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In this paper, the crystallization behavior of a novel poly(monothiocarbonate), poly(trimethylene monothiocarbonate) (PTMMTC), was investigated and compared with its polycarbonate analogue, poly(trimethylene carbonate) (PTMC). It is found that PTMMTC exhibits strong crystallizability, while unstretched PTMC is amorphous. DSC and DMA results reveal that PTMMTC possesses higher glass transition temperature (Tg) and β-transition temperature (Tβ) than PTMC. Simulation based on density functional theory (DFT) shows that, the bond angle of C-S-C is evidently smaller than that of C-O-C, and thus a larger dipole moment. This leads to the stronger intermolecular interaction and more rigid chain conformation in PTMMTC, which is the origin of sulfur-substitution enhanced crystallization. The crystal structure of PTMMTC was preliminarily determined for the first time. PTMMTC has an orthorhombic crystal structure with a planar zig-zag chain conformation. The parameters of unit cell are a = 10.74 A, b = 4.79 A, and c (fiber axis) = 7.74 A.

Fleeting intermediates constitute dynamically-stepwise mechanisms. They have been characterized in molecular dynamics trajectories, but whether these intermediates form a free energy minimum to become entropic intermediate remains elusively defined. We developed a computational protocol known as entropic path sampling to evaluate the entropic variation of reacting species along a reaction path based on an ensemble of trajectories. Using cyclopentadiene dimerization as a model reaction, we observed a shallow entropic trap (–T∆S = –0.8 kcal/mol) along the reaction path which originates from an enhanced conformational flexibility as the reacting species enter into a flat energy region. As the reacting species further approach product formation, unfavorable entropic restriction fails to offset the potential energy drop, resulting in no free energy minimum along the post-TS pathway. Our results show that cyclopentadiene dimerization involves an entropic trap that leads to dynamic intermediates with elongated lifetime, but the reaction does not involve entropic intermediates.

The transition-metal-catalyzed C-N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as -50 °C), enantioselective Ni-catalyzed C-N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2 -symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.

Microglia activation post traumatic spinal cord injury (SCI) provokes accumulation of inflammatory metabolites, leading to increasing neurological disruption. Our previous studies demonstrated that blocking MAPKs pathway mitigated microglia inflammatory activation and prevented cords from neuroinflammation-induced secondary injury. Transforming growth factor-β-activated kinase 1 (TAK1) is an upstream gate regulating activation of MAPKs signaling. To validate the therapeutic effect of TAK1 inhibition in neuroinflammation post SCI, in the current study, cultures of microglia BV2 line was undergone lipopolysaccharide (LPS) stimulation in the presence of TAK1 inhibitor 5Z-7-Oxozeaenol (ZO), LPS, or control. LPS triggered inflammatory level, cell migration, and matrix metalloproteinase (MMP) 2/9 production, which was reduced in ZO-treated cultures. TAK1 inhibition by ZO also decreased activation of MAPKs pathway, indicating that ZO-mediated alleviation of neuroinflammation is likely modulated via TAK1/MAPKs axis. In vivo, neuroinflammatory level and tissue destruction were assessed in adult male mice that were undergone SCI by mechanical trauma, and treated with ZO by intraperitoneal injection. Compared with SCI mice, ZO-treated mice exhibited less microglia pro-inflammatory activation and accumulation adjacent to injured core linked to reduced MMP2/9 expression, leading to minor tissue damage and better locomotor recovery. To sum up, the obtained data proved that in the early phase post SCI, TAK1 inhibition impedes microglia biological activities including activation, enzymatic synthesis, and migration via downregulation of MAPKs pathway, and the effects may be accurately characterized as potent anti-inflammation.

Selective separation of phenanthrene (PHE) from aromatic isomer mixtures is a big challenge in industry. In this work, a light-responsive water-soluble azobenzene-based macrocycle 1 is synthesized and an aqueous solution of E,E-1 is employed to separate PHE from anthracene via a solid-liquid extraction method under ambient conditions. After five extraction cycles, the average purity for PHE is about 91.1% and macrocycle 1 can be reused at least five times without obvious reduction of separation performance for PHE. This work not only comprises a new and clean way to separate PHE by taking advantage of a macrocyclic host but also promotes the application of host-guest chemistry.

The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure. However, the lack of an efficient strategy for the synthesis of structurally diverse chiral peptoids has hampered the studies. Herein, we report the efficient synthesis of a wide variety of N-aryl peptoid atropisomers in good yields with excellent enantioselectivities (up to 99% yield and 99% ee) by palladium-catalyzed asymmetric C–H alkynylation. The inexpensive and commercially available l-pyroglutamic acid was used as an efficient chiral ligand. The exceptional compatibility of the C–H alkynylation with various peptoid oligomers renders this procedure valuable for peptoid modifications. Computational studies suggested that the amino acid ligand distortion controls the enantioselectivity in the Pd/l-pGlu-catalyzed C–H bond activation step., The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure.

A greener and more practical strategy for the site-selective C–H arylation of (NH)-indoles via coupling of (hetero)aryl bromides was developed, in which β-cyclodextrin, acting as both a ligand for Na2PdCl4 and a host for indoles, enables the reactions to occur easily in water. The key advantage of this method is the ingenious merging of aqueous homogeneous catalysis and ligand mediation, leading to the highly regioselective formation of C3-arylindoles with a broad substrate scope and functional-group tolerance. Moreover, the regioselectivity can be switched from the C3 to the C2-position by varying the nature of the base without recourse to employing ArI as substrates.

The syntheses and crystal structures of a [15]paracyclophenone and its two fluorenone-containing derivatives I and II are reported. The nerve agent mimics binding behaviors with 2 and I driven by the ‘non-traditional’ aryl-CH hydrogen bonding interactions are demonstrated in the solid state and supported by DFT calculations. The affinity of compound I towards the real nerve agents via this binding mode is also predicted by the computational method.

