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  • 201.
    Lindholm, Petra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Johansson, Senia
    Claeson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Cyclotides: a novel type of cytotoxic agents2002Ingår i: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 1, nr 6, s. 365-369Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytotoxic activities of three naturally occurring macrocyclic peptides (cyclotides) isolated from the two violets, Viola arvensis Murr. and Viola odorata L., were investigated. A nonclonogenic fluorometric microculture assay was used to examine cytotoxicity in a panel of 10 human tumor cell lines representing defined types of cytotoxic drug resistance. Additionally, primary cultures of tumor cells from patients, and for comparison normal lymphocytes, were used to quantify cytotoxic activity. All three cyclotides, varv A, varv F, and cycloviolacin O2, exhibited strong cytotoxic activities, which varied in a dose-dependent manner. Cycloviolacin O2 was the most potent in all cell lines (IC50 0.1– 0.3 _M), followed by varv A (IC50 2.7–6.35 _M) and varv F (IC50 2.6 –7.4 _M), respectively. Activity profiles of the cyclotides differed significantly from those of antitumor drugs in clinical use, which may indicate a new mode of action. This, together with the exceptional chemical and biological stability of cyclotides, makes them interesting in particular for their potential as pharmacological tools and possibly as leads to antitumor agents.

  • 202.
    Lindholm, Petra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Larsson, Sonny
    Gupta, Mahabir
    Larsson, Rolf
    Backlund, Anders
    Cytotoxicity of small peptides of misletoes in the familiy Loranthaceae, SantalalesManuskript (Övrigt vetenskapligt)
  • 203.
    Liu, B
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Diaz, F
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Vasange, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Quantitative determination of antiinflammatory principles in some Polypodium species as a basis for standardization1998Ingår i: Phytomedicine, ISSN 0944-7113, E-ISSN 1618-095X, Vol. 5, nr 3, s. 187-194Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently, several, compounds including polyunsaturated fatty acids (linoleic, linolenic, arachidonic), the triflavonoid selligueain and a sulfonoglycolipid (SQDG) have been isolated from the South American fern, Polypodium decumanum using bioactivity directed fractionation. The present study describes the quantitative analysis using HPLC methods of these three classes of compounds in the leaves and rhizomes of the five Polypodium species. Furthermore, extracts of the five ferns are studied in three in vitro bioassays using platelet activating factor (PAF) and leukotriene B-4 (LTB4). The models are the same that previously have led to the isolation of the active principles in Polypodium decumanum. The objective of this study was to investigate if the identified active compounds could be used for standardization of the extracts. Since the SQDG was found to be present in pharmacologically detectable amounts in the crude extracts and since it presents a specific mode of action it is recommended that quantitative analysis of this constituent should be used for future standardization of the extracts.

  • 204. Luo, Cheng
    et al.
    He, Ming-liang
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Is COX-2 a perpetrator or a protector? Selective COX-2 inhibitors remain controversial2005Ingår i: Acta Pharmacologica Sinica, ISSN 1671-4083, E-ISSN 1745-7254, Vol. 26, nr 8, s. 926-933Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    COX-2(cyclooxygenase-2) has sparked a surge in pharmaceutical interest since its discovery at the beginning of the 1990s. Several COX-2 selective inhibitors that avoid gastrointestinal side effects have been successfully launched into the market in recent years. The first selective COX-2 inhibitor, celecoxib, entered the market in December 1998 [corrected] However, there are a few organs that physiologically and functionally express COX-2, particularly the glomeruli of the kidney and the cortex of the brain. Inhibition of COX-2 expression in these organs possibly causes heart attack and stroke in long-term COX-2 inhibitor users. Recently, a USA Food and Drug Agency (FDA) advisory panel re-evaluated COX-2 inhibitors and unanimously concluded that the entire class of COX-2 inhibitors increase the risk of cardiovascular problems. Thus the use of COX-2 inhibitors is still controversial, and there is a challenge for not only pharmacologists, but also the pharmaceutical industry, to develop improved painkilling and anti-inflammatory drugs. This may involve exploring a new generation of COX-2 inhibitors with different inhibitory mechanisms through computer-aided design, screening different sources of inhibitors with lower selectivity, or seeking completely new targets. Synthetic COX-2 inhibitors have high selectivity and the advantage of irreversible inhibition, whereas naturally derived COX-2 inhibitors have lower selectivity and fewer side effects, with the medical effects in general not being as striking as those achieved using synthetic inhibitors. This review discusses the mechanism of COX-2 inhibitor therapy and a possible new way of exploration in the development of anti-inflammatory, analgetic, and antipyretic drugs.

  • 205.
    Luo, Cheng
    et al.
    Zhejiang Ocean Univ, Sch Food & Pharm, 1 Ocean Univ S Rd, Zhoushan 316022, Zhejiang, Peoples R China..
    Wang, Xin
    Zhejiang Ocean Univ, Sch Food & Pharm, 1 Ocean Univ S Rd, Zhoushan 316022, Zhejiang, Peoples R China..
    An, Can
    Zhejiang Ocean Univ, Sch Food & Pharm, 1 Ocean Univ S Rd, Zhoushan 316022, Zhejiang, Peoples R China..
    Hwang, Chin-Fa
    Hung Kuang Univ, Dept Food Sci & Technol, Taichung 43302, Taiwan..
    Miao, Wenhua
    Zhejiang Ocean Univ, Sch Food & Pharm, 1 Ocean Univ S Rd, Zhoushan 316022, Zhejiang, Peoples R China..
    Yang, Lu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Xu, Maonian
    Univ Helsinki, Div Food Chem, Dept Food & Environm Sci, F-00014 Helsinki, Finland..
    Bai, Aiping
    Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA..
    Deng, Shanggui
    Zhejiang Ocean Univ, Sch Food & Pharm, 1 Ocean Univ S Rd, Zhoushan 316022, Zhejiang, Peoples R China..
    Molecular inhibition mechanisms of cell migration and invasion by coix polysaccharides in A549 NSCLC cells via targeting S100A42017Ingår i: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 15, nr 1, s. 309-316Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    S100 calcium binding protein A4 (S100A4) promotes extracellular signal transduction, intercellular adhesion, motility and mobility. Different extracts from Coix lachryma-jobi have been used for the treatment of various types of cancer in Asia. In our previous study, the polysaccharide fraction extact, CP1, induced cell apoptosis of non-small cell lung cancer cells. In the current study, CP1 inhibited migration and invasion of A549 cells in a scratch wound healing assay and matrigel invasion assay, respectively. Furthermore, reverse transcription-polymerase chain reaction and western blotting demonstrated that CP1 downregulated the gene and protein expression levels of SI00A4. In silico docking analysis demonstrated that polysaccharides may not interfere with dimerization, whereas, the affinity of polysaccharides for an S100A4-NMIIA pocket was margnially greater than at the dimerization sites. Thus, CP1 inhibited A549 cell migration and invasion potentially via downregulation of S100A4, and may also interact with the binding site of S100A4-NMIIA, which indicated that CP1 has potential as an alternative cancer chemotherapeutic by targeting S100A4.

  • 206.
    Malik, Sohaib Zafar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Interaction of cyclotides and bacteria: A study of the cyclotide action and the bacterial reaction2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The growing problem of antibiotic resistance and the lack of promising prospective antibiotics have forced us to search for new classes of antibiotics. Among the candidates to develop into future antibacterials are antimicrobial peptides (AMPs). These

    potent, broad spectrum compounds are important components of innate immunity of organism from all kingdoms of life. One such family of mini-proteins from plants is called cyclotides, whose members are defines by cyclic backbone and a cystine knot (CCK), which confers to them extreme stability in the face of biological, chemical and physical insults.

        Some cyclotides possess Gram-negative specific antibacterial activity; the purpose of this thesis was to characterize how these molecules kill bacteria, and how bacteria would respond to treatment with cyclotides. For this purpose, Salmonella enterica and Escherichia coli mutants resistant to the cyclotides cycloviolacin O2 and cycloviolacin O19, respectively, were selected. These mutants were characterized by whole genome sequencing, genetic reconstitution, fitness measurements, and cross-resistance studies. These studies identified a number of genetic pathways for resistance development to cyclotides. These mutants displayed variable fitness profiles in laboratory growth media and in mice competition experiments, with some mutants possessing a fitness advantage in mice. Cross-resistance studies resulted in the identification of several cases of cross-resistance and collateral sensitivity between cyclotides and other AMPs/antibiotics.

         Antimicrobial effects of cyclotides were assayed in different conditions and in bacterial organisms with different surface characteristics. In addition, immunolocalization experiments were performed to explore the biological distribution of cyclotides in plants and to determine the mechanism of action of cyclotides in bacteria, respectively. Antibodies raised against cyO2 were used for this purpose. Immunohistochemical techniques applied to plant cells, tissues and organs provided the information that cyclotides were distributed in all plant organs, and were found in tissues vulnerable to pathogen attack, and that cyclotides were stored in the vacuoles of plant cells. Immunogold staining of cyclotide treated cells of S. typhimurium, showed effects of cyclotide treatment on the cell envelope components as well as cytoplasm. A higher number of cyclotide molecules was associated with the cell envelope, but a considerable fraction of them penetrated into the cytoplasm.

    Delarbeten
    1. Immunolocalization of cyclotides in plant cells, tissues and organ supports their role in host defense
    Öppna denna publikation i ny flik eller fönster >>Immunolocalization of cyclotides in plant cells, tissues and organ supports their role in host defense
    Visa övriga...
    2016 (Engelska)Ingår i: Planta, ISSN 0032-0935, E-ISSN 1432-2048, Vol. 244, nr 5, s. 1029-1040Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Main conclusionThe distribution of cyclotides was visualized in plant cells, tissues and organs using immunohistochemistry. Finding of cyclotides in tissues potentially vulnerable to pathogen attacks supports their role as defense molecules. The cyclotide family of plant peptides is characterized by the cyclic cystine knot motif and its diverse biological activities. Given their insecticidal and antimicrobial properties, the role of cyclotides in planta is probably associated with host defense. Our current understanding of the cellular compartmentalization of cyclotides in the vacuole is based on indirect studies on transgenic model plants that do not express cyclotides naturally. Matrix-assisted laser desorption ionization (MALDI) imaging has also been used to study the distribution of cyclotides, but the technique's resolution was insufficient to determine their tissue or cell distribution. To avoid the limitations of these approaches, immunohistochemical visualization methods were used. Antibodies were raised in rabbits using cycloviolacin O2 (cyO2), and their specificity was determined by Western and dot blot experiments. Slides for immunohistochemical analysis were prepared from leaf, petiole and root fragments of Viola odorata and Viola uliginosa, and specimens were visualized using indirect epifluorescence microscopy. The antibodies against cyclotides were specific against selected bracelet cyclotides with high similarity (cyO2, cyO3, cyO8, cyO13) and suitable for immunohistochemistry. The tissue distribution of the cyclotides visualized in this way is consistent with their proposed role in host defense-relatively large quantities were observed in the leaf and petiole epidermis in both Viola species. Cyclotides were also found in vascular tissue in all the assessed plant organs. The vacuole storage of cyclotides was directly shown.

