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  • 1. Abdissa, Negera
    et al.
    Fangfang, Pan
    Gruhonjic, Amra
    Gräfenstein, Jürgen
    Fitzpatrick, Paul A
    Landberg, Göran
    Rissanen, Kari
    Yenesew, Abiy
    Erdelyi, Mate
    Naphthalene Derivatives from the Roots of Pentas parvifolia and Pentas bussei.2016In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 79, no 9, p. 2181-2187Article in journal (Refereed)
    Abstract [en]

    The phytochemical investigation of the CH2Cl2/MeOH (1:1) extract of the roots of Pentas parvifolia led to the isolation of three new naphthalenes, parvinaphthols A (1), B (2), and C (3), two known anthraquinones, and five known naphthalene derivatives. Similar investigation of the roots of Pentas bussei afforded a new polycyclic naphthalene, busseihydroquinone E (4), a new 2,2'-binaphthralenyl-1,1'-dione, busseihydroquinone F (5), and five known naphthalenes. All purified metabolites were characterized by NMR and MS data analyses, whereas the absolute configurations of 3 and 4 were determined by single-crystal X-ray diffraction studies. The E-geometry of compound 5 was supported by DFT-based chemical shift calculations. Compounds 2-4 showed marginal cytotoxicity against the MDA-MB-231 human triple-negative breast cancer cell line with IC50 values ranging from 62.3 to 129.6 μM.

  • 2.
    Bjerketorp, Joakim
    et al.
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Levenfors, Jolanta J
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Sahlberg, Christer
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Nord, Christina L
    Swedish Univ Agr Sci, Uppsala, Sweden; Medivir AB, Huddinge, Sweden.
    Andersson, Pierre F
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Guss, Bengt
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Öberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Ultupharma AB, Uppsala, Sweden.
    Broberg, Anders
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Antibacterial 3,6-Disubstituted 4-Hydroxy-5,6-dihydro-2H-pyran-2-ones from Serratia plymuthica MF371-22017In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 80, no 11, p. 2997-3002Article in journal (Refereed)
    Abstract [en]

    Bioassay-guided fractionation of culture extracts of Serratia plymuthica strain MF371-2 resulted in the isolation of two new antibacterial compounds with potent activity against Gram-positive bacteria, including Staphylococcus aureus LMG 15975 (MRSA). A spectroscopic investigation, in combination with synthesis, enabled the characterization of the compounds as 3-butyryl-4-hydroxy-6-heptyl-5,6-dihydro2H-pyran-2-one (plymuthipyranone A, 1) and 3-butyry1-4-hydroxy-6-nony1-5,6-dihydro-2H-pyran-2-one (plymuthipyranone B, 2). The MIC values for 1 and 2 against S. aureus LMG 15975 were determined to be 1-2 mu g mL(-1) and 0.8 mu g mL(-1), respectively. Compound 2 was found to have potent activity against many strains of S. aureus, including several mupirocin-resistant strains, other species of Staphylococcus, and vancomycin-resistant enterococci. Compound 2 was slightly cytotoxic for human cells, with CC50 values between 4.7 and 40 mu g mL(-1), but the CC50/MIC ratio was >= 10 for many tested combinations of human cells and bacteria, suggesting its possible use as an antibacterial agent. Several analogues were synthesized with different alkyl groups in the 3- and 6-positions (6-13), and their biological properties were evaluated. It was concluded that the activity of the compounds increased with the lengths of the alkyl and acyl substituents.

  • 3.
    Boldbaatar, Delgerbat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Natl Univ Mongolia, Sch Engn & Appl Sci, Ulaanbaatar 46, Mongol Peo Rep..
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis, Structural Characterization, and Bioactivity of the Stable Peptide RCB-1 from Ricinus communis2015In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 78, no 11, p. 2545-2551Article in journal (Refereed)
    Abstract [en]

    The Ricinus communis biomarker peptides RCB-1 to -3 comprise homologous sequences of 19 (RCB-1) or 18 (RCB-2 and -3) amino acid residues. They all include four cysteine moieties, which form two disulfide bonds. However, neither the 3D structure nor the biological activity of any of these peptides is known. The synthesis of RCB-1, using microwave-assisted, Fmoc-based solid-phase peptide synthesis, and a method for its oxidative folding are reported. The tertiary structure of RCB-1, subsequently established using solution-state NMR, reveals a twisted loop fold with antiparallel ?-sheets reinforced by the two disulfide bonds. Moreover, RCB-1 was tested for antibacterial, antifungal, and cytotoxic activity, as well as in a serum stability assay, in which it proved to be remarkably stable.

