Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an ...attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7 − 12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Natural products have laid the foundation for the discovery and development of medicines for centuries. Early Ayurvedic medicine involved the use of cocktails of several naturally occurring molecules ...for the treatment of common illnesses. Today natural products remain the mainstay of therapeutic intervention in the treatment of several debilitating diseases. Compounds accessed from natural sources have also been the source of inspiration in the discovery of several non-natural pharmaceuticals.The diverse and complex structural features of natural products and their limited availability, however, presents a significant roadblock in accessing these molecules on scales where they can have the greatest impact. Currently, the de novo synthesis of natural products is challenging, expensive, and low yielding. To address this, chemists strive to access structures with the greatest efficiency and practicality. Despite decades of efforts we are still faced with the challenge of synthetic efficiency.Herein, the cytotoxic agent Peloruside A, the antibiotic tobramycin, the multi-drug resistance reversal agent N-acetyl-ardeemin have inspired the discovery and development of methods to streamline the synthesis of these molecules and their analogs. Detailed is an account of the efforts dedicated towards accessing these natural products in high efficiency and in enantiomerically enriched form using novel disconnections which have led to the development of several new methods. Peloruside A has inspired the development of the asymmetric desymmetrization of 2-alkyl-1,3-propanediols. This method was found to be highly general and rapidly afforded several chiral building blocks. One of these is applied towards the synthesis of an important fragment in this natural product.Peloruside A also highlighted the deficiencies in using esters in direct asymmetric aldol reactions. The development of a diazoester aldol using of commercially available ethyl diazoacetate and a range of aldehydes is a viable alternative to the use of chiral pool-based auxiliaries. To minimize the use of protecting groups the use of an alkyne as a masked α-hydroxyketone has been explored in the formation of the pyran ring in peloruside A via a 6-endo-dig cyclization.The development of the asymmetric diazoester aldol reaction led to the synthesis of vicinal diols bearing a tertiary alcohol. The oxidation of β-hydroxy-α-diazoesters affords β-hydroxy-α-ketoesters that undergo alkyl transfer with minimal erosion in chirality and in high diastereocontrol with alkyl, allyl, and propargyl nucleophiles. One of the products from this method is present in azithromycin and related natural products. Furthermore, the asymmetric diazoester aldol reaction enables the exploration of a direct stereospecific C-O to C-N exchange reaction unique to diazoesters towards the synthesis of β-amido-α-diazoesters. The products from this reaction can be transformed into β-amido-α-hydroxyesters and undergo a rather unusual 1,3-C-H insertion reaction to afford aminocyclopropanes.The use of nitrogen nucleophiles in Pd-catalyzed asymmetric allylic alkylations enabled the synthesis of two diastereoisomers of 2-deoxystreptamine. This motif is present in all clinically relevant aminoglycoside antibiotics; however, the biological effects of aminoglycosides that are diastereomeric at the 2-deoxystreptamine core are unexplored. A synthetic sequence that furnishes scaffolds that have the potential of being transformed into novel aminoglycosides is presented. This project highlighted the challenge of generating diamines. Recognizing this, a collaboration with the Du Bois group at Stanford University was initiated where the use of a bifunctional nucleophile in sequential palladium- and rhodium-catalyzed processes afforded several nitrogenated architectures that cannot be readily accessed by pre-existing methods and can serve as building blocks in drug discovery. One interesting facet of this work was the use of π-prenylpalladium species in directing attack of a nitrogen nucleophile at the more substituted carbon of a prenyl electrophile.The reverse prenylated hexahydropyrrolo2,3-bindoline substructure is present in several natural products such as N-acetyl-ardeemin. One reason for the challenge associated in employing π-prenylpalladium complexes to access these natural products lies in the concomitant control of the regio- and enantioselectivity with sterically more demanding carbon based nucleophiles. Although usually Pd-catalyzed allylic alkylations result in attack at the less hindered terminus of a π-allyl, described are conditions where the regioselectivity can be controlled in accessing either linear or branched prenylated products in high optical purities. In one example the enantio-, regio- and diastereoselective synthesis of vicinal quaternary stereogenic centers has been achieved using palladium catalyzed allylic alkylations.
3-(Imidazo1,2-
apyridin-3-yl)-, its aza-analogs, and 3-(pyrazolo1,5-
apyridin-3-yl)-4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl))maleimides are very potent inhibitors of GSK3 (⩽5
nM) ...with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII.
Many 3-aryl-4-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100
nM IC
50), although few show significant selectivity (>100
×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo1,2-
apyridin-3-yl), 3-(pyrazolo1,5-
apyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (⩽5
nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
Synthesis of indolo6,7-apyrrolo3,4-ccarbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the ...synthesis of 2 were identified that required new methods for the synthesis of 7-substituted indole acetamides 3 and N-methyl (indol-7-yl)oxoacetates 6. The chemistry developed enabled introduction of functionality (−OR, NR2) at C12 and N13 facilitating structure−activity relationship (SAR) evaluation of this indolocarbazole platform.
The synthesis and CDK inhibitory properties of a series of indolo6,7-
apyrrolo3,4-
ccarbazoles is reported. In addition to their potent CDK activity, the compounds display antiproliferative activity ...against two human cancer cell lines. These inhibitors also effect strong G1 arrest in these cell lines and inhibit Rb phosphorylation at Ser780 consistent with inhibition of cyclin D1/CDK4.