    Nyckelord
    Cyclotides, Immunohistochemistry, Host defense peptides, Viola
    Nationell ämneskategori
    Läkemedelskemi Botanik
    Identifikatorer
    urn:nbn:se:uu:diva-307522 (URN)10.1007/s00425-016-2562-y (DOI)000385251200004 ()27394154 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 621-2007-5167Stiftelsen för strategisk forskning (SSF), F06-0058
    Tillgänglig från: 2016-11-17 Skapad: 2016-11-17 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    2. Resistance to the cyclotide cycloviolacin O2 in Salmonella enterica caused by different mutations that often confer cross-resistance or collateral sensitivity to other antimicrobial peptides
    Öppna denna publikation i ny flik eller fönster >>Resistance to the cyclotide cycloviolacin O2 in Salmonella enterica caused by different mutations that often confer cross-resistance or collateral sensitivity to other antimicrobial peptides
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-318016 (URN)
    Tillgänglig från: 2017-03-24 Skapad: 2017-03-24 Senast uppdaterad: 2017-04-13
    3. Mutations in osmosensitive proteins of Escherichia coli confer resistance to cyclotides
    Öppna denna publikation i ny flik eller fönster >>Mutations in osmosensitive proteins of Escherichia coli confer resistance to cyclotides
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-318022 (URN)
    Tillgänglig från: 2017-03-24 Skapad: 2017-03-24 Senast uppdaterad: 2017-04-13
    4. Morphological changes in Salmonella enterica induced by the cyclotide cycloviolacin O2
    Öppna denna publikation i ny flik eller fönster >>Morphological changes in Salmonella enterica induced by the cyclotide cycloviolacin O2
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-318024 (URN)
    Tillgänglig från: 2017-03-24 Skapad: 2017-03-24 Senast uppdaterad: 2017-04-13
    5. An insight into the antimicrobial activity of the cycloviolacin cyclotides
    Öppna denna publikation i ny flik eller fönster >>An insight into the antimicrobial activity of the cycloviolacin cyclotides
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-318026 (URN)
    Tillgänglig från: 2017-03-24 Skapad: 2017-03-24 Senast uppdaterad: 2017-04-13
  • 207.
    Malik, Sohaib Zafar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Andersson, Dan I.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Characterization of Resitant Mutants Points Towards Mechanism of Action of Cyclotides2014Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 20, s. S108-S109Artikel i tidskrift (Övrigt vetenskapligt)
  • 208.
    Malik, Sohaib Zafar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Andersson, Dan I
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Bacterial Resistance To A Cyclic Antimicrobial Peptide2016Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 22, nr S2, s. S180-S180Artikel i tidskrift (Övrigt vetenskapligt)
  • 209.
    Malik, Sohaib Zafar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Linkevicius, Marius
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Andersson, Dan I
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Resistance to the Cyclotide Cycloviolacin O2 in Salmonella enterica Caused by Different Mutations That Often Confer Cross-Resistance or Collateral Sensitivity to Other Antimicrobial Peptides2017Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, nr 8, artikel-id e00684-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antimicrobial peptides (AMPs) are essential components of innate immunity in all living organisms, and these potent broad-spectrum antimicrobials have inspired several antibacterial development programs in the past 2 decades. In this study, the development of resistance to the Gram-negative bacterium-specific peptide cycloviolacin O2 (cyO2), a member of the cyclotide family of plant miniproteins, was characterized in Salmonella enterica serovar Typhimurium LT2. Mutants isolated from serial passaging experiments in increasing concentrations of cyO2 were characterized by whole-genome sequencing. The identified mutations were genetically reconstituted in a wild-type background. The additive effect of mutations was studied in double mutants. Fitness costs, levels of resistance, and cross-resistance to another cyclotide, other peptide and nonpeptide antibiotics, and AMPs were determined. A variety of resistance mutations were identified. Some of these reduced fitness and others had no effect on fitness in vitro, in the absence of cyO2. In mouse competition experiments, four of the cyO2-resistant mutants showed a significant fitness advantage, whereas the effects of the mutations in the others appeared to be neutral. The level of resistance was increased by combining several individual resistance mutations. Several cases of cross-resistance and collateral sensitivity between cyclotides, other AMPs, and antibiotics were identified. These results show that resistance to cyclotides can evolve via several different types of mutations with only minor fitness costs and that these mutations often affect resistance to other AMPs.

  • 210.
    Melander, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eriksson, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Jansson, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Hammarlund-Udenaes, Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Improved method for quantitative analysis of the cyclotide kalata B1 in plasma and brain homogenate2016Ingår i: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 106, nr 6, s. 910-916Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study provides a new method for quantifying the cyclotide kalata B1 in both plasma and brain homogenate. Cyclotides are ultra-stable peptides with three disulfide bonds that are interesting from a drug development perspective as they can be used as scaffolds. In this study we describe a new validated LC-MS/MS method with high sensitivity and specificity for kalata B1. The limit of quantification was 2 ng/mL in plasma and 5 ng/gmL in brain homogenate. The method was linear in the range 2-10,000 ng/mL for plasma and 5-2000 ng/g for brain. Liquid Chromatographic separation was performed on a HyPurity C18 column, 50 3 4.6 mm, 3 mm particle size. The method had inter-and intra-day precision and accuracy levels <15% and 12% respectively. Applying the method to in vivo plasma samples and brain homogenate samples from equilibrium dialysis yielded satisfying results and was able to describe the plasma pharmacokinetics and brain tissue binding of kalata B1. The described method is quick, reproducible and well suited to quantifying kalata B1 in biological matrices.

  • 211.
    Miclescu, Adriana A
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Svahn, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Evaluation of the protein biomarkers and the analgesic response to systemic methylene blue in patients with refractory neuropathic pain: a double-blind, controlled study2015Ingår i: Journal of Pain Research, ISSN 1178-7090, E-ISSN 1178-7090, Vol. 8, s. 387-397Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIM: This study was carried out in patients with neuropathic pain in order to assess the analgesic effects and changes in protein biomarkers after the administration of methylene blue (MB), a diaminophenothiazine with antioxidant and anti-inflammatory properties, and with inhibitory effects on nitric oxide.

    MATERIALS AND METHODS: Ten patients with chronic refractory neuropathic pain were randomized to receive either MB (10 mg/mL Methylthioninium chloride) 2 mg/kg (MB group) or MB 0.02 mg/kg (control group) infused over 60 minutes. Sensory function and pain (Numerical Rating Scale) were evaluated at baseline and at 60 minutes after the start of the infusion. The patients kept a pain diary during the next 24 hours and for the following 4 days. Plasma and urinary concentrations of 8-isoprostane-prostaglandin F2α (8-iso-PGF2α) and plasma protein biomarkers prior to and after the infusions were measured with radioimmunoassay and with proximity extension assay.

    RESULTS: A decrease of the Numerical Rating Scale at 60 minutes in comparison with baseline was observed in the MB (P=0.047) group. The decrease was significant between the MB and the control group on the day of and day after MB infusion (P=0.04 and P=0.008, respectively). There was no difference in systemic protein expressions between groups except for prolactin (PRL) (P=0.02). Three patients demonstrated diminished dynamic mechanical allodynia.

    CONCLUSION: MB decreased the pain levels in patients with chronic therapy-resistant neuropathic pain on the first 2 days after administration. Known as an endocrine modulator on the anterior pituitary gland, MB infusion produced a decrease of PRL. The detailed role of PRL effects in chronic neuropathic pain remains undetermined.

  • 212. Morrow, Christine
    et al.
    Cardenas, Paco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Systematisk biologi.
    Proposal for a revised classification of the Demospongiae (Porifera)2015Ingår i: Frontiers in Zoology, ISSN 1742-9994, E-ISSN 1742-9994, Vol. 12, artikel-id 7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Demospongiae is the largest sponge class including 81% of all living sponges with nearly 7,000 species worldwide. Systema Porifera (2002) was the result of a large international collaboration to update the Demospongiae higher taxa classification, essentially based on morphological data. Since then, an increasing number of molecular phylogenetic studies have considerably shaken this taxonomic framework, with numerous polyphyletic groups revealed or confirmed and new clades discovered. And yet, despite a few taxonomical changes, the overall framework of the Systema Porifera classification still stands and is used as it is by the scientific community. This has led to a widening phylogeny/classification gap which creates biases and inconsistencies for the many end-users of this classification and ultimately impedes our understanding of today's marine ecosystems and evolutionary processes. In an attempt to bridge this phylogeny/classification gap, we propose to officially revise the higher taxa Demospongiae classification. Discussion: We propose a revision of the Demospongiae higher taxa classification, essentially based on molecular data of the last ten years. We recommend the use of three subclasses: Verongimorpha, Keratosa and Heteroscleromorpha. We retain seven (Agelasida, Chondrosiida, Dendroceratida, Dictyoceratida, Haplosclerida, Poecilosclerida, Verongiida) of the 13 orders from Systema Porifera. We recommend the abandonment of five order names (Hadromerida, Halichondrida, Halisarcida, lithistids, Verticillitida) and resurrect or upgrade six order names (Axinellida, Merliida, Spongillida, Sphaerocladina, Suberitida, Tetractinellida). Finally, we create seven new orders (Bubarida, Desmacellida, Polymastiida, Scopalinida, Clionaida, Tethyida, Trachycladida). These added to the recently created orders (Biemnida and Chondrillida) make a total of 22 orders in the revised classification. We propose the abandonment of the haplosclerid and poecilosclerid suborders. The family content of each order is also revised. Summary: The deletion of polyphyletic taxa, the use of resurrected or new names for new clades and the proposal of new family groupings will improve the comparability of studies in a wide range of scientific fields using sponges as their object of study. It is envisaged that this will lead to new and more meaningful evolutionary hypotheses for the end-users of the Demospongiae classification.