Dearomative functionalization reactions represent an important strategy for the synthesis of valuable three-dimensional molecules from simple planar aromatics. Naphthalene is a challenging arene towards transition-metal-catalyzed dearomative difunctionalization reactions. Reported herein is an application of naphthalene as a masked conjugated diene in a palladium-catalyzed dearomative 1,4-diarylation or 1,4-vinylarylation reaction via tandem Heck/Suzuki sequence. Three types of 1,4-dihydronaphthalene-based spirocyclic compounds are achieved in excellent regio- and diastereoselectivities. Key to this transformation is the inhibition of a few competitive side reactions, including intramolecular naphthalenyl C-H arylation, intermolecular Suzuki cross-coupling, dearomative 1,2-difunctionalization, and dearomative reductive-Heck reaction. Density functional theory (DFT) calculations imply that the facile exergonic dearomative insertion of a naphthalene double bond disrupts the sequence of direct Suzuki coupling, leading to the tandem Heck/Suzuki coupling reaction. The observed regioselectivity towards 1,4-difunctionalization is due to the steric repulsions between the introduced aryl group and the spiro-scaffold in 1,2-difunctionalization., Naphthalene is a challenging arene towards transition-metal-catalyzed dearomative difunctionalization. Here, the authors show that naphthalene may act as a masked conjugated diene in palladium-catalyzed dearomative 1,4-diarylation or 1,4-vinylarylation via a tandem Heck/Suzuki sequence.

The present study was designed to investigate the targets and synergistic mechanism of Shenfu Decoction (SFD) in the treatment of heart failure. A heart failure animal models was established to evaluate the pharmacological effects of SFD for anti-heart failure, then constructed ingredient-target interaction network by developing ingredient and target databases, the Discovery sdudio software was used for molecular docking. In addition, we validated the predicted protein targets of active ingredients in SFD by using surface plasmon resonance (SPR) technology. Our results demonstrated that SFD could enhance ejection fraction, alleviate myocardial histopathological characteristics, and reduce the level of angiotensin converting enzyme (ACE), aldosterone (ALD), atrial natriuretic polypeptide (ANP) and Renin (REN) in heart failure rat model. In addition, the ingredient database including 349 constituents and target database including 236 proteins were established, and 75 proteins were screened and identified by molecular docking strategy. 22 core target proteins were identified through network pharmacology, and the component-core target network was constructed. Finally, the affinity between the compounds and targets were verified by the SPR analysis method. The present study suggested that SFD may act on ACE 2, REN, ACE, ICAM-1, EGF, HTR2B, PARP1, NPPB and other proteins through AC, BAC, ACN, Re, Rg1, Rb1 to exert synergistic effects against heart failure.

With the aid of a class of newly discovered Trost-type bisphosphine ligands bearing a chiral cycloalkane framework, the Pd-catalyzed decarboxylative dearomative asymmetric allylic alkylation (AAA) of benzofurans was achieved with high efficiency [0.2-1.0 mol% Pd2(dba)3/L], good generality, and high enantioselectivity (>30 examples, 82-99% yield and 90-96% ee). Moreover, a diversity-oriented synthesis (DOS) of previously unreachable flavaglines is disclosed. It features a reliable and scalable sequence of the freshly developed Tsuji-Trost-Stoltz AAA, a Wacker-Grubbs-Stoltz oxidation, an intra-benzoin condensation, and a conjugate addition, which allows the efficient construction of the challenging and compact cyclopenta[b]benzofuran scaffold with contiguous stereocenters. This strategy offers a new avenue for developing flavagline-based drugs.

Strawberry (Fragaria × ananassa) is an ideal model plant for studies on non-climacteric fruit ripening. Although much progress has been made towards understanding the molecular mechanism of strawberry fruit ripening regulated by abscisic acid (ABA), little is known about the interactions between members of the FaPYR/PYL and FaPP2C families. Here, using RNA-seq, qPCR, and yeast two-hybrid analyses, we found that the FaPYR/PYL and FaPP2C gene families both have nine members, respectively, among which FaPYL2/4/8/9/11/12 and FaABI1/FaPP2C16/51/16L2/16L1/37 showed relatively higher expression at the mRNA level during ripening. The transcript abundance of candidate members of the FaPYR/PYLs and FaPP2Cs families tended to increase and decrease, respectively, at the onset of fruit reddening. In phylogenetic analyses, FaPYL2, FaPYL4, FaPYL11/FaPYL12, and FaPYL8/FaPYL9 were classified into four subgroups, and FaABI1/FaPP2C16/FaPP2C16L/FaPP2C6, FaPP2C24/FaPP2C37, and FaPP2C8/FaPP2C51 were classified into three subgroups. In yeast two-hybrid analyses, FaPYL4/9/11 and FaABI1/FaPP2C16 were able to interact with each other. ABA could not promote interactions between un-interacted pairs of FaPYL2/8/12 and FaPP2C16/51/37. FaABI1 and FaPYL2 interaction may play a major role in ripening. This is the first report on the analysis of interactions between members of the FaPYR/PYLs and FaPP2Cs families in strawberry. The results provide insights into ABA signal transduction during non-climacteric fruit ripening.

We report here a deep mechanistic study of the "click" ortho-quinone methide (oQM) cycloaddition between ortho-quinolinone quinone methide (oQQM) and thio-vinyl ether (TV), named as TQ-ligation. DFT calculations revealed the unexpected fact that dehydration of oQQM precursors is the rate-determining step of this transformation, and two highly reactive oQQM precursors were predicted. Guided by the calculations, a new "click" oQM cycloaddition which shows significantly improved kinetics and remarkable efficiency on protein labeling was developed.

