44 results on '"Fischer NH"'
Search Results
2. Klaus Fischer (PSNA Phytochemistry Pioneer)☆
- Author
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Fischer Nh
- Subjects
Phytochemistry ,Philosophy ,Plant Science ,General Medicine ,Horticulture ,Molecular Biology ,Biochemistry ,Classics - Published
- 2007
3. Self-Promoted Glycosylation of Carbamoylated Peptides on Solid Phase.
- Author
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Fischer NH, Vævest BN, Dam AK, Diness F, and Pedersen CM
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- Glycosylation, Chloroacetates chemistry, Carbamates chemistry, Acetamides chemistry, Solid-Phase Synthesis Techniques methods, Peptides chemistry
- Abstract
Self-promoted glycosylations with trichloroacetimidate glycosyl donors are demonstrated on solid-phase-anchored peptides orthogonally deprotected and tosylcarbamoylated on the side-chains of cysteine and serine, respectively. The donor scope included glucosyl as well as mannosyl trichloroacetimidates, carrying benzyl, acetyl, or isopropylidene protecting groups. Isopropylidene groups were found to be removed under the acidic conditions used for release of the neoglycopeptides from the solid support, yielding neoglycopeptides with unprotected hydroxyl groups. Glycosylation of a peptide containing a carbamoylated tyrosine was attempted as well, but the desired neoglycopeptide could not be synthesized due to thermal instability of the carbamate., (© 2024 The Authors. ChemPlusChem published by Wiley-VCH GmbH.)
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- 2024
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4. Hydrodynamic Control of Alzheimer Aβ Fibrillation with Glucosaminic Acid Containing Click-Cyclized β-Bodies.
- Author
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Zhang Y, Borch LA, Fischer NH, and Meldal M
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- Humans, Hydrodynamics, Amino Acids chemistry, Peptide Fragments chemistry, Amyloid beta-Peptides chemistry, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Glucosamine analogs & derivatives
- Abstract
It is well established that the dynamic hydration shell plays a vital role in macromolecular functions such as protein-ligand, protein-protein, protein-DNA, and protein-lipid interactions. Here we investigate how the water modality affects conformational changes, solubility, and motion of fibrillar proteins. The hypothesis is that the introduction of a poly hydroxyl amino acid would increase solvation of the fibril forming peptides, preventing their misfolding and aggregation. For the amyloid β (Aβ) peptide, which is considered to be connected with nervous system diseases, including dementia and cognitive decline in Alzheimer's disease, the formation of β-sheet fibrils always occurs with a conformational change and a decrease in the dynamic hydration shell around Aβ(1-42). We present novel cyclic d-amino acid peptides that effectively inhibit fibrillation through affecting the dynamic hydration shell of Aβ(1-42) in vitro. Using de novo design within the software Molecular Operating Environment (MOE), five different peptides that recognize Alzheimer's fibrils were designed and synthesized. Three of them were cyclic all-d-amino acid peptides incorporating the same polyhydroxy building block derived from d-glucosaminic acid ( GA ). One peptide was the parent cyclic all d-amino acid inhibitor with no GA incorporated, and another was an all l-amino acid linear fibrillation inhibitor. The GA -containing peptides were found to show significantly improved inhibition of Aβ(1-42) aggregation. The inhibition was dramatically improved by the synergistic application of two GA peptides targeting each end of the growing fibril. The present study may facilitate future developments of intervention strategies for Alzheimer's disease and similar neurodegenerative diseases.
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- 2024
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5. Chemical modification of proteins - challenges and trends at the start of the 2020s.
- Author
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Fischer NH, Oliveira MT, and Diness F
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- Proteins chemistry, Amino Acids
- Abstract
Ribosomally expressed proteins perform multiple, versatile, and specialized tasks throughout Nature. In modern times, chemically modified proteins, including improved hormones, enzymes, and antibody-drug-conjugates have become available and have found advanced industrial and pharmaceutical applications. Chemical modification of proteins is used to introduce new functionalities, improve stability or drugability. Undertaking chemical reactions with proteins without compromising their native function is still a core challenge as proteins are large conformation dependent multifunctional molecules. Methods for functionalization ideally should be chemo-selective, site-selective, and undertaken under biocompatible conditions in aqueous buffer to prevent denaturation of the protein. Here the present challenges in the field are discussed and methods for modification of the 20 encoded amino acids as well as the N -/ C -termini and protein backbone are presented. For each amino acid, common and traditional modification methods are presented first, followed by more recent ones.
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- 2023
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6. Radiolabeled albumin through S N Ar of cysteines as a potential pretargeting theranostic agent.
- Author
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Fischer NH, Lopes van den Broek SI, Herth MM, and Diness F
- Abstract
Human serum albumin (HSA) has been shown to be a promising tumor targeting vector and target for generating theranostics by bioconjugation. Unstable chemical conjugation to HSA via a cysteine (Cys34) by reversible Michael additions is most commonly applied for this purpose. Herein, we describe utilization of our recently developed site-selective irreversible S
N Ar conjugation to Cys34 using perfluorobenzene sulfonyl derivatives to introduce a trans -cyclooctene (TCO) handle. The TCO could then be bioorthogonally ligated within minutes through an inverse-electron demand Diels-Alder reaction (IEDDA) to tetrazines (Tzs) containing a radionuclide. The methodology opens up a wide range of chemistries including pretargeting, 'click-to-release' tumor selective drug delivery or ultra-fast and complete conjugation of any drug. The proof-of-principle study demonstrated that the conjugation chemistry is feasible, robust and easy to carry out, being promising for pretargeted imaging and therapy studies as well as selective drug delivery using HSA., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)- Published
- 2022
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7. Carbon dioxide enhances sulphur-selective conjugate addition reactions.
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Yang Y, Fischer NH, Oliveira MT, Hadaf GB, Liu J, Brock-Nannestad T, Diness F, and Lee JW
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- Alkylation, Chemical Phenomena, Humans, Sulfur, Carbon Dioxide, Nitrogen
- Abstract
Sulphur-selective conjugate addition reactions play a central role in synthetic chemistry and chemical biology. A general tool for conjugate addition reactions should provide high selectivity in the presence of competing nucleophilic functional groups, namely nitrogen nucleophiles. We report CO
2 -mediated chemoselective S -Michael addition reactions where CO2 can reversibly control the reaction pHs, thus providing practical reaction conditions. The increased chemoselectivity for sulphur-alkylation products was ascribed to CO2 as a temporary and traceless protecting group for nitrogen nucleophiles, while CO2 efficiently provide higher conversion and selectivity sulphur nucleophiles on peptides and human serum albumin (HSA) with various electrophiles. This method offers simple reaction conditions for cysteine modification reactions when high chemoselectivity is required.- Published
- 2022
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8. Tuning Peptide Structure and Function through Fluorobenzene Stapling.
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Fischer NH, Fumi E, Oliveira MT, Thulstrup PW, and Diness F
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- Circular Dichroism, Cyclization, Peptides, Cyclic, Protein Structure, Secondary, Fluorobenzenes, Peptides
- Abstract
Cyclic peptides are promising next-generation therapeutics with improved biological stability and activity. A catalyst-free stapling method for cysteine-containing peptides has been developed that enables fine-tuning of the macrocycle by using the appropriate regioisomers of fluorobenzene linkers. Stapling was performed on the unprotected linear peptide or, more conveniently, directly on-resin after peptide synthesis. NMR spectroscopy and circular dichroism studies demonstrate that the type of stapling can tune the secondary structures of the peptides. The method was applied to a set of potential agonists for melanocortin receptors, generating a library of macrocyclic potent ligands with ortho, meta or para relationships between the thioethers. Their small but significant differences in potency and efficacy demonstrate how the method allows facile fine-tuning of macrocyclic peptides towards biological targets from the same linear precursor., (© 2021 Wiley-VCH GmbH.)