  • 213.
    Muhammad, Taj
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gunasekera, Sunithi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Strömstedt, Adam A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Engineering Of A Minimalized Domain Derived From Human Host Defense Peptide LL-37 Into A Stable And Potent Antimicrobial Drug Lead2016Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 22, nr S2, s. S184-S186Artikel i tidskrift (Övrigt vetenskapligt)
  • 214.
    Muigg, Patrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Rosen, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    In silico comparison of marine, terrestrial and synthetic compounds using ChemGPS-NP for navigating chemical space2013Ingår i: Phytochemistry Reviews, ISSN 1568-7767, E-ISSN 1572-980X, Vol. 12, nr 3, s. 449-457Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Nature represents a vast source of chemical diversity, which is supposed to cover broader areas of chemical space than synthetically obtained substances typical of medicinal chemistry. With regard to drug discovery from nature, the terrestrial environment has been the most and longest studied source, while the investigation of compounds produced by marine organisms is still in its infancy. With the objective of demonstrating the enormous chemical diversity of nature, in particular that of the marine environment, we used the chemical space navigation tool ChemGPS-NP to compare sets of marine, terrestrial and synthetic compounds with respect to physico-chemical properties and their occupation of the biologically relevant chemical space. Despite considerable overlap, the three datasets clearly differ from each other by occupying and extending into different, specific, regions in chemical space. Synthetic compounds are e.g. comparably small, with some of them being highly flexible, while marine and terrestrial products are larger and characterised by higher and lower molecular flexibility, respectively, with increasing size. Moreover, the three datasets differ to some degree in polarity, aromaticity and heteroatom content. Taken together, ChemGPS-NP has been proven to be a useful tool for navigating large volumes of biologically relevant chemical space. In this study we demonstrated the chemical uniqueness and differences of large sets of natural products, with particular emphasis on marine substances. The hence de-veiled differences further underline the relevance of natural products, of both marine and terrester origin, for future drug discovery.

  • 215.
    Noreen, Ylva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Two new isoflavones from Ceiba pentandra and their effect on cyclooxygenase-catalyzed prostaglandin biosynthesis1998Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, nr 1, s. 8-12Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The new isoflavone glucoside vavain 3'-O-beta-d-glucoside (1) and its aglycon, vavain (2), were isolated from the bark of Ceiba pentandra, together with the known flavan-3-ol, (+)-catechin, These novel structures were elucidated by one- and two-dimensional NMR experiments and by MS, IR, and UV spectroscopy as 5-hydroxy-7,4',5'-trimethoxyisoflavone 3'-O-beta-D-glucoside (1) and 5,3'-dihydroxy-7,4',5'-trimethoxyisoflavone (2), respectively. The compounds were isolated following bioactivity-directed fractionation, using a cyclooxygenase-1-catalyzed prostaglandin biosynthesis assay in vitro, in which compounds 1 and 2 and (+)-catechin exhibited IC50 values of 381, 97, and 80 microM, respectively (standard: indomethacin, IC50 1,1 microM). When further tested for their inhibitory effects on cyclooxygenase-2-catalyzed prostaglandin biosynthesis, 1 and 2 were found to be inactive (IC50 > 1200 and > 900 microM, respectively).

  • 216.
    Noreen, Ylva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Ringbom, Therese
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Danielson, Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Development of a radiochemical cyclooxygenase-1 and 2 in vitro assay for identification of natural products as inhibitors of prostaglandin biosynthesis1998Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, nr 1, s. 2-7Artikel i tidskrift (Refereegranskat)
  • 217.
    Noreen, Ylva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Serrano, Gudelia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Flavan-3-ols isolated from some medicinal plants inhibiting COX-1 and COX-2 catalysed prostaglandin biosynthesis1998Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 64, nr 6, s. 520-524Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Extracts from the four plant species Atuna racemosa Raf. ssp. racemosa, Syzygium corynocarpum (A. Gray) C. Muell., Syzygium malaccense (L.) Merr. & Perry and Vantanea peruviana Macbr., traditionally used for inflammatory conditions, were fractionated using a cyclooxygenase-1 catalysed prostaglandin biosynthesis in vitro assay. The flavan-3-ol derivatives (+)-catechin, (+)-gallocatechin, 4'-O-Me-ent-gallocatechin, ouratea-catechin and ouratea-proanthocynidin A were isolated as active principles. The IC50 values ranged from 3.3 mu M to 138 mu M whilst indomethacin under the same test conditions had an IC50 value of 1.1 mu M. The flavonol rhamnosides mearnsitrin, myricitrin and quercitrin were also isolated. When further tested for inhibitory effect on cyclooxygenase-2 catalysed prostaglandin biosynthesis, the five flavan-3-ol derivatives exhibited from equal to weaker inhibitory potencies, as compared to their cyclooxygenase-l inhibitory effects. The flavonol rhamnosides were inactive towards both enzymes.

  • 218.
    Ogundaini, Abiodun
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Farah, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Samuelsson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Isolation of two new antiinflammatory biflavanoids from Sarcophyte piriei1996Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 59, nr 6, s. 587-590Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two new flavano flavanone glycosides, diinsininol (1) and diinsinin (2), have been isolated from the rhizome of Sarcophyte piriei, together with one known flavanone glycoside, naringenin 5-glucoside. Their structures were elucidated on spectroscopic evidence as 5,7,3',4'-tetrahydroxyflavanyl-7-O-beta-glucosyl-(4 beta-8;2 beta-O-7)-eriodictyol (1) and 5,7,3',4'-tetrahydroxyflavanyl-7-O-beta-glucosyl-(4 beta-8;2 beta-O-7)-naringenin (2), respectively. The compounds were tested for their ability to inhibit prostaglandin synthesis, with 1 and 2 giving IC50 values of 9.20 mu M and 13.14 mu M, respectively, and in the inhibition of platelet-activating-factor-induced exocytosis, IC50 values of 49 and 39 mu M.

  • 219.
    Ortlepp, Sofia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Sjögren, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Dahlström, Mia
    Weber, Horst
    Ebel, Rainer
    Edrada, RuAngelie
    Thoms, Carsten
    Schupp, Peter
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Proksch, Peter
    Antifouling activity of bromotyrosine-derived sponge metabolites and synthetic analogues2007Ingår i: Marine Biotechnology, ISSN 1436-2228, E-ISSN 1436-2236, Vol. 9, nr 6, s. 776-785Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Eighteen brominated sponge-derived metabolites and synthetic analogues were analyzed for antilarval settlement of Balanus improvisus. Only compounds exhibiting oxime substituents including bastadin-3 (4), -4 (1), -9 (2), and -16 (3), hemibastadin-1 (6), aplysamine-2 (5), and psammaplin A (10) turned out to inhibit larval settling at 1 to 10 microM. Analogues of hemibastadin-1 (6) were synthesized and tested for structure activity studies. Debromohemibastadin-1 (8) inhibited settling of B. improvisus, albeit at lower concentrations than hemibastadin-1 (6). Both 6 and 8 also induced cyprid mortality. 5,5'-dibromohemibastadin-1 (7) proved to be nontoxic, but settlement inhibition was observed at 10 microM. Tyrosinyltyramine (9), lacking the oxime function, was not antifouling active and was non-toxic at 100 microM. Hemibastadin-1 (6) and the synthetic products showed no general toxicity when tested against brine shrimp larvae. In contrast to the lipophilic psammaplin A (10), the hydrophilic sulfated psammaplin A derivative (11) showed no antifouling activity even though it contains an oxime group. We therefore hypothesize that the compound needs to cross membranes (probably by diffusion) and that the target for psammaplin A lies intracellularly.

  • 220. Ovesen, Rikke G.
    et al.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Hansen, Steen H.
    Nielsen, John
    Hansen, Hans Christian B.
    A liquid chromatography-electrospray ionization-mass spectrometry method for quantification of cyclotides in plants avoiding sorption during sample preparation2011Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, nr 44, s. 7964-7970Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are plant-produced, bioactive, cyclic mini-proteins with interesting pharmaceutical and agricultural applications. A reverse phase liquid chromatography electrospray ionization mass spectrometry (RP-LC-ESI-MS) method for analysis of cyclotides in plant materials with a minimum of sample pretreatment is presented. Three exemplary cyclotides (kalata B1, kalata B2 and cycloviolacin 02) were used as reference substances for the method development. Linearity (r(2) > 0.99) was achieved in the concentration range 0.05-10 mg/L and the limit of detection was 1.7-4.0 mu g/L. The present study is the first to demonstrate that cyclotides dissolved in water sorb to glass vials, but the addition of 15% of acetonitrile or 40 mg/L of bovine serum albumin is sufficient to keep the cyclotides in solution. Cyclotides were extracted from candied violets, violet tea, and the plants Oldenlandia affinis and Viola odorata using 70% methanol containing 0.1% formic acid (v/v). The plant content was determined to be 23.5-14,200 mu g/g (dry weight). The highest content of cyclotide was found in wild Danish V. odorata, and it is the highest content of cyclotide in a plant reported hitherto. Candied violets contained 0.00-8.66 mu g/g (dry weight), while no cyclotides were detected in commercial violet tea.

  • 221. Ovesen, Rikke Gleerup
    et al.
    Brandt, Kristian Koefoed
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Nielsen, John
    Hansen, Hans Christian Bruun
    Cedergreen, Nina
    Biomedicine in the environment: Cyclotides constitute potent natural toxins in plants and soil bacteria2011Ingår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 30, nr 5, s. 1190-1196Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bioactive compounds produced by plants are easily transferred to soil and water and may cause adverse ecosystem effects. Cyclotides are gene-encoded, circular, cystine-rich mini-proteins produced in Violaceae and Rubiaceae in high amounts. Based on their biological activity and stability, cyclotides have promising pharmaceutical and agricultural applications. We report the toxicity of the cyclotides: kalata B1, kalata B2, and cycloviolacin O2 extracted from plants to green algae (Pseudokirchneriella subcapitata), duckweed (Lemna minor L.), lettuce (Lactuca sativa L.), and bacteria extracted from soil measured as [3H]leucine incorporation. Quantification by liquid chromatography-mass spectrometry demonstrated up to 98% loss of cyclotides from aqueous solutions because of sorption to test vials. Sorption was prevented by adding bovine serum albumin (BSA) to the aqueous media. Cyclotides were toxic to all test organisms with EC50 values of 12 through 140 µM (algae), 9 through 40 µM (duckweed), 4 through 54 µM (lettuce), and 7 through 26 µM (bacteria). Cycloviolacin O2 was the most potent cyclotide in all assays examined. This report is the first to document toxic effects of cyclotides in plants and soil bacteria and to demonstrate that cyclotides are as toxic as commonly used herbicides and biocides. Hence, cyclotides may adversely affect soil and aquatic environments, which needs to be taken into account in future risk assessment of cropping systems for production of these highly bioactive compounds.