Paeoniflorin is a natural monoterpene glucoside from Paeoniae Radix with neuroprotective properties. However, it is still unclear whether paeoniflorin has neuroprotective effects on subarachnoid hemorrhage (SAH). This study explores the effect of paeoniflorin on early brain injury (EBI) using rat SAH model. We found that paeoniflorin significantly improves neurological deficits, attenuates brain water content and Evans blue extravasation at 72 h after SAH. Paeoniflorin attenuates the oxidative stress following SAH as evidenced by decrease of reactive oxygen species (ROS), malondialdehyde (MDA), 3-Nitrotyrosine, and 8-Hydroxy-2-deoxy guanosine (8-OHDG) level, increase of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase activity, and up-regulates the nuclear factor erythroid‑related factor 2 (Nrf2)/heme oxygenase‑1 (HO-1) pathway. Inhibition of microglia activation and neuro-inflammatory response both contributed to paeoniflorin's protective effects. Moreover, paeoniflorin treatment significantly reduces the ratio of Bax/Bcl-2, active caspase-3/ neuronal nuclei (NeuN) and TUNEL/DAPI positive cells at 72 h following SAH. Our results indicate that paeoniflorin may attenuate early brain injury after experimental SAH.

Abdominal aortic aneurysm (AAA) is the vascular disease forming when aorta in the abdomen swells. AAA with the size of 5.5 and above has possibility to rupture and leads a death. Insulin-like Growth Factor 1 (IGF1) is the circulating biomarker for AAA diagnosis, in this study IGF1 was detected by the improved Enzyme linked Immunoassay (ELISA). The conventional ELISA necessitates the improvement due to the lesser sensitivity than modern sensors. Higher biomolecular immobilization is one of the wise ways to enhance the sensitivity. This study was aimed to capture a higher number of IGF1 on ELISA surface through the aminated silica (SiO2) nanoparticle with the size measured to be 80−100 nm. On the amine-SiO2 modified surface, Glutaraldehyde (GLU) complexed IGF1 was chemically bonded. It was found that 400 pM of IGF1 detected on amine-SiO2 modified ELISA, whereas the conventional ELISA without nanoparticle mediation shows the limit of detection as 12.5 nM with ∼30 times lower detection. The selectivity experiment was carried out with the mixture of IGF1 and relevant proteins (IGF2 and IGFBP3), and it was noticed that anti-IGF1 selectively detected IGF1. This nanoparticle-mediated surface immobilization captured a higher rate of antigen on a larger surface created for high-performance detection.

Diabetes mellitus is considered to be a major risk factor for cardiovascular disease, the most common cause of death in diabetes. However, therapeutic strategies for myocardial protection in patients with diabetes are still limited. Cordycepin is a traditional Tibetan medicine with a long history of widespread use, and exerts a wide range of anti-tumor, anti-inflammatory, and anti-oxidative effects. In recent years, although the therapeutic potential of cordycepin has attracted the attention of researchers, it remains unknown whether cordycepin plays a protective role in myocardial ischemia/reperfusion (MI/R) injury in diabetic patients. Here, using a diabetic mouse model, we found that cordycepin protected diabetic hearts from MI/R injury by promoting mitochondrial fusion and Mfn2 expression. Our in vitro results showed that cordycepin enhanced Mfn2-medicated mitochondrial fusion, improved mitochondrial function, and reduced cardiomyocyte apoptosis in high-glucose/high-fat cultured simulated ischemia/reperfusion cardiomyocytes. Furthermore, we found that knockout of Mfn2 significantly blocked the cardioprotective effects of cordycepin in diabetic mice. Finally, an AMPK-dependent pathway was found to upregulate Mfn2 expression upon cordycepin treatment, indicating that cordycepin protected diabetic hearts via AMPK/Mfn2-dependent mitochondrial fusion. Collectively, our study firstly demonstrated that cordycepin could be a potential cardioprotective agent for MI/R injury, and we established a novel mechanism by which upregulated AMPK/Mfn2-dependent mitochondrial fusion contributes to the cardioprotective role of cordycepin.

Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.

The selective 1,2-aminoacylation of olefins provides opportunities for the rapid construction of nitrogen-containing molecules. However, the lack of CO-free acylation reactions has limited their application. By using photoredox proton-coupled electron transfer (PCET)/Ni dual-catalysis, a highly regio- and diastereoselective amidoacylation of unactivated olefins has been developed. Various acyl electrophiles are compatible, including alkyl- and aryl acyl chlorides and anhydrides, as well as in situ activated carboxylic acids. Hammett studies and other mechanistic experiments to elucidate features of the diastereoselectivity, a transient absorption study of the PCET step, as well as computational evidence, provide an in-depth understanding of the disclosed transformation.

Transition metal-catalyzed single bond metathesis has recently emerged as a useful strategy for functional group transfer. In this work, we explored the mechanism and reactivity profile of Pd/PhI-cocatalyzed C-P bond metathesis between aryl phosphines using density functional theory (DFT) calculations. The overall single bond metathesis involves two Pd(ii)-catalyzed C-P reductive eliminations and two Pd(0)-catalyzed C-P oxidative additions, which allows the reversible C-P bond cleavage and formation of the phosphonium cation. Distortion/interaction analysis indicates that the facile C-P bond cleavage and formation of the phosphonium cation are due to the involvement of coordinating aryl phosphine in the process. In addition, the substituent effects on the reaction kinetics and thermodynamics of metathesis were computed, which provides helpful mechanistic information for the design of related single bond metathesis reactions.

