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.

Melatonin derivative 6a as a PARP-1 inhibitor for the treatment of Parkinson's disease.

Both continuous oxidative stress and poly (ADP-ribose) polymerase 1 (PARP-1) activation occur in neurodegenerative diseases such as Parkinson's disease. PARP-1 inhibition can reverse mitochondrial damage and has a neuroprotective effect. In a previous study, we synthesized melatonin derivative 6a (MD6a) and reported that it has excellent antioxidant activity and significantly reduces α-synuclein aggregation in Caenorhabditis elegans; however, the underlying mechanism is largely unknown. In the present study, we revealed that MD6a is a potential PARP-1 inhibitor, leading to mammalian targe of rapamycin/heat shock factor 1 signaling downregulation and reducing heat shock protein 4 and 6 expression, thus helping to maintain protein homeostasis and improve mitochondrial function. Together, these findings suggest that MD6a might be a viable candidate for the prevention and treatment of Parkinson's disease.

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.

Total Synthesis of (+)-Peniciketal B.

An efficient synthesis of (+)-peniciketal B has been accomplished in 15 steps from the commercially available materials atraric acid, acryloyl chloride, and (+)-homoallylic alcohol. A convergent synthetic approach that is quite concise for constructing either "hemisphere" of (+)-peniciketal B with a common intermediate is employed that relies on a cascade intermolecular FeCl3-mediated "inner sphere" Michael-type reaction/double cyclization of an α,ß-unsaturated ketone and substituted phenol to build the benzo-fused 2,8-dioxabicyclo[3.3.1]nonane with excellent diastereoselectivity. The generality of the transformation was also demonstrated by the broad scope of substrates that would be potential candidates for natural product synthesis and medicinal chemistry. Benzannulated [6,6]spiroketal was installed by a late-stage acid-catalyzed spiroketalization.

Enantioselective synthesis of α,α-diarylketones by sequential visible light photoactivation and phosphoric acid catalysis.

Chiral ketones and their derivatives are useful synthetic intermediates for the synthesis of biologically active natural products and medicinally relevant molecules. Nevertheless, general and broadly applicable methods for enantioenriched acyclic α,α-disubstituted ketones, especially α,α-diarylketones, remain largely underdeveloped, owing to the easy racemization. Here, we report a visible light photoactivation and phosphoric acid-catalyzed alkyne-carbonyl metathesis/transfer hydrogenation one-pot reaction using arylalkyne, benzoquinone, and Hantzsch ester for the expeditious synthesis of α,α-diarylketones with excellent yields and enantioselectivities. In the reaction, three chemical bonds, including C═O, C─C, and C─H, are formed, providing a de novo synthesis reaction for chiral α,α-diarylketones. Moreover, this protocol provides a convenient and practical method to synthesize or modify complex bioactive molecules, including efficient routes to florylpicoxamid and BRL-15572 analogs. Computational mechanistic studies revealed that C-H/π interactions, π-π interaction, and the substituents of Hantzsch ester all play crucial roles in the stereocontrol of the reaction.

Bismuth(III)-Catalyzed 1,8-Addition/Cyclization/Rearrangement of Propargylic para-Quinone Methides with 2-Vinylphenol: Synthesis of Indeno[2,1-c]chromenes.

The unique reactivity of in situ generated propargylic para-quinone methides as a new type of five-carbon synthon has been discovered by a novel bismuth(III)-catalyzed tandem annulation reaction. This 1,8-addition/cyclization/rearrangement cyclization cascade reaction is characterized by unusual structural reconstruction of 2-vinylphenol, involving cleavage of the C1'═C2' bond and formation of four new bonds. This method provides a convenient and mild approach to generate synthetically important functionalized indeno[2,1-c]chromenes. The mechanism of the reaction is proposed from several control experiments.

An accurate and reliable analytical strategy for simultaneous determination of target furanocoumarins and flavonoids in cosmetic and pharmaceutical samples by ultra-high performance supercritical fluid chromatography.

Furanocoumarins and flavonoids have various important biological activities and wide application. In the present study, a rapid and reliable supercritical fluid chromatography method was proposed for the separation of 10 target components including 8 furanocoumarins and 2 flavonoids. After detailed condition optimization, the 10 target compounds can be baseline separated on a Trefoil CEL1 (3.0 mm × 150 mm, 2.5 µm) column using gradient elution. A 0.07% (v/v) trifluoroacetic acid in ethanol was determined to be the most proper mobile phase for the separation of target compounds. The column temperature, back pressure, flow rate were set at 36 â„ƒ, 2000 psi, 1.0 mL min-1 to 1.4 mL min-1, respectively. The ten target compounds were analyzed within 24 min using the optimized conditions. Under the optimized conditions, all the target compounds showed good linearity with linear correlation coefficients higher than 0.995, and satisfactory recovery in the range of 83.52-112.92%. All these results showed that the developed ultra-high performance supercritical fluid chromatography method was reliable and effective. Finally, the application of the developed method to cosmetic, Psoraleae fructus and Angelicae dahuricae radix samples were presented. The results highlight the applicability of the ultra-high performance supercritical fluid chromatography method to the analysis of interested compounds in pharmaceutical and cosmetic samples.

Studies toward synthesis of the core skeleton of spiroaspertrione A.

Bioassay-guided isolation of spiroaspertrione A from cultures of Aspergillus sp. TJ23 in 2017 demonstrated potent resensitization of oxacillin against methicillin-resistant Staphylococcus aureus by lowering the oxacillin minimal inhibitory concentration up to 32-fold. To construct this unique spiro[bicyclo[3.2.2]nonane-2,1'-cyclohexane] system, a protocol for ceric ammonium nitrate-induced intramolecular cross-coupling of silyl enolate is disclosed.

Brønsted acid catalyzed remote C6 functionalization of 2,3-disubstituted indoles with ß,γ-unsaturated α-ketoester.

A metal-free catalytic approach for the remote C6-functionalization of 2,3-disubstituted indoles has been developed. In the presence of catalytic amounts of Brønsted acid, the ß,γ-unsaturated α-ketoesters react with 2,3-disubstituted indoles at the C6 position selectively. Under mild reaction conditions, a range of C6-functionalized indoles were prepared with good yields and excellent regioselectivity. This methodology provides a concise and efficient route for the synthesis of C6-functionalized indole derivatives.

Catalytic Enantioselective Desymmetrization of Prochiral Triacylamines via Pseudopeptidic Guanidine-Guanidinium Catalysis.

Triacylamines with Cs symmetry have been explored in asymmetric organocatalysis, leading to the development of a novel catalytic enantioselective desymmetrization of prochiral triacylamines by methanolysis under the catalysis of chiral pseudopeptidic guanidine-guanidinium salt having a weakly coordinating anion. This organocatalytic methodology provides an effective approach to the synthetically useful chiral imide-esters with a 1,5-dicarbonyl moiety, and its synthetic potential has been manifested in the asymmetric synthesis of two GABA analogue drugs, (R)-Baclofen·HCl and (S)-Pregabalin.

A comparative study of three chemometrics methods combined with excitation-emission matrix fluorescence for quantification of the bioactive compounds aesculin and aesculetin in Cortex Fraxini.

Cortex Fraxini is an important traditional Chinese herbal medicine with various medical functions. Aesculin and aesculetin are the main effective components of Cortex Fraxini. The fluorescence signals of the two compounds have a high degree of overlap with each other, making quantitative analysis difficult with conventional analytical methods. In the present study, different chemometrics methods, including lasso regression (LAR), interval partial least squares (iPLS), and multidimensional partial least squares (N-PLS) methods, were employed and combined with excitation-emission matrix (EEM) fluorescence for the purpose of accurate quantification of aesculin and aesculetin in Cortex Fraxini samples. The most satisfactory results were obtained by using the N-PLS method based on the EEM spectra without scatterings, with correlation coefficient of calibration and prediction values higher than 0.9972 and 0.9962, respectively, root mean squared errors for calibration and prediction values lower than 0.0304 and 0.1165, respectively, and recovery values in the range of 83.32%-104.62%. The obtained credible models indicated that the N-PLS method combined with EEM spectra has the advantages of being green, low cost, and accurate and it is a good strategy for the determination of active compounds in complex samples. To further confirm the accuracy of the obtained results, the same samples were analyzed by the recognized ultra-performance liquid chromatography method.

Pien Tze Huang Inhibits Migration and Invasion of Hepatocellular Carcinoma Cells by Repressing PDGFRB/YAP/CCN2 Axis Activity.