  • 222. Park, Ki-Ryong
    et al.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Origin of the cyathium-bearing Euphorbieae (Euphorbiaceae): phylogenetic study based on morphological characters2002Ingår i: Botanical bulletin of Academia Sinica, ISSN 0006-8063, Vol. 43, nr 1, s. 57-62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A cladistic analysis of the subfamily Euphorbioideae was undertaken to elucidate the origin of the cyathium-bearing Euphorbieae and to provide hypotheses about evolutionary relationships within the subfamily. Twenty-one species representing most of the genera within the study group and three outgroup taxa from the subfamilies Acalyphoideae and Crotonoideae were selected for parsimony analysis. An unweighted parsimony analysis of 24 morphological characters resulted in five equally parsimonious trees with consistency indices of 0.67 and tree lengths of 39 steps. The strict consensus tree supported monophyly of the cyathium-bearing Euphorbieae. The sister group relationships of cyathium bearing Euphorbieae with Maprounea (subtribe Hippomaninae) were supported weakly, and the origin of cyathium is possibly in Hippomaneae, or in the common ancestor of Euphorbieae and remaining taxa of Euphorbioideae plus Acalyphoideae. Within the tribe Euphorbieae, both subtribes Euphorbiinae and Neoguilauminiinae are monophyletic, but the African endemic subtribe Anthosteminae is unresolved. The resulting trees support the monophyly of the tribe Stomatocalyceae while the tribe Hippomaneae does not consistently form a clade.

  • 223.
    Park, Sungkyu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Cyclotides evolve: Studies on their natural distribution, structural diversity, and activity2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The cyclotides are a family of naturally occurring peptides characterized by cyclic cystine knot (CCK) structural motif, which comprises a cyclic head-to-tail backbone featuring six conserved cysteine residues that form three disulfide bonds. This unique structural motif makes cyclotides exceptionally resistant to chemical, thermal and enzymatic degradation. They also exhibit a wide range of biological activities including insecticidal, cytotoxic, anti-HIV and antimicrobial effects.

    The cyclotides found in plants exhibit considerable sequence and structural diversity, which can be linked to their evolutionary history and that of their host plants. To clarify the evolutionary link between sequence diversity and the distribution of individual cyclotides across the genus Viola, selected known cyclotides were classified using signature sequences within their precursor proteins. By mapping the classified sequences onto the phylogenetic system of Viola, we traced the flow of cyclotide genes over evolutionary history and were able to estimate the prevalence of cyclotides in this genus. In addition, the structural diversity of the cyclotides was related to specific features of the sequences of their precursor proteins, their evolutionary selection and expression levels.

    A number of studies have suggested that the biological activities of the cyclotides are due to their ability to interact with and disrupt biological membranes. To better explain this behavior, quantitative structure-activity relationship (QSAR) models were developed to link the cyclotides’ biological activities to the membrane-interactive physicochemical properties of their molecular surfaces. Both scalar quantities (such as molecular surface areas) and moments (such as the distributions of specific properties over the molecular surface) were systematically taken into account in the development of these models. This approach allows the physicochemical properties of cyclotides to be geometrically interpreted, facilitating the development of guidelines for drug design using cyclotide scaffolds.

    Finally, an optimized microwave-assisted Fmoc-SPSS procedure for the total synthesis of cyclotides was developed. Microwave irradiation is used to accelerate and improve all the key steps in cyclotide synthesis, including the assembly of the peptide backbone by Fmoc-SPPS, the cleavage of the protected peptide, and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. 

    Delarbeten
    1. Insights into cyclotide evolution from transcriptomic analyses and studies on their distribution in violets
    Öppna denna publikation i ny flik eller fönster >>Insights into cyclotide evolution from transcriptomic analyses and studies on their distribution in violets
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Cyclotides are a family of plant-derived proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK) motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. Cyclotides exert much of their biological activity via interactions with cell membranes. In this work, we explore cyclotide evolution by sequencing and analyzing the transcriptomes of Viola albida var. takahashii, V. mandshurica, V. orientalis, V. verecunda and V. acuminata, in combination with reported precursor sequences. The distribution of the cyclotide precursors in the genus Viola was analyzed in relation to the infrageneric phylogeny, providing insights into the overall distribution of cyclotides within the genus. The structures and activities of predicted cyclotides are linked to the evolution of their precursors and the associated selective pressures. Furthermore, sequence variations between related precursors were generalized to deduce evolutionary trends, and to shed light on the evolution into novel mature cyclotides with the emergence of new functions. 

    Nationell ämneskategori
    Evolutionsbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-292958 (URN)
    Tillgänglig från: 2016-05-11 Skapad: 2016-05-11 Senast uppdaterad: 2016-07-26Bibliografiskt granskad
    2. Cyclotide Structure-Activity Relationships: Qualitative and Quantitative Approaches Linking Cytotoxic and Anthelmintic Activity to the Clustering of Physicochemical Forces
    Öppna denna publikation i ny flik eller fönster >>Cyclotide Structure-Activity Relationships: Qualitative and Quantitative Approaches Linking Cytotoxic and Anthelmintic Activity to the Clustering of Physicochemical Forces
    2014 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 3, s. e91430-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Cyclotides are a family of plant-derived proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK) motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. Cyclotides exert much of their biological activity via interactions with cell membranes. In this work, we qualitatively and quantitatively analyze the cytotoxic and anthelmintic membrane activities of cyclotides. The qualitative and quantitative models describe the potency of cyclotides using four simple physicochemical terms relevant to membrane contact. Specifically, surface areas of the cyclotides representing lipophilic and hydrogen bond donating properties were quantified and their distribution across the molecular surface was determined. The resulting quantitative structure-activity relation (QSAR) models suggest that the activity of the cyclotides is proportional to their lipophilic and positively charged surface areas, provided that the distribution of these surfaces is asymmetric. In addition, we qualitatively analyzed the physicochemical differences between the various cyclotide subfamilies and their effects on the cyclotides' orientation on the membrane and membrane activity.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-224356 (URN)10.1371/journal.pone.0091430 (DOI)000333678100003 ()
    Tillgänglig från: 2014-05-13 Skapad: 2014-05-09 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
    3. Exposing the true bactericidal potency of cyclotides: explained by lipid selectivity, structural characteristics and correlating antimicrobial activities
    Öppna denna publikation i ny flik eller fönster >>Exposing the true bactericidal potency of cyclotides: explained by lipid selectivity, structural characteristics and correlating antimicrobial activities
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Cyclotides are a family of plant peptides characterized by a cystine knot embedded in a macrocyclic backbone. They bind to and disrupt phospholipid membranes, which explain their activity against eukaryotic cells and enveloped viruses. In the current study, we show that potent antibacterial activity is frequent among cyclotides as long as the activity inhibiting presence of rich growth media is avoided. For that purpose a modified microdilution assay protocol was developed. This, the largest and most diverse set of cyclotides to be tested for antibacterial and antifungal activity, show that most cyclotides are active in this respect, especially against Gram-negative bacteria. Activity was observed at sub-micromolar concentrations for three of the cyclotides surpassing that of the potent control peptides melittin and LL-37. Noteworthy, two net anionic cyclotides were active on Pseudomonas aeruginosa at low micromolar concentrations. Activity against Staphylococcus aureus or Candida albicans was lower and less frequent. Permeabilizing activity on liposomes of various compositions was compared with effects on bacteria, Candida and lymphoma cells to which physiochemical properties of the cyclotides could be assigned. Analysis of quantitative structure-activity relationship found correlations between molecular patterns, phospholipid specificity and antimicrobial activity. Although certain bracelet cyclotides, with broad-spectrum activity, relied more on electrostatic and hydrophobic parameters for their bioactivity, those with primarily Gram-negative activity, in particular against P. aeruginosa, were achieving membrane binding and disruption in a phospholipid specific manner, namely a high affinity for phosphatidylethanolamine (PE). We conclude that the high PE-selectivity is linked to the potency of antibacterial activity.

    Nyckelord
    cyclotide; membrane; phosphatidylethanolamine; cytotoxicity; antibacterial; antifungal; peptide surface chemistry
    Nationell ämneskategori
    Fysikalisk kemi
    Forskningsämne
    Farmakognosi; Fysikalisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-292756 (URN)
    Tillgänglig från: 2016-05-09 Skapad: 2016-05-09 Senast uppdaterad: 2016-07-26Bibliografiskt granskad
    4. An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    Öppna denna publikation i ny flik eller fönster >>An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    2010 (Engelska)Ingår i: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, nr 3, s. 167-176Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Cyclotides are mini-proteins of approximately 30 amino acid residues that have a unique structure consisting of a head-to-tail cyclized backbone and a knotted arrangement of three disulfide bonds. This unique cyclotide structure provides exceptional stability to chemical, enzymatic and thermal treatments and has been implicated as an ideal drug scaffold for the development into agricultural and biotechnological agents. In the current work, we present the first method for microwave assisted Fmoc-SPPS of cyclotides. This protocol adopts a strategy that combines optimized microwave assisted chemical reactions for Fmoc-SPPS of the peptide backbone, the cleavage of the protected peptide and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. To exemplify the utility of this protocol in the synthesis of a wide array of different cyclotide sequences we synthesized representative members from the three cyclotide subfamilies-the Mobius kalata B1, the bracelet cycloviolacin O2 and the trypsin inhibitory MCoTI-II. In addition, a "one pot" reaction promoting both cyclization and oxidative folding of crude peptide thioester was adapted for kalata B1 and MCoTI-II.

