Enantioselective [2+2]-cycloadditions with triplet photoenzymes.

Naturally evolved enzymes, despite their astonishingly large variety and functional diversity, operate predominantly through thermochemical activation. Integrating prominent photocatalysis modes into proteins, such as triplet energy transfer, could create artificial photoenzymes that expand the scope of natural biocatalysis1-3. Here, we exploit genetically reprogrammed, chemically evolved photoenzymes embedded with a synthetic triplet photosensitizer that are capable of excited-state enantio-induction4-6. Structural optimization through four rounds of directed evolution afforded proficient variants for the enantioselective intramolecular [2+2]-photocycloaddition of indole derivatives with good substrate generality and excellent enantioselectivities (up to 99% enantiomeric excess). A crystal structure of the photoenzyme-substrate complex elucidated the non-covalent interactions that mediate the reaction stereochemistry. This study expands the energy transfer reactivity7-10 of artificial triplet photoenzymes in a supramolecular protein cavity and unlocks an integrated approach to valuable enantioselective photochemical synthesis that is not accessible with either the synthetic or the biological world alone.

Chlorpyrifos-induced dysregulation of synaptic plasticity in rat hippocampal neurons.

Chlorpyrifos (CPF) is a widely used organophosphorus pesticide. Increasing evidence has shown that exposure to CPF in early life might induce neurodevelopmental disorders, but the pathogenesis remains uncertain. Synaptic plasticity plays a crucial role in neurodevelopment. This study aimed to investigate the effect of CPF on synaptic plasticity in hippocampal neurons and establish the cellular mechanism underlying these effects. Using CPF-exposed rat and primary hippocampal neurons model, we analyzed the impact of CPF on the synaptic morphology, the expression level of a presynaptic protein, a postsynaptic protein and ionotropic glutamate receptors (iGluRs), as well as the effects on the Wnt/ß-catenin pathway. We found that the synapses were shortened, the spines were decreased, and the expression of synaptophysin (Syp), postsynaptic density-95 (PSD-95), GluN1, GluA1 and Wnt7a, as well as active ß-catenin in primary hippocampal neurons was decreased. Our study suggests that CPF exposure induced dysregulation of synaptic plasticity in rat hippocampal neurons, which might provide novel information regarding the mechanism of CPF-induced neurodevelopmental disorders.

Expanding the Promiscuity of a Copper-Dependent Oxidase for Enantioselective Cross-Coupling of Indoles.

Herein, we disclose the highly enantioselective oxidative cross-coupling of 3-hydroxyindole esters with various nucleophilic partners as catalyzed by copper efflux oxidase. The biocatalytic transformation delivers functionalized 2,2-disubstituted indolin-3-ones with excellent optical purity (90-99 % ee), which exhibited anticancer activity against MCF-7 cell lines, as shown by preliminary biological evaluation. Mechanistic studies and molecular docking results suggest the formation of a phenoxyl radical and enantiocontrol facilitated by a suited enzyme chiral pocket. This study is significant with regard to expanding the catalytic repertoire of natural multicopper oxidases as well as enlarging the synthetic toolbox for sustainable asymmetric oxidative coupling.

Catalytic Atroposelective Electrophilic Amination of Indoles.

Reported here is the first catalytic atroposelective electrophilic amination of indoles, which delivers functionalized atropochiral N-sulfonyl-3-arylaminoindoles with excellent optical purity. This reaction was furnished by 1,6-nucleophilic addition to p-quinone diimines. Control experiments suggest an ionic mechanism that differs from the radical addition pathway commonly proposed for 1,6-addition to quinones. The origin of 1,6-addition selectivity was investigated through computational studies. Preliminary studies show that the obtained 3-aminoindoles atropisomers exhibit anticancer activities. This method is valuable with respect to enlarging the toolbox for atropochiral amine derivatives.

A Carbene-Extended ATRA Reaction.