  • 4.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chemistry and Biology of Cyclotides: Circular Plant Peptides Outside the Box2014In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 77, no 3, p. 724-736Article, review/survey (Refereed)
    Abstract [en]

    Cyclotides stand out as the largest family of circular proteins of plant origin hitherto known, with more than 280 sequences isolated at peptide level and many more predicted from gene sequences. Their unusual stability resulting from the signature cyclic cystine knot (CCK) motif has triggered a broad interest in these molecules for potential therapeutic and agricultural applications. Since the time of the first cyclotide discovery, our laboratory in Uppsala has been engaged in cyclotide discovery as well as the development of protocols to isolate and characterize these seamless peptides. We have also developed methods to chemically synthesize cyclotides by Fmoc-SPPS, which are useful in protein grafting applications. In this review, experience in cyclotide research over two decades and the recent literature related to their structures, synthesis, and folding as well the recent proof-of-concept findings on their use as "epitope" stabilizing scaffolds are summarized.

  • 5.
    Carstens, Bodil B.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia..
    Rosengren, K. Johan
    Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia..
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Schempp, Stefanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Dahlstrom, Mia
    SP Tech Res Inst Sweden, Dept Chem Mat & Surfaces, SE-41346 Gothenburg, Sweden..
    Clark, Richard J.
    Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Isolation, Characterization, and Synthesis of the Barrettides: Disulfide-Containing Peptides from the Marine Sponge Geodia barretti2015In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 78, no 8, p. 1886-1893Article in journal (Refereed)
    Abstract [en]

    Two disulfide-containing peptides, barrettides A (1) and B (2), from the cold-water marine sponge Geodia barretti are described. Those 31 amino acid residue long peptides were sequenced using mass spectrometry methods and structurally characterized using NMR spectroscopy. The structure of 1 was confirmed by total synthesis using the solid-phase peptide synthesis approach that was developed. The two peptides were found to differ only at a single position in their sequence. The three-dimensional structure of 1 revealed that these peptides possess a unique fold consisting of a long beta-hairpin structure that is cross-braced by two disulfide bonds in a ladder-like arrangement. The peptides are amphipathic in nature with the hydrophobic and charged residues clustered on separate faces of the molecule. The barrettides were found not to inhibit the growth of either Escherichia coli or Staphylococcus aureus but displayed antifouling activity against barnacle larvae (Balanus improvisus) without lethal effects in the concentrations tested.

  • 6.
    Claeson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Johansson, Senia
    Luijendijk, Teus
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fractionation protocol for the isolation of polypeptides from plant biomass1998In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, no 1, p. 77-81Article in journal (Refereed)
    Abstract [en]

    A fractionation protocol for the isolation of a highly purified polypeptide fraction from plant biomass is described. The procedure dereplicates ubiquitous substance classes known to interfere with bioassays often used in natural product-based drug discovery programs. The protocol involves pre-extraction with dichloromethane, extraction with ethanol (50%), removal of tannins with polyamide, removal of low-molecular-weight components with size-exclusion chromatography over Sephadex G-10, and final removal of salts and polysaccharides with solid-phase extraction using reversed-phase cartridges. The method has been applied to the aerial parts of Viola arvensis, resulting in the isolation of a peptide fraction that on further separation yielded a novel 29-residue macrocyclic polypeptide named varv peptide A, cyclo(-TCVGGTCNTPGCSCSWPVCTRNGLPVCGE-).

