Xanthones with α‐Glucosidase Inhibitory Activities from Aspergillus versicolor,a Fungal Endophyte of Huperzia serrata

Three new xanthones, namely huperxanthones A–C ( 1 – 3 , resp.), were obtained from the cultures of Aspergillus versicolor, a fungal endophyte of Huperzia serrata, together with 1,7‐dihydroxy‐8‐(methoxycarbonyl)xanthone‐3‐carboxylic acid ( 4 ), β‐diversonolic acid methyl ester ( 5 ), 4‐hydroxyvertixanthone ( 6 ), and sydowinin B ( 7 ). The structures of the new compounds were established by detailed NMR and MS analysis, especially by 2D‐NMR experiments. All xanthones were evaluated for their effects on α‐glucosidase. Compound 4 exhibited a potent inhibitory activity against α‐glucosidase with an IC₅₀ value of 0.24 mM (vs. 0.38 mM for acarbose). The rest of the compounds showed weak or no activity against α‐glucosidase.     

Fragmentation pathways of metopimazine and its metabolite using ESI‐MSn,HR‐MS and H/D exchange

Metopimazine (MPZ) is a phenothiazine derivative used to prevent emesis during chemotherapy where few structural analysis of the aforementioned compound have been described in the literature. Thus, this work reports, for the first time, the detailed study of fragmentation pathways of MPZ and its metabolite (AMPZ) using electrospray ionization (EI) with multistage mass spectrometry (ESI‐MSⁿ) in positive‐ion mode. The structures of 21 product ions were identified and their accurate masses were determined using high resolution mass spectrometry (HRMS) experiments. Characteristic product ions of these two phenothiazine derivatives are more particularly displayed along with differences between their relative abundances and their structures checked by H/D exchange experiments. Copyright © 2010 John Wiley & Sons, Ltd.     

Selectfluor and NFSI exo‐Glycal Fluorination Strategies Applied to the Enhancement of the Binding Affinity of Galactofuranosyltransferase GlfT2 Inhibitors

Two complementary methods for the synthesis of fluorinated exo‐glycals have been developed, for which previously no general reaction had been available. First, a Selectfluor‐mediated fluorination was optimized after detailed analysis of all the reaction parameters. A dramatic effect of molecular sieves on the course of the reaction was observed. The reaction was generalized with a set of biologically relevant furanosides and pyranosides. A second direct approach involving carbanionic chemistry and the use of N‐fluorobenzenesulfonimide (NFSI) was performed and this method gave better diastereoselectivities. Assignment of the Z/E configuration of all the fluorinated exo‐glycals was achieved based on the results of HOESY experiments. Furthermore, fluorinated exo‐glycal analogues of UDP‐galactofuranose were prepared and assayed against GlfT2, which is a key enzyme involved in the cell‐wall biosynthesis of major pathogens. The fluorinated exo‐glycals proved to be potent inhibitors as compared with a series of C‐glycosidic analogues of UDP‐Galf, thus demonstrating the double beneficial effect of the exocyclic enol ether functionality and the fluorine atom.     

Oxepine‐Containing Diketopiperazine Alkaloids from the Algal‐Derived Endophytic Fungus Paecilomyces variotii EN‐291

Two new oxepine‐containing diketopiperazine‐type alkaloids, varioloids A and B ( 1 and 2 , resp.), were isolated from the algal‐derived fungus Paecilomyces variotii EN‐291. The structures and absolute configurations were determined by detailed interpretation of 1D‐ and 2D‐NMR spectroscopic data and by analysis of acidic hydrolysates. Compounds 1 and 2 exhibited potent activity against the plant‐pathogenic fungus Fusarium graminearum with MIC values of 8 and 4 μg/ml, respectively.     

Synthesis and biological activities of 2‐alkylthio‐5‐furylmethylidene‐4H‐imidazolin‐4‐ones

Novel 2‐alkylthio‐5‐furylmethylidene‐4H‐imidazolin‐4‐ones 4 have been synthesized via tandem aza‐ Wittig reaction. The structures were determined by ir, nmr, mass spectroscopy, and elemental analysis. They were screened for fungicidal activities against Fusarium oxysporium, Botryosphaeria berengeriana and Rhizoctonia solani, and growth inhibition of Barnyard grass and Cole root and stalk. A few of them possess significant biological activities.     

