High Ee Research Articles

Development of an NAD(H)‐Driven Biocatalytic System for Asymmetric Synthesis of Chiral Amino Acids

AbstractChiral amino acids are extensively applied in the pharmaceutical, food, cosmetic, and agricultural industries. As a representative example, l‐phosphinothricin (l‐PPT, a chiral non‐natural amino acid) is a broad‐spectrum herbicide. An NAD(H)‐driven biocatalytic system for the asymmetric synthesis of chiral amino acids (focused on l‐PPT) with high efficiency and low cost is highly desired. The key for the development of such biocatalytic system is to obtain an NADH‐dependent biocatalyst with high catalytic performance toward l‐PPT pro‐ketone PPO. Herein, an engineered glutamate dehydrogenase from Lysinibacillus composti (LcGluDH) with desired activity was obtained by gene mining and protein engineering. In silico analyses suggested that the volume of substrate‐binding pocket was substantially enlarged from 330.5 Å3 to 409.6 Å3. The stability of LcGluDH was increased (Tm value increased from 47.3 °C to 65.3 °C) by introducing positively charged amino acids or aromatic amino acids at position 375. The desired biocatalytic system was constructed by coupling the engineered LcGluDH and an NAD+‐dependent FDH. Through this biocatalytic system, the batch production of l‐PPT exhibited high space‐time yield (207.3 g ⋅ L−1 ⋅ day−1) with strict stereoselectivity (ee of l‐PPT>99%). Furthermore, eight other chiral amino acids were synthesised by the developed NAD(H)‐driven biocatalytic system with high ee values.magnified image

Palladium-Catalyzed Asymmetric (3 + 2) Cycloaddition of Vinyl Epoxides with Substituted Propiolates. Enantioselective Formation of 2,3,4-Trisubstituted 2,3-Dihydrofurans.

Alkynyl esters are viable dipolarophiles for the palladium-catalyzed asymmetric (3 + 2) cycloaddition with vinyl epoxides. The chiral dihydrofurans are obtained in high yields and high ee values. The use of a chiral benzylic substituted P,N-ligand is essential. The usefulness of the synthetic method has been demonstrated; 2,3-cis-tetrahydrofuran was also provided.

Rhodium-Catalyzed Desymmetric Arylation of γ,γ-Disubsituted Cyclohexadienones: Asymmetric Synthesis of Chiral All-Carbon Quaternary Centers.

The desymmetric arylation of prochiral cyclohexadienones with ArZnCl in the presence of an (R)-segphos-rhodium catalyst gave high yields of the corresponding cyclohexenones, which contain a chiral arylated carbon center at the β-position and a chiral all-carbon quaternary center at the γ-position, with high diastereo- and enantioselectivities. This catalytic system was also applied to the arylation of spirocarbocyclic cyclohexadienones and afforded the corresponding cyclohexenones bearing a chiral spiro quaternary carbon with high dr and ee.

Microencapsulation of Purple Mashua Extracts Using Andean Tuber Starches Modified by Octenyl Succinic Anhydride.

This work is aimed at optimising the spray drying conditions of the phenolic extracts of purple mashua microencapsulated with octenyl succinic anhydride (OSA) Andean tuber starches. Purple mashua extracts were obtained and spray dried using native and OSA starches of yellow oca, pink oca, and yellow olluco (140°C, 4% starch). The powders obtained were analysed by encapsulation efficiency of anthocyanin (EE), total phenol content, and antioxidant capacity to select the best starch for optimisation purposes. OSA pink oca starch was selected because the obtained powder presented the highest EE. The spray drying conditions optimised were obtained using a central composite rotatable design (CCRD) and response surface methodology. The encapsulant proportion of OSA pink oca starch (2-12%) and the inlet drying temperature (IDT, 120-160°C) were used as factors of the design. The optimised spray drying condition was 160°C IDT and 2% encapsulant; this condition maximised the EE, total phenol content, antioxidant capacity, and solubility and minimised the water activity and hygroscopicity of the powder. The OSA pink oca starch could be used as an encapsulating agent of phenolic extracts because it can produce powder with high antioxidant capacity and high EE.