    Nyckelord
    Cyclotides, Microwave chemistry, Fmoc-SPPS, Circular proteins, Cystine knot, Native chemical ligation
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-134899 (URN)10.1007/s10989-010-9221-0 (DOI)000281682600007 ()
    Tillgänglig från: 2010-12-02 Skapad: 2010-12-02 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
  • 224.
    Park, SungKyu
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gunasekera, Sunithi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Aboye, Teshome L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Microwave-assisted total synthesis of macrocyclic cystine knot miniproteins2010Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 16, nr S1, s. 79-79Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Microwave-assisted total synthesis of macrocyclic cystine knot miniproteins

    SK Park, S Gunasekera, T Aboye, U Göransson Division of pharmacognosy, Uppsala university, UPPSALA, Sweden Cyclotides are mini-proteins of approximately 30 amino acids residues that have a unique structure consisting of a head-to-tail cyclic backbone with a knotted arrangement of three disulfide bonds [1]. This unique structure provides exceptional stability to chemical, enzymatic and thermal treatments [2,3]. Cyclotides display various bioactivities, such as anti-HIV, uterotonic, cytotoxic, and insecticidal activity [4]. Due to the unique structural stability, cyclotides have been implicated as ideal drug scaffolds and for development into agricultural and biotechnological agents [2]. In the current work, we represent the first method for total synthesis of cyclotides based on Fmoc-SPPS assisted by microwave. This protocol adopts a strategy that combines the optimized microwave assisted chemical reactions for Fmoc-SPPS of peptide backbone synthesis, thioesterification of the C-terminal carboxylic acid of the peptide and a one pot reaction that promotes cyclisation through native chemical ligation and oxidative folding. The application of this protocol was exemplified for the synthesis of two prototypic cyclotides; kalata B1 and MCOTI-II

  • 225.
    Park, Sungkyu
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gunasekera, Sunithi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Aboye, Teshome Leta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Department of Pharmaceutical ChemistrySchool of Pharmacy, Addis Ababa UniversityAddis AbabaEthiopia.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS2010Ingår i: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, nr 3, s. 167-176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are mini-proteins of approximately 30 amino acid residues that have a unique structure consisting of a head-to-tail cyclized backbone and a knotted arrangement of three disulfide bonds. This unique cyclotide structure provides exceptional stability to chemical, enzymatic and thermal treatments and has been implicated as an ideal drug scaffold for the development into agricultural and biotechnological agents. In the current work, we present the first method for microwave assisted Fmoc-SPPS of cyclotides. This protocol adopts a strategy that combines optimized microwave assisted chemical reactions for Fmoc-SPPS of the peptide backbone, the cleavage of the protected peptide and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. To exemplify the utility of this protocol in the synthesis of a wide array of different cyclotide sequences we synthesized representative members from the three cyclotide subfamilies-the Mobius kalata B1, the bracelet cycloviolacin O2 and the trypsin inhibitory MCoTI-II. In addition, a "one pot" reaction promoting both cyclization and oxidative folding of crude peptide thioester was adapted for kalata B1 and MCoTI-II.

  • 226.
    Park, Sungkyu
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Strömstedt, Adam A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Cyclotide Structure-Activity Relationships: Qualitative and Quantitative Approaches Linking Cytotoxic and Anthelmintic Activity to the Clustering of Physicochemical Forces2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 3, s. e91430-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are a family of plant-derived proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK) motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. Cyclotides exert much of their biological activity via interactions with cell membranes. In this work, we qualitatively and quantitatively analyze the cytotoxic and anthelmintic membrane activities of cyclotides. The qualitative and quantitative models describe the potency of cyclotides using four simple physicochemical terms relevant to membrane contact. Specifically, surface areas of the cyclotides representing lipophilic and hydrogen bond donating properties were quantified and their distribution across the molecular surface was determined. The resulting quantitative structure-activity relation (QSAR) models suggest that the activity of the cyclotides is proportional to their lipophilic and positively charged surface areas, provided that the distribution of these surfaces is asymmetric. In addition, we qualitatively analyzed the physicochemical differences between the various cyclotide subfamilies and their effects on the cyclotides' orientation on the membrane and membrane activity.

  • 227.
    Park, Sungkyu
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Yoo, Ki-Oug
    Kangwon National University, Department of Biological Sciencesi.
    Marcussen, Thomas
    University of Oslo, Centre for Ecological and Evolutionary Synthesis, Department of Biosciences.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Jacobsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Rosengren, K. Johan
    The University of Queensland, School of Biomedical Sciences.
    Doo, Inseok
    Dong-A Pharm Co Ltd, Biotech Research Center, Biotech Research Team.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Cyclotide Evolution: Insights from the Analyses of Their Precursor Sequences, Structures and Distribution in Violets (Viola)2017Ingår i: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 8, artikel-id 2058Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are a family of plant proteins that are characterized by a cyclic backbone and a knotted disulfide topology. Their cyclic cystine knot (CCK) motif makes them exceptionally resistant to thermal, chemical, and enzymatic degradation. By disrupting cell membranes, the cyclotides function as host defense peptides by exhibiting insecticidal, anthelmintic, antifouling, and molluscicidal activities. In this work, we provide the first insight into the evolution of this family of plant proteins by studying the Violaceae, in particular species of the genus Viola. We discovered 157 novel precursor sequences by the transcriptomic analysis of six Viola species: V. albida var. takahashii, V. mandshurica, V. orientalis, V. verecunda, V. acuminata, and V. canadensis. By combining these precursor sequences with the phylogenetic classification of Viola, we infer the distribution of cyclotides across 63% of the species in the genus (i.e., ~380 species). Using full precursor sequences from transcriptomes, we show an evolutionary link to the structural diversity of the cyclotides, and further classify the cyclotides by sequence signatures from the non-cyclotide domain. Also, transcriptomes were compared to cyclotide expression on a peptide level determined using liquid chromatography-mass spectrometry. Furthermore, the novel cyclotides discovered were associated with the emergence of new biological functions.

  • 228.
    Pathmasiri, Wimal
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    el-Seedi, Hesham R
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Han, Xiao
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Ytbioteknik, Centrum för ytbioteknik.
    Janson, Jan-Christer
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Ytbioteknik, Centrum för ytbioteknik.
    Huss, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Aryl ketones from Acronychia pedunculata with cyclooxygenase-2 inhibitory effects2005Ingår i: Chemistry & biodiversity, ISSN 1612-1872, Vol. 2, nr 4, s. 463-469Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    1-[2,4-Dihydroxy-6-methoxy-3,5-bis(3-methylbut-2-en-1-yl)phenyl]ethanone (1), and a new aryl ketone, named acrovestenol (2), were isolated as cyclooxygenase-2 (COX-2) inhibitory principles from a CH2Cl2 extract of the bark of Acronychia pedunculata by a bioassay-guided fractionation procedure. Compound 2 inhibited COX-2 with an IC50 value of 142.0+/-2.15 microM, compared to the COX-2 inhibitory reference compound NS-398 with an IC50 value of 11.3+/-1.12 microM. Compound 1 inhibited COX-2-catalyzed PG biosynthesis with 68% at a concentration of 500 microM. The structures were determined by UV, IR, and 1D- and 2D-NMR, including TOCSY, HSQC-DEPT, and HMBC, and MS investigations.

  • 229.
    Perera, Premila
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Ringbom, T
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Huss, U
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Vasänge, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Search for natural products with effect on cyclooxygenase-22001Ingår i: Bioactive Compounds from Natural Sources / [ed] Corrado Tringali, London: Taylor & Francis , 2001Kapitel i bok, del av antologi (Övrigt vetenskapligt)
  • 230.
    Persson, Anita Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Rosén, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Multivariate data analysis of factors affecting the in vitro dissolution rate and the apparent solubility for a model basic drug substance in aqueous media2010Ingår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, nr 7, s. 1309-1317Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Purpose. To evaluate the usefulness of a miniaturized rotating disk equipment for the determination of factors influencing the in vitro dissolution rate, G, of a model basic drug substance (terfenadine) in different aqueous media, using experimental design and multivariate data analysis. The apparent solubility, S, was included in the chemometric study.

    Methods. The dissolution rate was determined with a miniaturized rotating disk apparatus and the solubility by shake-flask methodology. Media were based on acetate, phosphate or maleate buffers. The later used in fasted state simulated intestinal fluid (FaSSIF-V2). The chemometric analyses included fractional factorial design, principal component analysis (PCA) and orthogonal partial least squares (OPLS). Quantifications were made with a RP-HPLC-DAD system.

    Results. The most influential factor for both G and S of terfenadine in the different media was pH. Apart from the ionic strength and sodium chloride concentration in the acetate medium, the effects of the other variables were insignificant implying no wetting effect of the surfactants.

    Conclusions. The miniaturized rotating disk equipment was suitable to use, in conjunction with the chemometric analyses, in the evaluation of the factors affecting the in vitro dissolution rate. The apparent solubility was found to be influenced by the same factors as G.

  • 231.
    Pettersson, Jenny
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Karlsson, Pernilla Christina
    Choi, Young Hae
    Verpoorte, Robert
    Rafter, Joseph James
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    NMR metabolomic analysis of fecal water from subjects on a vegetarian diet2008Ingår i: Biological and Pharmaceutical Bulletin, ISSN 0918-6158, E-ISSN 1347-5215, Vol. 31, nr 6, s. 1192-1198Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A vegetarian diet rich in phytochemicals may prevent colon carcinogenesis by affecting biochemical processes in the colonic mucosa. Compounds passing the digestive system reaching the colon could potentially be detected in fecal water. We previously reported that intact fecal water samples from human volunteers significantly decreased prostaglandin production and COX-2 protein expression in colonic cells. The aim with the present study was to further study the composition of the fecal waters, using NMR spectroscopy and multivariate data analysis, and to trace the COX-2 inhibiting activity. Intact fecal water samples and fractions thereof were analyzed for their ability to inhibit prostaglandin E2 production in the human colon cell line HT-29. The majority of the tested aqueous phases derived from intact fecal water showed ability to inhibit prostaglandin production in cells (13.8+/-1.34% inhibition, p=0.01). NMR analysis indicated the presence of significant quantities of amino acids and fatty acids. Major metabolites included; acetic acid, butanoic acid, propanoic acid, glutamic acid and alanine. Smaller amounts of glycine and fumaric acid, which are known to have anti-inflammatory and anti-tumorigenic properties, were also detected. This study describes for the first time NMR metabolomic analysis of fecal water from subjects on a vegetarian diet.

