Cooperative Cu/Pd-Catalyzed 1,5-Boroacylation of Cyclopropyl-Substituted Alkylidenecyclopropanes.

A Cu/Pd-cocatalyzed 1,5-boroacylation of cyclopropyl-substituted ACPs with B2pin2 and acid chlorides has been developed. Using cyclopropyl-substituted ACPs as the starting material, a broad range of 1,5-boroacylated products with multiple functional groups was prepared in good yields with excellent regio- and stereoselectively. Both aromatic and aliphatic acid chlorides were tolerated in this reaction.

Lewis-Acid-Catalyzed (3+2) Annulation of 2-Indolylmethanols with Propargylic Alcohols to Access Cyclopenta[b]indoles.

Herein, a Sc(OTf)3-catalyzed (3+2) annulation of 2-indolylmethanols with propargylic alcohols is reported. The reaction proceeds via a Friedel-Crafts-type allenylation/5-exo-annulation cascade. In the reaction, 2-indolylmethanol is used as a three-carbon synthon, and propargyl alcohol is used as a two-carbon synthon. This method provides a direct and high-yield pathway for synthetically useful cyclopenta[b]indoles. In general, the method features easily accessible substrates with broad scope and generality, the formation of multiple bonds with high efficiency, and easy scale-up.

Palladium-Catalyzed Intramolecular Heck/Aminocarbonylation of Alkene-Tethered Iodobenzenes with Nitro Compounds: Synthesis of Carbamoyl-Substituted Benzoheterocycles.

A palladium-catalyzed intramolecular Heck/aminocarbonylation of alkene-tethered iodobenzenes with nitro compounds has been developed for the synthesis of carbamoyl-substituted benzoheterocycles. Using Mo(CO)6 as a solid CO source, no external reductant or additives were needed in this procedure. Both nitroarenes and nitroalkanes were well tolerated. A range of carbamoyl-substituted dihydrobenzofurans and indolines were prepared in moderate to high yields.

K2CO3-Promoted oxy-Michael Addition/Cyclization of α,ß-Unsaturated Carbonyl Compounds with Naphthols: Synthesis of Naphthopyrans.

A potassium carbonate promoted tandem oxy-Michael addition/cyclization of α,ß-unsaturated carbonyl compounds with naphthol derivatives for the synthesis of 2-substituted naphthopyrans was developed. Using the readily available, inexpensive potassium carbonate as the promoter, a range of different substituted naphthopyrans were prepared.

Base-promoted [4 + 2] annulation of pyrrole-2-carbaldehyde derivatives with ß,γ-unsaturated α-ketoesters: syntheses of 5,6-dihydroindolizines.

A base-promoted [4 + 2] annulation of pyrrole-2-carbaldehyde derivatives with ß,γ-unsaturated α-ketoesters for the syntheses of multisubstituted 5,6-dihydroindolizines was developed. Using DBN as a base, the reaction proceeds smoothly under mild conditions to provide the target products in moderate to high yields, and many useful functional groups can be tolerated.

Formal (3 + 4)-Annulation of Propargylic p-Quinone Methides with 2-Indolylmethanols: Synthesis of Polysubstituted Indole-Fused Oxepines.

A novel Brønsted acid catalyzed 1,8-addition mediated (3 + 4)-annulation of in situ generated propargylic p-quinone methides with 2-indolylmethanols is described. This method provides a convenient and mild approach to structurally interesting and synthetically important polysubstituted indole-fused oxepines in high yields. Moreover, 2-indolylmethanols as four-atom synthons in the (3 + 4)-annulations under Brønsted acid conditions have been explored for the first time.

Dearomatization of 2,3-Disubstituted Indoles via 1,8-Addition of Propargylic (Aza)-para-Quinone Methides.

Dearomatization of indole is a useful strategy to access indolimines: a motif widely exists in biologically active molecules and natural products. Herein, an efficient method for the dearomatization of 2,3-disubstituted indoles to generate diverse indolimines with tetrasubstituted allenes is described. This work accomplishes dearomatization of 2,3-disubstituted indoles through 1,8-addition of (aza)-para-quinone methides, which are generated in situ from propargylic alcohols. A series of synthetically useful indolimines containing quaternary carbon centers and tetrasubstituted allenes can be accessed in good yields (up to 99%). Additionally, the separability of product isomers, diversified product transformations, and easy scale-up of the reaction demonstrate the potential application of this method.

