino Cyclopentanones.

A α-iminol rearrangement triggered by Pd-catalyzed C-H addition of electronic-rich heteroarenes to cyclobutanone-derived O-acyl cyanohydrins was described, which provided a practical and efficient protocol for the preparation of functionalized α-amino cyclopentanones in an atom- and step-economic fashion. In addition, further synthetic transformations of products have also been demonstrated.

Brønsted Acid-Promoted Cyclodimerization of Indolyl Ketones: Construction of Indole Fused-Oxabicyclo[3.3.1]nonane and -Cyclooctatetraene Ring Systems.

A Brønsted acid-promoted cyclodimerization of C(3)-, C(2)-, or N(1)-substituted indole ketone derivatives is described. A wide range of structurally diverse bisindole fused-9-oxabicyclo[3.3.1]nonane and bisindole fused-cyclooctatetraene (COT) derivatives can be prepared in good to high yields with high efficiency.

CF3 SO2 Na as a Bifunctional Reagent: Electrochemical Trifluoromethylation of Alkenes Accompanied by SO2 Insertion to Access Trifluoromethylated Cyclic N-Sulfonylimines.

An unprecedented electrochemical trifluoromethylation/SO2  insertion/cyclization process has been achieved in an undivided cell in an atom-economic fashion. The protocol relies on tandem cyclization of N-cyanamide alkenes by using Langlois' reagent as a source of both CF3 and SO2 under direct anodically oxidative conditions, in which two C-C bonds, two C-X bonds (N-S and S-C), and two rings were formed in a single operation. This transformation enabled efficient construction of various trifluoromethylated cyclic N-sulfonylimines from readily accessible materials.

Organocatalytic Isomerization/Allylic Alkylation of O-Acylated Hemithioacetals and Their Application in Tandem Sequence to Access 2,7-Dioxabicyclo[2.2.1]heptan-3-one Derivatives.

A novel protocol for the efficient preparation of α-hydroxy allylic thioesters via a Lewis base-catalyzed tandem isomerization/allylic alkylation process is reported. The resulting allylic thioesters can serve as valuable scaffolds to undergo a stereoselective intramolecular cyclization to deliver 2,7-dioxabicyclo[2.2.1]heptan-3-one derivatives in a catalytically atom-economic fashion.

Brain Function Network and Young Adult Smokers: A Graph Theory Analysis Study.

Cigarette smoking is associated with abnormalities in the widespread inter-regional functional connectivity of the brain. However, few studies focused on the abnormalities in the topological organization of brain functional networks in young smokers. In the current study, resting-state functional magnetic resonance images were acquired from 30 young male smokers and 32 age-, gender-, and education-matched healthy male nonsmokers. A functional network was constructed by calculating the Pearson correlation coefficients among 246 subregions in the human Brainnetome Atlas. The topological parameters were compared between smokers and nonsmokers. The results showed that the functional network of both young smokers and nonsmokers had small-world topology. Compared to nonsmokers, young smokers exhibited a decreased clustering coefficient (Cp) and local network efficiency (Elocal). Cp and Elocal were negatively correlated with the duration of cigarette use. In addition, increased nodal efficiency (Enodal) was mainly located in the prefrontal cortex (PFC), cingulate gyrus, insula, and caudate. Decreased connectivities among the PFC, cingulate gyrus, insula, basal ganglia (of specific node), and thalamus were also observed. In sum, we revealed the abnormal topological organization of brain functional networks in young smokers, which may improve our understanding of the neural mechanism of young smokers from a brain functional network topological organization perspective.

Thiophene Derivatives as New Anticancer Agents and Their Therapeutic Delivery Using Folate Receptor-Targeting Nanocarriers.

A series of thiophene derivatives were synthesized by functionalization of 2,3-fused thiophene scaffolds. Their cytotoxicity was assessed against HeLa and Hep G2 cells. Compound 480 was identified as a promising candidate because of its low IC50 in HeLa (12.61 µg/mL) and Hep G2 (33.42 µg/mL) cells. The drug was loaded into folic acid (FA)-coated nanoparticles (NPs) to address its poor water solubility and to improve its selectivity for cancer cells. Compound 480 was shown to induce apoptosis by changes in mitochondrial membrane potential (ΔΨm) and the reactive oxygen species level. Furthermore, FA-modified NPs enhanced uptake capacity compared to unmodified controls by flow cytometry. This drug delivered in folate nanocarriers is promising for the treatment of cancers.

Synthesis of 2,4,5-Trisubstituted Oxazoles via Pd-Catalyzed C-H Addition to Nitriles/Cyclization Sequences.

A practical and flexible intermolecular protocol for the diverse synthesis of trisubstituted oxazole derivatives via a Pd-catalyzed direct C-H addition of electronic-rich heteroarenes to O-acyl cyanohydrins bearing an α-hydrogen/cyclization sequence is described. A wide range of trisubstituted oxazoles can be prepared from readily available starting materials in good to high yields with high efficiency under redox neutral reaction conditions.

The Chemical Synthesis and Applications of Tropane Alkaloids.

Tropanes are an important class of alkaloid natural products that are found in plants all over the world. These compounds can exhibit significant biological activity and are among the oldest known medicines. In the early 19th century, tropanes were isolated, characterized, and synthesized by notable chemical researchers. Their significant biological activities have inspired tremendous research efforts toward their synthesis and the elucidation of their pharmacological activity both in academia and in industry. In this chapter, which addresses the developments in this field since 1994, the focus is on the synthesis of these compounds, and several examples of sophisticated synthetic protocols involving both asymmetric and catalytic approaches are described. In addition, the structures of more than 100 new alkaloids are included as well as the applications and pharmacological properties of some tropane alkaloids.