  • 232.
    Pettersson, Jenny
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Karlsson, Pernilla Christina
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Rafter, Joseph James
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    The flavouring phytochemical 2-pentanone reduces prostaglandin production and COX-2 expression in colon cancer cells2008Ingår i: Biological and Pharmaceutical Bulletin, ISSN 0918-6158, E-ISSN 1347-5215, Vol. 31, nr 3, s. 534-537Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Many phytochemicals found in the diet may prevent colon carcinogenesis by affecting biochemical processes in the colonic mucosa. Inflammation and subsequent elevation of the enzyme cyclooxygenase-2 (COX-2) are two such factors involved in the development of colon cancer, and inhibition of these processes could be important targets for chemoprevention. We have previously shown COX-2 inhibitory activity locally in the colon; e.g. in human fecal water from a group of vegetarians. In this study we focus on 2-pentanone, a frequently occurring compound in common foods such as banana and carrot. The aim was to study the inhibitory effects on prostaglandin production and COX-2 protein expression in tumour necrosis factor-alpha stimulated colon cancer cells (HT29) by radioimmunoassay and Western blotting. 2-Pentanone inhibited both prostaglandin production and COX-2 protein expression in human colon cancer cells. A concentration of 400 mumol/l 2-pentanone inhibited the prostaglandin production by 56.9+/-12.9% which is in the same range as the reference compound NS398 (59.8+/-7.6%). The two highest concentrations of 2-pentanone were further analyzed by Western blot, and 400 micromol/l and 200 micromol/l 2-pentanone resulted in a 53.3+/-9.6% and +/-27.1% reduction of the COX-2 protein levels respectively. Further studies on flavouring compounds, for example 2-pentanone, as colon cancer chemopreventives would be very valuable, and such results may contribute to future dietary recommendations.

  • 233. Plan, Manuel Rey R
    et al.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Clark, Richard J
    Daly, Norelle L
    Colgrave, Michelle L
    Craik, David J
    The cyclotide fingerprint in Oldenlandia affinis: elucidation of chemically modified, linear and novel macrocyclic peptides2007Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 8, nr 9, s. 1001-1011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The complete suite of cyclotides present in Oldenlandia affinis (Rubiaceae), the plant that was originally found to contain this unique family of circular proteins, has been characterised. This study expands the number of known cyclotides in this plant to 17, of which nine new sequences (kalata B9-B17) were characterised in this work. In addition, five derivatives that contain oxidation products of the conserved tryptophan were identified, and it was shown that the formation of these derivatives is catalysed by exposure to sunlight. Furthermore, we describe two linear cyclotide analogues. These acyclic peptides have three intact disulfide bonds, and their N and C termini coincide with the hypothesised cleavage sites from the precursor protein. This work increases our knowledge about the sequence variation that is accommodated by the cyclic cystine knot scaffold, confirms its applicability as a template for drug design, and also shows the first natural degradation pathways for cyclotides. These pathways have important implications for the persistence and environmental fate of the cyclotides if used as crop-protection agents.

  • 234. Proszenyák, Agnes
    et al.
    Charnock, Colin
    Hedner, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Larsson, Rolf
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gundersen, Lise-Lotte
    Synthesis, antimicrobial and antineoplastic activities for agelasine and agelasimine analogs with a beta-cyclocitral derived substituent.2007Ingår i: Archiv der Pharmazie, ISSN 0365-6233, E-ISSN 1521-4184, Vol. 340, nr 12, s. 625-634Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Agelasines and agelasimines are antimicrobial and cytotoxic purine derivatives isolated from marine sponges (Agelas sp.). We have synthesized structurally simplified analogs of these natural products starting from beta-cyclocitral. The novel compounds were found to be strong inhibitors of a wide variety of pathogenic microorganisms (incl. Mycobacterium tuberculosis) as well as cancer cell lines. The biological activities were generally in the same range as those previously found for the structurally more complex agelasines and agelasimines isolated in small amounts from natural sources. We also report for the first time that agelasine and agelasimine analogs inhibit growth of protozoa (Acanthamoeba castellanii and Acanthamoeba polyphaga). Acanthamoeba keratitis is an increasingly common and severe corneal infection, closely associated with contact lens wear.

  • 235.
    Pränting, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Lööv, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Burman, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Andersson, Dan I
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    The cyclotide cycloviolacin O2 from Viola odorata has potent bactericidal activity against Gram-negative bacteria2010Ingår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 65, nr 9, s. 1964-1971Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES:

    To determine the antibacterial activity of small cyclic plant proteins, i.e. cyclotides, and the importance of the surface exposed charged residues for activity.

    METHODS:

    Prototypic cyclotides, including the Möbius kalata B1 and the bracelet cycloviolacin O2 (cyO2), were isolated using reversed-phase HPLC. Initial activity screenings were conducted using radial diffusion assays (RDAs) and MIC assays with Salmonella enterica serovar Typhimurium LT2, Escherichia coli and Staphylococcus aureus as test strains. For the most active peptide, cyO2, time-kill kinetics was determined in sodium phosphate buffer (containing 0.03% trypticase soy broth) against several Gram-negative and Gram-positive bacterial species. Charged residues in cyO2 were chemically modified and activity was determined in time-kill assays.

    RESULTS:

    CyO2 was the most active cyclotide and efficiently inhibited the growth of S. enterica serovar Typhimurium LT2 and E. coli in RDAs and MIC assays, while the other peptides were less active. In time-kill assays, cyO2 also had bactericidal activity against the Gram-negative species Klebsiella pneumoniae and Pseudomonas aeruginosa. In contrast, none of the cyclotides had high activity against S. aureus. Chemical masking of the charged Glu and Lys residues in cyO2 caused a near total loss of activity against Salmonella, while masking Arg caused a less pronounced activity reduction.

    CONCLUSIONS:

    CyO2 is a cyclotide with potent activity against Gram-negative bacteria. The charged residues in cyO2 are all required for optimum antibacterial activity. In combination with its previously demonstrated cytotoxic activity against cancer cells and the general stability of cyclotides, cyO2 provides a promising scaffold for future drug design.

  • 236.
    Raschig, Judith
    et al.
    Univ Hosp Tuebingen, Internal Med 1, Tubingen, Germany..
    Mailaender-Sanchez, Daniela
    Univ Hosp Tuebingen, Internal Med 1, Tubingen, Germany..
    Berscheid, Anne
    Univ Tubingen, Interfac Inst Microbiol & Infect Med, Dept Microbial Bioact Cpds, Tubingen, Germany..
    Berger, Juergen
    Max Planck Inst Dev Biol, Electron Microscopy, Tubingen, Germany..
    Strömstedt, Adam A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Courth, Lioba F.
    Univ Hosp Tuebingen, Internal Med 1, Tubingen, Germany..
    Malek, Nisar P.
    Univ Hosp Tuebingen, Internal Med 1, Tubingen, Germany..
    Broetz-Oesterhelt, Heike
    Univ Tubingen, Interfac Inst Microbiol & Infect Med, Dept Microbial Bioact Cpds, Tubingen, Germany..
    Wehkamp, Jan
    Univ Hosp Tuebingen, Internal Med 1, Tubingen, Germany..
    Ubiquitously expressed Human Beta Defensin 1 (hBD1) forms bacteria-entrapping nets in a redox dependent mode of action2017Ingår i: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 13, nr 3, artikel-id e1006261Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ever since the discovery of endogenous host defense antimicrobial peptides it has been discussed how these evolutionary conserved molecules avoid to induce resistance and to remain effective. Human beta-defensin 1 (hBD1) is an ubiquitously expressed endogenous antimicrobial peptide that exhibits qualitatively distinct activities between its oxidized and reduced forms. Here, we explore these antimicrobial mechanisms. Surprisingly, using electron microscopy we detected a so far unknown net-like structure surrounding bacteria, which were treated with the reduced but not the oxidized form of hBD1. A transmigration assay demonstrated that hBD1-derived nets capture bacteria and inhibit bacterial transmigration independent of bacterial killing. The presence of nets could completely prevent migration of hBD1 resistant pathogens and are stable in the presence of human duodenal secretion with a high amount of proteases. In contrast to HD6, cysteins are necessary for net formation. This redox-dependent function serves as an additional mechanism of action for hBD1 and differs from net formation by other defensins such as Paneth cell-derived human alpha-defensin 6 (HD6). While hBD1red and hBD1ox have distinct antimicrobial profiles and functions, only the reduced form provides additional host protection by entrapping bacteria in extracellular net structures preventing bacterial invasion. Better understanding of the modes of action of endogenous host peptides will help to find new antimicrobial strategies.

  • 237.
    Ringbom, Therese
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bioassay Development for Identification of Cyclooxygenase-2 Inhibitors of Natural Origin2002Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    To examine cyclooxygenase-2 (COX-2) inhibitory effects of natural compounds and structurally related compounds, a radiochemical assay for measuring inhibition of COX-2 and COX-1 catalysed prostaglandin biosynthesis was optimised. That process resulted in the development of a reliable assay for finding COX-2 inhibitors in plants, and for investigating plant constituents pertaining to the inhibition of COX-2 and COX-1.

    By means of bioassay-guided isolation of the plant Plantago major L., several inhibitors of COX-2 were found: ursolic, oleanolic, a-linolenic and linoleic acid. Subsequently, structural derivatives of these triterpenoids and fatty acids were investigated. The polyunsaturated and the thioether containing fatty acids were the most potent COX-2 and COX-1 inhibitors, with a-linolenic and all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid expressing selectivity toward COX-2.

    For rapid evaluation of plant constituents, a COX-2 assay using scintillation proximity assay-technology was used to evaluate 49 ubiquitous plant metabolites of different biosynthetic origin for inhibition of COX-2. Eugenol, cinnamaldehyde, and pyrogallol expressed inhibition. Later, in an attempt to find COX-2 inhibitors in plants, but without prior purification, several approaches to the surface plasmon resonance technique were examined, with the measurement of prostaglandin E2 being most successful.

    In mouse macrophage cells, two fatty acids were analysed for effects on COX-2 and iNOS, mRNA, protein, prostaglandin E2, and nitrite levels. 5-Thia-8,11,14,17-eicosatetraenoic acid decreased COX-2 protein expression.

    This thesis contributes to our growing knowledge of methods for measuring COX-2 inhibition, and also knowledge of COX-2 inhibitory effects of commonly occurring compounds in plants, herbal drugs and functional food. Thus the experimental results can facilitate future searches for new COX-2 inhibitors of natural origin.

  • 238.
    Ringbom, Therese
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Huss, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Stenholm, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Flock, S
    Skattebol, L
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Cox-2 inhibitory effects of naturally occurring and modified fatty acids2001Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 64, nr 6, s. 745-749Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2.