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- 2022
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9. C-Terminal lactamization of peptides.
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Fischer NH, Nielsen DS, Palmer D, Meldal M, and Diness F
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- Drug Stability, Humans, Lipopeptides chemical synthesis, Lipopeptides chemistry, Peptides blood, Peptides chemical synthesis, Lactams chemistry, Peptides chemistry, Solid-Phase Synthesis Techniques
- Abstract
Solid-phase synthesis of peptides (SPPS) with release through formation of C-terminal γ-, δ-, or ε-lactams is presented. The natural products ciliatamide A and C were synthesized in up to 90% yield. Peptides carrying C-terminal lactams were shown to possess increased bio-stability and comparable biological activity as compared to the parent non-lactamized peptide amides.
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- 2021
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10. Constituents of Calamintha ashei: effects on Florida sandhill species.
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Menelaou MA, Henandez HP, Macías FA, Weidenhamer JD, Williamson GB, Fronczek FR, Fischer HD, and Fischer NH
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- Flavonoids chemistry, Flavonoids toxicity, Florida, Furans chemistry, Furans toxicity, Magnetic Resonance Spectroscopy, Molecular Structure, Plant Extracts chemistry, Poaceae drug effects, Poaceae growth & development, Sesquiterpenes, Germacrane chemistry, Sesquiterpenes, Germacrane toxicity, X-Ray Diffraction, Flavonoids isolation & purification, Furans isolation & purification, Lamiaceae chemistry, Plant Components, Aerial chemistry, Plant Extracts isolation & purification, Sesquiterpenes, Germacrane isolation & purification
- Abstract
Chemical constituents of the perennial shrub Calamintha ashei have been characterized as part of our investigation of the allelopathic properties of this plant. Besides the known monoterpenes, (+)-evodone, (-)-calaminthone and (+)-desacetylcalaminthone, fresh aerial parts of C. ashei provided six new menthofurans, two new germacrane sesquiterpenes, and the six, known flavonoids: 5-desmethoxynobiletin, 5-hydroxy-6,7,8,4'-tetramethoxyflavone, 5,4'-dihydroxy-6,7,8,3'-tetramethoxyflavone, thymonin, 5,4'-dihydroxy-6,7-dimethoxyflavone and 6-hydroxy-7,3'-dimethoxyluteolin. The structures of the new compounds were elucidated by spectroscopic methods and comparison of their 1H NMR spectra with those of structurally related compounds. The molecular structures of (+)-evodone, 5-desmethoxynobiletin (5-hydroxy-6,7,8,3',4'-pentamethoxyflavone) and the triacetate of thymonin (7,8,3'-trimethoxy-5,6,4'-triacetoxyflavone), were determined by single crystal X-ray diffraction. Saturated aqueous solutions of menthofuran, (+)-evodone, (-)-calaminthone, (+)-desacetylcalaminthone, 4alpha,5beta-diacetoxymenthofuran, as well as mixtures of (+)-evodone and (+)-desacetylcalaminthone inhibited the germination and root growth of Schizachyrium scoparium and Leptochloa dubia, two native Florida sandhill grasses, as well as Lactuca sativa. (+)-Evodone and (+)-desacetylcalaminthone were the most active. 5-Hydroxy-6,7,8,3',4'-pentamethoxyflavone and 5,4'-dihydroxy-6,7,8,3'-tetramethoxyflavone and mixtures of the two flavonoids in aqueous as well as in saturated aqueous solutions ofursolic acid were tested on the same species, but showed no significant activity.
- Published
- 2010
11. 11β,13-Dihydro-lactucin-8-O-acetate hemihydrate.
- Author
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Fronczek CF, Gomez-Barrios ML, Fischer NH, and Fronczek FR
- Abstract
THE TITLE STRUCTURE (SYSTEMATIC NAME: 9-hydroxy-methyl-3,6-di-methyl-3-methyl-ene-2,7-dioxo-3,3a,4,5,9a,9b-hexa-hydro-azu-leno[4,5-b]furan-4-yl acetate hemihydrate), C(17)H(20)O(6)·0.5H(2)O, from Lactuca floridana, has two independent sesquiterpene lactone mol-ecules in the asymmetric unit. Both have their seven-membered rings in the chair conformation. In the crystal, the OH groups and the water mol-ecule form classical O-H⋯O hydrogen bonds with O⋯O distances in the range 2.6750 (17)-2.8160 (18) Å.
- Published
- 2009
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12. Neolignans from North American Magnolia species with cyclooxygenase 2 inhibitory activity.
- Author
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Schühly W, Khan SI, and Fischer NH
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- Animals, Cell Survival drug effects, Chlorocebus aethiops, Cyclooxygenase 2 Inhibitors adverse effects, Cyclooxygenase 2 Inhibitors isolation & purification, Dinoprostone biosynthesis, Fibroblasts drug effects, Fibroblasts enzymology, Lignans isolation & purification, Lipopolysaccharides pharmacology, Macrophages drug effects, Macrophages enzymology, Magnolia growth & development, Mice, Molecular Structure, North America, Plant Extracts adverse effects, Plant Extracts isolation & purification, Plant Leaves chemistry, Seeds chemistry, Vero Cells, Cyclooxygenase 2 Inhibitors pharmacology, Lignans pharmacology, Magnolia chemistry, Plant Extracts pharmacology
- Abstract
Objectives: Based upon reported ethnomedicinal use by Native Americans, extracts and pure isolates from leaves and seeds of Magnolia grandiflora, M. virginiana, M. acuminata and M. macrophylla, all native to the Southeastern United States, were investigated for their anti-inflammatory potential against cyclooxygenase 2 (COX-2)., Material and Methods: The extracts and pure compounds from Magnolia species were tested for their production of prostaglandin E(2) (PGE(2)) using a mouse macrophage (RAW 264.7) assay where cells were stimulated by lipopolysaccharide., Results: Leaf extracts were moderately active (44-58% inhibition at 50 microg/ml) whereas seed extracts showed significant activity of 54-88% inhibition, respectively. In the seed extract of M. grandiflora, honokiol, magnolol and 4'-O-methylhonokiol strongly inhibited COX-2 (IC(50): 1.2-2.0 microg/ml), 3-O-methylmagnolol was moderately active while a new compound was inactive towards COX-2. The neolignans were not cytotoxic to macrophages (RAW 264.7) and kidney fibroblast (VERO) cells in vitro., Conclusions: The results indicate that the reported ethnomedicinal use of the investigated Magnolia species is in agreement with anti-inflammatory activity of their respective compounds.
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- 2009
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13. Inhibition of NF-kappaB-mediated transcription and induction of apoptosis by melampolides and repandolides.