Burnout and Long-term Sickness Absence From the Teaching Function: A Cohort Study

BackgroundThe present objective was to verify whether burnout (emotional exhaustion [EE], depersonalization [DP] and low professional efficacy [PE]) is a risk factor for long-term sickness absence (LTSA; ≥30 consecutive days) from the teaching role. MethodsThis was a prospective cohort study with two years of follow-up that investigated 509 elementary and high-school teachers. Burnout was identified by Maslach Burnout Inventory. Poisson regression with robust variance was used to adjust for possible confounders. ResultsThe incidence of LTSA was 9.4%. High EE levels were associated with LTSA in the crude analysis, but the association lost statistical significance after adjustments (for sex, age, perception of work-life balance, general self-rated health, chronic pain and depression). High DP levels were associated with this outcome, even after all adjustments (relative risk = 1.80; 95% confidence interval: 1.05–3.09). Low PE levels were not related to LTSA. ConclusionThe results reinforce the need to improve teachers' work conditions to reduce burnout, particularly DP, and its consequences.

Intranasal repaglinide-solid lipid nanoparticles integrated in situ gel outperform conventional oral route in hypoglycemic activity

Repaglinide (REP) loaded solid-lipid nanoparticles (SLNs) for intranasal administration is the subject of the current work aiming enhancement of diabetes pharmacotherapy. SLNs were prepared by applying 32 factorial-design using the hot-melt emulsion technique. Surfactant and lipid types were selected as the independent variables. The optimized formula composed of glyceryl monostearate and Poloxamer 188 was further integrated into gellan gum (GG 0.5%w/v) in situ gel for ease of administration. The optimized SLNs integrated into situ gel (SLNF1.ISG0.5) showed small particle size (96.34nm), high EE (80.57%), and outstanding sustained release of only 83.3% after 30h. ISG formula showed pseudo-plastic behavior, mucoadhesive property, and physical stablility. TEM showed spherical nanoparticles associated with the hydrogel matrix. In vivo pharmacodynamic study results in diabetic rats’ proved to be safe and succeeded to show superior hypoglycemic-activity for REP after nasal administration versus oral route manifested by higher 1.2-fold % maximum reduction, the 2.5-fold total decrease in blood glucose level with a significantly longer duration of action > 48h. Conclusively, the developed intranasal drug-loaded-SLNs integrated in-situ gel formula succeeded to achieve the maximum therapeutic outcome of repaglinide in dose reduction frequency for diabetes mellites treatment.

In vitro release, ex vivo penetration, and in vivo dermatokinetics of ketoconazole-loaded solid lipid nanoparticles for topical delivery.

The study focused to evaluate and investigate optimized (using QbD) and novel ketoconazole (KTZ)-loaded solid lipid nanoparticles (KTZ-SLNs; 2% w/v KTZ) for enhanced permeation across skin. KTZ-SLNs were evaluated for size, distribution, zeta potential (ZP), percent entrapment efficiency (%EE), drug release, morphology (HRTEM and FESEM), thermal behaviour (DSC), spectroscopic (FTIR), and solid-state/diffraction characterization (X-ray diffraction, XRD). Moreover, ex vivo permeation and drug deposition into rat skin were conducted using Franz diffusion cell. The same was confirmed using human dermatome skin and fluorescence, confocal Raman, and vibrational ATR-FTIR microscopic methods. An in vivo dermatokinetics study was performed in rats to assess the extent of KTZ permeation into the skin. Stability including accelerated and photostability studies were conducted at different temperatures (2-8, 30, and 40°C) for 12months. The spherical, optimized KTZ-SLN formulation (KOF1) showed particle size of 293nm and high EE of 88.5%. Results of FTIR, DSC, and XRD confirmed formation of KTZ-SLNs and their amorphous nature due to presence of KTZ in a dissolved state in the lipid matrix. In vitro release was slow and sustained whereas ex vivo permeation parameters were significantly high in KTZ-SLNs as compared to free drug suspension (KTZ-SUS) and marketed product (Nizral®; 2% KTZ w/v). Drug retention was 10- and five-fold higher than KTZ-SUS and marketed product, respectively. In vivo dermatokinetics parameters improved significantly with SLN formulation (410-900% enhanced). Confocal Raman spectroscopy experiment showed that KTZ-SLNs could penetrate beyond the human stratum corneum into viable epidermis. Fluorescent microscopy also indicated improved penetration of KTZ-SLNs. KTZ-SLNs were photostable and showed long-term stability over 12months under set conditions.