Brønsted Acid-Catalyzed Formal (3+3)-Annulation of Propargylic (Aza)-para-Quinone Methides with 4-Hydroxycoumarins and 1,3-Dicarbonyl Compounds.

Herein, we describe a highly effective 1,8-conjugate-addition-mediated formal (3+3)-annulation of (aza)-para-quinone methides in situ generated from propargylic alcohols with 4-hydroxycoumarins and 1,3-dicarbonyl compounds under the catalysis of a Brønsted acid. This methodology affords efficient and practical access to synthetically important and highly functionalized pyranocoumarins and pyrans in excellent yields under mild conditions. Importantly, these products exhibit impressive inhibitory activity toward α-glucosidase.

Development and validation of ultra-high performance supercritical fluid chromatography method for quantitative determination of six compounds in Guizhi Fuling capsule and tablet samples.

A fast and simple ultra-high performance supercritical fluid chromatography method has been developed for the determination of six analytes, namely (paeonol, coumarin, cinnamic alcohol, cinnamic acid, paeoniflorin, and amygdalin) in Guizhi Fuling capsule and tablet samples. The influence of the key chromatographic parameters for the separation purposes was evaluated. The optimal column was Trefoil CEL1 column. The optimal mobile phase was a gradient mixture of carbon dioxide and methanol at flow rate of 1.0 mL/min. The back pressure of the system was set to 1.38 × 107  Pa and the temperature to 45°C. The six compounds were separated within 11 min by the proposed ultra-high performance supercritical fluid chromatography method with satisfactory resolution. Method validation confirmed that the procedure is accurate with the recovery rates from 87.04 to 104.30%, intraday precision values less than 4.81% and interday precision less than 5.22%, and linear with R2 higher than 0.9967. Therefore, this work provides a simple and novel method for the simultaneous analysis of six compounds in Guizhi Fuling capsule and tablet samples.

Genetic parameters of seven immune factors in turbot (Scophthalmus maximus) infected with Vibrio anguillarum.

In this study, 1,800 turbot (Scophthalmus maximus) individuals from 30 full-sib families were experimentally infected with Vibrio anguillarum, and the expression levels of the immune factors lysozyme, hepcidin, heat-shock protein 70 (HSP70), HSP90, immunoglobulin M (IgM), C-type lectin and Lily-type lectin in the liver were measured by real-time PCR. Heritability values of the seven immune factors were 0.289 ± 0.087, 0.092 ± 0.024, 0.282 ± 0.043, 0.244 ± 0.027, 0.343 ± 0.081, 0.092 ± 0.011 and 0.084 ± 0.009, respectively. The ranges of phenotypic, genetic and environmental correlations were -0.889 to 0.759, -0.841 to 0.888 and -0.919 to 0.883, respectively. The heritability values of HSP70, HSP90 and IgM were moderate, and the genetic correlations between HSP70, HSP90 and IgM were moderate to highly positive, which suggests that the immunocompetence of turbot against V. anguillarum can be improved by genetically improving these three immune characters via multi-trait integrated breeding technology or indirect selection.

Synthesis of Naphthopyrans via Formal (3+3)-Annulation of Propargylic (Aza)-para-Quinone Methides with Naphthols.

Herein, we report an efficient Brønsted acid-catalyzed formal (3+3)-annulation of (aza)-para-quinone methides generated in situ from propargylic alcohols with naphthol derivatives, which involves a 1,8-conjugate addition/6-endo annulation process. This protocol provides an effective method for preparing important functionalized pyranocoumarins under mild conditions.

Aligning retention time shifts in HPLC three-dimensional spectra by icoshift approach combined with data arrangement methods and the release of a graphical user interface.

High-performance liquid chromatography coupled with photodiode array detection has been extensively applied in many fields and the peaks among the analyzed samples can be shifted due to the variations of instrumental and experimental conditions. In multivariate analysis, retention time alignment is an important pretreatment step. Hence, the shifted peaks in high-performance liquid chromatography coupled with photodiode array detection three-dimensional spectra should be aligned for further analysis. Being motivated by this purpose, the interval correlated shifting method combined with the proposed data arrangement methods are recommended and employed on high-performance liquid chromatography coupled with photodiode array detection data as a demonstration. We validate the alignment performance of the proposed method through comparison the consistency of the retention time before and after alignment. The obtained results demonstrated that the proposed method is capable of successful aligning the employed data. Additionally, the interval correlated shifting method combined with the data arrangement modes is implemented in an easy-to-use graphical user interface environment and so can be operated easily by users not familiar with programming languages.

