Synthesis and Biological Evaluation of Andrographolide C‐Glycoside Derivatives as α‐Glycosidase Inhibitors

A series of new andrographolide C‐glycoside derivatives were synthesized by a facile route. The new compounds showed higher potency than the parent andrographolide evaluated as α‐glycosidase inhibitors in the preliminary study.     

Six new andrographolide metabolites in rats

Six new andrographolide metabolites M-5-M-10 were isolated from rat urine, feces, and the contents of the small intestine. Three (M-5-M-7) as sulfate ester compounds were identified as new compounds. The structures of these six metabolites were determined to be 14-deoxy-12(R)-sulfo andrographolide 3-sulfate (M-5), 14-deoxy-12(S)-sulfo andrographolide 3-sulfate (M-6), 14-sulfo isoandrographolide 3-sulfate (M-7), 14-deoxy-11,12-didehydroandrographolide (M-8), isoandrographolide (M-9), and 14-deoxy andrographolide (M-10), respectively, based on chemical evidence and spectroscopic analysis.     

Parallel solution-phase synthesis of acrylonitrile scaffolds carrying L-alpha-amino acidic or D-glycosyl residues

A practical and straightforward protocol for the preparation of a solution-phase library of acrylonitrile scaffolds is reported. Target compounds were obtained in high yield, stereoselectivity, and purity by two simple and practical steps from cyanoacetic acid. Moreover, our study proposes a synthetic approach starting from the constructed library to obtain three-membered heterocycles.     

Synthesis of 14-deoxy-benzylidene-8,17-epoxy-diene-andrographolide derivatives and evaluation of their anticancer activities

Synthesis of 14-deoxy-benzylidene-8,17-epoxy-diene-andrographolide derivatives from andrographolide and evaluation of their anticancer activities were described herein. 3,19 hydroxy groups of andrographolide were protected by benzylidene which undergo m-chloroperbenzoic acid mediated epoxydation in moderate yield to form corresponding epoxy derivatives. Thereafter mild basic condition was applied to perform de-hydroxylation at C-14 which resulted in conjugated diene derivatives of benzylidene epoxy andrographolide. These compounds were examined against different human cancer cell lines and were found to inhibit their proliferation at IC₅₀ in the range of 3–20 μM in order to elucidated the role of allylic hydroxyl group at C-14.     

穿心莲内酯NO供体衍生物的合成

利用协同前药原理, 在穿心莲内酯衍生物的结构上引入硝酸酯, 合成了硝酸酯NO供体新化合物9个, 以期找到生物利用度更高、抗癌作用更好的新药; 目标化合物结构经¹H NMR, ¹³C NMR和MS确证.     

Quality control of medicinal herbs Fructus gardeniae, Common Andrographis Herb and their preparations for their active constituents by high-performance liquid chromatography-photodiode array detection-electrospray mass spectrometry

Dehydroandrographolide, andrographolide and geniposide are the main active constituents of many herbal medicines, e.g., Fructus gardeniae, Common Andrographis Herb. They are used as the markers to control the quality of such herbal medicines and their herbal preparations. In this paper, a simple and sensitive high-performance liquid chromatographic (HPLC) method coupled with photodiode array detection (DAD) and electrospray mass spectrometry (ESI/MS) were developed to determine the three compounds simultaneously in extracts of medicinal herbs and herbal preparations produced by different companies. The extracts were separated on a C₁₈ reversed phase HPLC column, with a gradient solvent system, the time for the separation of the three target analytes was 10 min. The abundance ions were recorded using selected ion monitoring (SIM) mode with m/z 297.3, 297.3 and 411.1 for dehydroandrographolide, andrographolide and geniposide, respectively. The limit of detection for dehydroandrographolide, andrographolide and geniposide were 20, 30 and 150 ng mL⁻¹, respectively. The proposed method was successfully applied to the determination of the contents of the compounds in related to medicinal herbs and preparations.     