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Ma G, Khan SI, Benavides G, Schühly W, Fischer NH, Khan IA, and Pasco DS
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- Asteraceae chemistry, Cell Cycle drug effects, Cell Line, Cell Line, Tumor, Cyclooxygenase 2 genetics, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 Inhibitors chemistry, Cyclooxygenase 2 Inhibitors isolation & purification, Cyclooxygenase 2 Inhibitors pharmacology, Dose-Response Relationship, Drug, G2 Phase drug effects, HL-60 Cells, Humans, Inhibitory Concentration 50, Lactones chemistry, Lactones isolation & purification, Lactones pharmacology, Luciferases genetics, Luciferases metabolism, Macrophages drug effects, Macrophages metabolism, Microscopy, Fluorescence, Molecular Structure, NF-kappa B genetics, NF-kappa B metabolism, Plant Extracts chemistry, Plant Extracts isolation & purification, Plant Extracts pharmacology, Sesquiterpenes chemistry, Sesquiterpenes isolation & purification, Sp1 Transcription Factor metabolism, Tetradecanoylphorbol Acetate pharmacology, Apoptosis drug effects, NF-kappa B antagonists & inhibitors, Sesquiterpenes pharmacology, Transcription, Genetic drug effects
- Abstract
Purpose: Nuclear factor-kappaB (NF-kappaB) plays a crucial role in the regulation of inflammatory processes, cell proliferation, and apoptosis. Blocking NF-kappaB signaling may represent a therapeutic strategy in cancer and inflammation therapy. The aim of this study was to investigate the effects of sesquiterpenes isolated from Asteraceae, namely melampolides (enhydrin, tetraludin A) and repandolides (repandins A, B, D and E) on the activation of NF-kappaB, cell growth of cancer cells, cell cycle progression and apoptosis. In addition, their effects on the activity of cyclooxygenase-2 (COX-2) enzyme were also evaluated., Methods: Cell-based reporter gene assay was conducted in SW1353 cells. COX-2 enzyme activity and cell growth inhibition was determined by enzyme immunoassay and MTT assay respectively. Cell cycle analysis was carried out by flow cytometry and apoptosis was observed by DAPI staining assay., Results: In SW1353 cells, transcription mediated by NF-kappaB was inhibited by enhydrin, tetraludin A and repandins A, B, D and E, while Sp-1 mediated transcription was not affected. COX-2 enzyme activity was inhibited by enhydrin, repandin A and E, but not by tetraludin A, repandin B and D. These compounds were effective in inhibiting the growth of a panel of human tumor cell lines in a concentration-dependent manner. Cell cycle analysis and DAPI staining indicated cell cycle arrest in G(2)/M phase and induction of apoptosis., Conclusions: Enhydrin, tetraludin A and repandins A, B, D and E inhibited tumor cell growth and induced cell cycle arrest and apoptosis. These effects may be related to inhibition of NF-B activation.
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- 2007
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14. New perspectives on natural products in TB drug research.
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Pauli GF, Case RJ, Inui T, Wang Y, Cho S, Fischer NH, and Franzblau SG
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- Animals, Antitubercular Agents chemistry, Antitubercular Agents therapeutic use, Antitubercular Agents toxicity, Biological Assay, Biological Products chemistry, Biological Products therapeutic use, Biological Products toxicity, Humans, Mycobacterium tuberculosis drug effects, Tuberculosis microbiology, Antitubercular Agents pharmacology, Biological Products pharmacology, Tuberculosis drug therapy
- Abstract
The challenge of discovering new, urgently needed anti-TB drugs from natural sources requires a truly interdisciplinary research. Cutting-edge mycobacteriology and innovative natural products chemistry tools have to be developed and employed in tandem, in order to meet these demands. The present review provides cross-linkage to the most recent literature on anti-TB active natural products and summarizes the recent developments in both fields and their potential to impact the early steps of the TB drug discovery process.
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- 2005
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15. A novel inhibitor of respiratory syncytial virus isolated from ethnobotanicals.
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Ojwang JO, Wang YH, Wyde PR, Fischer NH, Schuehly W, Appleman JR, Hinds S, and Shimasaki CD
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- Antiviral Agents isolation & purification, Cell Culture Techniques, Quinic Acid isolation & purification, Quinic Acid pharmacology, Respiratory Syncytial Virus Infections drug therapy, Antiviral Agents pharmacology, Drugs, Chinese Herbal pharmacology, Plants, Medicinal chemistry, Quinic Acid analogs & derivatives, Respiratory Syncytial Viruses drug effects
- Abstract
A novel low molecular weight compound, CJ 4-16-4, isolated from ethnobotanicals using bioassay-guided fractionation, was found to be a potent inhibitor of respiratory syncytial virus (RSV) in vitro and in vivo. In vitro, a very low micromolar efficacious dose was obtained against at least four of subtype A (RSV-Long, RSV A2, and RSV A6 57754) and one of subtype B (Washington) RSV strains without seeing any significant cytotoxicity to Hep-2, MDCK or Vero cell lines. The drug inhibits growth of RSV in Hep-2 cells maintained in tissue culture at a very low concentration (approximately 0.07 microM) with cell toxicity >400 microM (TI>5880). In a cotton rat model of RSV infection, the drug was able to reduce viral titers by approximately 1 log at dose 12.5 and 25 mg/kg/day, and by >2 log at 100 mg/kg/day. This antiviral activity was specific as influenza A and B and herpes simplex 1 and 2 viruses were not inhibited. The results obtained indicate that CJ 4-16-4 warrants clinical development.
- Published
- 2005
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16. Anti-inflammatory and anti-hyperalgesic effects of sesquiterpene lactones from Magnolia and Bear's foot.
- Author
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Feltenstein MW, Schühly W, Warnick JE, Fischer NH, and Sufka KJ
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- Analgesics, Non-Narcotic chemistry, Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Carrageenan, Indomethacin pharmacology, Inflammation drug therapy, Inflammation etiology, Lactones chemistry, Lactones isolation & purification, Lactones pharmacology, Male, Molecular Structure, Rats, Rats, Sprague-Dawley, Sesquiterpenes chemistry, Analgesics, Non-Narcotic isolation & purification, Analgesics, Non-Narcotic pharmacology, Anti-Inflammatory Agents, Non-Steroidal isolation & purification, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Asteraceae chemistry, Magnolia chemistry, Sesquiterpenes isolation & purification, Sesquiterpenes pharmacology
- Abstract
Sesquiterpene lactones possess a variety of biological activities, including anti-inflammatory activity. Two plants native to the southeastern United States, Magnolia grandiflora (L.) and Smallanthus uvedalius (L.) [syn Polymnia uvedalius (L.)], are novel sources of the sesquiterpene lactones parthenolide and enhydrin, respectively. In this study, the anti-inflammatory and anti-hyperalgesic effects of these isolated lactones from these two plant sources were evaluated in the rat carrageenan inflammation model. Rats received ip injections of either vehicle (propylene glycol), indomethacin (5 mg/kg), 11,13-dihydroparthenolide (20 mg/kg), parthenolide (5 or 20 mg/kg) or enhydrin (5 or 20 mg/kg). A 100-microl injection of 2.0% carrageenan was made into the plantar surface of the right hindpaw. Paw withdrawal latencies and paw volumes in both inflamed and non-inflamed paws were recorded at four test intervals: pre-inflammation baseline (0 time point), and 1, 2 and 4 h post-carrageenan injection. Vehicle-treated animals exhibited a significant time-dependent hyperalgesic and edema response that was greatest at the 4-h test interval. Indomethacin significantly blocked the hyperalgesic response and modestly attenuated the edema response. Parthenolide (20 mg/kg) and enhydrin (20 mg/kg) significantly blocked the hyperalgesic response and significantly attenuated the edema response; 11,13-dihydroparthenolide did not affect either inflammation or hyperalgesia. These findings suggest that parthenolide and enhydrin from these plant sources may be useful in the treatment of inflammatory pain.
- Published
- 2004
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17. Three ginkgolide hydrates from Ginkgo biloba L.: ginkgolide A monohydrate, ginkgolide C sesquihydrate and ginkgolide J dihydrate, all determined at 120 K.
