Atroposelective synthesis of biaxial bridged eight-membered terphenyls via a Co/SPDO-catalyzed aerobic oxidative coupling/desymmetrization of phenols.

Bridged chiral biaryls are axially chiral compounds with a medium-sized ring connecting the two arenes. Compared with plentiful methods for the enantioselective synthesis of biaryl compounds, synthetic approaches for this subclass of bridged atropisomers are limited. Here we show an atroposelective synthesis of 1,3-diaxial bridged eight-membered terphenyl atropisomers through an Co/SPDO (spirocyclic pyrrolidine oxazoline)-catalyzed aerobic oxidative coupling/desymmetrization reaction of prochiral phenols. This catalytic desymmetric process is enabled by combination of an earth-abundant Co(OAc)2 and a unique SPDO ligand in the presence of DABCO (1,4-diaza[2.2.2]bicyclooctane). An array of diaxial bridged terphenyls embedded in an azocane can be accessed in high yields (up to 99%) with excellent enantio- (>99% ee) and diastereoselectivities (>20:1 dr).

Catalytic Asymmetric Polycyclization of Tertiary Enamides with Silyl Enol Ethers: Total Synthesis of (-)-Cephalocyclidin A.

A catalytic enantioselective polycyclization of tertiary enamides with terminal silyl enol ethers has been developed by virtue of Cu(OTf)2 catalysis with a novel spiropyrroline-derived oxazole (SPDO) ligand. This tandem reaction offers an effective approach to assemble bicyclic and tricyclic N-heterocycles bearing both aza- and oxa-quaternary stereogenic centers, which are primal subunits in a range of natural alkaloids. Strategic application of this methodology and a late-stage radical cyclization as key steps have been showcased in the concise total synthesis of (-)-cephalocyclidin A.

NiH-Catalyzed Regio- and Enantioselective Hydroalkylation for the Synthesis of ß- or γ-Branched Chiral Aromatic N-Heterocycles.

A nickel hydride-catalyzed regio- and enantioselective hydroalkylation reaction was developed to give access to a library of chiral ß- or γ-branched aromatic N-heterocycles. This intriguing asymmetric transformation features excellent selectivities, step- and atom-economies, and generating two kinds of chiral products through one synthetic strategy. Furthermore, the possible reaction mechanism was extensively investigated using numerous control experiments and density functional theory calculations.

Asymmetric Intramolecular Hydroalkylation of Internal Olefin with Cycloalkanone to Directly Access Polycyclic Systems.

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.

Catalytic Enantioselective Steglich-Type Rearrangement of Enol Lactones: Asymmetric Synthesis of Spirocyclic 1,3-Diketones.

An example of asymmetric Steglich-type rearrangement of enol lactones is reported. This highly enantioselective acyl transfer reaction is catalyzed by chiral isothiourea at ambient temperature and provides a useful synthetic approach to access enantioenriched spirotricyclic ß,ß'-diketones from a broad range of indanone or tetralone-derived lactones. Preliminary mechanistic studies suggest the initial formation of an N-acylated iminium cation intermediate that induces a following facial selective condensation.

Facile Benzylic Alkylation of Arenes with Alcohols by Catalysis with Spirocyclic NHC IrIII Pincer Complex.

A facile benzylic alkylation of indenes and other arenes was developed from readily available primary and secondary alcohols using our newly investigated CCC pincer IrIII catalyst (SNIr-H). Excellent regioselectivity and yield (89 %) of the C3-alkylated indenes were obtained. Additionally, the challenging sp2 C-alkylation was readily accomplished. This method could be utilized for the synthesis of the analogs of a histamine H1 receptor antagonist and the functional material template molecule, indeno[2,1-a]indene. A hemilabile IrIII -dihydride intermediate was proposed based on control experiments and previous density functional theory (DFT) calculations for the borrowing hydrogen mechanism and is key to the success of this IrIII catalyst in the reduction of unactivated multi-substituted olefin intermediates.

Chiral 1,2,3-Triazolium Salt Catalyzed Asymmetric Mono- and Dialkylation of 2,5-Diketopiperazines with the Construction of Tetrasubstituted Carbon Centers.

Novel asymmetric mono- and dialkylation reactions of α-substituted 2,5-diketopiperazines catalyzed by new chiral spirocyclic-amide-derived triazolium organocatalysts have been developed, resulting in a range of enantioenriched 2,5-diketopiperazine derivatives containing one or two tetrasubstituted carbon stereocenters. The reactions feature high yields (up to 98%), and excellent cis-diastereo- and enantioselectivities (up to >20:1 dr, >99 % ee), and they provide a new asymmetric synthetic approach to important functionalized 2,5-diketopiperazine skeletons. Furthermore, a possible reaction mechanism was proposed based on both control experiments and extensive DFT calculations.

Brønsted acid-catalyzed solvent-controlled regioselective hydrothiolation and diastereoselective cascade cyclization of dienes.

A highly regio- and diastereo-selective Brønsted acid-catalyzed tandem hydrothiolation/Friedel-Crafts reaction of linear 1,3-dienes has been developed for the first time, which provides a metal-free and atom-economic way of constructing thiochromane derivatives. Meanwhile, by changing the solvent, 4,3-addition hydrothiolation of 1,3-dienes was also discovered. The origin of the observed selectivity was explained by density functional theory calculations.