Combined computational and experimental studies elucidated the distinctive mechanistic features of electrochemical cobalt-catalyzed C–H oxygenation. A sequential electrochemical–chemical (EC) process was identified for the formation of an amidylcobalt(iii) intermediate. The synthesis, characterization, cyclic voltammetry studies, and stoichiometric reactions of the related amidylcobalt(iii) intermediate suggested that a second on-cycle electro-oxidation occurs on the amidylcobalt(iii) species, which leads to a formal Co(iv) intermediate. This amidylcobalt(iv) intermediate is essentially a cobalt(iii) complex with one additional single electron distributed on the coordinating heteroatoms. The radical nature of the coordinating pivalate allows the formal Co(iv) intermediate to undergo a novel carboxylate-assisted HAT mechanism to cleave the arene C–H bond, and a CMD mechanism could be excluded for a Co(iii/i) catalytic scenario. The mechanistic understanding of electrochemical cobalt-catalyzed C–H bond activation highlights the multi-tasking electro-oxidation and the underexplored reaction channels in electrochemical transition metal catalysis., A formal Co(iv) intermediate in electrochemical cobalt-catalyzed C–H oxygenation allows pivalate to break the arene C–H bond via a hydrogen-atom-transfer mechanism.

The Lewis acid-promoted generation of destabilized vinyl cations from β-hydroxy diazo ketones leads to an energetically favorable 1,2-shift across the alkene followed by an irreversible C-H insertion to give cyclopentenone products. This reaction sequence overcomes typical challenges of counter ion trapping and rearrangement reversibility of vinyl cations and has been used to study the migratory aptitudes of non-equivalent substituents in an uncommon C(sp(2)) to C(sp) vinyl cation rearrangement. The migratory aptitude trends were consistent with those observed in other cationic rearrangements; the substituent that can best stabilize a cation more readily migrates. However, DFT calculations show that the situation is more complex. Selectivity in the formation of one conformational isomer of the vinyl cation, and facial selective migration across the alkene due to an electrostatic interaction between the vinyl cation and the adjacent carbonyl oxygen work in concert to determine which group migrates. This study provides valuable insight for predicting migration preferences when applying this methodology to the synthesis of structurally complex cyclopentenones that are differentially substituted at the α and β positions.

The lithiacarborane [Li-CB11 H11 ]- plays a central role in carborane chemistry, as it is a key intermediate to achieve the selective functionalization of the monocarba-closo-dodecaborate [CB11 H12 ]- for applications in various fields. Also, it is an organometallic species of fundamental interest because it represents a 3D analogue of phenyllithium featuring an exo C-Li bond in addition to the delocalized negative endo charge of the spherical cluster. For the first time, the elusive and highly reactive endo/exo formal dianion [CB11 H11 ]2- has been isolated as its lithiate as well as zincate in pure form and fully characterized. DFT calculations corroborate the experimental findings and underscore the remarkably high reactivity of the lithiacarborane. Subsequent derivatizations demonstrate the relevance of its initial clean formation.

We describe the direct synthesis of organophosphorus compounds from ubiquitous aryl and vinyl carboxylic acids via decarbonylative palladium catalysis. The catalytic system shows excellent scope and tolerates a wide range of functional groups (>50 examples). The utility of this powerful methodology is highlighted in the late-stage derivatization directly exploiting the presence of the prevalent carboxylic acid functional group. DFT studies provided insight into the origin of high bond activation selectivity and P(O)-H isomerization pathway.

Ionothermal synthesis has been widely used for the preparation of aluminophosphate-based molecular sieves, coordination polymers, metal-organic frameworks, and covalent organic frameworks. However, this method is still challenging for synthesis of silica-based zeolites. Herein, we show a generalized ionothermal route to synthesize silica-based zeolites with MTT, TON, ITW, and MFI structures in the presence of NH4F as a mineralizing agent and ionic liquid as a solvent and/or structure directing agent. The presence of a suitable amount of NH4F plays a key role for the successful synthesis of these silica-based zeolites. This methodology might open a pathway to ionthermally synthesize silica-based zeolites.

Summary The biaryl motif is a building block in many drugs, agrochemicals, and materials, and as such it is highly desirable as a synthesis target. The state-of-the-art process for biaryl synthesis from ubiquitous carboxylic acids is decarboxylative cross-coupling involving loss of carbon dioxide (CO2). However, the scope of these methods is severely limited, mainly due to specific substitution required to promote decarboxylation. The present report implements a decarbonylative version with loss of carbon monoxide (CO) that enables to directly engage carboxylic acids in a Suzuki-Miyaura cross-coupling to produce biaryls as a general method with high cross-coupling selectivity using a well-defined Pd(0)/(II) catalytic cycle. This protocol shows a remarkably broad scope (>80 examples) and is performed in the absence of exogenous inorganic bases. In a broader context, the approach shows promise for routine applications in the synthesis of biaryls by carefully controlled decarbonylation of prevalent carboxylic acids., Graphical Abstract, Highlights • First decarbonylative Suzuki cross-coupling of carboxylic acids via Pd catalysis • Rapid synthesis of functionalized biaryls from ubiquitous carboxylic acids • Mechanistic insights from DFT studies point at the origin of high selectivity • CO loss as a strategy for expanding access to aryl metals (cf. CO2 loss), Chemistry; Catalysis; Organic Chemistry

An efficient Co-catalyzed hydro-difluoromethylthiolation/hydro-trifluoromethylthiolation reaction of unactivated alkenes was described. Both reactions were conducted at room temperature and a variety of common functional groups such as halogen, ester, aldehyde, enolizable ketone or ester, nitro or cyano group, sulfonate and carbamate were compatible with the reaction conditions. Radical cyclization and radical inhibitor experiments suggested that the reaction proceeds through a free radical process.

A copper-catalyzed carbene insertion into the sulfur–sulfur bond of trifluoromethyl/difluoromethyl/diphenyldisulfides under mild conditions has been developed. Diverse dithioketal derivatives were synthesized in moderate to good yields in an atom-economic process.

A new TiIII -mediated reductive epoxide-opening/ Beckwith-Dowd rearrangement process efficiently assembles the bicyclo[3.2.1]octane framework of highly oxidized grayanane diterpenoids. By incorporation of a Cu(tbs)2 -catalyzed (tbs=N-tert-butylsalicylaldiminato) intramolecular cyclopropanation, a diastereoselective oxidative dearomatization-induced Diels-Alder cycloaddition and a MeReO3 -catalyzed Rubottom oxidation, this approach has enabled the first total syntheses of rhodomolleins XX and XXII in 23 and 22 steps, respectively.