Asymmetric Synthesis and Antitumor Activity of Spiro‐Oxadiazole Derivatives from 1,4:3,6‐Dianhydro‐D‐fructose

A series of spiro‐oxadiazoles were synthesized from 1,4:3,6‐dianhydro‐D ‐fructose and hydrazides via a stereo‐ selective two‐step reaction sequence. The structures of newly synthesized compounds were established by spectral analysis. The absolute configuration of compound 2a was further confirmed by single crystal X‐ray analysis. All the synthesized compounds were screened for their in vitro antitumor activity, showing that these compounds have poor inhibitory activities against A549, MGC‐803 tumor cells.     

Détermination par Résonance Magnétique Nucléaire de la Configuration d'alcools Bicycliques [4.2.0] et Tricycliques [6.4.0.02,7] ou [5.4.0.02,6]

The configuration of various bicyclo[4.2.0]octanols has been established by ¹H NMR spectroscopy, with Eu(dpm)₃ as shift reagent. The intrinsic parameters Δ and K have been obtained and used as structural probes. Moreover, detailed data analysis showed that, contrary to the generally accepted concept, the vicinal coupling constant between trans cyclobutanic protons can be larger than that between cis protons. The chemical shifts obtained by ¹³C NMR spectroscopy are consistent with the proposed structures. The results have been extensively used to determine unambiguously the configuration of tricyclo[6.4.0.0^2,7]dodecanols and tricyclo[5.4.0.0^2,6]undecanol.     

Synthesis and in vitro Antibacterial Activities of 5‐(2,3,4,5‐Tetrahydro‐1H‐chromeno[2,3‐d]pyrimidin‐5‐yl)pyrimidione Derivatives

A series of novel 5‐(2,3,4,5‐tetrahydro‐1H‐chromeno[2,3‐d]pyrimidin‐5‐yl)pyrimidione derivatives have been synthesized from substituted salicylaldehydes and barbituric acid or 2‐thiobarbituric acid in water catalyzed by phase transfer catalysis of triethylbenzyl ammonium chloride (TEBA). Elemental analysis, IR, ¹H NMR, and ¹³C NMR elucidated the structures of all the newly synthesized compounds. In vitro antimicrobial activities of synthesized compounds have been investigated against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa. These newly synthesized derivatives exhibited significant in vitro antibacterial activity.     

ZnO Nanocatalyst Mediated Convergent Synthesis of Highly Substituted Imidazole and Imidazole‐derived Bi‐heterocyclic Scaffolds as Potential Antibacterial Agents

A new series of novel highly substituted imidazole and imidazole bi‐heterocycles have been synthesized via atom economic, one‐pot condensation reaction using benzil, substituted benzaldehydes, various amine scaffolds, and ammonium acetate using ZnO nanoparticles as effective catalyst. Simple operation, cheap catalyst, good to excellent yield, etc, are some of the advantages of this protocol. The characterization of the synthesized imidazole analogues was performed by Fourier transform infrared, nuclear magnetic resonance (¹H and ¹³C), mass analysis, and elemental analysis. The structures were unequivocally confirmed by single‐crystal X‐ray diffraction analysis. Synthesized compounds were tested for antibacterial activities by resazurin reduction assay. All compounds tested showed significant activity against bacteria. Among the 24 compounds tested, compounds 1c , 1i , 2c , 2g , and 3a proved to be more active against the bacterial strain tested.     

Absolute‐structure reports

All the 139 noncentrosymmetric crystal structures published in Acta Crystallographica Section C between January 2011 and November 2012 inclusive have been used as the basis of a detailed study of the reporting of absolute structure. These structure determinations cover a wide range of space groups, chemical composition and resonant‐scattering contribution. Defining A and D as the average and difference of the intensities of Friedel opposites, their level of fit has been examined using 2AD and selected‐D plots. It was found, regardless of the expected resonant‐scattering contribution to Friedel opposites, that the Friedel‐difference intensities are often dominated by random uncertainty and systematic error. An analysis of data collection strategy is provided. It is found that crystal‐structure determinations resulting in a Flack parameter close to 0.5 may not necessarily be from crystals twinned by inversion. Friedif_stat is shown to be a robust estimator of the resonant‐scattering contribution to Friedel opposites, very little affected by the particular space group of a structure nor by the occupation of special positions. There is considerable confusion in the text of papers presenting achiral noncentrosymmetric crystal structures. Recommendations are provided for the optimal way of treating noncentrosymmetric crystal structures for which the experimenter has no interest in determining the absolute structure.<!?tpb=25.7pt>     

Pregnane‐Based Steroids from a Formosan Gorgonian Subergorgia Mollis

A new steroid, 11α, 15α‐diacetoxy‐17α‐pregna‐4,20‐dien‐3‐one ( 1 ), and a known one, 17α‐pregna‐4,20‐dien‐3‐one ( 2 ), have been isolated from a Formosan gorgonian Subergorgia mollis. The structures of both compounds were determined on the basis of extensive NMR experiments, including HMQC, HMBC, ¹H‐¹H COSY and NOESY. Metabolite 2 has not been isolated from a natural source before. The detailed ¹H and ¹³C NMR spectral data of 2 are reported for the first time.     