  • 7.
    Claeson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Johansson, Senia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Luijendijk, Teus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fractionation protocol for the isolation of polypeptides from plant biomass1998In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, no 1, p. 77-81Article in journal (Refereed)
  • 8. Deyou, Tsegaye
    et al.
    Marco, Makungu
    Heydenreich, Matthias
    Pan, Fangfang
    Gruhonjic, Amra
    Fitzpatrick, Paul A
    Koch, Andreas
    Derese, Solomon
    Pelletier, Jerry
    Rissanen, Kari
    Yenesew, Abiy
    Erdelyi, Mate
    Isoflavones and Rotenoids from the Leaves of Millettia oblata ssp. teitensis.2017In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 80, no 7, p. 2060-2066Article in journal (Refereed)
    Abstract [en]

    A new isoflavone, 8-prenylmilldrone (1), and four new rotenoids, oblarotenoids A-D (2-5), along with nine known compounds (6-14), were isolated from the CH2Cl2/CH3OH (1:1) extract of the leaves of Millettia oblata ssp. teitensis by chromatographic separation. The purified compounds were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of the rotenoids were established on the basis of chiroptical data and in some cases by single-crystal X-ray crystallography. Maximaisoflavone J (11) and oblarotenoid C (4) showed weak activity against the human breast cancer cell line MDA-MB-231 with IC50 values of 33.3 and 93.8 μM, respectively.

  • 9.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Antimicrobial arylcoumarins from Asphodelus microcarpus2007In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 70, no 1, p. 118-120Article in journal (Refereed)
    Abstract [en]

    A new aryl coumarin glucoside, asphodelin A 4'-O-beta-d-glucoside (1), and its aglycon, asphodelin A (2), were isolated from Asphodelus microcarpus. The structures were determined by detailed spectroscopic analysis and chemical transformation as 3-(2'-hydroxy-p-O-beta-d-glucopyranosyloxyphenyl)-4,7-dihydroxy-2H-1-benzopyran-2-one (1) and 3-(2',4'-dihydroxyphenyl)-4,7-dihydroxy-2H-1-benzopyran-2-one (2), respectively. These compounds were isolated following bioactivity-directed fractionation, using antimicrobial activity, in which 1 and 2 exhibited moderate and potent activities, respectively. This is the first report of a 3-arylcoumarin derivative, a rare class of isoflavonoids, from a plant in the family Liliaceae.

  • 10. Endale, Milkyas
    et al.
    Ekberg, Annabel
    Akala, Hoseah M
    Alao, John Patrick
    Sunnerhagen, Per
    Yenesew, Abiy
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Busseihydroquinones A-D from the roots of Pentas bussei2012In: Journal of Natural Products, ISSN 0163-3864, E-ISSN 1520-6025, Vol. 75, no 7, p. 1299-1304Article in journal (Refereed)
    Abstract [en]

    Four new naphthohydroquinones, named busseihydroquinones A-D (1-4), along with a known homoprenylated dihydronaphthoquinone (5), were isolated from the CH(2)Cl(2)/MeOH (1:1) extract of the roots of Pentas bussei. Although the genus Pentas is frequently used by traditional healers for the treatment of malaria, only marginal activities against the chloroquine-sensitive (D6) and the chloroquine-resistant (W2) strains of Plasmodium falciparum were observed for the crude root extract and the isolated constituents of this plant.

  • 11.
    Felth, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Rosén, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wickström, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindskog, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs2009In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 72, no 11, p. 1969-1974Article in journal (Refereed)
    Abstract [en]

    Cardiac glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies against colorectal cancer are lacking. In a screening procedure aimed at identifying natural products with activity against colon cancer, several cardiac glycosides were shown to be of interest, and five of these were further evaluated in different colorectal cancer cell lines and primary cells from patients. Convallatoxin (1), oleandrin (4), and proscillaridin A (5) were identified as the most potent compounds (submicromolar IC50 values), and digitoxin (2) and digoxin (3), which are used in cardiac disease, exhibited somewhat lower activity (IC50 values 0.27−4.1 μM). Selected cardiac glycosides were tested in combination with four clinically relevant cytotoxic drugs (5-fluorouracil, oxaliplatin, cisplatin, irinotecan). The combination of 2 and oxaliplatin exhibited synergism including the otherwise highly drug-resistant HT29 cell line. A ChemGPS-NP application comparing modes of action of anticancer drugs identified cardiac glycosides as a separate cluster. These findings demonstrate that such substances may exhibit significant activity against colorectal cancer cell lines, by mechanisms disparate from currently used anticancer drugs, but at concentrations generally considered not achievable in patient plasma.