- Author
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Zhao J, Muhammad I, Dunbar DC, Khan IA, Fischer NH, and Fronczek FR
- Subjects
- Crystallography, X-Ray, Ginkgolides, Hydrogen Bonding, Magnetic Resonance Spectroscopy, Models, Molecular, Diterpenes, Ginkgo biloba chemistry, Lactones chemistry
- Abstract
A low-temperature structure of ginkgolide A monohydrate, (1R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11aS)-3-(1,1-dimethylethyl)-hexahydro-4,7b-dihydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3',2':3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione monohydrate, C(20)H(24)O(9) x H(2)O, obtained from Mo K alpha data, is a factor of three more precise than the previous room-temperature determination. A refinement of the ginkgolide A monohydrate structure with Cu K alpha data has allowed the assignment of the absolute configuration of the series of compounds. Ginkgolide C sesquihydrate, (1S,2R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11S,11aR)-3-(1,1-dimethylethyl)-hexahydro-2,4,7b,11-tetrahydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3',2':3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione sesquihydrate, C(20)H(24)O(11) x 1.5H(2)O, has two independent diterpene molecules, both of which exhibit intramolecular hydrogen bonding between OH groups. Ginkgolide J dihydrate, (1S,2R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11aS)-3-(1,1-dimethylethyl)-hexahydro-2,4,7b-trihydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3',2':3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione dihydrate, C(20)H(24)O(10) x 2H(2)O, has the same basic skeleton as the other ginkgolides, with its three OH groups having the same configurations as those in ginkgolide C. The conformations of the six five-membered rings are quite similar across ginkgolides A-C and J, except for the A and F rings of ginkgolide A.
- Published
- 2002
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18. Stigmasterol hemihydrate.
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Benavides GA, Fronczek FR, and Fischer NH
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- Asteraceae chemistry, Crystallography, X-Ray, Hydrogen Bonding, Models, Molecular, Molecular Conformation, Stigmasterol chemistry
- Abstract
The title compound, stigmasta-5,22-dien-3beta-ol hemihydrate, C(29)H(48)O x 0.5H(2)O, previously thought to be the monohydrate, has two sterol molecules and one water molecule in the asymmetric unit. In both sterol molecules, the methyl group of the ethyl substituent at the end of the hydrocarbon chain is disordered over two sites. The OH group of molecule A donates a hydrogen bond to a water molecule and accepts a hydrogen bond from the OH group of molecule B. The OH group of molecule B accepts two hydrogen bonds from water molecules.
- Published
- 2002
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19. Antimycobacterial plant terpenoids.
- Author
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Cantrell CL, Franzblau SG, and Fischer NH
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- Antitubercular Agents chemistry, Cycadopsida, Humans, Magnoliopsida, Mycobacterium tuberculosis drug effects, Plant Preparations chemistry, Sterols chemistry, Sterols isolation & purification, Sterols therapeutic use, Structure-Activity Relationship, Terpenes chemistry, Terpenes isolation & purification, Antitubercular Agents therapeutic use, Phytotherapy, Plant Preparations therapeutic use, Terpenes therapeutic use, Tuberculosis drug therapy
- Abstract
Abstract. Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis, is the leading killer among all infectious diseases worldwide and is responsible for more than two million deaths annually. For over thirty years no antitubercular agents with new mechanisms of action have been developed. The recent increase in the number of multi-drug resistant clinical isolates of M. tuberculosis has created an urgent need for the discovery and development of new antituberculosis leads. This review covers recent reports on plant-derived terpenoids that have demonstrated moderate to high activity in in vitro bioassays against M. tuberculosis. In this review, mono-, sesqui-, di- and triterpenes, and sterols, their structural analogs and semisynthetic derivatives will be discussed, with particular emphasis on the structural features essential for antimycobacterial activity.
- Published
- 2001
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20. Two stereoisomeric pentacyclic oxindole alkaloids from Uncaria tomentosa: uncarine C and uncarine E.
- Author
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Muhammad I, Khan IA, Fischer NH, and Fronczek FR
- Subjects
- Crystallography, X-Ray, Models, Molecular, Molecular Structure, Oxindoles, Stereoisomerism, Alkaloids chemistry, Indoles chemistry, Plants, Medicinal chemistry, Spiro Compounds chemistry
- Abstract
The chloroform solvate of uncarine C (pteropodine), (1'S,3R,4'aS,5'aS,10'aS)-1,2,5',5'a,7',8',10',10'a-octahydro-1'-methyl-2-oxospiro[3H-indole-3,6'(4'aH)-[1H]pyrano[3,4-f]indolizine]-4'-carboxylic acid methyl ester, C(21)H(24)N(2)O(4).CHCl(3), has an absolute configuration with the spiro C atom in the R configuration. Its epimer at the spiro C atom, uncarine E (isopteropodine), (1'S,3S,4'aS,5'aS,10'aS)-1,2,5',5'a,7',8',10',10'a-octahydro-1'-methyl-2-oxospiro[3H-indole-3,6'(4'aH)-[1H]pyrano[3,4-f]indolizine]-4'-carboxylic acid methyl ester, C(21)H(24)N(2)O(4), has Z' = 3, with no solvent. Both form intermolecular hydrogen bonds involving only the oxindole, with N.O distances in the range 2.759 (4)-2.894 (5) A.
- Published
- 2001
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21. The ethnomedicinal uses of magnoliaceae from the southeastern United States as leads in drug discovery.
- Author
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Schühly W, Khan I, and Fischer NH
- Abstract
In Asia and North America, members of the family Magnoliaceae have been and are presently used extensively in indigenous herbal medicine. Many taxa of the genus Magnolia produce lignans and sesquiterpene lactones, some with considerable in vitro bioactivities. This review focuses on selected natural products of the genus Magnolia from the southeastern United States with demonstrated biological and pharmacological properties. Ethnomedicinal data obtained from the Native Americans of the southeastern United States correlate well with the results of pharmacological investigations.
- Published
- 2001
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22. Dibenzocyclooctadiene-type lignans from Magnolia pyramidata.
- Author
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Song Q, Fronczek FR, and Fischer NH
- Subjects
- Circular Dichroism, Crystallography, X-Ray, Lignans chemistry, Magnetic Resonance Spectroscopy, Molecular Conformation, Lignans isolation & purification, Magnoliopsida chemistry
- Abstract
Eight dibenzocyclooctadiene-type lignans, pyramidatin A-H, were isolated from the leaves of Magnolia pyramidata. Their structures were established by spectral methods, mainly 2D NMR spectroscopic techniques, which involved combined applications of COSY, DEPT. 1H, 13C correlations, COLOC, INAPT and long-range inverse 1H, 13C NMR correlations. The molecular structures of pyramidatin A and B were determined by single crystal X-ray diffraction. The absolute configurations of all eight lignans were derived from CD spectral correlations with structurally related dibenzocyclooctadienes of known absolute configuration.
- Published
- 2000
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23. Evaluation of the total peroxyl radical-scavenging capacity of flavonoids: structure-activity relationships.