Synthesis and biological activities of cis and trans 5‐amino‐3‐[(6‐chloro‐3‐pyridyl)methyl]amino‐1‐(5,5‐dimethyl‐2‐oxo‐4‐substitutedphenyl‐1,3,2‐dioxaphosphinan‐2‐yl)‐4‐cyano(ethoxycarbonyl)‐1H‐pyrazoles

A series of novel title compounds have been designed and synthesized by a multi‐step reaction, the stereochemistry of the reaction was investigated, the structures of all compounds prepared have been confirmed by ¹H NMR, IR, EI‐MS spectroscopy and elemental analysis. The crystal structures of cis 6b and trans 6b were determined by single crystal X‐ray diffraction. The results of preliminary bioassay indicate that some compounds possess a certain extent inhibition effect against aphides at the concentration of 250 ppm.     

New ent‐Abietanoids from Isodon rubescens

Six new ent‐abietane diterpenoids, rubescensins I–M ( 1 – 5 ) and P ( 6 ), along with two related acetonide derivatives ( 7 and 8 ), were isolated from Isodon rubescens. Their structures were elucidated by detailed spectroscopic analysis. Compound 5 is the first N‐containing diterpenoid from the genus Isodon, exhibiting notable cytotoxicity against human tumor K562 cells.     

The Stereochemistry of 1,2,3‐Triols Revealed by 1H NMR Spectroscopy: Principles and Applications

The conformational compositions of the tris(α‐methoxy‐α‐phenylacetic acid) ester derivatives of 1,2,3‐prim,sec,sec‐triols are presented. These conformations have been determined by theoretical and experimental data (i.e., energy‐ and chemical‐shift calculations, circular dichroism (CD) experiments, coupling‐constant analysis, enantioselective deuteration experiments, and low‐temperature NMR spectroscopic studies). A detailed analysis of the anisotropic effects due to the most significant conformers in the ¹H NMR spectra supported the correlation between the ¹H NMR spectra (Δδ^RS value of H(3′) and |Δ(Δδ^RS)| parameters) and the absolute configuration of the substrate. The study also allows the identification of the pro‐R and pro‐S methylene protons from their vicinal coupling constants and relative chemical shifts.     

Solvent‐free microwave synthesis of bis‐pyrazolo[3,4‐b:4′,3′‐e]‐pyridines and study of their antifungal properties

The synthesis of a series of bis‐pyrazolo[3,4‐b:4′,3′‐e]pyridines ( 3 ) in the reaction of 5‐amino‐3‐methyl‐1‐phenylpyrazole ( 1 ) with aldehydes ( 2 ) under microwave irradiation and solvent‐free conditions is described. The structure elucidation of the products is based on detailed nmr analysis of experiments such as ¹H‐COSY, NOESY, DEPT, HSQC and HMBC. These compounds showed moderate antifungal in vitro activity against dermatophytes.     

Fulvynes,antimicrobial polyoxygenated acetylenes from the Mediterranean sponge Haliclona fulva

Nine linear polyoxygenated acetylenes, fulvynes A–I (1–9), exhibiting the uncommon 2-yne carboxylic acid functionality, have been isolated from the butanolic extract of the Mediterranean sponge Haliclona fulva. Their structures possess a long alkyl chain with several oxygenated carbons, and were established by detailed spectroscopic analysis. All fulvynes were found to be active against a chloramphenicol-resistant strain of Bacillus subtilis.     

Anthracene and Anthraquinone Derivatives from the Stem Bark of Juglans mandshurica Maxim.

One new anthracene derivative, juglanthracenoside A ( 1 ), two new anthraquinones, juglanthraquinone A ( 2 ) and juglanthraquinone B ( 3 ), along with a new naturally occurring anthraquinone, 9,10‐dihydro‐4,8‐dihydroxy‐9,10‐dioxoanthracene‐2‐carboxylic acid ( 4 ), have been isolated from the stem bark of Juglans mandshurica. Their structures were established by detailed spectroscopic analysis and comparison of the NMR data with those of related compounds. Compound 1 displayed noticeable antioxidant activity in both 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) and 2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) free radical‐scavenging assays, while compound 4 showed strong cytotoxicity against HepG2, SGC7901, HCT‐8, and A549 cell lines in vitro.     