Chiral Sulfide/Phosphoric Acid Cocatalyzed Enantioselective Intermolecular Oxysulfenylation of Alkenes with Phenol and Alcohol O -Nucleophiles

Chiral Sulfide/Phosphoric Acid Cocatalyzed Enantioselective Intermolecular Oxysulfenylation of Alkenes with Phenol and Alcohol <i>O</i> -Nucleophiles

Formulation, characterization, and optimization of aripiprazole-loaded lyotropic liquid crystalline nanoparticle for sustained release and better encapsulation efficiency against psychosis disorder

Lyotropic liquid crystalline nanoparticles (LLCNPs) have recently received much attention in the application of drug delivery systems, due to their ordered and versatile internal nanostructures that are considered as a key factor in improving loading efficiency of various poorly soluble therapeutic agents. To take advantage on their unique well-defined and flexible internal nanostructures, aripiprazole-loaded LLCNPs consisted of a binary mixture of soy phosphatidylcholine (SPC) and citric acid ester of monoglyceride (citrem) were developed in this study. Despite exhibiting low aqueous solubility which lead to difficulties in formulation, aripiprazole, a class of psychotropic drug called atypical anti-psychotics has been used in the treatment of schizophrenia and bipolar disorder with few side effects. The utmost interest in this study is to explore the potential of LLCNPs in improving the percentage of encapsulation efficiency (EE%) of aripiprazole, their effect on the internal nanostructure of LLCNPs mesophases as well as the drug release performance from LLCNPs. The particle size of drug-loaded LLCNPs produced was in the range of 161–186 nm, with polydispersity index (PDI) between 0.11–0.16, and negative zeta potential of -21.5 to -23.8 mV. Small-angle X-ray scattering (SAXS) measurements indicated that the internal nanostructures of LLCNPs are of inverse hexagonal (H2) with a negligible difference in the lattice parameter before and after drug loading. Transmission electron microscopy (TEM) was used to observe the morphology and overall size distribution of drug-free and drug-loaded nanodispersions, which supported both SAXS and particles size findings. Differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy demonstrated that aripiprazole interacted physically with binary mixture of citrem/SPC within the nanodispersions. Moreover, the results showed that aripiprazole was successfully encapsulated into LLCNPs nanoparticles, where the EE% was all above 92%. These LLCNPs were not only have a high EE% value, but also exhibited a sustained release performance of aripiprazole with the release capacity of around 97% up to 96 h. From the current study, the potential use of LLCNPs as a promising nanocarrier for aripiprazole delivery is anticipated to improve the pharmacokinetics of this drug whilst enduring the internal nanostructural stability of the LLCNPs upon exposure to physiological environment.

Cu(ii)-thiophene-2,5-bis(amino-alcohol) mediated asymmetric Aldol reaction and Domino Knoevenagel Michael cyclization: a new highly efficient Lewis acid catalyst.

The highly efficient Lewis acid-catalytic system Cu(ii)-thiophene-2,5-bis(amino-alcohol) has been developed for enantioselective Aldol reaction of isatin derivatives with ketones. The new catalytic system also proved to be highly enantioselective for the one pot three-component Domino Knoevenagel Michael cyclization reaction of substituted isatin with malononitrile and ethylacetoacetate. The chiral ligand (2S,2′S)-2,2′-((thiophene-2,5-diylbis(methylene))bis(azanediyl))bis(3-phenylpropan-1-ol) (L1) in combination with Cu(OAc)2·H2O employed as a new Lewis acid catalyst, furnished 3-substituted-3-hydroxyindolin-2-ones derivatives (3a–s) in good to excellent yields (81–99%) with high enantioselectivities (up to 96% ee) and spiro[4H-pyran-3,3-oxindole] derivatives (6a–l) in excellent yields (89–99%) with high ee (up to 95%). These aldol products and spiro-oxindoles constitute a core structural motif in a large number of pharmaceutically active molecules and natural products.

Lecithin-based nanocapsule loading sucupira (Pterodon emarginatus) oil effects in experimental mucositis