- Author
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Dugas AJ Jr, Castañeda-Acosta J, Bonin GC, Price KL, Fischer NH, and Winston GW
- Subjects
- Flavonoids chemistry, Structure-Activity Relationship, Flavonoids pharmacology, Peroxides
- Abstract
The antioxidant activity of a series of flavonoids against peroxyl radicals generated from thermal homolysis of 2, 2'-azobis-amidinopropane was determined by the Total Oxyradical Scavenging Capacity (TOSC) assay. Seven flavonoids with hydroxy and/or methoxy substitution were analyzed and compared to the water-soluble vitamin E analogue Trolox. The most active compound was the flavonol quercetin, followed by its 3-glycoside derivative rutin; these were 7 and 5 times, respectively, better scavengers of peroxyl radical than Trolox. Among the flavones with both hydroxy and methoxy substitution, the most active against peroxyl radicals was the 5,6,4'-trihydroxy-7,8,3'-trimethoxyflavone (thymonin), with a TOSC value 1.5 times greater than that of Trolox. The activity of the remaining flavones was in the following relative order: 5, 4'-dihydroxy-6,7,8,3'-tetramethoxyflavone > 5-hydroxy-3,6,7,3', 4'-pentamethoxyflavone (artemetin) > 5,4'-dihydroxy-3,6, 7-trimethoxyflavone > 5,6,7,8,2',3',4',5'-octamethoxyflavone (agehoustin A). The data suggest a potential role for dietary intake of flavonoid-containing foods in lowering the risk of certain pathophysiologies that have been associated with free-radical-mediated events.
- Published
- 2000
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24. Taraxerol acetate at 100 K.
- Author
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Billodeaux DR, Benavides GA, Fischer NH, and Fronczek FR
- Subjects
- Crystallography, X-Ray, Models, Molecular, Molecular Conformation, Oleanolic Acid chemistry, Plant Extracts chemistry, Oleanolic Acid analogs & derivatives, Plant Roots chemistry, Triterpenes chemistry
- Abstract
The title triterpene, D-friedoolean-14-en-3 beta-yl acetate, C32H52O2, was isolated from dichloromethane extracts of the roots of common ragweed Ambrosia artemisiifolia. The skeleton contains five fused six-membered rings with an average Csp3-Csp3 bond distance of 1.549 (6) A and one double bond of length 1.348 (6) A. The D and E rings are cis-fused. The compound also contains a beta-oriented acetate group with a C-O distance 1.461 (5) A.
- Published
- 1999
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25. Antimycobacterial ergosterol-5,8-endoperoxide from Ajuga remota.
- Author
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Cantrell CL, Rajab MS, Franzblau SG, Fronczek FR, and Fischer NH
- Subjects
- Antitubercular Agents chemistry, Antitubercular Agents isolation & purification, Crystallography, X-Ray, Ergosterol chemistry, Ergosterol isolation & purification, Ergosterol pharmacology, Microbial Sensitivity Tests, Molecular Structure, Antitubercular Agents pharmacology, Ergosterol analogs & derivatives, Mycobacterium tuberculosis drug effects, Plant Extracts pharmacology, Plants chemistry
- Abstract
In a bioassay-guided search for antimycobacterial natural products from higher plants, we have chemically investigated the methanol extract of aerial parts of Ajuga remota Benth. (Labiatae) for its active constituent(s). Bioactive chromatographic fractions of the crude extract provided the known triterpene ergosterol-5,8-endoperoxide plus the diterpenes clerodin, ajugarin-I, and ajugarin-II, which had been previously isolated from A. remota. This is the first report on the isolation of ergosterol-5,8-endoperoxide from this plant. The above compounds were tested in a radiorespirometric bioassay for activity against Mycobacterium tuberculosis. Ergosterol-5,8-endoperoxide showed a minimum inhibitory concentration (MIC) of 1 microgram/ml, while ergosterol-5,8-endoperoxide acetate, ergosterol, and ergosta-5,7,9(11),22-tetraen-3 beta-ol gave MICs of 8 micrograms/ml, > 128 micrograms/ml, and 128 micrograms/ml, respectively. Clerodin, ajugarin-I, and ajugarin-II were inactive with MICs of > 128 micrograms/ml.
- Published
- 1999
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26. Antimycobacterial eudesmanolides from Inula helenium and Rudbeckia subtomentosa.
- Author
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Cantrell CL, Abate L, Fronczek FR, Franzblau SG, Quijano L, and Fischer NH
- Subjects
- Antitubercular Agents chemistry, Antitubercular Agents pharmacology, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Molecular Structure, Sesquiterpenes chemistry, Sesquiterpenes pharmacology, Structure-Activity Relationship, Antitubercular Agents isolation & purification, Inula chemistry, Mycobacterium tuberculosis drug effects, Sesquiterpenes isolation & purification
- Abstract
In a bioassay guided search for antimycobacterial compounds from higher plants, the root extracts of Elecampane (Inula helenium L.; Asteraceae) and Sweet Coneflower (Rudbeckia subtomentosa Pursh.; Asteraceae) were chemically investigated for their active constituents. Chromatographic fractions of root extracts of l. helenium, which exhibited significant activity against Mycobacterium tuberculosis, provided the known eudesmanolides alantolactone, isoalantolactone, and 11 alpha H, 13-dihydroisoalantolactone. Peracid epoxidation of alantolactone and isoalantolactone provided 5 alpha-epoxyalantolactone and 4(15) alpha-epoxyisoalantolactone, respectively and oxidation of alantolactone with OsO4 gave 11,13-dihydroxyalantolactone. Active fractions from R subtomentosa contained the known alloalantolactone and 3-oxoalloalantolactone. The structures of the above compounds were established by spectroscopic methods including 1D and 2D NMR techniques as well as spectral comparison with previously reported data. The molecular structure of 5 alpha-epoxyalantolactone was determined by single crystal X-ray diffraction. Eleven natural and semisynthetic eudesmanolides were tested in a radiorespirometric bioassay for activity against M. tuberculosis. 5 alpha-Epoxyalantolactone and encelin from Montanoa speciosa showed minimum inhibitory concentrations (MICs) of 8 and 16 micrograms ml-1, respectively. Alantolactone, isoalantolactone and its 4 alpha, 15-epoxide, 1,2-dehydro-3-epi-isotelekin and alloalantolactone gave MICs of 32 micrograms ml-1. All other compounds showed MIC values of 128 micrograms ml-1 or higher.
- Published
- 1999
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27. Antimycobacterial triterpenes from Melia volkensii.
- Author
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Cantrell CL, Rajab MS, Franzblau SG, and Fischer NH
- Subjects
- Antitubercular Agents isolation & purification, Chromatography, High Pressure Liquid, Kenya, Lactones isolation & purification, Magnetic Resonance Spectroscopy, Mass Spectrometry, Methanol, Mycobacterium tuberculosis metabolism, Oxygen metabolism, Seeds chemistry, Spectrophotometry, Ultraviolet, Antitubercular Agents pharmacology, Lactones pharmacology, Mycobacterium tuberculosis drug effects, Plants, Medicinal chemistry
- Abstract
In a bioassay-guided search for antimycobacterial compounds from higher plants, we have chemically investigated methanolic extracts of seeds of Melia volkensii. Chromatographic fractions provided two new euphane (20R)-type triterpenoids. The structures of the new compounds, 12beta-hydroxykulactone (1) and 6beta-hydroxykulactone (2), were elucidated by 1D and 2D NMR (13C, 1H, 1H-1H COSY, HMQC, HMBC, and NOESY spectra) and FABMS studies and shown to be hydroxyl derivatives of kulactone (3). Also isolated was the known kulonate (4). In a radiorespirometric bioassay against Mycobacterium tuberculosis, compounds 1, 2, and 4 exhibited minimum inhibitory concentrations of 16, 4, and 16 microg/mL, respectively.
- Published
- 1999
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28. Antimycobacterial matricaria esters and lactones from Astereae species.
- Author
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Lu T, Cantrell CL, Robbs SL, Franzblau SG, and Fischer NH
- Subjects
- Antitubercular Agents chemistry, Antitubercular Agents pharmacology, Esters, Lactones, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Molecular Structure, Antitubercular Agents isolation & purification, Asteraceae chemistry, Mycobacterium avium Complex drug effects, Mycobacterium tuberculosis drug effects
- Abstract
Six matricaria esters (MEs) and two matricaria lactones (MLs), isolated from members of the tribe Astereae (Asteraceae), were tested against Mycobacterium tuberculosis and M. avium, using a radiorespirometric bioassay. (2Z,8Z)-ME and (2E-8Z)-ME gave minimum inhibitory concentrations (MICs) of 50 micrograms ml-1 against M. tuberculosis and respective MICs of 25 and 50 micrograms ml-1 against M. avium. The (4Z,8Z)-ML, (2Z)-8-dehydro-ME and (2Z,8Z)-10-angeloyloxy-(2Z,8Z)-ME showed respective MICs of 12.5, 25, 25 micrograms ml-1 against M. tuberculosis and MICs of 50, 25, 25 micrograms ml-1 against M. avium, respectively. The MICs of (2Z,8Z)-10-tigloyloxy-ME and (2E,8Z)-10-angeloyloxy-ME and (4E,8Z)-ML ranged from 50 to > 100 micrograms ml-1 against both pathogenic mycobacteria.
- Published
- 1998
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29. Antimycobacterial activities of dehydrocostus lactone and its oxidation products.
- Author
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Cantrell CL, Nuñez IS, Castañeda-Acosta J, Foroozesh M, Fronczek FR, Fischer NH, and Franzblau SG
- Subjects
- Antitubercular Agents metabolism, Asteraceae chemistry, Lactones metabolism, Microbial Sensitivity Tests, Mycobacterium avium drug effects, Mycobacterium tuberculosis drug effects, Oxidation-Reduction, Sesquiterpenes metabolism, Structure-Activity Relationship, Antitubercular Agents pharmacology, Lactones pharmacology, Mycobacterium drug effects, Sesquiterpenes pharmacology
- Abstract
In an attempt to study the structural dependence of antimycobacterial activity of the guaianolide dehydrocostus lactone and its derivatives, m-chloroperoxybenzoic acid oxidations of dehydrocostus lactone (1a) were performed. Three new monoepoxides, one previously synthesized diepoxide, and two new diepoxides were obtained. Two of the monoepoxides are C-10 epimers (3a, 3b), while the 4(15)-monoepoxide (2) has the 4alpha-O-configuration. The known diepoxide (4a) contains a C-10 alpha-epoxide and a beta-epoxide at C-4. The diepoxides 4b and 4c, each with a C-4 alpha-epoxy group, differ in the configuration of the epoxide ring at C-10. Allylic oxidation of dehydrocostus lactone (1a) with selenium dioxide/tert-butyl hydroperoxide afforded the known 3-epizaluzanin C (1b). The relative configurations of compounds 1b-4c were established by 1D and 2D NMR techniques (1H, 13C, COSY, NOESY, HMQC, and HMBC) as well as comparison with literature data. The molecular structures of lactones 1b, 4a, and 4c were determined by single-crystal X-ray diffraction. In radiorespirometric bioassays against Mycobacterium tuberculosis and Mycobacterium avium, dehydrocostus lactone (1a) exhibited minimum inhibitory concentrations of 2 and 16 microgram/mL, respectively. In contrast, its monoepoxides (2, 3a, and 3b) and diepoxides (4a-c), as well as its hydrogenated derivatives and other analogues (1b, 1c, 5, and 6), showed significantly lower activities against M. tuberculosis.
- Published
- 1998
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30. Antimycobacterial evaluation of germacranolides.
- Author
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Fischer NH, Lu T, Cantrell CL, Castañeda-Acosta J, Quijano L, and Franzblau SG
- Subjects
- Microbial Sensitivity Tests, Anti-Bacterial Agents pharmacology, Mycobacterium avium drug effects, Mycobacterium tuberculosis drug effects, Sesquiterpenes pharmacology
- Abstract
The minimum inhibitory concentrations (MIC) against Mycobacterium tuberculosis and M. avium of parthenolide, costunolide, 1 (10)-epoxycostunolide and other germacranolide-type sesquiterpene lactones and derivatives were determined by use of a radiorespirometric bioassay. Structure-activity relationship studies with natural and semisynthetic sesquiterpene lactones suggested that the alpha-methylene-gamma-lactone moiety is an essential, but not sufficient, structural requirement for significant in vitro activity against M. tuberculosis and M. avium.
- Published
- 1998
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31. Antimycobacterial crude plant extracts from South, Central, and North America.
- Author
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Cantrell CL, Fischer NH, Urbatsch L, McGuire MS, and Franzblau SG
- Abstract
Two-hundred and thirty crude organic extracts from 118 plant species distributed among 10 families were evaluated for anti-mycobacterial activity. Activity was determined against Mycobacterium tuberculosis H(37)Rv and Mycobacterium avium using the BACTEC 460 radiorespirometric assay. At 100 μg/ml, twenty-four and ten of the extracts caused more than 95% inhibition of growth of M. tuberculosis and M. avium, respectively. The most active plant species (100% inhibition) were Borrichia frutescens, Solidago arguta, and Inula helenium against M. tuberculosis, Euthamia leptocephala against M. avium, and Erigeron strigosus and Magnolia acuminata against both mycobacteria., (Copyright © 1998 Gustav Fischer Verlag. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 1998
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32. New Sesquiterpene Lactones from Illicium floridanum
- Author
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Schmidt TJ, Schmidt HM, Müller E, Peters W, Fronczek FR, Truesdale A, and Fischer NH
- Abstract
In continuation of our phytochemical investigation of Illicium floridanum Ellis (American star anise, star bush), three new sesquiterpene lactones possessing the anisatin-type carbon skeleton (8,9-seco-prezizaane skeleton), 14-acetoxy-3-oxofloridanolide (1), 13-acetoxy-14-(n-butyryloxy)floridanolide (2), and 3beta-acetoxy-14-n-butyryloxy-10-deoxyfloridanolide (3), were isolated from fruits of this plant. Their structures were elucidated by 1D and 2D NMR measurements. The molecular structure of 1 was obtained by single crystal X-ray diffraction. The 11,3-delta-lactone structure of the compound previously described as debenzoyldunnianin in our previous communication, on grounds of NMR spectral evidence and X-ray crystallographic analysis is revised to a delta-lactone closed between C-11 and C-7 (compound 4). The neurotoxic sesquiterpene lactone anisatin (5) and its isomer 2alpha-hydroxyneoanisatin (3-deoxy-2alpha-hydroxyanisatin, 6) were also isolated and identified by spectroscopic means. The presence of the neurotoxin 5 in relatively high amounts in the fruits and leaves confirms and explains early reports on the toxicity of this plant.
- Published
- 1998
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33. Antimycobacterial activity of (E)-phytol and derivatives: a preliminary structure-activity study.
- Author
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Rajab MS, Cantrell CL, Franzblau SG, and Fischer NH
- Subjects
- Antitubercular Agents chemistry, Antitubercular Agents isolation & purification, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Mycobacterium tuberculosis drug effects, Phytol chemistry, Phytol isolation & purification, Plants, Medicinal chemistry, Structure-Activity Relationship, Antitubercular Agents pharmacology, Phytol pharmacology
- Abstract
The crude methanol extract of the Kenyan shrub Leucas volkensii Gürke (Labiatae) displayed in a radiorespirometric bioassay antimycobacterial activity against Mycobacterium tuberculosis. Bioassay-guided fractionation of the crude extract led to the identification of (E)-phytol as the principal active component with a minimum inhibitory concentration (MIC) of 2 micrograms/ml, a value also observed for (3R,S,7R,11R)-phytanol, (Z)-phytol, and a commercially available 2:1 mixture of (E)- and (Z)-phytol. The derivatives (E)-phytol acetate, a mixture of the (2S,3S)- and (2R,3R)-isomers of (E)-phytol epoxide and (3R,S,7R,11R)-phytanic acid displayed lower activities with MICs of 8, 16, and > 128 micrograms/ml, respectively. Geraniol and farnesol, displayed MICs of 64 and 8 micrograms/ml, respectively. The activities of (E)-phytol, (Z)-phytol and (3R,S,7R,11R)-phytanol were found to be in the same range as ethambutol, a clinically useful drug with an MIC in the range 0.95-3.8 micrograms/ml.