Genetic parameters for resistance against Vibrio anguillarum in turbot Scophthalmus maximus.

Genetic parameters for resistance to Vibrio anguillarum in Scophthalmus maximus were estimated using three different statistical models. Data were recorded from an experimental infection performed on 2,400 individuals from 30 full-sib groups. Cross-sectional linear model and cross-sectional threshold probit model were used to analyse the test-period survival; the cross-sectional threshold logit models were used to analyse the test-day survival. The heritability values estimated by cross-sectional linear model (CSL), cross-sectional threshold (probit) model (THRp) and cross-sectional threshold (logit) model (THRl) were 0.202 ± 0.101, 0.296 ± 0.168 and 0.110 ± 0.023, respectively. The correlation coefficients between the full-sib families' estimated breeding values (EBVs) based on these three models were over 0.993. An almost identical ranking of families was generated using any of these models. Accuracy of selection using CSL, THRp and THRl models was 0.783, 0.789 and 0.801, respectively. Accuracy of selection based on the THRl model was higher than that based on CSL and THRp models.

Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives.

Poylcyclic tetrahydroxanthones comprise a large class of cytototoxic natural products. No mechanism of action has been described for any member of the family. We report the synthesis of kibdelone C and several simplified analogs. Both enantiomers of kibdeleone C show low nanomolar cytotoxicity toward multiple human cancer cell lines. Moreover, several simplified derivatives with improved chemical stability display higher activity than the natural product itself. In vitro studies rule out interaction with DNA or inhibition of topoisomerase, both of which are common modes of action for polycyclic aromatic compounds. However, celluar studies reveal that kibdelone C and its simplified derivatives disrupt the actin cytoseketon without directly binding actin or affecting its polymerization in vitro.

Ruthenium-Catalyzed Carbonylation of α-Aminoaryl-Tethered Alkylidenecyclopropanes: Synthesis of Eight-Membered Benzolactams.

The synthesis of medium-sized lactams is a great challenge because of the unfavorable transannular interactions and entropic barriers in the transition state. We have developed a ruthenium-catalyzed carbonylation of α-aminoaryl-tethered alkylidenecyclopropanes (ACPs) that allows for the efficient preparation of valuable eight-membered benzolactams under ligand-free conditions. The amino group served a dual role of both directing group and nucleophile to facilitate the metallacycle formation and the carbonylation.

Acid-Promoted Cyclization of α-Azidobenzyl Ketones through C═N Bond Formation: Synthesis of 6-Substituted Quinoline Derivatives.

An acid-promoted cyclization of α-azidobenzyl ketones has been developed for the synthesis of 6-substituted quinoline derivatives. A variety of synthetically useful 6-OTf or -OMs quinoline derivatives were obtained in moderate to good yields. The reaction proceeds via C═N bond formation without organophosphine, providing convenient access to structurally interesting and synthetically important 6-substituted quinoline derivatives in moderate to good yields. A mechanistic perspective that is different from the traditional intramolecular Schmidt reaction has been proposed.

[Association of matrix metalloproteinase-3 gene polymorphisms with subtypes of ischemic stroke].