We have thoroughly studied four kinds of different palladacycles with 8-aminoquinoline as the auxiliary and carbon monoxide (CO), acetonitrile (CH3CN), pyridine, and dimethyl sulfoxide (DMSO) as the ligands, respectively, using crystallographic analysis, cyclic voltammetry (CV), stoichiometric reactions, and computational calculations. A higher oxidation potential in CV and lower chemical reactivities to react with weaker electrophilic reagents are presented for CO-coordinated palladacycles, which has been supported by DFT studies that the CO-coordinated Pd complex has the highest ΔG value for the initial ligand exchange process. Meanwhile, a rigid structure can be observed and relatively high activation energy (ΔG⧧ = 54.2 kcal/mol) is needed for further migratory insertion. All this evidence suggests that the CO-coordinated Pd complex is a kinetically and thermodynamically stable intermediate, which accounts for its reluctance for migratory insertion and the formation of the corresponding carbonylation p...

Glycyrrhiza uralensis is the major plant source of licorice. This study was to identify bioactive compounds from the plant's leaves in order to make better use of its aerial part. An ethanol extract of the leaves was subjected to repeated chromatography to yield 15 compounds. The structures were determined to be three novel dihydrostilbenes, based on their various spectroscopic data-glycypytilbene A (1), glycydipytilbene (2), and glycypytilbene B (3)-and 12 known compounds, α,α'-dihydro-3,5,4'-trihydroxy-4,3'-diisopentenylstilbene (4), α,α'-dihydro-3,5,3',4'-tetrahydroxy-2,5'-diisopentenylstilbene (5), 6-prenyleriodictyol (6), 5'-prenyleriodictyol (7), 6-prenylquercetin-3-Me ether (8), 5'-prenylquercetin (9), 6-prenylquercetin (10), 6-prenylnaringenin (11), 3'-prenylnaringenin (12), sigmoidin C (13), 8-[(E)-3-hydroxymethyl-2- butenyl]-eriodictyol (14), and quercetin-3-Me ether (15). Most of these chemical constituents inhibited α-glucosidase activity, with the two prenylated quercetin derivatives (9 to 10) being the greatest active (IC50 < 4.0 µg/mL). Compounds 1, 3 to 4, 6 to 7, 9 to 12 impeded the growth of human hepatic stellate cells, with the prenylated flavonoids (6 to 7, 9 to 12) being more robust than their unprenylated counterparts. PRACTICAL APPLICATIONS: This study found that Glycyrrhiza uralensis leaves contain prenylated dihydrostilbenes and flavonoids with inhibiting effects on α-glucosidase and on the proliferation of human hepatic stellate cells, which should prompt the development of G. uralensis leaves for healthy products with anti-diabetic or liver fibrosis-preventing effects.

Summary Chiral organosilanes are of great value in asymmetric synthesis, functional materials, and medicinal chemistry. Compared with single-silyl compounds, bis(silyl) ones are understudied because of the lack of the efficient synthetic protocols. The development of efficient synthetic approaches to access bis(silyl) compounds is highly desirable for studying their basic properties and potential utilities. Here, a cobalt-catalyzed sequential double hydrosilylation of aliphatic alkynes was developed to synthesize highly enantioenriched gem-bis(silyl)alkanes. This protocol used simple aliphatic alkynes and silanes to construct valuable chiral gem-bis(silyl)alkanes. The control experiments, isotopic labeling experiments, kinetic studies, and density functional theory calculations were conducted to elucidate the reaction mechanism. The synthetic versatility of gem-bis(silyl)alkanes was demonstrated by the synthesis of chiral organosilanols, α-hydroxysilanes through selective C–Si bond transformation and hydrosilylation of alkynes to construct chiral silanes containing adjacent C-stereocenter and Si-stereocenter.

Background:MicroRNA (miRNA) therapy, which was widely considered to treat a series of cancer, has been confronted with numerous obstacles to being delivered into target cells because of its easy biodegradation and instability.Methods:In this research, we successfully constructed 11-mercaptoundecanoic acid modified gold nanocages (AuNCs)/polyethyleneimine (PEI)/miRNA/hyaluronic acid (HA) complexes (abbreviated as AuNCs/PEI/miRNA/HA) using a layer-by-layer method for target-specific intracellular delivery of miRNA by HA receptor mediated endocytosis.Results:The results of UV spectra, hydrodynamic diameter and zeta potential analyses confirmed the formation of AuNCs/PEI/ miRNA/HA complex with its average particle size of ca. 153 nm and surface charge of ca. -9.43 mV. Next, we evaluated the antitumor effect of the nanocomplex mediated by the combination of gene therapy and photothermal therapy (PTT) against hepatocellular carcinoma (HCC) in vitro.Conclusion:Our experimental results indicated that the AuNCs/PEI/miRNA/HA complex effectively delivered miRNA to the target cells and its antitumor effect was significantly enhanced by the combination of gene therapy and photothermal therapy. In addition, anti-miR-181b could promote Bel-7402 cell arrest in S phase and improve TIMP-3 mRNA expression. All these results suggested that AuNCs/PEI/miRNA/HA gene delivery system with combination of gene therapy and photothermal therapy might be exploited for HCC treatment.