Atom-transfer radical addition (ATRA) reactions have gained a strong foothold in organic synthesis by virtue of their operational simplicity, synthetic versatility, and perfect atom economy. A rich chemical space can be accessed through clever combinations of the simple starting materials. Many variations of this general motif have been reported. However, the vast majority involve the addition of an organic halide across a C=C double bond, resulting in the formation of 1,2-bifunctional products. This report introduces a significant expansion of this general reactivity concept to give 1,3-bifunctional adducts through the combination of 1,1-ATRA to a carbenoid and 1,2-ATRA to an alkyne. Both processes operate under mild conditions (RT, 5 h) with the same commercial catalyst (CoBr2 , dppbz).

Aromatic substitutions of arenediazonium salts via metal catalysis, single electron transfer, and weak base mediation.

The re-discovery of arenediazonium salts as stable and easily accessible electrophiles for radical aromatic substitutions initiated by single-electron transfer has led to the development of numerous protocols. The diverse set of methods involving metal-mediated, transition metal-catalyzed, photoredox-catalytic and electrochemical electron-transfer mechanisms has recently been complemented by reactions that operate under the mild conditions of very weak inorganic bases. This method provides great advantages with regard to operational simplicity, price, hazard potential, and scalability. The scope of weak base-mediated radical aromatic substitutions has been greatly expanded to include various C-C and C-heteroatom bond forming reactions, cyclizations and rearrangements, and even reactions that preserve the reduction-labile dinitrogen functionality within the product structure. The recent reports of highly fruitful synthetic applications have impressively documented that non-hazardous, inexpensive, and easily accessible inorganic bases can mimic the reducing ability of metal salts, complex reductants, or photo/electrochemical setups. This review covers a concise summary of the most important development in the field and provides detailed analyses of reaction scopes and mechanisms.

Palladium-Catalyzed Oxygenative Cross-Coupling of Ynamides and Benzyl Bromides by Carbene Migratory Insertion.

A palladium-catalyzed oxygenative cross-coupling of ynamides and benzyl bromides has been developed. After subsequent hydrogenation, α,α-disubstituted amide derivatives were obtained in good yields. Migratory insertion of α-oxo palladium carbene species, generated by intermolecular oxidation, is proposed as the key step in this reaction. The study demonstrates the potential of ynamides to serve as carbene precursors in palladium-catalyzed C-C bond-forming cross-coupling reactions.

Racial Variation in the Utility of Urinary Biomarkers PCA3 and T2ERG in a Large Multicenter Study.

PURPOSE: To our knowledge it is unknown whether urinary biomarkers for prostate cancer have added utility to clinical risk calculators in different racial groups. We examined the utility of urinary biomarkers added to clinical risk calculators for predicting prostate cancer in African American and nonAfrican American men. MATERIALS AND METHODS: Demographics, PCPT (Prostate Cancer Prevention Trial) risk scores, data on the biomarkers data PCA3 (prostate cancer antigen 3) and T2ERG (transmembrane protease serine 2 and v-ets erythroblastosis virus E26 oncogene homolog gene fusion), and biopsy pathology features were prospectively collected on 718 men as part of EDRN (Early Detection Research Network). Utility was determined by generating ROC curves and comparing AUC values for the baseline multivariable PCPT model and for models containing biomarker scores. RESULTS: PCA3 and T2ERG added utility for the prediction of prostate cancer and clinically significant prostate cancer when combined with the PCPT Risk Calculator. This utility was seen in nonAfrican American men only for PCA3 (AUC 0.64 increased to 0.75 for prostate cancer and to 0.69-0.77 for clinically significant prostate cancer, both p <0.001) and for T2ERG (AUC 0.64-0.74 for prostate cancer, p <0.001, and 0.69-0.73 for clinically significant prostate cancer, p = 0.029). African American men did not have an added benefit with the addition of biomarkers, including PCA3 (AUC 0.75-0.77, p = 0.64, and 0.65-0.66, p = 0.74) and T2ERG (AUC 0.75-0.74, p = 0.74, and 0.65-0.64, p = 0.88), for prostate cancer and clinically significant prostate cancer, respectively. Limitations include the small number of African American men (72). The post hoc subgroup analysis nature of the study limited findings to being hypothesis generating. CONCLUSIONS: As novel biomarkers are discovered, clinical utility should be established across demographically diverse cohorts.

Changes in psychiatry residents' attitudes towards individuals with substance use disorders over the course of residency training.

BACKGROUND AND OBJECTIVES: Psychiatry residents provide care for individuals diagnosed with co-occurring mental illness and substance use disorders (SUDs). Small studies have shown that clinicians in general possess negative attitudes towards these dually diagnosed individuals. This is a serious concern, as clinicians' stigmatizing attitudes towards individuals with mental illnesses may have a particularly potent adverse impact on treatment. The goal of this study was to examine the attitudes of psychiatry residents towards individuals with diagnoses of schizophrenia, multiple SUDs, co-occurring schizophrenia and SUDs, and major depressive disorder. METHODS: A questionnaire was sent to psychiatry residents (N = 159) around the country. It was comprised of two sections: (i) demographic information, which included information about level of training; and (ii) the 11-item Medical Condition Regard Scale (MCRS) for individuals with the four different diagnoses. RESULTS: Psychiatry residents had more stigmatizing attitudes towards individuals with diagnoses of SUDs with and without schizophrenia than towards those individuals with diagnoses of schizophrenia or major depressive disorder alone. Senior residents possessed more negative attitudes towards individuals with SUDs than junior residents. DISCUSSION AND CONCLUSIONS: The attitudes of psychiatry residents' towards individuals with SUDs with and without schizophrenia were negative and were worse among senior residents. There were many potential reasons for these findings, including repeat negative experiences in providing care for these individuals. SCIENTIFIC SIGNIFICANCE: The negative attitudes of psychiatry residents towards individuals with SUDs are worrisome. Future work is needed to better understand these attitudes and to develop interventions to improve them. (Am J Addict 2017;26:75-79).

Copper(I)-Catalyzed Chemoselective Coupling of Cyclopropanols with Diazoesters: Ring-Opening C-C Bond Formations.

Reported herein is an exceptional chemoselective ring-opening/C(sp3 )-C(sp3 ) bond formation in the copper(I)-catalyzed reaction of cyclopropanols with diazo esters. The conventional O-H insertion product is essentially suppressed by judicious choice of reaction conditions. DFT calculations provide insights into the reaction mechanism and the rationale for this unusual chemoselectivity.

First Trimester Levels of BV-Associated Bacteria and Risk of Miscarriage Among Women Early in Pregnancy.

OBJECTIVES: Prior studies have examined the role of bacterial vaginosis (BV) and increased risk of miscarriage; however the risk has been modest and many BV positive pregnant women deliver at term. BV is microbiologically heterogeneous, and thus the identification of specific BV-associated bacteria associated with miscarriage is warranted. METHODS: We measured the presence and level of seven BV-associated bacteria prior to 14 weeks gestation among urban pregnant women seeking routine prenatal care at five urban obstetric practices at Temple University Hospital in Philadelphia PA from July 2008 through September 2011. 418 Pregnant women were included in this assessment and 74 experienced a miscarriage. RESULTS: Mean log concentration of BVAB3 was significantly higher among women experiencing a miscarriage (4.27 vs. 3.71, p value = 0.012). Younger women with high levels of BVAB3 had the greatest risk of miscarriage. In addition, we found a significant decreased risk of miscarriage among women with higher log concentrations of Leptotrichia/Sneathia species or Megasphaera phylotype 1-like species early in pregnancy. CONCLUSIONS FOR PRACTICE: The identification of selected vaginal bacteria associated with an increased risk of miscarriage could support screening programs early in pregnancy and promote early therapies to reduce early pregnancy loss.

Silver(I)-Catalyzed N-Trifluoroethylation of Anilines and O-Trifluoroethylation of Amides with 2,2,2-Trifluorodiazoethane.

A straightforward N-trifluoroethylation of anilines has been developed based on silver-catalyzed N-H insertions with 2,2,2-trifluorodiazoethane (CF3CHN2). Mechanistically, the reaction is proposed to involve migratory insertion of a silver carbene as the key step. In contrast, when amides are employed as the substrates under similar reaction conditions, O-trifluoroethylation occurs to afford trifluoroethyl imidates.

Copper(I)-catalyzed alkylation of polyfluoroarenes through Direct C-H bond functionalization.

The copper(I)-catalyzed alkylation of electron-deficient polyfluoroarenes with N-tosylhydrazones and diazo compounds has been developed. This reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of C(sp(2) )-C(sp(3) ) bonds with polyfluoroarenes through direct C-H bond functionalization. Mechanistically, copper(I) carbene formation and subsequent migratory insertion are proposed as the key steps in the reaction pathway.

Synthesis of α-aryl esters and nitriles: deaminative coupling of α-aminoesters and α-aminoacetonitriles with arylboronic acids.

Transition-metal-free synthesis of α-aryl esters and nitriles using arylboronic acids with α-aminoesters and α-aminoacetonitriles, respectively, as the starting materials has been developed. The reaction represents a rare case of converting C(sp(3))-N bonds into C(sp(3))-C(sp(2)) bonds. The reaction conditions are mild, demonstrate good functional-group tolerance, and can be scaled up.

Accessing ladder-shape azetidine-fused indoline pentacycles through intermolecular regiodivergent aza-Paternò-Büchi reactions.

Small molecules with conformationally rigid, three-dimensional geometry are highly desirable in drug development, toward which a direct, simple-to-complexity synthetic logic is still of considerable challenges. Here, we report intermolecular aza-[2 + 2] photocycloaddition (the aza-Paternò-Büchi reaction) of indole that facilely assembles planar building blocks into ladder-shape azetidine-fused indoline pentacycles with contiguous quaternary carbons, divergent head-to-head/head-to-tail regioselectivity, and absolute exo stereoselectivity. These products exhibit marked three-dimensionality, many of which possess 3D score values distributed in the highest 0.5% region with reference to structures from DrugBank database. Mechanistic studies elucidated the origin of the observed regio- and stereoselectivities, which arise from distortion-controlled C-N coupling scenarios. This study expands the synthetic repertoire of energy transfer catalysis for accessing structurally intriguing architectures with high molecular complexity and underexplored topological chemical space.

Visible-Light-Induced Radical gem-Iodoallylation of 2,2,2-Trifluorodiazoethane.

A visible-light-induced radical gem-iodoallylation of CF3CHN2 was developed under mild conditions, delivering a variety of α-CF3-substituted homoallylic iodide compounds in moderate to excellent yields. The transformation features broad substrate scope, good functional group compatibility, and operational simplicity. The described protocol provides a convenient and attractive tool to apply CF3CHN2 as CF3-introduction reagent in radical synthetic chemistry.

Iodine-Mediated Coupling of 2,2,2-Trifluorodiazoethane and Alkynes To Access Bistrifluoromethylated 1,3,5-Trienes.

Multi-component reaction of higher degree ultilization of diazo molecules for polyene formation is highly intriuging but still underexplored. We present herein an unprecedented coupling of 2,2,2-trifluorodiazoethane and aryl alkynes mediated by iodine under visible light. The multi-component reaction involving two diazo units and two alkyne units provides a straightforward and step-economic access to bistrifluoromethylated 1,3,5-trienes in high stereoselectivity by creation of three C═C bonds in a single step under mild conditions.

Copper-catalyzed direct benzylation or allylation of 1,3-azoles with N-tosylhydrazones.

Cu-catalyzed cross-coupling of N-tosylhydrazones with 1,3-azoles leads to the direct C-H benzylation or allylation. Cu carbene migratory insertion is proposed to play the key role in this transformation.

Corrigendum to "Hydrogen Gas Attenuates Hypoxic-Ischemic Brain Injury via Regulation of the MAPK/HO-1/PGC-1a Pathway in Neonatal Rats".

[This corrects the article DOI: 10.1155/2020/6978784.].

Hemin-Catalyzed Oxidative Phenol-Hydrazone [3+3] Cycloaddition Enables Rapid Construction of 1,3,4-Oxadiazines.

Herein, we present a hemin-catalyzed oxidative phenol-hydrazone [3+3] cycloaddition that accommodates a broad spectrum of N-arylhydrazones, a class of less exploited 1,3-dipoles due to their significant Lewis basicity and weak tendency to undergo 1,2-prototropy to form azomethine imines. It renders expedient assembly of diversely functionalized 1,3,4-oxadiazines with excellent atom and step economy. Preliminary mechanistic studies point to the involvement of a one-electron oxidation pathway, which likely differs from the base-promoted aerobic oxidative scenario.