Synthesis and biological evaluation of new 4‐(4‐(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)phenyl)‐2‐phenylthiazole derivatives

A novel series of 4‐(4‐(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)phenyl)‐2‐substitutedthiazole derivatives ( 8a‐l) have been synthesized by [3 + 2] cycloaddition reaction of 4‐(4‐ethynylphenyl)‐2‐substitutedthiazole with substituted benzyl azide in aqueous DMF. Starting compounds 4‐(4‐ethynylphenyl)‐2‐substitutedthiazole ( 6a‐d ) were synthesized by reaction of 4‐(2‐substitutedthiazol‐4‐yl)benzaldehyde with Ohira‐Bestmann reagent in methanol. The structures of these novel triazole‐thiazole clubbed derivatives were confirmed by the spectral analysis. The title compounds ( 8a‐l ) were tested for antimycobacterial activity against Mycobacterium tuberculosis H37Ra active and dormant (MTB, ATCC 25177) and antimicrobial activity against standard Gram‐positive bacteria, Staphylococcus aureus (NCIM 2602) and Bacillus subtilis (NCIM 2162), and Gram‐negative bacteria, Escherichia coli (NCIM 2576) and Pseudomonas flurescence (NCIM 2059). Compounds 8a , 8b , 8c , and 8h reported good activity against B subtilis, compounds 8a , 8b , and 8c showed good activity against S aureus, and compound 8b showed good activity against dormant M tuberculosis H37Rv strain. Compounds 8b and 8c found more potent against Gram positive and dormant M tuberculosis H37Rv strains. These novel triazole‐thiazole clubbed analogues found to be a capable leads for further optimization and development.     

Conformational changes in Akt1 activation probed by amide hydrogen/deuterium exchange and nano‐electrospray ionization mass spectrometry

Amide hydrogen exchange coupled to nano‐electrospray ionization mass spectrometry (nano‐ESI‐MS) has been used to identify and characterize localized conformational changes of Akt upon activation. Active or inactive Akt was incubated in D₂O buffer, digested with pepsin, and analyzed by nano‐ESI‐MS to determine the deuterium incorporation. The hydrogen/deuterium (H/D) exchange profiles revealed that Akt undergoes considerable conformational changes in the core structures of all three individual domains after activation. In the PH domain, four β‐strand (β1, β2 β5 and β6) regions containing membrane‐binding residues displayed higher solvent accessibility in the inactive state, suggesting that the PH domain is readily available for the binding to the plasma membrane for activation. In contrast, these β‐strands became less exposed or more folded in the active form, which is favored for the dissociation of Akt from the membrane. The beginning α‐helix J region and the C‐terminal locus (T450‐470P) of the regulatory domain showed less folded structures that probably enable substrate entry. Our data also revealed detailed conformational changes of Akt in the kinase domain due to activation, some of which may be attributed to the interaction of the basic residues with phosphorylation sites. Our H/D exchange results indicating the conformational status of Akt at different activation states provided new insight for the regulation of this critical protein involved in cell survival. Published in 2009 by John Wiley & Sons, Ltd.     

Metabolomics‐based approach for ranking the candidate structures of unidentified peaks in capillary electrophoresis time‐of‐flight mass spectrometry

One of the technical challenges encountered during metabolomics research is determining the chemical structures of unidentified peaks. We have developed a metabolomics‐based chemoinformatics approach for ranking the candidate structures of unidentified peaks. Our approach uses information about the known metabolites detected in samples containing unidentified peaks and involves three discrete steps. The first step involves identifying “precursor/product metabolites” as potential reactants or products derived from the unidentified peaks. In the second step, candidate structures for the unidentified peak are searched against the PubChem database using a molecular formula. These structures are then ranked by structural similarity against precursor/product metabolites and candidate structures. In the third step, the migration time is predicted to refine the candidate structures. Two simulation studies were conducted to highlight the efficacy of our approach, including the use of 20 proteinogenic amino acids as pseudo‐unidentified peaks, and leave‐one‐out experiments for all of the annotated metabolites with and without filtering against the Human Metabolome Database. We also applied our approach to two unidentified peaks in a urine sample, which were identified as glycocyamidine and N ‐acetylglycine. These results suggest that our approach could be used to identify unidentified peaks during metabolomics analysis.