OBJECTIVE: To assess the association between matrix metalloproteinase-3 (MM-3) gene polymorphisms and subtypes of ischemic stroke (IS) in northern Han Chinese population. METHODS: A total of 289 patients with acute IS (within 3 days after the onset, including 185 with large artery atherosclerosis (LAA) and 104 for small artery occlusion (SAO)) and 175 matched healthy controls were recruited for this case-control study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or sequenc-based typing (SBT) was carried out to analyze 3 SNPs of the MMP-3 gene. RESULTS: An incomplete linkage disequilibrium (LD) block was constructed with the 3 SNPs, and the distribution of genotypes of the 3 SNPs differed between the LAA group and controls in a dominant model: Carriers of 5A allele (5A5A+5A6A) of the rs3025058 locus were 1.72 times more susceptible to LAA stroke compared with carriers of 6A6A alleles (P=0.017, OR=1.72, 95% CI: 1.10-2.69), carriers of G alleles (GG+AG) of the rs522616 locus were 0.52 times more susceptible to LAA stroke compared with carriers of AA alleles (P=0.005, OR=0.52, 95% CI: 0.33-0.82), whilst carriers of A allele of the rs679620 locus were 1.55 times more susceptible to LAA stroke compared with carriers of GG alleles (P=0.042, OR=1.55, 95% CI: 1.01-2.37). However, no significant difference has been found between particular genotypes of such SNPs between SAO patients and controls (P> 0.05). Furthermore, 5A-A-A and 6A-A-A haplotypes were significantly more common in LAA group than the controls (P< 0.05), whilst 6A-G-G haplotype has been the opposite (P< 0.01). CONCLUSION: Our study has demonstrated that serum MMP-3 level is significantly increased at acute stage of LAA as well as SAO type strokes. There may be an association of rs3025058, rs522616 and rs679620 of MMP-3 gene with susceptibility to LAA stoke in northern Han Chinese population.

Total synthesis of bi-magnolignan.

Bi-magnolignan, isolated from the leaves of Magnolia officinalis, has shown excellent physiological activity against tumor cells. An efficient strategy for the first total synthesis of bi-magnolignan is reported. The bi-dibenzofuran skeleton was constructed via functional group interconversions of commercially available materials 1,2,4-trimethoxybenzene and 4-allylanisole. Then, the dibenzofuran skeleton was afforded by subsequent Suzuki coupling and intramolecular dehydration. The total synthesis of natural product was accomplished through FeCl3 catalyzed oxidative coupling.

Exosomal miR-320e as a Novel Potential Biomarker for Cerebral Small Vessel Disease.

Background: Cerebral small vessel disease (CSVD) with an insidious onset can cause overall neurological dysfunction and dementia, bringing a massive burden to society. However, the pathogenesis of CSVD is complex and reliable non-invasive biomarkers for diagnosis are still not available at present. Our study aimed to investigate abnormal exosomal miRNA patterns via microarray analysis and identify candidate biomarkers for CSVD. Methods: We isolated exosomes from the plasma of all subjects and identified exosomes via currently universally accepted methods. The miRNAs were profiled through microarrays, and then the expression of selected differentially expressed miRNAs was validated through RT-PCR. GO and KEGG analysis predicted possible functions of differentially expressed miRNAs. Receiver operating characteristic (ROC) curve was employed to observe the diagnostic value of selective miRNAs. Finally, the relationship between the expression of miR-320e and the CSVD burden was analyzed. Results: A total of 14 miRNAs displayed differential enrichment levels with |fold change|≥1.5 and p<0.05 through miRNA microarray analysis. The RT-PCR analysis validated that exosomal miR-320e was significantly downregulated in CSVD patients (p<0.0001). ROC curve analysis of exosomal miR-320e showed the area under the curve of 0.752. According to the multivariable analysis, miR-320e was an independent predictor of white matter hyperintensity ([aOR]= 0.452, 95% confidence interval [CI]= 0.258-0.792, p=0.006) and exhibited a negative correlation with the load of periventricular white matter hyperintensities (p=0.0021) and deep white matter hyperintensities (p=0.0018), respectively. In addition, it exhibited a negative correlation with total CSVD burden score (r=-0.276, p=0.001). Conclusion: In our study, plasma exosomal miR-320e has a certain diagnostic value for CSVD, and a significant correlation with imaging burden of CSVD. Overall, exosomal miR-320e has the potential to be a novel biomarker for CSVD, but further research with a large sample size is necessary to assess its clinical utility.

Molybdenum-Mediated Reductive Hydroamination of Vinylcyclopropanes with Nitroarenes: Synthesis of Homoallylamines.

A molybdenum-mediated reductive hydroamination of vinylcyclopropanes with nitroarenes has been developed. A broad range of substituted homoallylamines were prepared in good to excellent yields from readily available starting materials. No noble metal catalysts were used in this reaction, and Mo(CO)6 acted as both catalyst and reductant. This protocol provides an effective method for the selective synthesis of substituted homoallylamines from easily available nitroarenes.