Synthesis and Characterization of Andrographolide Derivatives as Regulators of βAPP Processing in Human Cells

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder, one of the main characteristics of which is the abnormal accumulation of amyloid peptide (Aβ) in the brain. Whereas β-secretase supports Aβ formation along the amyloidogenic processing of the β-amyloid precursor protein (βAPP), α-secretase counterbalances this pathway by both preventing Aβ production and triggering the release of the neuroprotective sAPPα metabolite. Therefore, stimulating α-secretase and/or inhibiting β-secretase can be considered a promising anti-AD therapeutic track. In this context, we tested andrographolide, a labdane diterpene derived from the plant Andrographis paniculata, as well as 24 synthesized derivatives, for their ability to induce sAPPα production in cultured SH-SY5Y human neuroblastoma cells. Following several rounds of screening, we identified three hits that were subjected to full characterization. Interestingly, andrographolide (8,17-olefinic) and its close derivative 14α-(5′,7′-dichloro-8′-quinolyloxy)-3,19-acetonylidene (compound 9) behave as moderate α-secretase activators, while 14α-(2′-methyl-5′,7′-dichloro-8′-quinolyloxy)-8,9-olefinic compounds 31 (3,19-acetonylidene) and 37 (3,19-diol), whose two structures are quite similar although distant from that of andrographolide and 9, stand as β-secretase inhibitors. Importantly, these results were confirmed in human HEK293 cells and these compounds do not trigger toxicity in either cell line. Altogether, these findings may represent an encouraging starting point for the future development of andrographolide-based compounds aimed at both activating α-secretase and inhibiting β-secretase that could prove useful in our quest for the therapeutic treatment of AD.     

Four new andrographolide metabolites in rats

Four new sulfonate metabolites of andrographolide, 14-deoxy-12(R)-sulfo andrographolide (Metabolite 1), 14-deoxy-12(S)-sulfo andrographolide (Metabolite 2), 14-deoxy-12(R)-sulfo-9(S)-andrographolide (Metabolite 3) and 14-sulfo isoandrographolide (Metabolite 4), were isolated from urine and feces in rats. Their structures were elucidated by chemical and spectroscopic analyses. These four metabolites were formed through a rare metabolic reaction and were all new compounds.     

Synthesis and Bioactivities of Andrographolide Derivatives: New (−)‐Limonidilactone Analogues

In this study, a novel route to (−)‐limonidilactone analogues 10 , 11 by way of stereoselective reaction of andrographolide ( 5 ) from 8 , 9 was reported. The anti‐tumor and α‐glucosidsae inhibition activities of some synthetic compounds were screened.     

New synthetic pathway to diverse 2-substituted quinolines based on a multicomponent reaction: solution-phase and solid-phase applications

Using Kobayashi's modification of the Grieco reaction, we were able to synthesize diverse 4-phenylthio-1,2,3,4-tetrahydroquinolines. These intermediates were oxidized and subsequently pyrolized to provide the corresponding quinolines. This new approach to 2-substituted quinolines was exemplified by liquid-phase production of a 25-member library. This was extended to solid-phase chemistry, starting from (l)-4-nitrophenylalanine on Wang resin, for production of a 16-member library. The latter compounds possess potentially interesting VLA-4 antagonist properties.     

Natural products in parallel chemistry--novel 5-lipoxygenase inhibitors from BIOS-based libraries starting from alpha-santonin

Recently, we developed a concept known as biology-oriented synthesis (BIOS), which targets the design and synthesis of small- to medium-sized compound libraries on the basis of genuine natural product templates to provide screening compounds with high biological relevance. We herein describe the parallel solution phase synthesis of two BIOS-based libraries starting from alpha-santonin (1). Modification of the sesquiterpene lactone 1 by introduction of a thiazole moiety followed by a Lewis-acid-mediated lactone opening yielded a first library of natural product analogues. An acid-mediated dienone-phenol rearrangement of 1 and a subsequent etherification/amidation sequence led to a second natural product-based library. After application of a fingerprint-based virtual screening on these compounds, the biological screening of 23 selected library members against 5-lipoxygenase resulted in the discovery of four potent novel inhibitors of this enzyme.     

Synthesis and structure anti-inflammatory activity relationships studies of andrographolide derivatives

Abstract

Andrographolide is a main bioactive diterpene lactone in A. paniculata with anti-inflammatory activity. In this study, a series of andrographolide derivatives were synthesized and evaluated for their structure-anti-inflammatory activity relationships in vivo. Among all compounds, isoandrographolide and 14-deoxyandrographolide showed stronger anti-inflammatory activity than andrographolide. The results indicated that the introduction of tetrahydrofuran ring and cyclic olefinic bond plays an important role in enhancing the anti-inflammatory activity of andrographolide derivatives. Isoandrographolide and 14-deoxyandrographolide are potent inhibitor of inflammation.

     

Synthesis of coumarin based Knoevenagel-Ugi adducts by a sequential one pot five-component reaction and their biological evaluation as anti-bacterial agents

An efficient multicomponent synthesis of Ugi compounds comprising coumarin backbone has been achieved by employing one pot five component sequential Knoevenagel-Ugi reaction. This method offers the advantages of easy handling procedure, atom economy, mild reaction conditions and good yields of products. A molecular library was synthesized by changing the substituents on two of the independent starting materials. The synthesized compounds were also tested for anti-microbial activities and were found to be moderate to good anti-bacterial agents.     