Graphic
To perform an intraindividual comparison of the quality of vision and the effect of decentration between two aspheric intraocular lenses: aspheric balanced curve (ABC) design Vivinex iSert XY1 (Hoya ...Surgical Optics, Singapore) and anterior aspheric design Tecnis ZCB00 (Abbott Medical Optics, CA).
Tertiary Eye Care Centre.
Prospective, randomized comparative study using a random number table.
Thirty patients were randomized to the implantation of Vivinex iSert XY1 in one eye and Tecnis ZCB00 in the contralateral eye. Then, 12 weeks postoperatively, a laser ray-tracing aberrometer was used to evaluate the visual Strehl ratio, higher-order aberrations (HOA), decentration of IOL from the visual axis and geometric axis, angle alpha, and angle kappa. Contrast sensitivity was measured using the functional visual analyzer.
The visual internal Strehl ratio was higher ( P < 0.05) at all pupil sizes and the spherical aberrations values were lower ( P < 0.05) at larger pupil sizes (5 mm and 6 mm) in the Vivinex group. The mean decentration from the visual axis in the Vivinex group was significantly more than that in the Tecnis group ( P < 0.01). With an increase in angle alpha, there was a greater decline in the visual Strehl ratio for Tecnis; however, there was a statistically significant decline at 3 mm pupil size for Tecnis ZCB00 ( P = 0.028). The contrast sensitivity was similar for both IOLs.
In comparison to an anterior aspheric design IOL, the ABC design IOL yielded better quality of vision, neutralized spherical aberrations to a larger extent, and provided a relatively superior quality of vision with decentration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Herein, we report a case of naturally occurring anti-Leb alloantibody identified in the plasma of a first time voluntary blood donor. The immunohematology workup was done on the pilot sample tubes ...collected during blood donation by the conventional tube technique and using ID-Micro Column System Glass Beads card (anti-IgG, C3d; Ortho-Clinical Diagnostics, Raritan, New Jersey, USA). Blood group of the donor was confirmed to be B RhD positive, and the alloantibody in his plasma was identified as anti-Leb, having clinically significant characteristics. Since in this particular case, anti-Leb was IgM and IgG in nature, it was clinically significant and can lead to hemolytic transfusion reaction, especially if such fresh frozen plasma unit is transfused to Leb negative patients.
Purpose
Augmented Reality (AR) and Virtual Reality (VR) technologies possess the potential to transform the scenario of making real estate investment decisions through the immersive experience they ...offer. From the literature it was observed that the research in this domain is still emergent and there is a need to identify the latent variables that influence real estate investment decisions. Therefore, by examining the effects of these technologies on investment decision-making, the purpose of the study is to provide valuable insights into how AR and VR could be applied to enhance customers' property buying experiences and assist in their decision-making process.
Design/methodology/approach
From an extensive review of the literature four latent variables and their measure were identified, and based on these a survey instrument was developed. The survey was distributed online and received 300 responses from the respondents including home buyers, developers, AEC professionals and real estate agents. To validate the latent variables exploratory factor analysis was used whereas to establish their criticality second-order confirmatory factor analysis was used.
Findings
From the results, the four latent constructs were identified based on standard factor loadings (SFL) that is Confident Value Perception (CVP, SFL = 0.70), Innovative Investment Appeal (IIA, SFL = 0.60), Trusted Property Transactions (TPT, SFL = 0.58) and Effortless Property Engagement (EPE, SFL = 0.54), that significantly influence investor decision-making and property purchase experience.
Originality/value
This study contributes to the literature on real estate investment decisions by providing empirical evidence on the role of AR and VR technologies. The identified key variables provided practical guidelines for developers, investors and policymakers in understanding and leveraging the potential of AR and VR technologies in the real estate industry.
Familial hypercholesterolemia (FH) is characterized by an increase in plasma low-density lipoprotein-cholesterol (LDL-C) levels. It presents with tendon/skin xanthomas and premature atherosclerotic ...cardiovascular disease. The most available treatment options for FH are lipid-lowering medications such as statins, lifestyle modification, and LDL apheresis. As per American Society for Apheresis guidelines 2019, the treatment of FH using LDL apheresis falls under Category I. Here, we are reporting an interesting case of a young patient who presented with chief complaints of progressively increasing yellowish lesions around eyes, neck, hands, and legs. She was thoroughly investigated and was diagnosed provisionally as a case of Type 2 FH. Her total serum cholesterol and LDL-C were 717.2 mg/dl and 690.6 mg/dl, respectively, at presentation. One cycle of LDL apheresis was planned for her. We found immediate post-procedural reduction of 55.8% and 55.3% for total serum and LDL cholesterol levels respectively while 70.58% and 77.41% reduction in the levels from the day of presentation to the hospital.
Kimura’s disease is a rare disorder of uncertain aetiology seen in Asian population, and presents as painless lymphadenopathy or subcutaneous masses in head-neck region. Peripheral eosinophilia, ...elevated levels of serum IgE, lymphoid proliferation and eosinophilic infiltration are its characteristic pathological features. We report a case of 40 year old male patient who presented with swelling behind right ear after successful ear surgery. The diagnosis was confirmed by histopathology and was treated by oral steroids.
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