A novel ion exchange strategy has been developed to enable the asymmetric construction of axially chiral sulfone-containing styrenes. This approach provides a practical synthesis pathway for various axially chiral sulfone-containing styrenes with good yields, exceptional enantioselectivities, and nearly complete E/Z selectivities. Additionally, the reaction mechanism is elucidated in detail through density functional theory (DFT) calculations.
Aliphatic allylic amines are common in natural products and pharmaceuticals. The oxidative intermolecular amination of C(sp3)-H bonds represents one of the most straightforward strategies to construct these motifs. However, the utilization of widely internal alkenes with amines in this transformation remains a synthetic challenge due to the inefficient coordination of metals to internal alkenes and excessive coordination with aliphatic and aromatic amines, resulting in decreasing the reactivity of the catalyst. Here, we present a regioselective Cu-catalyzed oxidative allylic C(sp3)-H amination of internal olefins with azodiformates to these problems. A removable bidentate directing group is used to control the regiochemistry and stabilize the π-allyl-metal intermediate. Noteworthy is the dual role of azodiformates as both a nitrogen source and an electrophilic oxidant for the allylic C-H activation. This protocol features simple conditions, remarkable scope and functional group tolerance as evidenced by >40 examples and exhibits high regioselectivity and excellent E/Z selectivity.
An efficient palladium-catalyzed enantioselective direct N-alkylation of indoles using a novel type of axially chiral styrene-phosphine ligand SJTU-PHOS-1 was developed. This reaction demonstrated good functional group compatibility and a wide range scope of substrates in mild conditions. Moreover, the DFT calculations expounded the coordination mode of the metal catalyst and the axially chiral styrene-phosphine ligand in the enantioselectivity control.
The short-chain dehydrogenase/reductase (SDR) superfamily members acyl-ACP reductases FabG and FabI are indispensable core enzymatic modules and catalytic orientation controllers in type-II fatty acid biosynthesis. Herein, we report their distinct substrate allosteric recognition and enantioselective reduction mechanisms. FabG achieves allosteric regulation of ACP and NADPH through ACP binding across two adjacent FabG monomers, while FabI follows an irreversible compulsory order of substrate binding in that NADH binding must precede that of ACP on a discrete FabI monomer. Moreover, FabG and FabI utilize a backdoor residue Phe187 or a "rheostat" α8 helix for acyl chain length selection, and their corresponding triad residues Ser142 or Tyr145 recognize the keto- or enoyl-acyl substrates, respectively, facilitating initiation of nucleophilic attack by NAD(P)H. The other two triad residues (Tyr and Lys) mediate subsequent proton transfer and (R)-3-hydroxyacyl- or saturated acyl-ACP production.
Fatty Acids , Oxidoreductases , Oxidoreductases/metabolism , Catalysis
An axially chiral styrene-based organocatalyst, featuring a combination of axially chiral styrene-based structure and a pyrrole ring, has been designed and synthesized. This catalyst demonstrates remarkable capabilities in producing a wide range of densely substituted spirooxindoles that feature an alkyne-substituted quaternary stereogenic center. These spirooxindoles are generated through mild cascade Michael/cyclization reactions, resulting in high conversion rates and exceptional enantioselectivity. Our catalytic model, based on experiments, X-ray structure analysis and DFT calculations suggests that chiral matched π-π interactions and multiple H-bonds between the organocatalyst and substrates play significant roles in controlling the stereoselectivity of the reaction.
Herein, we describe a stereoselective sulfa-Michael/aldol cyclization reaction promoted by a rationally designed novel axially chiral styrene-based organocatalyst. A variety of highly substituted tetrahydrothiophenes featuring an alkyne-substituted quaternary stereogenic center are obtained in good yields, excellent stereoselectivities, and exclusive trans selectivities. This process tolerates a broad range of alkynyl-substituted acrylamides under mind conditions. The utility of this approach is highlighted in its excellent asymmetric introduction, scalability, and attractive product diversification.
The first total syntheses of polycyclic diterpenes phomopsene (1), methyl phomopsenonate (2), and iso-phomopsene (3) have been accomplished through the unusual cascade reorganization of C-C single bonds. This approach features: (i) a synergistic Nazarov cyclization/double ring expansions in one-step, developed by authors, to rapid and stereospecific construction of the 5/5/5/5 tetraquinane scaffold bearing contiguous quaternary centers and (ii) a one-pot strategic ring expansion through Beckmann fragmentation/recombination to efficiently assemble the requisite 5/5/6/5 tetracyclic skeleton of the target molecules 1-3. This work enables us to determine that the correct structure of iso-phomopsene is, in fact, the C7 epimer of the originally assigned structure. Finally, the absolute configurations of three target molecules were confirmed through enantioselective synthesis.
An asymmetric intramolecular hydroalkylation of unactivated internal olefins with tethered cyclic ketones was realized by the cooperative catalysis of a newly designed chiral amine (SPD-NH2 ) and PdII complex, providing straightforward access to either bridged or fused bicyclic systems containing three stereogenic centers with excellent enantioselectivity (up to 99 % ee) and diastereoselectivity (up to >20 : 1 dr). Notably, the bicyclic products could be conveniently transformed into a diverse range of key structures frequently found in bioactive terpenes, such as Δ6 -protoilludene, cracroson D, and vulgarisins. The steric hindrance between the Ar group of the SPD-NH2 catalyst and the branched chain of the substrate, hydrogen-bonding interactions between the N-H of the enamine motif and the C=O of the directing group MQ, and the counterion of the PdII complex were identified as key factors for excellent stereoinduction in this dual catalytic process by density functional theory calculations.
Utilization of Freon-type methanes as functional one-carbon synthons in the synthesis of various deuterated indoline alkaloids was demonstrated here. A series of halomethyl radicals were generated from electro-reductive C-X cleavage of Freon-type methanes and captured efficiently by acrylamides to provide various halogenated oxindoles via radical cyclization. This reaction features good functional group tolerance, and deuterium and fluorine atoms could be introduced facilely from Freon-type methanes. Further transformation of halogenated oxindoles enabled the synthesis of many (labeled) bioactive drug molecules and skeletons, such as deuterated (±)-physostigmine, deuterated (±)-esermethole and deuterated (±)-lansai B.
Alkaloids , Methane , Alkaloids/chemistry , Chlorofluorocarbons , Oxindoles , Stereoisomerism
Bioinspired palladium-catalyzed intramolecular cyclization of amino acid derivatives containing a vinyl iodide moiety by C-H activation enabled rapid access to a wide range of functionalized proline derivatives with an exocyclic olefin. To demonstrate the practicality of this methodology, the functionalized prolines were used as intermediates for the synthesis of several natural products: lucentamycin A, oxotomaymycin, oxoprothracarcin, and barmumycin.
Biological Products , Palladium , Catalysis , Cyclization , Molecular Structure , Palladium/chemistry , Proline
The cell-wall recycling process is important for bacterial survival in nutrient-limited conditions and, in certain cases, is directly involved in antibiotic resistance. In the sophisticated cell-wall recycling process in Escherichia coli, the transcriptional repressor MurR controls the expression of murP and murQ, which are involved in transporting and metabolizing N-acetylmuramic acid (MurNAc), generating N-acetylmuramic acid-6-phosphate (MurNAc-6-P) and N-acetylglucosamine-6-phosphate (GlcNAc-6-P). Here, we report that both MurNAc-6-P and GlcNAc-6-P can bind to MurR and weaken the DNA binding ability of MurR. Structural characterizations of MurR in complex with MurNAc-6-P or GlcNAc-6-P as well as in the apo form revealed the detailed ligand recognition chemistries. Further studies showed that only MurNAc-6-P, but not GlcNAc-6-P, is capable of derepressing the expression of murQP controlled by MurR in cells and clarified the substrate specificity through the identification of key residues responsible for ligand binding in the complex structures. In summary, this study deciphered the molecular mechanism of the cell wall recycling process regulated by MurR in E. coli.
Escherichia coli Proteins/metabolism , Escherichia coli , Repressor Proteins/metabolism , Cell Wall/genetics , Cell Wall/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Escherichia coli Proteins/genetics , Glycoside Hydrolases/genetics , Ligands , Phosphates/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism
Misplaced or excessive hypochlorous acid in lysosomes has a close association with lots of diseases, so monitoring hypochlorous acid in lysosomes is particularly necessary. In the present work, a novel lysosome-targetable fluorescent probe (Lyso-R-HClO) for hypochlorous acid based on a HClO-mediated cyclization reaction was developed. In the fluorescent probe, the morpholine unit and the site of a HClO-mediated cyclization reaction were, respectively, used as the lysosome-targetable group and the response group. The probe has high selectivity and high sensitivity to hypochlorous acid, with a linear range from 5.0 × 10-8 to 3.0 × 10-6 M and a detection limit of 15 nM; it was successfully used to image endogenous and exogenous lysosomal HClO. Finally, Lyso-R-HClO was further applied to image lysosomal HClO produced in bacteria-infected macrophage with satisfactory results, which indicate that it is an useful tool for studies of lysosomal HClO and the role of lysosome.
Fluorescent Dyes , Hypochlorous Acid , Cyclization , Fluorescent Dyes/metabolism , Hypochlorous Acid/metabolism , Lysosomes/metabolism
Herein we disclose a highly efficient enantioselective para-C-H alkylation of aniline derivatives promoted by a base/Co/indeno-pybox ligand system. This methodology leads to the efficient construction of a series of enantioenriched aniline derivatives bearing all-carbon quaternary stereocenters. In addition, several special biologically or medicinally active indoles are facilely synthesized by our Co-catalyzed asymmetry synthesis method. Density functional theory calculations and experiment results suggest that the (acac)- anion of Co(acac)2 plays a very important role in chiral control during the nucleophilic reaction.
OBJECTIVE: Formaldehyde (FA) is known to induce lung injury, but the underlying molecular mechanism remains largely unclear. CDR1as is an important member of the circular RNAs (circRNAs) family and functions as miRNA sponges with gene-regulatory potential. Our earlier circRNA microarray data showed CDR1as was highly expressed in lung tissue exposed to FA. However, the mechanism of circRNA-CDR1as mediates the FA-exposed lung injury is still unclear. This study aimed to explore the role of CDR1as in lung injury. MATERIALS AND METHODS: In this study, FA was inhaled at doses of 0.5, 2.46, and 5 mg/m3, respectively. After exposure 8 weeks, lung histopathological examination, lung injury score, and IL-1ß in bronchoalveolar lavage fluid (BALF) were determined. The expressions of CDR1as, rno-miR-7b and Atg7 were detected and the potential interaction of circRNA/miRNA/mRNA was predicted by bioinformatics analysis, including drawing circRNA/miRNA/mRNA interaction network, GO and KEGG analysis. RESULTS: Our results indicated FA inhalation upregulated the expression of CDR1as in lung tissues in a dose-dependent manner while the expression of rno-miR-7b decreased and Atg7 increased. Moreover, the alteration of CDR1as was positively correlated with lung injury. DISCUSSION AND CONCLUSIONS: CircRNA/miRNA/mRNA prediction further explained the possible effect mechanisms of CDR1as. These data implicated that CDR1as might be a critical regulator involved in lung injury induced by FA.
Lung Injury , MicroRNAs , Formaldehyde/toxicity , Humans , Lung Injury/chemically induced , Lung Injury/genetics , MicroRNAs/genetics , RNA, Circular
High brightness Si nanocrystal white light-emitting diodes (WLED) based on differentially passivated silicon nanocrystals (SiNCs) are reported. The active layer was made by mixing freestanding SiNCs with hydrogen silsesquioxane, followed by annealing at moderately high temperatures, which finally led to a continuous spectral light emission covering red, green and blue regimes. The photoluminescence quantum yield (PLQY) of the active layer was 11.4%. The SiNC WLED was composed of a front electrode, electron transfer layer, front charge confinement layer, highly luminescent active layer, rear charge confinement layer, hole transfer layer, textured p-type Si substrate and aluminum rear electrode from top to bottom. The peak luminance of the SiNC WLED achieved was 2060 cd/m2. The turn-on voltage was 3.7â V. The chromaticity of the SiNC WLED indicated white light emission that could be adjusted by changing the annealing temperature of the active layer with color temperatures ranging from 3686 to 5291â K.
Herein, we have reported a nickel-catalyzed cascade reductive thiolation of aryl halides with sulfinates driven by paired electrolysis. This protocol uses sulfinates as the sulfur source, and various thioethers could be synthesized under mild conditions. By mechanism exploration, we find that a cascade chemical step is allowed on the electrode interface and could alter the reaction pathway in paired electrolysis, whose findings could help the discovery of novel cascade reactions with unique reactivity.
We report the efficient syntheses of chiral tetrahydroindole pyrazolinones by the asymmetric [3 + 2] cascade cyclizations (indolizations) of simple aniline derivatives with pyrazolinone ketimines as 2C synthons. The chiral phosphoric-acid-catalyzed system uses a concerted π-π interaction/dual H-bond control strategy to catalytically direct the asymmetric aniline, which undergoes a highly chemo-, regio-, and enantioselective [3 + 2] cascade annulation, furnishing a series of optically active tetra-hydroindole pyrazolinones with two contiguous chiral aza-quaternary carbon centers in excellent yields with excellent enantioselectivities. This method features a relatively broad substrate scope for amines and 2-naphthylamines and highlights the emerging value of direct chiral indolizations from simple amine sources in organic synthesis.
BACKGROUND: Traditional Chinese medicine manipulation (TCMM) is often used to treat human skeletal muscle injury, but its mechanism remains unclear due to difficulty standardizing and quantifying manipulation parameters. METHODS: Here, dexamethasone sodium phosphate (DSP) was utilized to induce human skeletal muscle cell (HSkMC) impairments. Cells in a three-dimensional environment were divided into the control normal group (CNG), control injured group (CIG) and rolling manipulation group (RMG). The RMG was exposed to intermittent pressure imitating rolling manipulation (IPIRM) of TCMM via the FX5000™ compression system. Skeletal muscle damage was assessed via the cell proliferation rate, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and creatine kinase (CK) activity. Isobaric tagging for relative and absolute protein quantification (iTRAQ) and bioinformatic analysis were used to evaluate differentially expressed proteins (DEPs). RESULTS: Higher-pressure IPIRM ameliorated the skeletal muscle cell injury induced by 1.2 mM DSP. Thirteen common DEPs after IPIRM were selected. Key biological processes, molecular functions, cellular components, and pathways were identified as mechanisms underlying the protective effect of TCMM against skeletal muscle damage. Some processes (response to oxidative stress, response to wounding, response to stress and lipid metabolism signalling pathways) were related to skeletal muscle cell injury. Western blotting for 4 DEPs confirmed the reliability of iTRAQ. CONCLUSIONS: Higher-pressure IPIRM downregulated the CD36, Hsp27 and FABP4 proteins in oxidative stress and lipid metabolism pathways, alleviating excessive oxidative stress and lipid metabolism disorder in injured HSkMCs. The techniques used in this study might provide novel insights into the mechanism of TCMM.
CD36 Antigens/metabolism , Dexamethasone/analogs & derivatives , Fatty Acid-Binding Proteins/metabolism , Heat-Shock Proteins/metabolism , Molecular Chaperones/metabolism , Muscle Fibers, Skeletal/cytology , Musculoskeletal Manipulations/methods , Biomechanical Phenomena , Cell Culture Techniques , Cells, Cultured , Dexamethasone/adverse effects , Down-Regulation , Humans , Lipid Metabolism/drug effects , Medicine, Chinese Traditional , Models, Biological , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/metabolism , Oxidative Stress/drug effects , Proteomics , Signal Transduction
