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.

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.

Novel cinnamic acid magnolol derivatives as potent α-glucosidase and α-amylase inhibitors: Synthesis, in vitro and in silico studies.

In this study, twenty novel cinnamic acid magnolol derivatives were synthesized, and screened for their anti-hyperglycemic potential. All synthesized compounds exhibited good to moderate α-glucosidase and α-amylase inhibitory activities with IC50 values: 5.11 ± 1.46-90.26 ± 1.85 µM and 4.27 ± 1.51-49.28 ± 2.54 µM as compared to the standard acarbose (IC50: 255.44 ± 1.89 µM and 80.33 ± 2.95 µM, respectively). Compound 6j showed the strongest inhibitory activity against α-glucosidase (IC50 = 5.11 ± 1.46 µM) and α-amylase (IC50 = 4.27 ± 1.51 µM). Kinetic study indicated that compound 6j was reversible and a mixed type inhibitor against α-glucosidase and α-amylase. In silico studies revealed the binding interaction between 6j and two enzymes, respectively. Finally, cells cytotoxicity assay revealed that compound 6j showed low toxicity against 3 T3-L1 cells and HepG2 cells.

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.

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.

A Simple Approach to the Toxicity Prediction of Anilines and Phenols Towards Aquatic Organisms.

Chemicals pollution in the environment has attracted attention all over the world, and the toxicity prediction of chemical pollutants has become quite important. In this paper, we introduce a simple approach to predict the toxicity of some chemical components, in which the Tchebichef image moment (TM) method was employed to extract useful chemical information from the images of molecular structures to establish quantitative structure-activity relationship (QSAR) prediction models. The proposed approach was applied to predict the toxicity of anilines and phenols for the aquatic organisms of P. subcapitata and V. fischeri, in which the obtained TMs were defined as the independent variables, while the biological toxicity (pEC50) was regarded to be the dependent variable. Then, the predictive models were established by stepwise regression, respectively. The obtained squared correlation coefficients of leave-one-out cross-validation (Q2) for training sets and the predictive squared correlation coefficients (Rp2) for test sets of the two groups of data were higher than 0.79 and 0.75, respectively, which indicated that the obtained models possessed satisfactory accuracy and reliability. Compared with several reported methods, the proposed approach was more convenient and has a higher predictive capability. Our study provides another perspective in QSAR research.

Tchebichef image moment approach to the prediction of protein secondary structures based on circular dichroism.

Circular dichroism (CD) spectroscopy is a widely used technique for the evaluation of protein secondary structures that has a significant impact for the understanding of molecular biology. However, the quantitative analysis of protein secondary structures based on CD spectra is still a hard work due to the serious overlap of the spectra corresponding to different structural motifs. Here, Tchebichef image moment (TM) approach is introduced for the first time, which can effectively extract the chemical features in CD spectra for the quantitative analysis of protein secondary structures. The proposed approach was applied to analyze reference set and the obtained results were evaluated by the strict statistical parameters such as correlation coefficient, cross-validation correlation coefficient and root mean squared error. Compared with several specialized prediction methods, TM approach provided satisfactory results, especially for turns and unordered structures. Our study indicates that TM approach can be regarded as a feasible tool for the analysis of the secondary structures of proteins based on CD spectra. An available TMs package is provided and can be used directly for secondary structures prediction.

Prediction of phosphorylation sites based on Krawtchouk image moments.

Protein phosphorylation is one of the most pervasive post-translational modifications and regulates diverse cellular processes in organisms. Under the catalysis of protein kinases, protein phosphorylation usually occurred in the residues serine (S), threonine (T), or tyrosine (Y). In this contribution, we proposed a novel scheme (named KMPhos) for the theoretical prediction of protein phosphorylation sites. First, the numerical matrix was obtained from a protein sequence fragment by replacing the characters of the residues with the chemical descriptors of amino acid molecules to approximately describe the chemical environment of the protein fragment, which was turned to the grayscale image. Then the Krawtchouk image moments were calculated and used to establish the support vector machine models. The accuracies of 10-fold cross validation for the obtained models on the training set are up to 89.7%, 88.6%, and 90.1% for the residues S, Y, and T, respectively. For the independent test set, the prediction accuracies are up to 90.7% (S), 87.8% (T), and 89.3% (Y). The results of ROC and other evaluations are also satisfactory. Compared with several specialized prediction tools, KMPhos provided the higher accuracy and reliability. An available KMPhos package is provided and can be used directly for phosphorylation sites prediction.