  • 12.
    Ferreira, Ricardo J.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Univ Lisbon, Fac Pharm, iMed ULisboa Res Inst Med, Ave Prof Gama Pinto, P-1649003 Lisbon, Portugal.
    Kincses, Annamaria
    Univ Szeged, Fac Med, Dept Med Microbiol & Immunobiol, Dom Ter 10, H-6720 Szeged, Hungary.
    Gajdacs, Mario
    Univ Szeged, Fac Med, Dept Med Microbiol & Immunobiol, Dom Ter 10, H-6720 Szeged, Hungary.
    Spengler, Gabriella
    Univ Szeged, Fac Med, Dept Med Microbiol & Immunobiol, Dom Ter 10, H-6720 Szeged, Hungary.
    dos Santos, Daniel J. V. A.
    Univ Lisbon, Fac Pharm, iMed ULisboa Res Inst Med, Ave Prof Gama Pinto, P-1649003 Lisbon, Portugal;Univ Porto, Dept Chem & Biochem, Fac Sci, LAQV REQUIMTE, Rua Campo Alegre, P-4169007 Porto, Portugal.
    Molnar, Joseph
    Univ Szeged, Fac Med, Dept Med Microbiol & Immunobiol, Dom Ter 10, H-6720 Szeged, Hungary.
    Ferreira, Maria-Jose U.
    Univ Lisbon, Fac Pharm, iMed ULisboa Res Inst Med, Ave Prof Gama Pinto, P-1649003 Lisbon, Portugal.
    Terpenoids from Euphorbia pedroi as Multidrug-Resistance Reversers2018In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 81, no 9, p. 2032-2040Article in journal (Refereed)
    Abstract [en]

    The phytochemical study of Euphorbia pedroi led to the isolation of a new tetracyclic triterpenoid with an unusual spiro scaffold, spiropedroxodiol (1), along with seven known terpenoids (2-8). Aiming at obtaining compounds with improved multidrug-resistance (MDR) reversal activity, compound 8, an ent-abietane diterpene, was derivatized by introducing nitrogen-containing and aromatic moieties, yielding compounds 9-14. The structures of compounds were characterized by detailed spectroscopic analysis, including 2D NMR experiments (COSY, HMQC/HSQC, HMBC, and NOESY). Compounds 1-14 were evaluated for their MDR-reversing activity on human ABCB1 gene transfected mouse lymphoma cells (L5178Y-MDR) through a combination of functional and chemosensitivity assays. The natural compounds 1-8 were further evaluated on resistant human colon adenocarcinoma cells (Colo320), and, additionally, their cytotoxicity was assessed on noncancerous mouse (NIH/3T3) and human (MRC-5) embryonic fibroblast cell lines. While spiropedroxodiol (1) was found to be a very strong MDR reversal agent in both L5178Y-MDR and Colo320 cells, the chemical modifications of helioscopinolide E (8) at C-3 positively contributed to increase the MDR reversal activity of compounds 10, 12, and 13. Furthermore, in combination assays, compounds 1 and 7-14 enhanced synergistically the cytotoxicity of doxorubicin. Finally, by means of molecular docking, the key residues and binding modes by which compounds 1-14 may interact with a murine P-glycoprotein model were identified, allowing additional insights on the efflux modulation mechanism of these compounds.