OBJECTIVE: To investigate the effects of Pien Tze Huang (PZH) on the migration and invasion of HCC cells and underlying molecular mechanism. METHODS: Cell counting kit-8 (CCK-8) was applied to evaluate the cell viabilities of SMMC-7721, SK-Hep-1, C3A and HL-7702 (6 × 103 cells/well) co-incubated with different concentrations of PZH (0, 0.2, 0.4, 0.6, 0.8 mg/mL) for 24 h. Transwell, wound healing assay, CCK-8 and Annexin V-FITC/PI staining were conducted to investigate the effects of PZH on the migration, invasion, proliferation and apoptosis of SK-Hep-1 and SMMC-7721 cells (650 µ g/mL for SK-Hep-1 cells and 330 µ g/mL for SMMC-7721 cells), respectively. In vivo, lung metastasis mouse model constructed by tail vein injection of HCC cells was used for evaluating the anti-metastasis function of PZH. SK-Hep-1 cells (106 cells/200 µ L per mice) were injected into B-NDG mice via tail vein. Totally 8 mice were randomly divided into PZH and control groups, 4 mice in each group. After 2-d inoculation, mice in the PZH group were administered with PZH (250 mg/kg, daily) and mice in the control group received only vehicle (PBS) from the 2nd day after xenograft to day 17. Transcriptome analysis based on RNA-seq was subsequently used for deciphering anti-tumor mechanism of PZH. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were applied to verify RNA-seq results. Luciferase reporter assay was performed to examine the transcriptional activity of yes-associated protein (YAP). RESULTS: PZH treatment significantly inhibited the migration, invasion, proliferation and promoted the apoptosis of HCC cells in vitro and in vivo (P<0.01). Transcriptome analysis indicated that Hippo signaling pathway was associated with anti-metastasis function of PZH. Mechanical study showed PZH significantly inhibited the expressions of platelet derived growth factor receptor beta (PDGFRB), YAP, connective tissue growth factor (CCN2), N-cadherin, vimentin and matrix metallopeptidase 2 (MMP2, P<0.01). Meanwhile, the phosphorylation of YAP was also enhanced by PZH treatment in vitro and in vivo. Furthermore, PZH played roles in inhibiting the transcriptional activity of YAP. CONCLUSION: PZH restrained migration, invasion and epithelial-mesenchymal transition of HCC cells through repressing PDGFRB/YAP/CCN2 axis.

Synthesis of Melatonin Derivatives and the Neuroprotective Effects on Parkinson's Disease Models of Caenorhabditis elegans.

Melatonin (MT) is a hormone with antioxidant activity secreted by the pineal gland in the human brain, which is highly efficient in scavenging free radicals and plays an important role in the neuro-immuno-endocrine system. Emerging evidence showed that MT supplementation was a potential therapeutic strategy for Parkinson's disease (PD), which inhibits pathways associated with oxidative stress in PD. In this study, we reported a C7-selective olefination of melatonin under rhodium catalysis with the aid of PIII-directing groups and synthesized 10 new melatonin-C7-cinnamic acid derivatives (6a-6j). The antioxidant potential of the compounds was evaluated both by ABTS and ORAC methods. Among these newly synthesized melatonin derivatives, 6a showed significantly higher activity than MT at 10-5 M. In the transgenic Caenorhabditis elegans model of PD, 6a significantly reduces alpha-synuclein aggregation and dopaminergic neuronal damage in nematodes while reducing intracellular ROS levels and recovers behavioral dysfunction induced by dopaminergic neurodegeneration. Further study of the mechanism of action of this compound can provide new therapeutic ideas and treatment strategies for PD.

Copper-catalyzed 1,2-Borylacylation of 1,3-Enynes: synthesis of ß-Alkynyl ketones.

A copper catalyzed 1,2-borylacylation of 1,3-enynes with B2pin2 and acid chlorides has been developed. Using readily available 1,3-enynes, B2pin2 and acid chlorides as substrates, a range of highly functionalized α,α-disubstituted ß-alkynyl ketones were readily prepared under mild conditions in moderate to good yields. The borylacylated products can be easily derivatized to give several valuable structures. Notably, treatment of the products with NaBO3·4H2O provided 1,2-allenyl ketones, which is proposed to proceed via a retro-aldol process of the corresponding homopropargyl alcohols.

Unprecedented Multicomponent Reaction of Indoles, CS2 and Nitroarenes: Stereoselective Synthesis of (Z)-3-((Arylamino)methylene)indoline-2-thiones.

An efficient method for the stereoselective synthesis of (Z)-3-((arylamino)methylene)indoline-2-thiones have been developed via a novel multicomponent reaction of indoles, CS2 and nitroarenes. A range of functionalized indoline-2-thiones were prepared in moderate to good yields from easily available starting materials. The indoline-2-thione products can be easily derivatized to give biologically active thieno[2,3-b]indole and thiopyrano[2,3-b]indole skeletons in high yields.

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.

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.

Visible-Light-Induced Carbonylation of Indoles with Phenols under Metal-Free Conditions: Synthesis of Indole-3-carboxylates.

A visible-light-induced carbonylation of indoles with phenols for the synthesis of indole-3-carboxylates has been developed. The reaction proceeded via a radical carbonylation process in which elementary I2 was used as an effective photosensitive initiator and, thus, avoided the use of transition metal catalysts. A series of different aryl indole-3-carboxylates were prepared in moderate to good yields. The broad applicability of this methodology was further highlighted by the late-stage functionalization of several phenol-containing natural products and pharmaceuticals.

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.

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.