Quantitative analysis of multiple components based on liquid chromatography with mass spectrometry in full scan mode.

Although liquid chromatography with mass spectrometry in full scan mode can obtain all the signals simultaneously in a large range and low cost, it is rarely used in quantitative analysis due to several problems such as chromatographic drifts and peak overlap. In this paper, we propose a Tchebichef moment method for the simultaneous quantitative analysis of three active compounds in Qingrejiedu oral liquid based on three-dimensional spectra in full scan mode of liquid chromatography with mass spectrometry. After the Tchebichef moments were calculated directly from the spectra, the quantitative linear models for three active compounds were established by stepwise regression. All the correlation coefficients were more than 0.9978. The limits of detection and limits of quantitation were less than 0.11 and 0.49 µg/mL, respectively. The intra- and interday precisions were less than 6.54 and 9.47%, while the recovery ranged from 102.56 to 112.15%. Owing to the advantages of multi-resolution and inherent invariance properties, Tchebichef moments could provide favorable results even in the situation of peaks shifting and overlapping, unknown interferences and noise signals, so it could be applied to the analysis of three-dimensional spectra in full scan mode of liquid chromatography with mass spectrometry.

Longest distance shifting: A simple and efficient approach for the alignment of shifted chromatographic peaks.

The preprocessing of chromatograms, such as the alignment of retention time shifts, is often a crucial step in the proper data analysis chain. Here, an efficient approach to align shifted chromatographic signals, longest distance shifting, is presented and highlighted. The performance of this novel strategy was demonstrated by using both simulated chromatograms that covered the different kinds of retention time shifts and the real experimental chromatograms of Pudilan Xiaoyan Tablets obtained by high-performance liquid chromatography with photodiode array detection. The averaged correlation coefficient for experimental chromatograms were in the range of 0.9517-0.9840 and the peak factor was 0.9989. As a comparison, all the chromatograms have also been aligned using correlation optimized warping and Interval Correlation Optimized Shifting algorithms. The obtained results indicate that the longest distance shifting algorithm is simpler, faster and more effective, and will be potentially suitable for the alignment of other types of signals.

The application of a Tchebichef moment method to the quantitative analysis of multiple compounds based on three-dimensional HPLC fingerprint spectra.

Three-dimensional (3D) fingerprint spectra provide a wealth of information for the quantitative analysis of multiple target compounds in mixtures. In this paper, a Tchebichef moment method based on the 3D fingerprint spectra obtained from high performance liquid chromatography coupled with a photodiode array detector was proposed and used to determine notoginsenoside R1, ginsenoside Rg1, ginsenoside Re and ginsenoside Rb1 in samples of a traditional Chinese Medicine (Sanqi Panax Notoginseng). The correlation coefficients of the established models were more than 0.9955 within the test ranges, the recovery ranged from 98.41% to 108.00%, and the intra- and inter-day precisions were less than 3.83% and 5.04%, respectively. The obtained results indicated that the Tchebichef moment method had effective feature representation capability and provided satisfactory quantification accuracy. Furthermore, several moment methods applied in analytical chemistry were compared, which provided a valuable insight into the application of moment methods in the analytical field.

High-performance liquid chromatography with photodiode array detection and chemometrics method for the analysis of multiple components in the traditional Chinese medicine Shuanghuanglian oral liquid.