  • 239.
    Ringbom, Therese
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Segura, Laura
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Noreen, Ylva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Perera, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Ursolic acid from Plantago major, a selective inhibitor of cyclooxygenase-2 catalyzed prostaglandin biosynthesis1998Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, nr 10, s. 1212-1215Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A hexane extract of Plantago major was investigated by bioactivity-directed fractionation, using an in vitro cyclooxygenase-2 (COX-2) catalyzed prostaglandin biosynthesis inhibition assay, and resulted in the isolation of ursolic acid (1). This triterpenoid showed a significant COX-2 inhibitory effect, directly on the enzyme activity, with an IC50 value of 130 microM and a COX-2/COX-1 selectivity ratio of 0.6. The structural isomer oleanolic acid (2) was found to be less active than 1, with an IC50 value of 295 microM, but showed a similar selectivity ratio (0.8). Furthermore, no significant inhibition on COX-2 or COX-1 was observed by the triterpenoid, 18beta-glycyrrhetinic acid (3). The direct inhibitory effect of 1 and 2 on COX-2 catalyzed prostaglandin biosynthesis increased with preincubation, indicating a time-dependent inhibition, while the effect on COX-1 was found to be independent of preincubation time.

  • 240. Roggen, Heidi
    et al.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Burman, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Charnock, Colin
    Felth, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gorbitz, Carl Henrik
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Tamm, Toomas
    Gundersen, Lise-Lotte
    2-Substituted agelasine analogs: Synthesis and biological activity, and structure and reactivity of synthetic intermediates2011Ingår i: Pure and Applied Chemistry, ISSN 0033-4545, E-ISSN 1365-3075, Vol. 83, nr 3, s. 645-653Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    2-Substituted N-methoxy-9-methyl-9H-purin-6-amines were synthesized either from their corresponding 6-chloro-9-methyl-9H-purines or 2-chloro-N-methoxy-9-methyl-9H-purin-6-amine. Great diversity in the amino/imino tautomeric ratios was observed and calculated based on H-1 NMR. The tautomers were identified by 1D and 2D H-1, C-13, and N-15 NMR techniques, and showed significant variation both in C-13 and N-15 shift values. Comparison of the tautomeric ratios with Hammett F values revealed that as the field/inductive withdrawing abilities of the 2-substituent increased, the ratio of amino: imino tautomers was shifted toward the amino tautomer. Computational chemistry exposed the significance of hydrogen bonding between solvent and the compound in question to reach accurate predictions for tautomeric ratios. B3LYP/def2-TZVP density functional theory (DFT) calculations resulted in quantitatively more accurate predictions than when employing the less expensive BP86 functional. N-7-Alkylation of the 2-substituted N-methoxy-9-methyl-9H-purin-6-amines showed that when the field/inductive withdrawing ability of the 2-substituent reached a certain point the reactivity drastically dropped. This correlated with the atomic charges on N-7 calculated using a natural bond orbital (NBO) analysis. Biological screening of the final 2-substituted agelasine analogs indicated that the introduction of a methyl group in the 2-position is advantageous for antimycobacterial and antiprotozoal activity, and that an amino function may improve activity against several cancer cell lines.

  • 241.
    Roggen, Heidi
    et al.
    Department of Chemistry, Oslo University.
    Charnock, Colin
    Faculty of Health Sciences, Oslo University.
    Burman, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Felth, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gundersen, Lise-Lotte
    Department of Chemistry, Oslo University.
    Antimicrobial and antineoplastic activities of Agelasine analogs modified in the purine 2-position2011Ingår i: Archiv der Pharmazie, ISSN 0365-6233, E-ISSN 1521-4184, Vol. 344, nr 1, s. 50-55Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Agelasines are 7,9-dialkylpurinium salts found in marine sponges (Agelas sp.), which display a variety of antimicrobial and cytotoxic effects. We have synthesized simplified agelasine analogs modified in the purine 2-position and examined their antimicrobial and anticancer activities. The compounds were screened against Staphylococcus aureus, Escherichia coli, Mycobacterium tuberculosis, Candida krusei, and Candida albicans, protozoa causing tropical diseases (Plasmodium falciparum, Leishmania infantum, Trypanosoma cruzi, and Trypanosoma brucei), a panel of human cancer cell lines (U-937 GTB, RPMI 8226/s, CEM/s, and ACHN) as well as VERO and/or MRC-5 cells. The results indicate that the introduction of a methyl group in the purine 2-position is beneficial for antimycobacterial and antiprotozoal activity, and that amino groups may enhance activity against several cancer cell lines.

  • 242.
    Rosén, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    ChemGPS-NP and the Exploration of Biologically Relevant Chemical Space2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Chemical space is basically infinite, and comprises all molecules that could possibly exist. Intelligent ways to efficiently navigate through chemical space and to select promising compounds in drug discovery are important tasks, and the focus of this thesis.

    In this work a new model for chemical space navigation, ChemGPS-NP, was developed. This model is based on a methodology where a global chemical space map is defined through principal component analysis of physico-chemical properties of a reference set of compounds. Through interpolation from the reference set, positions of novel compounds can be defined on this map and interpreted as chemical properties.

    ChemGPS-NP was demonstrated to be able to chart the entire biologically relevant chemical space, including both drug-like and natural compounds. This is an important improvement considering the present interest in natural products (NPs) in the pharmaceutical industry, as well as the track record of NPs to serve as basis for more than 50% of all marketed drugs. ChemGPS-NP proved able to handle and process large data sets, to aid in efficient selection of test objects, and to extract useful information from the results of high-throughput screening campaigns. Using ChemGPS-NP, it was shown that NPs occupy unique regions of chemical property space in comparison to drug-like compounds, and a number of features distinguishing NPs from medicinal chemistry compounds were identified.

    ChemGPS-NP was also shown to be able to reliably predict mode of action of anticancer agents based on chemical structure, a finding that has potential to improve cancer research efficiency. Applying a property based similarity search based on calculated eight dimensional Euclidean distances from ChemGPS-NP rendered a tool to identify NP inspired potential leads for drug discovery.

    Furthermore, ChemGPS-NPWeb, an online version of ChemGPS-NP, was developed, which provides scientists with open access to the tool via http://chemgps.bmc.uu.se/.

     

    Delarbeten
    1. ChemGPS-NP: tuned for navigation in biologically relevant chemical space
    Öppna denna publikation i ny flik eller fönster >>ChemGPS-NP: tuned for navigation in biologically relevant chemical space
    2007 (Engelska)Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 70, nr 5, s. 789-794Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Natural compounds are evolutionary selected and prevalidated by Nature, displaying a unique chemical diversity and a corresponding diversity of biological activities. These features make them highly interesting for studies of chemical biology, and in the pharmaceutical industry for development of new leads. Of utmost importance, for the discovery of new biologically active compounds, is the identification and charting of the corresponding biologically relevant chemical space. The primary key to this is the coverage of the natural products' chemical space. Here we introduce ChemGPS-NP, a new tool tuned for handling the chemical diversity encountered in natural products research, in contrast to previous tools focused on the much more restricted drug-like chemical space. The aim is to provide a framework for making compound classification and comparison more efficient and stringent, to identify volumes of chemical space related to particular biological activities, and to track changes in chemical properties due to, for example, evolutionary traits and modifications in biosynthesis. Physical-chemical properties not directly discernible from structural data can be discovered, making selection more efficient and increasing the probability of hit generation when screening natural compounds and analogues.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-16224 (URN)10.1021/np070002y (DOI)000246764300013 ()17439280 (PubMedID)
    Tillgänglig från: 2008-05-13 Skapad: 2008-05-13 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Novel chemical space exploration via natural products
    Öppna denna publikation i ny flik eller fönster >>Novel chemical space exploration via natural products
    Visa övriga...
    2009 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 52, nr 7, s. 1953-1962Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notable in coverage of chemical space, and tangible lead-like NPs were found to cover regions of chemical space that lack representation in WOMBAT. Property based similarity calculations were performed to identify NP neighbours of approved drugs. Several of the NPs revealed by this method, were confirmed to exhibit the same activity as their drug neighbours. The identification of leads from a NP starting point may prove a useful strategy for drug discovery, in the search for novel leads with unique properties.

    Nyckelord
    ChemGPS-NP, chemical space, natural product
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmakognosi
    Identifikatorer
    urn:nbn:se:uu:diva-89351 (URN)10.1021/jm801514w (DOI)000264835800017 ()19265440 (PubMedID)
    Tillgänglig från: 2009-02-12 Skapad: 2009-02-12 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    3. ChemGPS-NPweb: chemical space navigation online
    Öppna denna publikation i ny flik eller fönster >>ChemGPS-NPweb: chemical space navigation online
    Visa övriga...
    2009 (Engelska)Ingår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 23, nr 4, s. 253-259Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Internet has become a central source for information, tools, and services facilitating the work for medicinal chemists and drug discoverers worldwide. In this paper we introduce a web-based public tool, ChemGPS-NPWeb (http://chemgps.bmc.uu.se), for comprehensive chemical space navigation and exploration in terms of global mapping onto a consistent, eight dimensional map over structure derived physico-chemical characteristics. ChemGPS-NPWeb can assist in compound selection and prioritization; property description and interpretation; cluster analysis and neighbourhood mapping; as well as comparison and characterization of large compound datasets. By using ChemGPS-NPWeb, researchers can analyze and compare chemical libraries in a consistent manner. In this study it is demonstrated how ChemGPS-NPWeb can assist in interpreting results from two large datasets tested for activity in biological assays for pyruvate kinase and Bcl-2 family related protein interactions, respectively. Furthermore, a more than 30-year-old suggestion of “chemical similarity” between the natural pigments betalains and muscaflavins is tested.

    Nyckelord
    ChemGPS-NP, Natural products, Chemical space, Internet tool, Drug discovery, Biologically active compounds
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Farmakognosi
    Identifikatorer
    urn:nbn:se:uu:diva-89345 (URN)10.1007/s10822-008-9255-y (DOI)000263797300006 ()19082743 (PubMedID)
    Tillgänglig från: 2009-02-12 Skapad: 2009-02-12 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    4.
    Posten kunde inte hittas. Det kan bero på att posten inte längre är tillgänglig eller att du har råkat ange ett felaktigt id i adressfältet.
    5. ChemGPS-NP mapping of chemical compounds for prediction of anticancer mode of action
    Öppna denna publikation i ny flik eller fönster >>ChemGPS-NP mapping of chemical compounds for prediction of anticancer mode of action
    Visa övriga...
    2009 (Engelska)Ingår i: QSAR & combinatorial science (Print), ISSN 1611-020X, E-ISSN 1611-0218, Vol. 28, nr 4, s. 436-446Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A combined graph describing the growth inhibition values from a number of human cancer cell lines represents an activity profile for a compound. The fact that compounds with similar activity profiles often show similar mode of action (MOA) has frequently been used in prediction of MOA. Obtaining the profiles is demanding with respect to both time and resources. Therefore, as a work and time efficient alternative, we explore the central premise of medicinal chemistry that structurally similar molecules often have similar biological activity. In this study we investigate correlations between chemical structure and MOA, and subsequently use this as a complementing basis for prediction. The correlations between MOA and activity profile on one hand and between MOA and chemical structure on the other were analyzed for anticancer agents, classified with regard to MOA, using principal component analysis (PCA), chemographic mapping with ChemGPS-NP, and orthogonal partial least squares discriminant analysis (OPLS-DA). The compounds clustered according to MOA both based on chemical structures and activity profiles. The subsequent validation with external test sets showed that initial PCA scores prediction or chemographic mapping followed by OPLS-DA could be used for prediction of MOA as well as identification of novel MOAs in a highly accurate way. An efficient and straight forward procedure for prediction of MOA of anticancer agents is suggested. With today’s resistance problems in cancer therapy, there is a need for new anticancer agents and mechanisms. We believe that the fast initial virtual guidance this procedure implies, especially the novel step using ChemGPS-NP, could be of general use in early stages of cancer research.