- Published
- 1998
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34. Antimycobacterial cycloartanes from Borrichia frutescens.
- Author
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Cantrell CL, Lu T, Fronczek FR, Fischer NH, Adams LB, and Franzblau SG
- Subjects
- Acetylation, Animals, Antineoplastic Agents, Phytogenic pharmacology, Chlorocebus aethiops, Crystallography, X-Ray, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Plant Leaves chemistry, Plant Stems chemistry, Spectrophotometry, Infrared, Triterpenes isolation & purification, Vero Cells, Antitubercular Agents isolation & purification, Antitubercular Agents pharmacology, Mycobacterium drug effects, Plants chemistry, Triterpenes pharmacology
- Abstract
In a bioassay-guided search for antimycobacterial compounds from higher plants of the southeastern United States, we have chemically investigated the sea daisy (Borrichia frutescens) from coastal marshes of Louisiana for their active constituents. Bioactive chromatographic fractions provided two new triterpenes, (24R)-24,25-epoxycycloartan-3-one (1) and (23R)-3-oxolanosta-8,24-dien-23-ol (4), and (3 alpha H, 24R)-24,25-epoxycycloartan-3-ol (3a). Compound 3a had been previously isolated as a mixture of C-24 epimers. The structures of 1, 3a, and 4 were established by spectroscopic methods and chemical transformations, and the molecular structures of 1 and 4 were determined by single-crystal X-ray diffraction. In a radiorespirometric bioassay against Mycobacterium tuberculosis, the epoxycycloartanes 1 and 3a exhibited minimum inhibitory concentrations of 8 micrograms/mL. In contrast, the lanostadiene-type triterpene 4 showed no significant inhibition at 128 micrograms/mL, as did the acetate 3b. Cytotoxicity for Vero cells gave IC50 values of 71.8, 39.8, and 103.6 micrograms/mL for triterpenes 1, 3a, and 4, respectively.
- Published
- 1996
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35. Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases.
- Author
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Hwang D, Fischer NH, Jang BC, Tak H, Kim JK, and Lee W
- Subjects
- Animals, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Cell Line, Cyclooxygenase 2, Enzyme Induction, Enzyme Inhibitors pharmacology, Interleukin-1 biosynthesis, JNK Mitogen-Activated Protein Kinases, Lipopolysaccharides pharmacology, Macrophages, Macrophages, Alveolar drug effects, Male, Mice, Molecular Structure, Plants, Medicinal, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Tumor Necrosis Factor-alpha biosynthesis, Calcium-Calmodulin-Dependent Protein Kinases antagonists & inhibitors, Cytokines biosynthesis, Gene Expression drug effects, Isoenzymes biosynthesis, Macrophages, Alveolar enzymology, Macrophages, Alveolar immunology, Mitogen-Activated Protein Kinases, Prostaglandin-Endoperoxide Synthases biosynthesis, Sesquiterpenes pharmacology
- Abstract
In our previous studies (Refs. 1 and 2), it was shown that protein tyrosine kinase (PTK) inhibitors, radicicol and herbimycin A, inhibit the expression of the mitogen-inducible cyclooxygenase (COX-2) and proinflammatory cytokines. Radicicol and herbimycin A possess polarized double bonds which can conjugate sulphydryl groups of proteins. Parthenolide, the predominant sesquiterpene lactone in European feverfew (Tanacetum parthenium), contains alpha-methylene-gamma-lactone (MGL) and an epoxide in its structure. These moieties can interact with biological nucleophiles such as a sulfhydryl group. Parthenolide inhibited the expression of COX-2 and proinflammatory cytokines (TNF alpha and IL-1) in lipopolysaccharide (LPS)-stimulated macrophages. The structure-function relationship indicates that the MGL moiety confers the inhibitory effect. Parthenolide suppressed LPS-stimulated protein tyrosine phosphorylation in the murine macrophage cell line (RAW 264.7). This suppression was correlated with its inhibitory effect on the expression of COX-2 and the cytokines. Among tyrosine phosphorylated proteins, mitogen-activated protein kinases (MAPKs) exhibited the most dramatic inhibition.
- Published
- 1996
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36. Diterpenes from Solidago rugosa.
- Author
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Lu T, Vargas D, Franzblau SG, and Fischer NH
- Subjects
- Diterpenes chemistry, Magnetic Resonance Spectroscopy, Molecular Structure, Spectrometry, Mass, Fast Atom Bombardment, Spectrophotometry, Infrared, Diterpenes isolation & purification, Plants chemistry
- Abstract
Investigation of the roots and aerial parts of Solidago rugosa afforded the known diterpenes kolavenol, hardwickiic acid, (-)-kaur-16-en-19-oic acid, (+)-manool, (+)-3 beta-hydroxymanool, manoyl oxide and ent-abietic acid. In addition, the new labdane diterpene (+)-18-tigloyloxymanool and four new ent-abietanes were obtained. The structures of all known and new compounds were elucidated by spectroscopic methods, especially high-field 1H and 13C NMR, and inverse 1H-13C-correlation techniques, as well as chemical transformations. Six diterpenes were tested against Mycobacterium tuberculosis and M. avium, but showed no significant activities with minimum inhibitory concentrations of > 100 micrograms ml-1.
- Published
- 1995
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37. Allelopathic potential of menthofuran monoterpenes fromCalamintha ashei.
- Author
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Weidenhamer JD, Menelaou M, Macias FA, Fischer NH, Richardson DR, and Bruce Williamson G
- Abstract
A reversed-phase HPLC analysis was used to separate and quantify five menthofuran monoterpenes inCalamintha ashei leaf soaks and washes. (+)-Evodone and desacetylcalaminthone were the major constituents of both soaks and washes. Concentrations of (+)-evodone and desacetylcalaminthone were as high as 0.66 and 0.74 mM, respectively, in leaf soaks. The highest concentration of monoterpenes in leaf washes obtained by misting was 0.021 mM. Aqueous solubilities of the menthofurans were determined to exceed concentrations required for growth inhibition. Bioassays of individualCalamintha monoterpenes demonstrated effects on germination as low as 0.05 mM for (+)-evodone. An equimolar mixture of desacetylcalaminthone and (+)-evodone reducedRudbeckia hirta germination by 17% at a combined concentration of 0.025 mM forLeptochloa dubia. Confirmation of allelopathic effects byCalamintha ashei will require long-term bioassays ofCalamintha menthofurans on the growth of native sandhill species under conditions comparable to the harsh environment of the Florida scrub.
- Published
- 1994
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38. In search of allelopathy in the Florida scrub: The role of terpenoids.
- Author
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Fischer NH, Williamson GB, Weidenhamer JD, and Richardson DR
- Abstract
The hypothesis was tested that allelopathic agents released from fire-sensitive plants of the Florida scrub community deter the invasion of fireprone sandhill grasses. The structures of the constituents of four endemic scrub species,Conradina canescens, Calamintha ashei, Chrysoma pauciflosculosa, andCeratiola ericiodes, were established and their phytotoxic activity against two grasses of the sandhill was examined. Effects of the secondary metabolites from the above scrub species and their degradation products upon the germination and radicle growth of little bluestem (Schizachyrium scoparium) and green sprangletop (Leptochloa dubia), two native grasses of the Florida sandhill community, were determined. The studies included determination of the water solubility and release mechanism of terpenes and other allelopathic agents from the source plants and their aqueous transport to the target species. Some of the natural products were nontoxic until activated by light and/or oxidation after release from the source plant into the environment.