Shuanghuanlian oral liquid, a traditional Chinese medicine preparation, is a mixture of three herbs (Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae). In this study, the quantitative analysis of three main active compounds, chlorogenic acid, forsythin and baicalin in samples from different manufacturers was performed rapidly by high-performance liquid chromatography coupled with photodiode array detection followed by Contour Projection coupled to stepwise regression treatment of the obtained three-dimensional spectra in which the partial overlap between adjacent target components existed. The method was validated for linearity (R>0.9940), precision (RSD<1.25%), recovery (92.20-102.50%), limit of detection (0.01-0.02 µg/mL) and limit of quantification (0.03-0.07 µg/mL). The results indicated that the combination of the three-dimensional spectra of traditional Chinese medicine and Contour Projection-stepwise regression offered an accurate, simple, low-cost and eco-friendly way for the rapid quantitative analysis of Shuanghuanlian oral liquid samples.

Fast determination of four active compounds in Sanqi Panax Notoginseng Injection samples by high-performance liquid chromatography with a chemometric method.

The application of chemometric methods could decrease the requirements of separation and simplify time-consuming pretreatment and experimental optimization. In this report, the accumulated projection method was developed and utilized for the rapid simultaneous quantification of four active components (notoginsenoside R1, ginsenosides Rg1, ginsenosides Re, and ginsenosides Rb1) in Sanqi Panax Notoginseng Injection samples. The proposed method is based on the three-dimensional fingerprint spectra obtained from high-performance liquid chromatography coupled with photodiode array detection. Although the chromatograms consisted of overlapping peaks, retention time shifts, and unknown interference, all established models showed good linearity (R > 0.9869) within test ranges. The relative standard deviation for intra- and interday precision of the four compounds did not exceed 2.4 and 4.7%, respectively, and the overall recovery was 91.2-106.8%. Compared with N-way principal component analysis, our method provides more satisfactory results, which indicate that the proposed approach is simple, fast, and reliable for the determination of the four analytes in Sanqi Panax Notoginseng Injection samples.

A classification and identification model of extra virgin olive oil adulterated with other edible oils based on pigment compositions and support vector machine.

Adulteration identification of extra virgin olive oil (EVOO) is a vital issue in the olive oil industry. In this study, chromatographic fingerprint data of pigments combined with machine learning methodologies were successfully identified and classified EVOO, refined-pomace olive oil (R-POO), rapeseed oil (RO), soybean oil (SO), peanut oil (PO), sunflower oil (SFO), flaxseed oil (FO), corn oil (CO), extra virgin olive oil adulterated with rapeseed oil (EVOO-RO) and extra virgin olive oil adulterated with corn oil (EVOO-CO). Support vector machine (SVM) classification of EVOO, other edible oils, and EVOO adulteration identification achieved 100% accuracy for the training set sample and 94.44% accuracy for the test set sample. As a result, this SVM model could identify effectively the adulteration EVOO with the limit of 1% RO and 1% CO. Therefore, the excellent classification and predictive power of this model indicated pigments could be used as potential markers for identifying EVOO adulteration.

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.

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.

A hybrid variable selection and modeling strategy for the determination of target compounds in different spectral datasets.

In this paper, a hybrid technique is proposed to establish quantitative models for the determination of target compounds in different spectral datasets. The proposed hybrid method is the hybridization of interval partial least squares (iPLS) method with gradient descent (GD) algorithm. Here, the novelty of the proposed method is that the iPLS method is applied to variable selection and the GD algorithm is employed to establish quantitative models based on the selected optimal variables. In the application of the hybrid iPLS-GD method, the factors, i.e., the number of the interval for the iPLS method and the learning rate, the number of iterations for the GD method, that affect the quantitative accuracy of the method are optimized and determined. Then three spectral datasets, including the near-infrared spectroscopy (NIR) dataset, nuclear magnetic resonance (1H NMR) dataset and excitation-emission matrix fluorescence (EEM) dataset, are used to test and verify the performance of the iPLS-GD method. We compare the hybrid iPLS-GD method with the PLS and iPLS methods from the aspects of modeling ability and predictive ability. The results demonstrated that the iPLS-GD method can be used as an effective and promising tool for the determination of target compounds in complex samples in practice.