    Nyckelord
    ChemGPS-NP, prediction, mode of action, anticancer agent
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmakognosi
    Identifikatorer
    urn:nbn:se:uu:diva-89350 (URN)10.1002/qsar.200810162 (DOI)000265462900005 ()
    Tillgänglig från: 2009-02-12 Skapad: 2009-02-12 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
  • 243.
    Rosén, Josefin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gottfries, Johan
    Pharmnovo Inc., Göteborg.
    Muresan, Sorel
    DECS Global Compound Sciences, AstraZeneca R&D, Mölndal.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Oprea, Tudor I.
    Division of Biocomputing, MSC11 6145, University of New Mexico School of Medicine, Albuquerque, NM, USA.
    Novel chemical space exploration via natural products2009Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 52, nr 7, s. 1953-1962Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notable in coverage of chemical space, and tangible lead-like NPs were found to cover regions of chemical space that lack representation in WOMBAT. Property based similarity calculations were performed to identify NP neighbours of approved drugs. Several of the NPs revealed by this method, were confirmed to exhibit the same activity as their drug neighbours. The identification of leads from a NP starting point may prove a useful strategy for drug discovery, in the search for novel leads with unique properties.

  • 244.
    Rosén, Josefin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Lövgren, Anders
    Uppsala universitet.
    Gottfries, Johan
    Pharmnovo Inc. , Göteborg.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    ChemGPS-NPweb A tool tuned for navigation in biologically relevant chemical space2008Ingår i: Embnet.news, ISSN 1023-4144, Vol. 14, nr 2, s. 6-9Artikel i tidskrift (Övrigt vetenskapligt)
  • 245.
    Rosén, Josefin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Lövgren, Anders
    Uppsala universitet.
    Kogej, Thierry
    DECS Global Compound Sciences, AstraZeneca R&D, Mölndal.
    Muresan, Sorel
    DECS Global Compound Sciences, AstraZeneca R&D, Mölndal.
    Gottfries, Johan
    Pharmnovo Inc., Göteborg.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    ChemGPS-NPweb: chemical space navigation online2009Ingår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 23, nr 4, s. 253-259Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Internet has become a central source for information, tools, and services facilitating the work for medicinal chemists and drug discoverers worldwide. In this paper we introduce a web-based public tool, ChemGPS-NPWeb (http://chemgps.bmc.uu.se), for comprehensive chemical space navigation and exploration in terms of global mapping onto a consistent, eight dimensional map over structure derived physico-chemical characteristics. ChemGPS-NPWeb can assist in compound selection and prioritization; property description and interpretation; cluster analysis and neighbourhood mapping; as well as comparison and characterization of large compound datasets. By using ChemGPS-NPWeb, researchers can analyze and compare chemical libraries in a consistent manner. In this study it is demonstrated how ChemGPS-NPWeb can assist in interpreting results from two large datasets tested for activity in biological assays for pyruvate kinase and Bcl-2 family related protein interactions, respectively. Furthermore, a more than 30-year-old suggestion of “chemical similarity” between the natural pigments betalains and muscaflavins is tested.

  • 246.
    Rosén, Josefin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Rickardson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Gottfries, Johan
    Pharmnovo Inc., Göteborg.
    ChemGPS-NP mapping of chemical compounds for prediction of anticancer mode of action2009Ingår i: QSAR & combinatorial science (Print), ISSN 1611-020X, E-ISSN 1611-0218, Vol. 28, nr 4, s. 436-446Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A combined graph describing the growth inhibition values from a number of human cancer cell lines represents an activity profile for a compound. The fact that compounds with similar activity profiles often show similar mode of action (MOA) has frequently been used in prediction of MOA. Obtaining the profiles is demanding with respect to both time and resources. Therefore, as a work and time efficient alternative, we explore the central premise of medicinal chemistry that structurally similar molecules often have similar biological activity. In this study we investigate correlations between chemical structure and MOA, and subsequently use this as a complementing basis for prediction. The correlations between MOA and activity profile on one hand and between MOA and chemical structure on the other were analyzed for anticancer agents, classified with regard to MOA, using principal component analysis (PCA), chemographic mapping with ChemGPS-NP, and orthogonal partial least squares discriminant analysis (OPLS-DA). The compounds clustered according to MOA both based on chemical structures and activity profiles. The subsequent validation with external test sets showed that initial PCA scores prediction or chemographic mapping followed by OPLS-DA could be used for prediction of MOA as well as identification of novel MOAs in a highly accurate way. An efficient and straight forward procedure for prediction of MOA of anticancer agents is suggested. With today’s resistance problems in cancer therapy, there is a need for new anticancer agents and mechanisms. We believe that the fast initial virtual guidance this procedure implies, especially the novel step using ChemGPS-NP, could be of general use in early stages of cancer research.

  • 247.
    Ruhaak, Lucia Renee
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Felth, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Karlsson, Pernilla Christina
    Rafter, Joseph James
    Verpoorte, Robert
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Evaluation of the Cyclooxygenase Inhibiting Effects of Six Major Cannabinoids Isolated from Cannabis sativa2011Ingår i: Biological and Pharmaceutical Bulletin, ISSN 0918-6158, E-ISSN 1347-5215, Vol. 34, nr 5, s. 774-778Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclooxygenase enzymes (COX-1 and COX-2) catalyse the production of prostaglandins from arachidonic acid. Prostaglandins are important mediators in the inflammatory process and their production can be reduced by COX-inhibitors. Endocannabinoids, endogenous analogues of the plant derived cannabinoids, occur normally in the human body. The Endocannabinoids are structurally similar to arachidonic acid and have been suggested to interfere with the inflammatory process. They have also been shown to inhibit cancer cell proliferation. Anti-inflammatory effects of cannabinoids and endocannabinoids have been observed, however the mode of action is not yet clarified. Anti-inflammatory activity (i.e., inhibition of COX-2) is proposed to play an important role in the development of colon cancer, which makes this subject interesting to study further. In the present work, the six cannabinoids tetrahydrocannabinol (Delta(9)-THC), tetrahydrocannabinolic acid (Delta(9)-THC-A), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabigerol (CBG) and cannabigerolic acid (CBGA), isolated from Cannabis sativa, were evaluated for their effects on prostaglandin production. For this purpose an in vitro enzyme based COX-1/COX-2 inhibition assay and a cell based prostaglandin production radioimmunoassay were used. Cannabinoids inhibited cyclooxygenase enzyme activity with IC50 values ranging from 1.7.10(-3) to 2.0.10(-4) M.

  • 248.
    Saeed, Aamer
    et al.
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Haroon, Mehfooz
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Muhammad, Faisal
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Larik, Fayaz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Hesham, El-Seedi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Channar, Pervaiz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Advances in transition-metal-catalyzed synthesis of 3-substituted isocoumarins2017Ingår i: Journal of Organometallic Chemistry, ISSN 0022-328X, E-ISSN 1872-8561, Vol. 834, s. 88-103Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    3-Substituted isocoumarins are the most abundant class of naturally isocoumarins, found in several biologically active scaffolds and are precursors towards complex natural products. Considerable attempts have been devoted to the synthesis of these isocoumarins both by metal free or transition-metalcatalyzed reactions. Among the metal catalyzed reactions, the use of palladium, copper, gold, iron, nickel, rhodium, ruthenium, zinc, chromium, iridium, silver or thallium salts/complexes for the construction of 3-substituted isocoumarin ring is noteworthy due to being economical and good functional group tolerance. The current review focusses the recent reports on the Pd-, Cu-, Ag-, Fe-, Ni-, Rh-, Ru-, Zn, Cr-, Ir-, Ag- and Ti -catalyzed synthesis of isocoumarins.

  • 249.
    Sandberg, Finn
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Perera-Ivarsson, Premila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    El-Seedi, Hesham Rushdey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    A Swedish collection of medicinal plants from Cameroon2005Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 102, nr 3, s. 336-343Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A collection of 32 botanically identified medicinal plants from the slopes of Mt. Cameroon made by two Swedish settlers in the beginning of the last century is described and the literature is followed up. The drug names were found to be unaltered during the century passed.

  • 250. Savolainen, Vincent
    et al.
    Fay, Michael F.
    Albach, Dirk C.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    van der Bank, M
    Cameron, Kenneth M.
    Johnson, S A
    Lledo, M D
    Pintaud, J-C
    Powell, M
    Sheahan, M C
    Soltis, Douglas E.
    Soltis, Pamela S.
    Weston, P
    Whitten, W M
    Wurdack, K J
    Chase, Mark W.
    Phylogeny of the eudicots: a nearly complete familial analysis based on rbcL gene sequences2000Ingår i: Kew bulletin, ISSN 0075-5974, E-ISSN 1874-933X, Vol. 55, nr 2, s. 257-309Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A phylogenetic analysis of 589 plastid rbcL gene sequences representing nearly all eudicot families (a total of 308 families; seven photosynthetic and four parasitic families are missing) was performed, and bootstrap re-sampling was used to assess support for clades. Based on these data, the ordinal classification of eudicots is revised following the previous classification of angiosperms by the Angiosperm Phylogeny Group (APG). Putative additional orders are discussed (e.g. Dilleniales, Escalloniales, Vitales), and several additional families are assigned to orders for future updates of the APG classification. The use of rbcL alone in such a large matrix was found to be practical in discovering and providing bootstrap support for most orders. Combination of these data with other matrices for the rest of the angiosperms should provide the framework for a complete phylogeny to be used in macro-evolutionary studies.

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