Intestinal mucositis (IM) is a frequent adverse effect in anticancer therapy without standard treatment. The oil obtained from sucupira (Pterodon emarginatus) has anti-inflammatory properties, and the soybean lecithin reduces the intestinal toxicity of several xenobiotics. However, their water insolubility impairs the in vivo application. For this reason, we evaluated if the nanoencapsulation of sucupira oil (SO) in lecithin-based nanocapsules (SO-NC) could be a therapeutically effective system for the treatment of IM in murine cisplatin (CDDP)-induced intestinal mucositis model. SO was analyzed by LC-HRMS/MS and HPLC. SO-NC was prepared by nanoprecipitation and characterized using DLS, HPLC, and AFM. Mice body weight and food consumption were assessed daily during experimental mucositis induced by CDDP. The animals were euthanized, and intestinal permeability, inflammatory mediators, and intestinal histology were performed. SO-NC demonstrated adequate characteristics for oral administration as size under 300 nm, IP < 0.3, high EE, and spherical shape. In vitro cytotoxicity performed against RAW 264.7 cell lines resulted in cell viability above 80 % confirming the non-cytotoxic profile of SO (IC50 268 µg/mL) and SO-NC (IC50 118.5 µg/mL) up to 117.2 µg/mL. The untreated mice showed intestinal toxicity after i.p. of CDDP, principally weight loss, increased intestinal permeability, and MPO and TNF-α levels. Surprisingly, the administration of SO to CDDP-mucositis animals did not circumvent the CDDP effects and increased intestinal permeability. However, SO-NC proved efficient in mitigating the experimental intestinal mucositis by improving intestinal epithelium architecture, reducing intestinal permeability, and improving the MPO levels. In conclusion, SO-NC can positively impact intestinal mucositis by promoting mucosal recovery. This is a promising strategy for developing a new treatment for intestinal mucositis.

Heterocycle-containing Noyori-Ikariya catalysts for asymmetric transfer hydrogenation of ketones.

The synthesis of a range of N-(heterocyclesulfonyl)-functionalised Noyori-Ikariya catalysts is described. The complexes were prepared through a short sequence from C2-symmetric 1,2-diphenylethylene-1,2-diamine (DPEN) and were characterised by a range of methods including X-ray crystallography. The complexes were active catalysts for the asymmetric transfer hydrogenation (ATH) of a range of acetophenone derivatives, giving products of high ee in most cases, with notably good results for ortho-substituted acetophenones.

A nickel(ii)-catalyzed enantioselective all-carbon-based inverse-electron-demand Diels–Alder reaction of 2-pyrones with indenes

An asymmetric IEDDA reaction of 2-pyrones with indenes catalyzed by a chiral N,N′-dioxide/Ni(OTf)2 complex has been disclosed to construct highly functionalized hexahydrofluorenyl bridged-lactone scaffolds in high yields and ee.

Catalytic asymmetric amination of azlactones with azobenzenes.

We reported an efficient asymmetric amination of azlactones with N-aryl-N-aroyldiazenes through a chiral N,N'-dioxide-based Lewis acid catalyst. The multicoordination ability of Nd(III) enabled it to simultaneously activate and to locate the two reactants for N-selective addition. Hydrazine-bearing azlactone derivatives were obtained in moderate to good yields with high enantioselectivity.

Chiral Ionic Liquids Based on l-Cysteine Derivatives for Asymmetric Aldol Reaction

Structure, and consequently properties, of ionic liquids can be easily tailored by changing cation/anion combinations and/or attaching functional groups. By grafting enantiopure moieties to the framework of ionic liquid it is possible to prepare bioinspired chiral molecules that can serve as a reaction medium, additive or even asymmetric catalyst. In this context, new chiral ionic liquids (CILs), based on biomolecules, such as aminoacids (l-Cysteine derivatives), have been synthesised and tested in asymmetric aldol condensation of aldehydes and ketones. The best results were obtained for CILs composed of S-methyl-l-cysteine cation and bis(trifluoromethane)sulfonimide anion, in the reaction of 2- or 4-nitrobenzaldehyde with acetone or cyclohexanone, giving the aldol product in moderate yields 70–76% and high ee values (up to 96%).

Nickel-catalyzed enantioselective α-heteroarylation of ketones via C-F bond activation to construct all-carbon quaternary stereocenters.

Nickel-catalyzed asymmetric α-heteroarylation of ketones with fluorinated heteroarenes is reported via C-F bond activation. A series of ketones and 2-fluoropyridine derivatives with different functional groups proceed well to provide the corresponding products containing all-carbon quaternary stereocenters in good yields (up to 99% yield) and high ee values (up to 99% ee). In addition, drug molecule donepezil could also be compatible under the reaction conditions to afford late-stage diversification of pharmaceuticals.

Burnout Among Transplant Hepatologists in the United States.