Excessive reactive oxygen species (ROS) and apoptosis in nucleus pulposus (NP) cells accelerate the process of intervertebral disc degeneration (IDD). Here, we integrated pathological samples and in vitro and in vivo framework to investigate the impact of phosphorylation of eukaryotic initiation factor-2α (eIF2α)/activating transcription factor 4 (ATF4)/Indian hedgehog (Ihh) signaling in the IDD. From the specimen analysis of the IDD patients, we found phosphorylated eIF2α (p-eIF2α), ATF4 and Ihh protein levels were positively related while the NP tissue went degenerative. In vitro, tumor necrosis factor (TNF)-α caused the NP cell degeneration and induced a cascade of upregulation of p-eIF2α, ATF4, and Ihh. Interestingly, ATF4 could enhance Ihh expression through binding its promoter region, and silencing of ATF4 decreased Ihh and protected the NP cells from degeneration. Moreover, ISRIB inhibited the p-eIF2α, which resulted in a suppression of ATF4/Ihh, and alleviated the TNF-α-induced ROS production and apoptosis of NP cells. On the contrary, further activating p-eIF2α aggravated the NP cell degeneration, with amplification of ATF4/Ihh and a higher level of ROS and apoptosis. Additionally, applying cyclopamine (CPE) to suppress Ihh was efficient to prevent NP cell apoptosis but did not decrease the ROS level. In an instability-induced IDD model in mice, ISRIB suppressed p-eIF2α/ATF4/Ihh and prevented IDD via protecting the anti-oxidative enzymes and decreased the NP cell apoptosis. CPE prevented NP cell apoptosis but did not affect anti-oxidative enzyme expression. Taken together, p-eIF2α/ATF4/Ihh signaling involves the ROS level and apoptosis in NP cells, the pharmacological disruption of which may provide promising methods in preventing IDD.

International audience; The direct synthesis of nitrile from N2 under mild conditions is of great importance and has attracted much interest. Herein, we report a direct conversion of N2 into nitrile via a nitrile–alkyne cross-metathesis (NACM) process involving a N2-derived Mo nitride. Treatment of the Mo nitride with alkyne in the presence of KOTf afforded an alkyne-coordinated nitride, which was then transformed into MoV carbyne and the corresponding nitrile upon 1e oxidation. Both aryl and alkyl-substituted alkynes underwent this process smoothly. Experiments and DFT calculations have proved that the oxidation state of the Mo center plays a crucial role. This method does not rely on the nucleophilicity of the N2-derived metal nitride, offering a novel strategy for N2 fixation chemistry.

ConspectusTransition-metal-catalyzed C-O bond activation provides a useful strategy for utilizing alcohol- and phenol-derived electrophiles in cross-coupling reactions, which has become a research field of active and growing interest in organic chemistry. The synergy between computation and experiment elucidated the mechanistic model and controlling factors of selectivities in these transformations, leading to advances in innovative C-O bond activation and functionalization methods.Toward the rational design of C-O bond activation, our collaborations with the Jarvo group bridged the mechanistic models of C(sp2)-O and C(sp3)-O bond activations. We found that the nickel catalyst cleaves the benzylic and allylic C(sp3)-O bonds via two general mechanisms: the stereoinvertive SN2 back-side attack model and the stereoretentive chelation-assisted model. These two models control the stereochemistry in a wide array of stereospecific Ni-catalyzed cross-coupling reactions with benzylic or allylic alcohol derivatives. Because of the catalyst distortion, the ligands can differentiate the competing stereospecific C(sp3)-O bond activations. The PCy3 ligand interacts with nickel mainly through σ-donation, and the Ni(PCy3) catalyst can undergo facile bending of the substrate-nickel-ligand angle, which favors the stereoretentive benzylic C-O bond activation. The N-heterocyclic carbene SIMes ligand has additional d(metal)-p(ligand) back-donation with nickel, which leads to an extra energy penalty for the same angle bending. This results in the preference of stereoinvertive benzylic C-O bond activation under Ni/SIMes catalysis. In addition to ligand control, a Lewis acid can increase the selectivity for stereoinvertive C(sp3)-O activation by stabilizing the SN2 back-side attack transition state. The oxygen leaving group complexes with the MgI2 Lewis acid in the stereoinvertive activation, leading to the exclusive stereoinvertive Kumada coupling of benzylic ethers. We also identified that the competing C(sp3)-O bond activation models have noticeable differences in charge separation. This leads to the solvent polarity control of the stereospecificity in C(sp3)-O activations. Low-polarity solvents favor the neutral stereoretentive C-O bond activation, while high-polarity solvents favor the zwitterionic stereoinvertive cleavage.In sharp contrast to the nickel catalysts, the C(sp2)-O bond activation under palladium catalysis mainly proceeds via the classic three-membered ring oxidative addition mechanism instead of the chelation-assisted mechanism. This is due to the lower oxophilicity of palladium, which disfavors the oxygen coordination in the chelation-assisted-type activation. The three-membered ring activation model selectively cleaves the weak C-O bond, resulting in the exclusive chemoselectivity of acyl C-O bond activation in Pd-catalyzed cross-coupling reactions with aryl carboxylic acid derivatives. This explains the overall acylation in the Pd-catalyzed Suzuki-Miyaura coupling with aryl esters. In collaboration with the Szostak group, we revealed that the three-membered ring model applies in the Pd-catalyzed C-O bond activation of carboxylic acid anhydride, which stimulated the development of a series of Pd-catalyzed decarbonylative functionalizations of aryl carboxylic acids.

As a common factor of both type 2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS), circulating microparticles (MPs) may provide a link between these two diseases. The present study compared the content and function of MPs from patients with ACS with or without T2DM. MPs from healthy subjects (n=20), patients with ACS (n=24), patients with T2DM (n=20) and patients with combined ACS and T2DM (n=24) were obtained. After incubating rat thoracic tissue with MPs, the effect of MPs on endothelial‑dependent vasodilatation, expression of caveolin‑1 and endothelial nitric oxide synthase (eNOS), phosphorylation of eNOS at the S1177 and T495 sites and its association with heat shock protein 90 (Hsp90), and the generation of NO and superoxide anion (O2˙‑) were determined. MP concentrations were higher in patients with T2DM and patients with ACS with or without T2DM than in healthy subjects. Moreover, MPs from patients with T2DM or ACS led to impairment in endothelial‑dependent vasodilatation, decreased expression of NO, as well as eNOS and its phosphorylation at Ser1177 and association with Hsp90, but increased eNOS phosphorylation at T495, caveolin‑1 expression and O2˙‑ generation. These effects were strengthened by MPs from patients with ACS combined with T2DM. T2DM not only increased MP content but also resulted in greater vascular impairment effects in ACS. These results may provide novel insight into the treatment of patients with ACS and T2DM.

This study investigated the efficiency and the related mechanisms of a new absorption enhancer, DL-malic acid (MA), on the oral bioavailability of docetaxel (DTX). Polyethylene glycol polycarbonate (PEG-PCL) modified liposomes (PLip) were prepared for DTX, and incorporated into the pH-sensitive microspheres (MS) with sustained release. MA decreased the transepithelial electrical resistance (TEER) across a Caco-2 cell monolayer by 20% and 57% after 2 and 3 h of co-incubation with DTX-PLip and the cells, respectively, indicating that MA could open tight junctions but not instantaneously. After long enough exposure (4 h) of MA to the small intestine of rats, only the absorption rate constant (

Herein we report a highly enantioselective kinetic resolution of tertiary benzyl alcohols via palladium/chiral norbornene cooperative catalysis. With simple aryl iodides as the resolution reagent, a wide range of readily available racemic tertiary benzyl alcohols are applicable to this method. Both chiral tertiary benzyl alcohols and benzo[c]chromene products are obtained in good to excellent enantioselectivities (selectivity factor up to 544). The appealing synthetic utility of the obtained enantioenriched tertiary alcohols is demonstrated by the facile preparation of several valuable chiral heterocycles. Preliminary mechanism studies include DFT calculations to explain the origin of enantiodiscrimination and control experiments to uncover the formation of a transient axial chirality during the kinetic resolution step.

The direct conversion of alkyl esters to ketones has been hindered by the sluggish reactivity of the starting materials and the susceptibility of the product towards subsequent nucleophilic attack. We have now achieved a cross-coupling approach to this transformation using nickel, a bulky N-heterocyclic carbene ligand, and alkyl organoboron coupling partners. 65 alkyl ketones bearing diverse functional groups and heterocyclic scaffolds have been synthesized with this method. Catalyst-controlled chemoselectivity is observed for C(acyl)-O bond activation of multi-functional substrates bearing other bonds prone to cleavage by Ni, including aryl ether, aryl fluoride, and N-Ph amide functional groups. Density functional theory calculations provide mechanistic support for a Ni0 /NiII catalytic cycle and demonstrate how stabilizing non-covalent interactions between the bulky catalyst and substrate are critical for the reaction's success.

Major depressive disorder (MDD) is a debilitating mental illness affecting people worldwide. Although significant progress has been made in the development of therapeutic agents to treat this condition, fewer than half of all patients respond to currently available antidepressants, highlighting the urgent need for the development of new classes of antidepressant drugs. Here, we found that paeoniflorin (PF) produced rapid and sustained antidepressant-like effects in multiple mouse models of depression, including the forced swimming test and exposure to chronic mild stress (CMS). Moreover, PF decreased the bodyweight of mice without affecting food intake and glucose homeostasis, and also reduced the plasma levels of total ghrelin and the expression of ghrelin O-acyltransferase in the stomach; however, the plasma levels of ghrelin and the ghrelin/total ghrelin ratio were unaffected. Furthermore, PF significantly increased the expression of growth hormone secretagogue receptor 1 alpha (GHSR1α, encoded by the Ghsr gene) in the intestine, whereas the levels of GHSR1α in the brain were only marginally downregulated following subchronic PF treatment. Finally, the genetic deletion of Ghsr attenuated the antidepressant-like effects of PF in mice exposed to CMS. These results suggested that increased GHSR1α expression in the intestine mediates the antidepressant-like effects of PF. Understanding peripheral ghrelin/GHSR signaling may provide new insights for the screening of antidepressant drugs that produce fast-acting and sustained effects.

Translocation of full-length Her2 receptor into nucleus was reported by some studies. Here, we tested whether nuclear Her2 contributes to paclitaxel resistance in Her2-overexpressing breast cancer cells. Breast cancer cell was transfected with plasmids containing cDNA of wild-type Her2 or mutant-type Her2 lacking the nuclear localization signal (NLS) sequence which is required for Her2 nuclear transport. Cell resistance to paclitaxel was analyzed. Paclitaxel-resistant breast cancer cell was also developed and nuclear Her2 expression was tested. Then, correlation between nuclear Her2 and resistance to paclitaxel were analyzed. Expression of importin β1 was decreased to downregulate nuclear Her2 level and cell resistance to paclitaxel was tested. We found that Her2 overexpression increases Her2 nuclear expression and cells resistance to paclitaxel in MCF-7 cells. In the paclitaxel resistant cell (SK-BR-3/R), nuclear Her2 expression is upregulated compared with parental SK-BR-3 cells. Increased expression of nuclear Her2 after short-time (48 h) treatment of paclitaxel was also observed in SK-BR-3 cells. Further downregulation of Her2 nuclear expression through blocking expression of importin β1 sensitizes the cells to paclitaxel. The analysis showed that the Her2 nuclear expression increases the survivin expression which leads to resistance to paclitaxel. Her2 nuclear expression decreases paclitaxel-induced apoptosis. However, co-immunoprecipitation was applied, and the physical interaction of nuclear Her2 and survivin was not detected. We show for the first time that nuclear Her2 contributes to paclitaxel resistance in breast cancer cells which suggests that nuclear Her2 as a potential target to sensitize breast cancers to paclitaxel treatment.