Brønsted Acid-Catalyzed Regioselective Hydrothiolation of Dienes: Solvent-Controlled Divergent Synthesis of Sulfides.

A Brønsted acid-catalyzed 1,4-addition hydrothiolation of branched 1,3-dienes was explored for the first time. A solvent-controlled divergent synthesis of sulfides is also disclosed. Use of acetonitrile as a solvent gave allylic sulfides as hydrothiolation products, while thiochromane derivatives (hydrothiolation/Friedel-Crafts products) were obtained using dichloromethane as the solvent. The origin of the regioselectivity of hydrothiolation was explored through density functional theory calculations.

An effective and versatile strategy for the synthesis of structurally diverse heteroarylsilanes via Ir(iii)-catalyzed C-H silylation.

A versatile silylation of heteroaryl C-H bonds is accomplished under the catalysis of a well-defined spirocyclic NHC Ir(iii) complex (SNIr), generating a variety of heteroarylsilanes. A significant advantage of this catalytic system is that multiple types of intermolecular C-H silylation can be achieved using one catalytic system at α, ß, γ, or δ positions of heteroatoms with excellent regioselectivities. Mechanistic experiments and DFT calculations indicate that the polycyclic ligand of SNIr can form an isolable cyclometalated intermediate, which leaves a phenyl dentate free and provides a hemi-open space for activating substrates. In general, favorable silylations occur at γ or δ positions of chelating heteroatoms, forming 5- or 6-membered C-Ir-N cyclic intermediates. If such an activation mode is prohibited sterically, silylations would take place at the α or ß positions. The mechanistic studies would be helpful for further explaining the reactivity of the SNIr system.

Clinical Efficacy on Chaihu Shugansan Combined with Saccharomyces boulardii in Treatment of Functional Dyspepsia in Children / 中国实验方剂学杂志

Objective:To explore the clinical efficacy of Chaihu Shugansan combined with saccharomyces boulardii in treating functional dyspepsia (FD) in children and the effect on serum cytokines and gastrointestinal hormones expression. Method:Totally 120 cases were divided into control group (60 cases) and observation group (60 cases)．The control group was treated with Duopanlitong Pian 0.3 mg·kg-1, po， tid， and Saccharomyces boulardii 0.25 g，po，bid. The observation group was treated with Chaihu Shugansan, po，qd， and saccharomyces boulardii 0.25 g，po，bid. Four weeks was a course of treatment．The changes of serum Gastric Hunger Hormone and cytokines, Hamilton depression scale (HAMD) score, symptoms improvement time and clinical effect in the two groups were observed. And the recurrence rate was observed after 6 months follow-up. Result:The total effective rate was compared between control group (76.67%，46/60) and observation group (96.15%，57/60)，with significant differences (P<0.01). After treatment, serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in both groups were decreased, while serum levels of ghrelin of both group were increased. However，the decreasing range and the increasing range of observation group were statistically obvious than those of control group (P<0.01). HAMD score and disappearance time of clinical symptoms in observation group was significantly different from those in control group (P<0.01). In adverse reactions during treatment, the control group was inferior to the observation group (P<0.05). After the 6-month follow-up, the recurrence rate in observation group was lower than that in control group (P<0.01). Conclusion:Chaihu Shugansan combined with Saccharomyces boulardii was effective in treatment of FD in children, with a low recurrence rate and good compliance. The mechanism may be related to the effective regulation of brain-intestinal axis, balance of intestinal flora, inhibition of inflammatory reaction, regulation of cytokines and gastrointestinal hormone levels.

Clinical Efficacy of Xiaoer Anorexia Granule Combined with Saccharomyces Brassicus in Treatment of Pediatric Anorexia and Its Effect on Serum Cytokines / 中国实验方剂学杂志

Objective: To investigate the clinical efficacy of Xiaoer anorexia granule combined with Saccharomyces brassicus in the treatment of infantile anorexia and its effect on serum cytokines. Method: Totally 240 cases of infantile anorexia treated in Jinhua People's Hospital from October 2015 to October 2017 were randomly divided into three groups. Group A (combination group) orally took Xiaoer anorexia granule, 1 pack/time for 1-3 years old, 2 packs/time for 4-6 years old, 3 times a day, and combined with saccharomyces brasiliensis, 0.5 g/time, 2 times a day, 15-30 min before meal. Group B took saccharomyces brasiliensis by the same method as the combination group. Group C took Xiaoer anorexia granules by the same method as above,with 80 cases in each group. 8 weeks is a course of treatment. Serum inflammatory cytokines leptin, SP and Ghrelin were also detected. The clinical efficacy, body weight, height improvement and serum cytokine levels were observed in 3 groups. Result: The total improvement rate of group A was 91.25%, which was significantly higher than 71.25%of group B and 73.75%of group C, with statistically significant differences (PPPPPPPConclusion: Treatment of infantile anorexia with Xiaoer anorexia granules combined with Saccharomyces cerevisiae can improve the total clinical effective rate, adjust serum cytokine levels and increase height and body mass.