Solution-phase synthesis of a tricyclic pyrrole-2-carboxamide discovery library applying a stetter-Paal-Knorr reaction sequence

The solution-phase synthesis of a discovery library of 178 tricyclic pyrrole-2-carboxamides was accomplished in nine steps and seven purifications starting with three benzoyl-protected amino acid methyl esters. Further diversity was introduced by two glyoxaldehydes and 41 primary amines. The combination of Pauson-Khand, Stetter, and microwave-assisted Paal-Knorr reactions was applied as a key sequence. The discovery library was designed with the help of QikProp 2.1, and physicochemical data are presented for all pyrroles. Library members were synthesized and purified in parallel and analyzed by LC/MS. Selected compounds were fully characterized.     

Application of a Multilayer Perceptron Artificial Neural Network for the Prediction and Optimization of the Andrographolide Content in Andrographis paniculata

Andrographolide, the principal secondary metabolite of Andrographis paniculata, displays a wide spectrum of medicinal activities. The content of andrographolide varies significantly in the species collected from different geographical regions. Therefore, this study aims at investigating the role of different abiotic factors and selecting suitable sites for the cultivation of A. paniculata with high andrographolide content using a multilayer perceptron artificial neural network (MLP-ANN) approach. A total of 150 accessions of A. paniculata collected from different regions of Odisha and West Bengal in eastern India showed a variation in andrographolide content in the range of 0.28–5.45% on a dry weight basis. The MLP-ANN was trained using climatic factors and soil nutrients as the input layer and the andrographolide content as the output layer. The best topological ANN architecture, consisting of 14 input neurons, 12 hidden neurons, and 1 output neuron, could predict the andrographolide content with 90% accuracy. The developed ANN model showed good predictive performance with a correlation coefficient (R²) of 0.9716 and a root-mean-square error (RMSE) of 0.18. The global sensitivity analysis revealed nitrogen followed by phosphorus and potassium as the predominant input variables influencing the andrographolide content. The andrographolide content could be increased from 3.38% to 4.90% by optimizing these sensitive factors. The result showed that the ANN approach is reliable for the prediction of suitable sites for the optimum andrographolide yield in A. paniculata.     

Chemistry of andrographolide: formation of novel di-spiropyrrolidino and di-spiropyrrolizidino-oxindole adducts via one-pot three-component [3+2] azomethine ylide cycloaddition

A facile synthesis of novel di-spiro compounds has been achieved via 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatin derivatives and sarcosine to the conjugated double bond of andrographolide. When the amino acid was changed from sarcosine to l-proline, the product formation took a different course as determined by 2D NMR and X-ray crystallographic analysis.     

Synthesis of pyrido[1,2-a]indole malonates and amines through aryne annulation

Pyrido[1,2-a]indoles are known as medicinally and pharmaceutically important compounds, but there is a lack of efficient methods for their synthesis. We report a convenient and efficient route to these privileged structures starting from easily accessible 2-substituted pyridines and aryne precursors. A small library of compounds has been synthesized utilizing the developed method, affording variously substituted pyrido[1,2-a]indoles in moderate to good yields.     

Combinatorial synthesis of galactosyl-1,3,5-triazines as novel nucleoside analogues

Herein we report a parallel solid-phase synthesis of 1,3,5-triazine based nucleoside analogues by a three-step substitution, starting from 2,4,6-trichloro-1,3,5-triazine. A library of 80 galactosyl-1,3,5-triazine compounds was prepared in high purity without extensive reaction conditions or tedious purification, suggesting the generality of this method.     

Making "real" molecules in virtual space

Predicting "realistic" compounds of given chemical reactions with virtual synthesis tools usually requires the manual intervention of experienced chemists in the enumeration phase for the selection of appropriate reactants, assignment of the corresponding reaction sites, and removal of the unlikely products. To automate the virtual synthesis process, we have moved the expertise intensive parts from the compound library design phase to the reaction library design phase. ChemAxon is building an in silico reaction library containing important preparative transformations, where each reaction definition contains a generic transformation scheme and additional rules to handle the various starting compounds according to the corresponding chemo-, regio-, and stereoselectivity issues. Having well designed reaction definitions in hand, our software tool is able to generate synthetically feasible compound libraries with minimal effort in the enumeration phase.