Medium-sized rings, including those embedded in bridged and fused bicyclic scaffolds, are common core structures of myriad bioactive molecules. Among various synthetic strategies towards their ...synthesis, intermolecular higher-order cycloaddition provides great potential to build complex medium-sized rings from simple building blocks. Unfortunately, such transformations are often plagued with competitive reaction pathways and low levels of site- and stereoselectivity. Herein, we report catalyst-controlled divergent access to three classes of medium-sized bicyclic compounds in high efficiency and stereoselectivity, by palladium-catalysed cycloadditions of tropones with γ-methylidene-δ-valerolactones. Mechanistic studies and density functional theory calculations disclosed that the divergent reactions stem from the different reaction profiles of the diastereomeric intermediates. While one undergoes either O- or C-allylation to provide 5.5.0 or 4.4.1 bicyclic compounds, the unique conformation of the other diastereomer allows an unconventional alkene isomerization to deliver bridgehead alkene-containing bicyclo4.4.1 compounds. The conversion of these products to diverse complex polycyclic scaffolds has also been demonstrated.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The importance of axial chirality in enantioselective synthesis has been widely recognized for decades. The practical access to certain structures such as biaryl amino phenols known as NOBINs in ...enantiopure form, however, still remains a challenge. In drug delivery, the incorporation of axially chiral molecules in systematic screening has also received a great deal of interest in recent years, which calls for innovation and practical synthesis of structurally different axially chiral entities. Herein we present an operationally simple catalytic N-alkylation of sulfonamides using commercially available chiral amine catalysts to deliver two important classes of axially chiral compounds: structurally diverse NOBIN analogs as well as axially chiral N-aryl sulfonamides in excellent enantiopurity. Structurally related chiral sulfonamide has shown great potential in drug molecules but enantioselective synthesis of them has never been accomplished before. The practical catalytic procedures of our methods also bode well for their wide application in enantioselective synthesis.
Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients ...and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vestibular information processed first by the brainstem vestibular nucleus (VN), and further by cerebellum and thalamus, underlies diverse brain function. These include the righting reflexes and ...spatial cognitive behaviour. While the cerebellar and thalamic circuits that decode vestibular information are known, the importance of VN neurons and the temporal requirements for their maturation that allow developmental consolidation of the aforementioned circuits remains unclear. We show that timely unsilencing of glutamatergic circuits in the VN by NMDA receptor-mediated insertion of AMPAR receptor type 1 (GluA1) subunits is critical for maturation of VN and successful consolidation of higher circuits that process vestibular information. Delayed unsilencing of NMDA receptor-only synapses of neonatal VN neurons permanently decreased their functional connectivity with inferior olive circuits. This was accompanied by delayed pruning of the inferior olive inputs to Purkinje cells and permanent reduction in their plasticity. These derangements led to deficits in associated vestibular righting reflexes and motor co-ordination during voluntary movement. Vestibular-dependent recruitment of thalamic neurons was similarly reduced, resulting in permanently decreased efficiency of spatial navigation. The findings thus show that well-choreographed maturation of the nascent vestibular circuitry is prerequisite for functional integration of vestibular signals into ascending pathways for diverse vestibular-related behaviours.
•Unsilencing of NMDAR-only synapses in the vestibular nucleus at postnatal day 5–7 enables integration of inputs into ascending pathways.•Delayed unsilencing hinders pruning of inputs to Purkinje cells and reduces plasticity, impacting postural and motor coordination.•Such delay impairs cerebellar and thalamic connectivity of vestibular inputs into adulthood, with impacts on spatial cognition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We report herein a new class of polystyrene-supported cinchona alkaloid amide catalysts for enantioselective allylation of various aldehydes using allyltrichlorosilane under both batch and continuous ...flow conditions. The supported catalyst was synthesized using an environmentally benign coupling agent with a surfactant in aqueous media. Under batch conditions, consistently high yields and enantioselectivity were obtained for the allylation of aliphatic aldehydes with recycling and reuse of the catalyst for more than 10 runs. Subsequently, this catalytic system was successfully implemented into a packed bed flow reactor with similar efficiency and enantioselectivity. While flow is a viable option, the batch methodology has better potential for application at a larger-scale setting upon the comparison of space-time yield and catalyst loadings. With the sustainable synthesis and great recyclability of our polymeric catalyst, this methodology holds great potential for the large-scale delivery of valuable enantiopure homoallylic alcohols.
We report herein a new class of easily accessible and recyclable polystyrene-supported cinchona alkaloid amide catalysts for highly efficient heterogeneous enantioselective allylsilylation of aldehydes. Process intensity evaluation under both batch and continuous flow conditions demonstrated that batch methodology has better potential for application at a larger-scale setting due to catalyst recyclability and regeneration. Display omitted
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Currently, the provisional stenting technique is the gold standard in revascularization of lesions located in the left main (LM) bifurcation. The benefit of the routine kissing balloon technique ...(KBI) in bifurcation lesions is still debated, particularly following the single stent treatment. We compared the latest-generation drug-eluting stent (DES) with no side branch (SB) dilatation "keep it open" technique (KIO) vs. KBI technique vs. bifurcation dedicated drug-eluting stent (BD-DES) implantation. In vitro testing was performed under a static condition in bifurcation silicone vessel models. All the devices were implanted in accordance with the manufacturers' recommendations. As a result, computational fluid dynamics (CFD) analysis demonstrated a statistically higher area of high shear rate in the KIO group when compared to KBI. Likewise, the maximal shear rate was higher in number in the KIO group. Floating strut count based on the OCT imaging was significantly higher in KIO than in KBI and BD-DES. Furthermore, according to OTC analysis, the thrombus area was numerically higher in both KIO and KBI than in the BD-DES. Scanning electron microscopy (SEM) analysis shows the highest degree of strut coating damage in the KBI group. This model demonstrated significant differences in CFD analysis at SB ostia with and without KBI optimization in the LM setting. The adoption of KBI was related to a meaningful reduction of flow disturbances in conventional DES and achieved results similar to BD-DES.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Borrowing hydrogen has gained much interest in academia and industry as a green method in converting simple alcohols to valuable amines in a waste-free manner. Despite the considerable efforts in its ...development, many challenges in this strategy still remain and prevent its application to the final stages of drug synthesis, such as the high loadings of heavy metal catalysts, harmful solvents, and cumbersome purification procedures needed to obtain purity profiles that comply with regulatory guidelines. In view of these problems, we have explored possible alternatives that emphasize atom economy and circumvent the use of toxic solvents while ensuring scalability and low heavy metal content in the final API. We report herein a high productivity hydrogen borrowing synthesis of a range of commercial drugs including Cinacalcet (Sensipar) and a selection of antihistamines: Meclizine, Buclizine, and Cyclizine. This scalable synthetic approach avoids the generation of stoichiometric waste and yields good to excellent PMI values thanks to the intensified nature of the developed process (e.g., space–time yield of 29.8 g L–1 h–1 for the synthesis of Sensipar). The use of low iridium catalyst loadings (0.15 mol %) and benign reaction media (e.g., solventless), coupled with the efficient salt precipitation of the amine salts resulting in low iridium detected in the final product (below 10 ppm), renders this work a realistic green alternative for synthetic application in Pharma.
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IJS, KILJ, NUK, PNG, UL, UM
Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients ...and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10-11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10-12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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