Burnout among transplant hepatologists has not been well characterized. The goal of this study was to describe the prevalence and predictors of burnout among practicing transplant hepatologists in the United States. We designed a 69-item survey, including the Maslach Burnout Inventory (MBI)-Human Services Survey and questions on provider demographics, practice characteristics, and psychological factors. The survey was administered to practicing US transplant hepatologists between October and December 2019. We described burnout using MBI subscales (emotional exhaustion [EE], depersonalization [DP], and personal accomplishment [PA]) and determined significant predictors of burnout, which we defined as high EE, using univariate and multivariate analyses. A total of 185 transplant hepatologists completed the survey (response rate=25% of 738 practicing transplant hepatologists in the United States). A total of 40% reported high EE, whereas 17% and 16% reported high DP and low PA, respectively. On multivariate analysis, respondents with more than 5 colleagues (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.84) reporting adequate time for outpatient visits (OR, 0.42; 95% CI, 0.22-0.80), reporting greater comfort with their clinical caseload (OR, 0.61; 95% CI, 0.39-0.96), and reporting higher confidence in their prior training (OR, 0.49; 95% CI, 0.28-0.87) had a lower likelihood of high EE. Working 6 or more hours from home outside of work per week (OR, 2.04; 95% CI, 1.07-3.89) predicted a higher likelihood of burnout. Compensation, age, gender, career phase, caregiver status, and transplant center volume did not predict burnout. Of the surveyed transplant hepatologists, 40% experienced burnout, predicted mostly by factors related to work-time distribution, peer support, and affect. These findings should prompt development of system-level initiatives.

Combining Palladium and Chiral Organocatalysis for the Enantioselective Deconjugative Allylation of Enals via Dienamine Intermediates.

A catalytic enantioselective deconjugative allylation of enals is reported. A variety of enals underwent this transformation in high yield and ee, and products can be readily transformed into γ-allyl enals via a Cope rearrangement without erosion of ee. This transformation was used to install the quaternary stereocenter in (S)-bakuchiol, enabling completion of a concise formal synthesis.

Design and Optimization of Cationic Nanocapsules for Topical Delivery of Tretinoin: Application of the Box-Behnken Design, In Vitro Evaluation, and Ex Vivo Skin Deposition Study.

Cationic nanocapsules represent a promising approach for topical delivery purposes. We elaborated on a novel formulation based on the cationic nanocapsules to enhance the pharmacodynamic efficacy, user compliance, and photostability of tretinoin (TTN). To achieve this goal, TTN nanocapsules were prepared by the nanoprecipitation method. In order to statistically optimize formulation variables, a Box-Behnken design, using Design-Expert software, was employed. Three independent variables were evaluated: total weight of the cationic acrylic polymer (X1), oil volume (X2), and TTN amount (X3). The particle size and encapsulation efficiency percent (EE%) were selected as dependent variables. The optimal formulation demonstrated spherical morphology under scanning electron microscopy (SEM), optimum particle size of 116.3 nm, and high EE% of 83.2%. TTN-loaded nanocapsules improved photostability compared to its methanolic solution. The in vitro release study data showed that tretinoin was released in a sustained manner compared to the free drug. The ex vivo skin permeation study demonstrated that greater drug deposition into the epidermal region rather than the deep skin was observed with a gel containing TTN-loaded nanocapsules than that of drug solution, respectively. The skin irritation test revealed that the nanoencapsulation of the drug decreased its irritancy compared to the free drug. These results revealed the promising potential of cationic nanocapsules for topical delivery of tretinoin

From Enantioenriched Donor‐Acceptor Cyclopropylcarbinols to Axially Chiral Arylnaphthalenes through Aryldihydronaphthalenes: Central‐to‐Axial Chirality Exchange

AbstractTransformations of enantioenriched donor‐acceptor (D−A) cyclopropylcarbinols to enantioenriched 1‐arylnaphthalenes that bear anortho‐substituent on a benzene ring provided a successful chirality‐exchange method with a high level of stereoinduction. A central chirality‐transfer step, i. e., a Lewis‐acid‐mediated ring‐opening cyclization of enantioenriched D‐A cyclopropylcarbinols (97 to &gt;99 % ee), afforded 1‐aryl‐1,2‐dihydronaphthalenes with anortho‐substituent (Me, Br, OMe, OBn, or OiPr) on the benzene ring with high enantioselectivity (97 to &gt;99 % ee). The central‐to‐axial chirality‐exchange step, i. e., the dehydrogenation of the obtained enantioenriched 1‐aryl‐1,2‐dihydronaphthalenes using DDQ, furnished the axially chiral 1‐arylnaphthalenes with high enantioselectivity (90 to &gt;99 % ee). Importantly, we developed a highly enantioselective synthesis of a 1‐arylnaphthalene with anortho‐alkoxy group on the benzene ring. Moreover, we improved the chirality exchange to furnish a 1‐arylnaphthalene with anortho‐alkoxy‐substituted benzene ring in high yield with high ee.