Developing efficient adsorbents for the removal of water pollutants is of great significance for environmental protection. In this study, conjugated triaryl triazines (CTT), containing intramolecular hydrogen-bonding patterns, were recognized to be intriguing building blocks for the construction of porous organic polymer (POP) adsorbents. These planar monomers with multiple phenolic hydroxyl groups facilitated the formation of aza-linked polymers with hierarchical porous structures, sheet-like morphology, good surface wettability, and high degree of functionality. Such structural characteristics of the CTT-POP adsorbents provided superfast adsorption of various cationic dyes from water. For the adsorption of methylene blue dye, the pseudo-second-order rate constant of CTT-POP-1 is 12.9 g mg-1 min-1, superior to those reported in the existing literature. In addition, CTT-POP-1 can be regenerated at least seven times with no loss in performance, indicating its potential application in water treatment.

Paraquat (N, N'-dimethyl-4, 4'-bipyridinium dichloride, PQ) intoxication is a common cause of lethal poisoning. This study aimed to identify the risk of using liberal oxygen therapy in patients with PQ poisoning. This was a multi-center retrospective cohort study involving four medical institutions in Taiwan. Data were extracted from the Chang Gung Research Database (CGRD) from January 2004 to December 2016. Patients confirmed to have PQ intoxication with a urine PQ concentration ≥ 5 ppm were analyzed. Patients who received oxygen therapy before marked hypoxia (SpO2 ≥ 90%) were defined as receiving liberal oxygen therapy. The association between mortality and patient demographics, blood paraquat concentration (ppm), and liberal oxygen therapy were analyzed. A total of 416 patients were enrolled. The mortality rate was higher in the liberal oxygen therapy group (87.8% vs. 73.7%, P = 0.007), especially in 28-day mortality (adjusted odds ratio [aOR]: 4.71, 95% confidence interval [CI]: 1.533–14.471) and overall mortality (aOR: 5.97, 95% CI: 1.692–21.049) groups. Mortality in patients with PQ poisoning was also associated with age (aOR: 1.04, 95% CI: 1.015–1.073), blood creatinine level (aOR: 1.49, 95% CI: 1.124–1.978), and blood paraquat concentration (ppm) (aOR, 1.51; 95% CI: 1.298–1.766). Unless the evidence of hypoxia (SpO2 < 90%) is clear, oxygen therapy should be avoided because it is associated with increased mortality.

Azobenzene (azo)-based macrocycles are highly fascinating in supramolecular chemistry because of their light-responsiveness. In this work, a series of azo-based macrocyclic arenes 1, 2, 3, and 4, distinguished by the substituted positions of azo groups, is rationally designed and synthesized via a fragment-cyclization method. From the crystal and computed structures of 1, 2, and 3, we observe that the cavity size of these azo-macrocycles decreases gradually upon E→Z photoisomerization. Moreover, light-controlled host-guest complexations between azo-macrocycle 1 and guest molecules (7,7,8,8-tetracyanoquinodimethane, terephthalonitrile) are successfully achieved. This work provides a simple and effective method to prepare azo-macrocycles, and the light-responsive molecular-encapsulation systems in this work may further advance the design and applications of novel photo-responsive host-guest systems.

Perfluorooctanoic acid (PFOA) is bioaccumulative in crops. PFOA bioaccumulation potential varies largely among crop varieties. Root exudates are found to be associated with such variations. Concentrations of low-molecular-weight organic acids (LMWOAs) in root exudates from a PFOA-high-accumulation lettuce variety are observed significantly higher than those from PFOA-low-accumulation lettuce variety (p 80% attribution. Oxalic acid at rhizospheric concentrations (0.02-0.5 mM) can effectively inhibit PFOA sorption to soils by decreasing hydrophobic force, electrostatic attraction, ligand exchange, and cation-bridge effect. Oxalic acid enhances dissolution of metallic ions, iron/aluminum oxides, and organic matters from soils and forms oxalate-metal complexes, based on nuclear magnetic resonance spectra, ultraviolet spectra, and analyses of metal ions, iron/aluminum organometallic complexes, and dissolved organic carbon. The findings not only reveal the activation process of PFOA in soils by root exudates, particularly oxalic acid at rhizospheric concentrations, but also give an insight into the mechanism of enhancing PFOA accumulation in lettuce varieties.

Aim:To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa.Methods:This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A.Results:In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm ( p Conclusion:The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population. Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Isolating and stabilizing boron Oxidative dehydrogenation of propane can produce propene from shale gas and help to replace petroleum as a propene feedstock. Boron-based catalysts can have high selectivity to propene, but the water by-product can deactivate the catalyst by hydrolyzing boron. Zhou et al. synthesized boron-doped silicate zeolites containing isolated boron sites that were stable against hydrolysis. The catalyst could achieve one-pass propane conversions up to ∼44% with selectivities for propene and >80% for ethene. They observed no deactivation after a 210-hour continuous test. Science , this issue p. 76

In this work, quick hardening and high early strength engineered cementitious composites (ECC) was developed by using calcium sulfoaluminate (CSA) cement as the matrix material. The optimal mix design of CSA-ECC was studied with emphasis on the properties of fluidity and mechanical properties. It was found that CSA cement incorporated with 2% polycarboxylate-based superplasticizer (PSP), 1 % ultra-high-molecular weight polyethylene (UHMWPE) fiber and with cement to sand ratio of 0.5 shown the best performance in terms of fluidity, flexural strength and compressive strength. The fracture energy, tensile strength and strain capacity of CSA cement was significantly improved by proper mixing of UHMWPE fiber. After that, the performance of CSA-ECC in rapid repairing of concrete members was characterized. The experimental results suggest that the CSA-ECC has good bonding strength to the concrete matrix. Compared with plain concrete members, both flexural and compressive strength of concrete members were significantly reinforced after 1, 3 and 28d when CEA-ECC was applied as rapid repairing coating.