- Published
- 1994
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39. Just how insoluble are monoterpenes?
- Author
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Weidenhamer JD, Macias FA, Fischer NH, and Williamson GB
- Abstract
Prior generalizations about the ecological roles of monoterpenes may be misleading if based on the presumed insolubility of monoterpenes in water. We determined the aqueous solubility of 31 biologically active monoterpenes by gas chromatography. While hydrocarbons were of low solubility (< 35 ppm), oxygenated monoterpenes exhibited solubilities one or two orders of magnitude higher, with ranges of 155-6990 ppm for ketones and of 183-1360 ppm for alcohols. Many monoterpenes are phytotoxic in concentrations under 100 ppm, well below the saturated aqueous concentrations of oxygenated monoterpenes. Therefore, even dilute, unsaturated solutions of monoterpenes, occurring naturally in plant tissues and soil solutions, may act as potent biological inhibitors.
- Published
- 1993
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40. Biomimetic transformations of parthenolide.
- Author
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Castañeda-Acosta J, Fischer NH, and Vargas D
- Subjects
- Cyclization, Magnetic Resonance Spectroscopy, Sesquiterpenes, Structure-Activity Relationship, Sesquiterpenes, Guaiane chemistry
- Abstract
An investigation of BF3-mediated rearrangements of parthenolide [1] provided micheliolide [5] as a major product. Minor reaction products included 10 (14)-dehydro-5 alpha-hydroxy-trans-guaianolide [2], 9,10-dehydro-5 alpha-hydroxy-trans-guaianolide [3], the xanthanolide 2-desoxy-6-epi-parthemollin [4], 1,2-dehydro-4 alpha-hydroxyguaianolide [6], 11,13-dehydrocompressanolide [7], and bicyclo[6.2.0]dec-10(14)-en-12,6-olide [8]. Their mechanisms of formation were interpreted as rearrangements involving carbocation intermediates.
- Published
- 1993
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41. A bioassay for inhibition of serotonin release from bovine platelets.
- Author
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Marles RJ, Kaminski J, Arnason JT, Pazos-Sanou L, Heptinstall S, Fischer NH, Crompton CW, Kindack DG, and Awang DV
- Subjects
- Animals, Biological Assay, Blood Platelets drug effects, Cattle, Chromatography, High Pressure Liquid, In Vitro Techniques, Plants, Medicinal chemistry, Structure-Activity Relationship, Blood Platelets metabolism, Plant Extracts pharmacology, Serotonin blood
- Abstract
A bioassay was developed to study agents capable of inhibiting the release of serotonin from bovine blood platelets. It is a simple, inexpensive, and reproducible high-throughput bioassay suitable for quality control of feverfew, Tanacetum parthenium, a crude drug with proven migraine prophylactic activity that is being considered for governmental registration and regulation. The bioassay, which requires no experimental animals or human subjects, was used to assess the in vitro activity of T. parthenium samples grown from seed obtained from 10 different regions of Europe. The activity was found to vary significantly within and between samples, with no geographical correlation. Serotonin release inhibition was shown to be significantly correlated with the content of the germacranolide sesquiterpene lactone, parthenolide, although other sesquiterpene lactones from this plant and other members of the Asteraceae were also shown to be active. The activities of six other species of Tanacetum, as well as of Artemisia absinthium (wormwood) and Zingiber officinale (ginger), and two commercial drugs for migraine prophylaxis, verapamil hydrochloride and propranolol hydrochloride, were also assessed. The relevance of the bovine platelet serotonin release inhibition bioassay to antimigraine research is discussed.
- Published
- 1992
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42. Chemical inhibition of fire-prone grasses by fire-sensitive shrub,Conradina canescens.
- Author
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Williamson GB, Fischer NH, Richardson DR, and de la Peña A
- Abstract
In an investigation of potential chemical activity of fire-sensitive shrubs in Florida's sand pine scrub community, bioassays of foliar washes ofConradina canescens showed significant inhibitory activity on three native grasses that are known to fuel frequent surface fires; inhibition was concentrated seasonally in spring and summer. Application of runoff fromConradina leaves to one of the grasses caused a 50% reduction in growth over a 20-week period. Isolation of the biologically active fractions from the fresh leaves ofC. canescens yielded numerous monoterpenes, a number of which were identified from a GC-MS reference library and/or MS comparison to authentic compounds: 11 from the diethyl ether extract, 11 from steam distillation, and four from the foliar leaf wash. Numerous other monoterpenes present in the extractions were unknown. The terpenoid fraction completely inhibited seed germination of one of the native grasses and of lettuce. Saturated aqueous solutions of nine of the monoterpenes inhibited germination and radicle growth of two native grasses. SEM views of the leaf surfaces ofConradina reveal secretory trichomes that appear to be the source of the monoterpenes as well as the triterpene, ursolic acid. The biological activity ofC. canescens as a fire-sensitive component of the scrub community is reviewed in light of the chemical evidence.
- Published
- 1989
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43. Inhibition and promotion of germination by several sesquiterpenes.
- Author
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Fischer NH, Weidenhamer JD, and Bradow JM
- Abstract
The sesquiterpene lactones, burrodin, confertiflorin. desacetyl-confertiflorin, dihydroparthenolide, parthenin, and 7α-hydroxy-3-desoxyzaluzanin C, and the sesquiterpene ester guayulin A were assayed at concentrations of 1, 10, and 100 μM for effects on seed germination of 16 dicot and nine monocot species. Six of the dicot and two of the monocot species were affected by one or more of these compounds. Germination was both inhibited and promoted, depending on the compound and the specific species or cultivars, at concentrations as low as 1 μM. For example, guayulin A, which promoted the germination of lettuce at all concentrations tested, inhibited the germination of tomato. Confertiflorin stimulated germination of the lettuce cultivar Grand Rapids at 1 μM, but inhibited germination of a light-sensitive cultivar at all concentrations tested.
- Published
- 1989
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44. Neutron diffraction structure of melampodin: its role in the reclassification of the germacranolides.
- Author
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Watkins SF, Fischer NH, and Bernal I
- Abstract
The precise crystal and molecular structure of melampodin, C(21)H(24)O(9), was determined from three-dimensional neutron diffraction data collected by counter techniques and phases by direct statistical methods. Crystals are orthorhombic, P2(1)2(1)2(1), a = 8,990(9), b = 14.352(14), c = 16.294(16) A, V = 2102 A(3), d(calc.) = 1.328 g.cm(-3), Z = 4 molecules per unit cell. The structural model was refined by full matrix least-squares of 2303 observed independent reflections, with all 54 atoms treated anisotropically, to R(F) = 5.0%. Hydrogen bonds link melampodin molecules together in the solid state. The conformation of the cyclodeca-1,5-diene ring is such that one intraannular hydrogen atom interacts strongly with one double bond, but there is little or no transannular interaction between double bonds. Strain in the ten-membered ring and in the trans-fused lactone ring is discussed, as are chemical implications of the unsymmetric epoxide in the epoxyangelic acid side chain. The previously suggested reclassification of germacranolide sesquiterpene lactones into four subgroups is supported, and a new convention for configurational representations of the four subgroups is proposed.
- Published
- 1973
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