  • 13. Gerlach, Samantha L.
    et al.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Mondal, Debasis
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Isolation, Characterization, and Bioactivity of Cyclotides from the Micronesian Plant Psychotria leptothyrsa2010In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 73, no 7, p. 1207-1213Article in journal (Refereed)
    Abstract [en]

    Cyclotides, the largest known family of head-to-tail cyclic peptides, have approximately 30 amino acid residues with a complex structure containing a circular peptide backbone and a cystine knot. They are found in plants from the Violaceae and Rubiaceae families and are speculated to function in plant protection. In addition to their insecticidal properties, cyclotides display cytotoxic. anti-IIIV, antimicrobial, and inhibition of neurotensin binding activities. Although cyclotides are present in all violaceous species hitherto screened, their distribution and expression in Rubiaceae are not fully understood. In this study, we show that Psychotria leptothyrsa var. longicarpa (Rubiaceae) contains a suite of different cyclotides. The cyclotide fractions were isolated by RP-HPLC, and sequences of six new peptides, named psyles A-F. were determined by MS/MS sequencing. One or these, psyle C. is the first rubiaceous linear variant known. Psyles A, C, and E were analyzed in a fluorometric microculture assay to determine cytotoxicity toward the human lymphoma cell line U937-GTB. The IC50 values of psylcs A. C. and E were 26, 3.50, and 0.76 mu M. respectively. This study expands the number of known rubiaceous cyclotides and shows that the linear cyclotide maintains cytotoxicity.

  • 14. Gumula, Ivan
    et al.
    Alao, John Patrick
    Ndiege, Isaiah Omolo
    Sunnerhagen, Per
    Yenesew, Abiy
    Erdelyi, Mate
    Flemingins G-O, cytotoxic and antioxidant constituents of the leaves of Flemingia grahamiana.2014In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 77, p. 2060-2067Article in journal (Refereed)
    Abstract [en]

    The known flemingins A-C (1-3) and nine new chalcones, named flemingins G-O (4-12), along with deoxyhomoflemingin (13) and emodin (14) were isolated from a leaf extract of Flemingia grahamiana. The isolated chalcones were found to have a geranyl substituent modified into a chromene ring possessing a residual chain, as shown by spectroscopic methods. The leaf extract showed an IC50 value of 5.9 μg/mL in a DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay. The chalcones flemingins A, B, C, G, and H were active in the DPPH radical scavenging assay (ED50 4.4-8.9 μM), while flemingins A and C showed cytotoxicity against MCF-7 human breast cancer cells (IC50 8.9 and 7.6 μM, respectively).

  • 15.
    Göransson, Ulf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Luijendijk, Teus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Johansson, Senia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Seven novel macrocyclic polypeptides from Viola arvensis1999In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 62, no 2, p. 283-286Article in journal (Refereed)
    Abstract [en]

    Seven novel macrocyclic polypeptides, designated as varv peptides B-H, have been isolated from the aerial parts of Viola arvensis. Their primary structures have been elucidated by automated Edman degradation and mass spectrometry. They all consist of 29 or 30 amino acid residues, covalently cyclized via the amide backbone and by three internal disulfide bridges. Their amino acid sequences are as follows: varv peptide B, cyclo-(TCFGGTCNTPGCSCDPWPMCSRNGLPVCGE); varv peptide C, cyclo-(TCVGGTCNTPGCSCSWPVCTRNGVPICGE); varv peptide D, cyclo-(TCVGGSCNTPGCSCSWPVCTRNGLPICGE); varv peptide E, cyclo-(TCVGGTCNTPGCSCSWPVCTRNGLPICGE); varv peptide F, cyclo-(TCTLGTCYTAGCSCSWPVCTRNGVPICGE); varv peptide G, cyclo-(TCFGGTCNTPGCSCDPWPVCSRNGVPVCGE); and varv peptide H, cyclo-(TCFGGTCNTPGCSCETWPVCSRNGLPVCGE). The varv peptides B-H exhibited high degrees of homology with the hitherto known macrocyclic peptides varv peptide A, kalata B1, violapeptide I, circulins A and B, and cyclopsychotride A.

  • 16.
    Hedner, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Sjögren, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Frändberg, Per-Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Johansson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Dahlström, Mia
    Jonsson, Per R.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands2006In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 69, no 10, p. 1421-1424Article in journal (Refereed)
    Abstract [en]

    The brominated cyclodipeptides barettin(cyclo[(6-bromo-8-entryptophan) arginine]) and 8,9-dihydrobarettin ( cyclo[(6-bromotryptophan) arginine]) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose-dependent manner in concentrations ranging from 0.5 to 25 mu M. To further establish the molecular target and mode of action of these compounds, we investigated their affinity to human serotonin receptors. The tryptophan residue in the barettins resembles that of endogenous serotonin [5-hydroxytryptamine]. A selection of human serotonin receptors, including representatives from all subfamilies (1-7), were transfected into HEK-293 cells. Barettin selectively interacted with the serotonin receptors 5-HT2A, 5-HT2C, and 5-HT4 at concentrations close to that of endogenous serotonin, with the corresponding K-i values being 1.93, 0.34, and 1.91 mu M, respectively. 8,9-Dihydrobarettin interacted exclusively with the 5-HT2C receptor with a K-i value of 4.63 mu M; it failed to show affinity to 5-HT2A and 5-HT4, indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins.

  • 17.
    Hedner, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Sjögren, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hodzic, Said
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Andersson, Rolf
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jonsson, Per R.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Antifouling activity of a dibrominated cyclopeptide from the marine sponge Geodia barretti2008In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 71, no 3, p. 330-333Article in journal (Refereed)
    Abstract [en]

    Many sessile suspension-feeding marine organisms rely on chemical defense to keep their surfaces free from fouling organisms. The brominated cyclopeptides barettin (cyclo[(6-bromo-8-entryptophan)arginine]) (1) and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) (2) from the cold-water sponge Geodia barretti have previously displayed settlement inhibition of barnacle larvae in a dose-dependent manner. In this paper, we describe a novel dibrominated cyclopeptide, bromobenzisoxazolone barettin (cyclo[(6-bromo-8-(6-bromobenzioxazol-3(1H)-one)-8-hydroxy)tryptophan)]arginine) (3), which we have isolated from G. barretti and which displays settlement inhibition of barnacle larvae (Balanus improvisus) with an EC50 value of 15 nM. The chemical structure was determined using MS and 2D-NMR.

  • 18.
    Henz Ryen, Astrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Charting Angiosperm Chemistry: Evolutionary Perspective on Specialized Metabolites Reflected in Chemical Property Space2019In: Journal of Natural Products, ISSN 0163-3864, E-ISSN 1520-6025, Vol. 82, no 4, p. 798-812Article in journal (Refereed)
    Abstract [en]

    Plants possess an outstanding chemical diversity of specialized metabolites developed to adapt to environmental niches and increase fitness. The observed diversity is hypothesized to result from various evolutionary mechanisms, such as the continuous branching off and extension of existing biosynthetic pathways or enhanced levels of catalytic promiscuity in certain enzymes. In this study, ChemGPS-NP has been employed to chart the distribution and diversity of physicochemical properties for selected types of specialized metabolites from the angiosperms. Utilizing these charts, it is analyzed how different properties of various types of specialized metabolites change in different plant groups, and the chemical diversity from the volume they occupy in chemical property space is evaluated. In this context, possible underlying evolutionary mechanisms are discussed, which could explain the observed distribution and behavior in chemical property space. Based on these studies, it is demonstrated that evolutionary processes in plant specialized metabolism and the resultant metabolic diversification are reflected in chemical property space.

  • 19.
    Hsu, Yu-Ming
    et al.
    Kaohsiung Med Univ, Coll Pharm, Grad Inst Nat Prod, Kaohsiung 80708, Taiwan..
    Chang, Fang-Rong
    Kaohsiung Med Univ, Coll Pharm, Grad Inst Nat Prod, Kaohsiung 80708, Taiwan.;Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung 80708, Taiwan.;Kaohsiung Med Univ, Res Ctr Environm Med, Kaohsiung 80708, Taiwan.;Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung 80424, Taiwan.;Kaohsiung Med Univ Hosp, Ctr Canc, Kaohsiung 80708, Taiwan..
    Lo, I-Wen
    Kaohsiung Med Univ, Coll Pharm, Grad Inst Nat Prod, Kaohsiung 80708, Taiwan..
    Lai, Kuei-Hung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Kaohsiung Med Univ, Coll Pharm, Grad Inst Nat Prod, Kaohsiung 80708, Taiwan..
    El-Shazly, Mohamed
    Ain Shams Univ, Fac Pharm, Dept Pharmacognosy & Nat Prod Chem, Cairo 11566, