Nickel-Catalyzed Enantioselective Reductive Arylation of Common Ketones.

A nickel complex of chiral bisoxazolines catalyzed the stereoselective reductive arylation of ketones in high enantioselectivity. A range of common acyclic and cyclic ketones reacted without the aid of directing groups. Mechanistic studies using isolated complex of a chiral bis(oxazoline) (L)Ni(Ar)Br revealed that Mn reduction was not needed, while Lewis acidic titanium alkoxides were critical to ketone insertion.

Cobalt-Catalyzed Enantioselective Reductive Arylation, Heteroarylation, and Alkenylation of Michael Acceptors via an Elementary Mechanism of 1,4-Addition.

Cobalt complexes with chiral quinox ligands effectively promote the enantioselective conjugate addition of enones using aryl, heteroaryl, and alkenyl halides and sulfonates. Additionally, a cobalt complex with a strongly donating diphosphine, BenzP*, successfully catalyzes the asymmetric reductive arylation and alkenylation of α,ß-unsaturated amides. Both catalytic systems show broad scopes and tolerance of sensitive functional groups. Both reactions can be scaled up with low loadings of cobalt catalysts. Experimental results and density functional theory (DFT) calculations suggest a new mechanism of elementary 1,4-addition of aryl cobalt(I) complexes.

Cobalt-Catalyzed Enantioselective Cross-Electrophile Couplings: Stereoselective Syntheses of 5-7-Membered Azacycles.

Cobalt complexes of chiral pyrox ligands catalyzed enantioselective reductive couplings of nonconjugated iododienes with aryl iodides or alkenyl bromides. The reaction enabled stereoselective syntheses of 5-7-membered azacycles carrying quaternary stereocenters. Mechanistically, cross-electrophile selectivity originated from selective coupling of alkylcobalt(I) complexes generated after cyclization with aryl iodides.

Nickel-Catalyzed Enantioselective Reductive Arylation and Heteroarylation of Aldimines via an Elementary 1,4-Addition.

Nickel catalysts of chiral pyrox ligands promoted enantioselective reductive arylation and heteroarylation of aldimines, using directly (hetero)aryl halides and sulfonates. The catalytic arylation can also be conducted with crude aldimines generated from condensation of aldehydes and azaaryl amines. Mechanistically, density functional theory (DFT) calculations and experiments pointed to an elementary step of 1,4-addition of aryl nickel(I) complexes to N-azaaryl aldimines.

Inhibition of suplatast tosilate on EPSC in the single paratracheal ganglion neurons attached with presynaptic boutons.

Using single neurons of rat paratracheal ganglia (PTG) attached with presynaptic boutons, the effects of suplatast tosilate on excitatory postsynaptic currents (EPSCs) were investigated with nystatin-perforated patch-clamp recording technique. We found that suplatast concentration dependently inhibited the EPSC amplitude and its frequency in single PTG neurons attached with presynaptic boutons. EPSC frequency was higher sensitive to suplatast than EPSC amplitude. IC50 for EPSC frequency was 1.1 × 10-5 M, being similar to that for the effect on histamine release from mast cells and lower than that for the inhibitory effect on cytokine production. Suplatast also inhibited the EPSCs potentiated by bradykinin (BK), but it did not affect the potentiation itself by BK. Thus suplatast inhibited the EPSC of PTG neurons attached with presynaptic boutons at both the presynaptic and postsynaptic sites.NEW & NOTEWORTHY In this study, using single neurons of rat paratracheal ganglia (PTG) attached with presynaptic boutons, the effects of suplatast tosilate on excitatory postsynaptic currents (EPSCs) were investigated with patch-clamp recording technique. We found that suplatast concentration dependently inhibited the EPSC amplitude and its frequency in single PTG neurons attached with presynaptic boutons. Thus suplatast inhibited the function of PTG neurons at both of presynaptic and postsynaptic sites.

HPMA copolymer conjugated 5-aminolevulinic acid exhibits superior efficacy for photodynamic therapy with tumor-responsive and targeting properties.

In this study, we developed a nanoformulation of 5-aminolevulinic acid (5-ALA) for tumor-targeted photodynamic therapy, in which 5-ALA was conjugated with a biocompatible polymer N-(2-hydroxypropyl)methacrylamide (HPMA) through the hydrazone bond, i.e., P-ALA. P-ALA behaves as the nano-sized molecule with an average size of 5.5 nm in aqueous solution. P-ALA shows a largely increased release rate in acidic pH than physiological pH, suggesting the rapid release profile in acidic tumor environment. P-ALA did not show apparent cytotoxicity up to 0.1 mg/ml, however, under light irradiation, remarkable cell death was induced with the IC50 of 20-30 µg/ml. More importantly, we found significantly higher tumor accumulation of P-ALA than 5-ALA which benefit from its nano-size by taking advantage of the enhanced permeability and retention (EPR) effect. Consequently, P-ALA exhibited much improved in vivo antitumor efficacy without any apparent side effects. We thus anticipate the application of P-ALA as a nano-designed photosensitizer for anticancer photodynamic therapy.

Gender Differences in Anxiety, Depression, Insomnia, and Quality of Life in Heart Failure With Preserved Ejection Fraction: A Multicenter, Cross-sectional Study.

BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) are more often female, but gender differences in psychological distress in patients with HFpEF have not been determined. OBJECTIVE: We aimed to compare anxiety, depression, insomnia, and quality of life (QoL) between women and men with HFpEF. METHODS: A total of 263 consecutive hospitalized patients with HFpEF were enrolled in a multicenter study. Demographic and clinical characteristics were recorded. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS), insomnia was assessed by the Insomnia Severity Index and Pittsburgh Sleep Quality Index, and QoL was assessed by the Kansas City Cardiomyopathy Questionnaire. RESULTS: Women accounted for 59% and men accounted for 41% of the patients with HFpEF. Women and men had similar New York Heart Association functional class and N-terminal pro-brain natriuretic peptide levels. Between women and men with HFpEF, similar depression prevalence (HADS-D: 4.9 ± 3.7 vs 4.1 ± 3.6, P = .222), insomnia severity (Insomnia Severity Index: 9.3 ± 6.4 vs 8.0 ± 6.5, P = .120), and QoL (Kansas City Cardiomyopathy Questionnaire: 46.6 ± 12.6 vs 47.6 ± 12.7, P = .738) were found when adjusting for potential confounders. Women had more severe anxiety (HADS-Anxiety: 2.4 ± 2.9 vs 1.6 ± 2.3, P = .025) and worse sleep quality (Pittsburgh Sleep Quality Index: 9.9 ± 4.6 vs 8.7 ± 4.5, P = .046) compared with men after adjustment. CONCLUSIONS: There were no gender differences in depression, insomnia, and QoL in patients with HFpEF when adjusting for confounders. Women with HFpEF suffered more severe anxiety and sleep quality than men after adjustment. Thus, it is recommended that psychological distress in patients with HFpEF be assessed in clinical practice, and gender differences taken into consideration.

Metal-catalyzed asymmetric heteroarylation of alkenes: diverse activation mechanisms.

This review summarizes the state-of-the-art in transition metal-catalyzed asymmetric alkylation of heteroarenes using alkenes (covering literature from 2000 to late 2021). Based on elementary reactions on metals for substrate activation, these reactions are broadly classified in several categories: (A) concerted oxidative addition of heteroaryl C-H bonds on rhodium(I) and iridium(I), (B) ligand-to-ligand hydrogen transfer (LLHT) on low-valent 3d metal complexes of nickel and cobalt, (C) different ways for deprotonation of heteroaryl C-H bonds by late transition metal complexes, especially palladium, including electrophilic aromatic substitution and a related mechanism, base-assisted intramolecular electrophilic substitution, concerted and nonconcerted metalation deprotonation, (D) σ-bond metathesis by d0 early transition metal complexes, (E) electrophilic activation of olefins by Pd(II), Pt(II) and Au(I), and (F) metal hydride insertion of aryl olefins and dienes. The demand to achieve enantiocontrol in the heteroarylation reactions has also driven innovation in chiral ancillary ligands, exemplified by extremely bulky, chiral N-heterocyclic carbenes for nickel catalysts, bulky monodentate oxazolines for Wacker-type reactions and chiral cyclopentadienyl ligands for half-sandwich complexes of scandium.

Stroke survivors', caregivers' and nurse coaches' perspectives on health coaching program towards hospital-to-home transition care: A qualitative descriptive process evaluation.

AIMS AND OBJECTIVES: To explore the perspectives of stroke survivors, caregivers and nurse coaches on a health coaching program during hospital-to-home transitional care. BACKGROUND: Stroke is a major public health problem that seriously affects the health and safety of people in China. Nurse-led health coaching is a promising support option in enabling smooth hospital-to-home transition for stroke survivors and family caregivers. A qualitative study is valuable for gaining insight into their perspectives on using this program. DESIGN: An exploratory, descriptive qualitative process evaluation was conducted parallel with a former randomised controlled trial. Data were obtained from 26 stroke survivors, 33 caregivers and four nurse coaches with semi-structured interviews. The inductive reflexive thematic analysis approach was used for data analysis. The COREQ checklist was followed in reporting this study. RESULTS: Seven themes were generated from the data: (1) the applicability of individualised health coaching sessions, (2) driving self-efficacy to establish self-care skills, (3) the key role of nurse coaches, (4) coordination among healthcare teams during the transition, (5) adequate community and social support, (6) insufficient rehabilitative services after discharge and (7) perceived extra workload for nurse coaches. CONCLUSIONS: The study captured perspectives on a nurse-led health coaching program towards hospital-to-home transition care from stroke survivors, caregivers and nurse coaches. Individualised health coaching sessions and driving self-efficacy were perceived as facilitators for empowering the self-care skills of stroke survivors and caregivers. The key role of nurse coaches in coordinating healthcare teams and adequate community and social support were detected as the power frame of the program's implementation. However, health system obstacles, such as insufficient rehabilitative services and the high workload of nurses, still need to be addressed to ensure the sustainability of health coaching intervention in transitional care. RELEVANCE TO CLINICAL PRACTICE: The study suggested the feasibility of implementing nurse-led health coaching to smooth post-stroke hospital-to-home transitional care. The findings also highlighted the importance of qualitative process evaluation when implementing evidence-based interventions in health care. TRIAL REGISTRATION: The trial was registered with the Australia New Zealand Clinical Trials Registry (ID: ACTRN12619000321145).

Cobalt-Catalyzed Asymmetric Deuteration of α-Amidoacrylates for Stereoselective Synthesis of α,ß-Dideuterated α-Amino Acids.

A cobalt-catalyzed deuteration of amidoacrylates using deuterated methanol afforded α,ß-dideuterio-α-amino esters in excellent enantiomeric ratios (mostly >95 : 5) and almost complete deuteration (99 %). The new protocol was used to prepare dideuterio-α-amino acid fragments in some drugs. Furthermore, the stereoselective deuteration was applied in a concise synthesis of dideuterio l-DOPA.

Nickel-Catalyzed Enantioselective Reductive Conjugate Arylation and Heteroarylation via an Elementary Mechanism of 1,4-Addition.

A nickel complex of isoquinox promoted enantioselective conjugate arylation and heteroarylation of enones using aryl and heteroaryl halides directly. The reaction was successfully applied to stereoselective syntheses of ar-turmerone, chiral fragments of (+)-tolterodine and AZD5672. Mechanistically, experiments and calculations supported that an arylnickel(I) complex inserted to enones via an elementary 1,4-addition.

Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens.

We report a stereoselective conversion of terminal alkynes to α-chiral carboxylic acids using a nickel-catalyzed domino hydrocarboxylation-transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti-inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.

Enantioselective Three-Component Coupling of Heteroarenes, Cycloalkenes and Propargylic Acetates.

Asymmetric coupling proceeds efficiently between propargylic acetates, cycloalkenes and electron-rich heteroarenes including indoles, pyrroles, activated furans and thiophenes. 2,3-Disubstituted tetrahydrofurans and pyrrolidines are produced in trans configuration and excellent enantiomeric ratios. The reaction proceeds via Wacker-type attack of nucleophilic heteroarenes on alkenes activated by allenyl PdII species.

Enantioselective Intermolecular Heck and Reductive Heck Reactions of Aryl Triflates, Mesylates, and Tosylates Catalyzed by Nickel.

Nickel-catalyzed intermolecular Heck reaction of cycloalkenes proceeds well with aryl triflates, mesylates and tosylates in excellent enantiomeric ratios. The asymmetric reductive Heck reaction also works with a 2-cyclopentenone ketal, which is equivalent to conjugate arylation of the enone itself.

Asymmetric Wacker-Type Oxyallenylation and Azaallenylation of Cyclic Alkenes.

Palladium-catalyzed three-component carboetherification of cyclic alkenes proceeded to give trans adducts exclusively with excellent enantioselectivity through a Wacker-type pathway. The reaction is also applicable to other oxygen nucleophiles, such as water, phenols, and carboxylic acids, as well as some electron-poor aryl amines.

Asymmetric Three-Component Heck Arylation/Amination of Nonconjugated Cyclodienes.

Substituted cyclohexylamines are becoming increasingly important in drug discovery. Asymmetric Heck insertion/amination of nonconjugated cyclodienes proceeds to give 5-aryl cyclohexenylamines with good enantioselectivity and exclusive trans configurations. Primary and secondary anilines, indoline, and benzylamines are suitable amines. The weakly donating diphosphite Kelliphite forms a deep unsymmetrical pocket, which is essential for stereoselective anti attack of amines.

Asymmetric Reductive and Alkynylative Heck Bicyclization of Enynes to Access Conformationally Restricted Aza[3.1.0]bicycles.

Conformationally restricted azabicycles are becoming increasingly important in medicinal research. Asymmetric Heck bicyclization of enynes proceeds to give medicinally useful aza[3.1.0] and aza[4.1.0] bicycles with excellent enantioselectivity. The key organopalladium species after bicyclization can be trapped by silanes and terminal alkynes.

Anti-proliferative Activities towards Human Brain Glioma U251 Cells and Human Carcinoma Cells (KB3-1) of Some Twin-Drug Type Bivalent C2-Symmetrical Phenylboronic Acid Derivatives.

Derivatives of C2-symmetrical bivalent phenylboronic acid exhibit several remarkable biological activities such as anti-herpes simplex virus (HSV)-1 and cytotoxic activities against Vero cells and they can reverse the effect of anticancer drugs. Novel symmetrical bivalent molecules were synthesized and their biological activities were evaluated in vitro using a human brain glioma cell line (U251) and a human carcinoma cell line (KB3-1). Among the tested compounds (1a-i), bivalent C2-symmetrical phenylboronic acid derivative 1g showed the highest anti-proliferative activity towards both U251 and KB3-1 cells. The values of 50% anti-proliferative activity (IC50) of this compound against the two cell lines (U251 and KB3-1) were 19.0 and 3.78 µM, respectively. The anti-proliferative activity of compound 1g towards KB3-1 cells was higher than that of cisplatin. The bivalent C2-symmetrical compound 1g had a linear methylene linker in the molecule.

Anti-proliferative Activities of Some Bivalent Symmetrical 5-Substituted Hydantoin Derivatives towards Human Brain Glioma U251 Cells (U251) and Human Carcinoma Cells (KB3-1).

Novel bivalent twin-drug type hydantoin derivatives were evaluated in vitro using a human brain glioma cell line (U251) and a human carcinoma cell line (KB3-1). Among the 5-substituted hydantoin derivatives (1a-b and 2a-d) examined in this study, bivalent symmetrical 5-substituted hydantoin derivative 1b showed the highest anti-proliferative activity towards both U251 and KB3-1 cells. The values of anti-proliferative activity (IC50) of this hydantoin derivative against the two cell lines (U251 and KB3-1) were 0.46 and 5.21 µM, respectively. The anti-proliferative activity of all of the compounds except for compounds 2a and 2d against U251 cells was higher than that of cisplatin. Bivalent symmetrical compound 1b had a biphenylmethane linker in the molecule. All of the tested bivalent hydantoin derivatives showed higher activity against U251 cells than against KB3-1 cells. For twin-drug type hydantoin derivatives 2a-d, which have a linear methylene linker in the molecules, it was found that methylene linker length in these molecules have an effect on the anti-proliferative activity against U251 and KB3-1 cells.

Asymmetric Stepwise Reductive Amination of Sulfonamides, Sulfamates, and a Phosphinamide by Nickel Catalysis.

Asymmetric reductive amination of poorly nucleophilic sulfonamides was realized in the presence of nickel catalysts and titanium alkoxide. A wide range of ketones, including enolizable ketones and some biaryl ones, were converted into sulfonamides in excellent enantiomeric excess. The cyclization of sulfamates and intermolecular reductive amination of a diarylphosphinamide were also successful. Formic acid was used as a safe and economic surrogate of high-pressure hydrogen gas.