Clinical Efficacy of Modified Sinisan Combined with Saccharomyces Brasiliensis on Functional Dyspepsia in Children and Its Effect on Serum Cytokines / 中国实验方剂学杂志

Objective: To discuss the clinical efficacy of modified Sinisan (Qizhi Weitong granule) and saccharomyces boulardi in treating functional dyspepsia (FD) in children, and its effect on changes in serum cytokine and gastrointestinal hormones.Method: Totally 156 cases were divided into control group (78 cases) and observation group (78 cases). The control group was treated with saccharomyces boulardi, 0.25 g, po, bid, after meal. In addition to the therapy of control group, the observation group was also given modified Sinisan (Qizhi Weitong granule), 2.5 g, po, tid, 30 minutes before meal. Four weeks was a course of treatment. Then the clinical efficacy, the time of symptom improvement and the change of serum cytokine and gastrointestinal hormones were observed.Result: The total effective rate of observation group (96.15%) was higher than that of control group (82.05%), with statistical difference (Pγ(IFN-γ), tumor necrosis factor-α(TNF-α), plasma motilin(MTL) and Leptin of both groups had no statistical difference before treatment. After treatment, the serum levels of IL-10, MTL of both group were increased, while the serum levels of IFN-γ, TNF-α, Leptin of both group were decreased. However, the decreasing range and the increasing range of observation group were statistically obvious than those of control group (PConclusion: Modified Sinisan(Qizhi Weitong granule) combined with saccharomyces boulardi have an obvious clinical efficacy in treating child's FD, with a low recurrence. The mechanism may be correlated with the effect of integrated Chinese and Western medicines in regulating serum cytokine and gastrointestinal hormones levels.

Comparison of Gating Properties and Use-Dependent Block of Nav1.5 and Nav1.7 Channels by Anti-Arrhythmics Mexiletine and Lidocaine.

Mexiletine and lidocaine are widely used class IB anti-arrhythmic drugs that are considered to act by blocking voltage-gated open sodium currents for treatment of ventricular arrhythmias and relief of pain. To gain mechanistic insights into action of anti-arrhythmics, we characterized biophysical properties of Nav1.5 and Nav1.7 channels stably expressed in HEK293 cells and compared their use-dependent block in response to mexiletine and lidocaine using whole-cell patch clamp recordings. While the voltage-dependent activation of Nav1.5 or Nav1.7 was not affected by mexiletine and lidocaine, the steady-state fast and slow inactivation of Nav1.5 and Nav1.7 were significantly shifted to hyperpolarized direction by either mexiletine or lidocaine in dose-dependent manner. Both mexiletine and lidocaine enhanced the slow component of closed-state inactivation, with mexiletine exerting stronger inhibition on either Nav1.5 or Nav1.7. The recovery from inactivation of Nav1.5 or Nav1.7 was significantly prolonged by mexiletine compared to lidocaine. Furthermore, mexiletine displayed a pronounced and prominent use-dependent inhibition of Nav1.5 than lidocaine, but not Nav1.7 channels. Taken together, our findings demonstrate differential responses to blockade by mexiletine and lidocaine that preferentially affect the gating of Nav1.5, as compared to Nav1.7; and mexiletine exhibits stronger use-dependent block of Nav1.5. The differential gating properties of Nav1.5 and Nav1.7 in response to mexiletine and lidocaine may help explain the drug effectiveness and advance in new designs of safe and specific sodium channel blockers for treatment of cardiac arrhythmia or pain.

Trigger factor of Streptococcus suis is involved in stress tolerance and virulence.

Streptococcus suis serotype 2 is an important zoonotic pathogen that causes serious diseases such as meningitis, septicemia, endocarditis, arthritis and septic shock in pigs and humans. Little is known about the regulation of virulence gene expression in S. suis serotype 2. In this study, we cloned and deleted the entire tig gene from the chromosome of S. suis serotype 2 SC21 strain, and constructed a mutant strain (Δtig) and a complementation strain (CΔtig). The results demonstrated that the tig gene, encoding trigger factor from S. suis serotype 2 SC21, affects the stress tolerance and the expression of a few virulence genes of S. suis serotype 2. Deletion of the tig gene of S. suis serotype 2 resulted in mutant strain, ΔTig, which exhibited a significant decrease in adherence to cell line HEp-2, and lacked hemolytic activity. Tig deficiency diminishes stresses tolerance of S. suis serotype 2 such as survive thermal, oxidative and acid stresses. Quantification of expression levels of known S. suis serotype 2 SC21 virulence genes by real-time polymerase chain reaction in vitro revealed that trigger factor influences the expression of epf, cps, adh, rpob, fbps, hyl, sly, mrp and hrcA virulence-associated genes. ΔTig was shown to be attenuated in a LD50 assay and bacteriology, indicating that trigger factor plays an important part in the pathogenesis and stress tolerance of. S. suis serotype 2 infection. Mutant ΔTig was 100% defective in virulence in CD1 mice at up to 107 CFU, and provided 100% protection when challenged with 107 CFU of the SC21 strain.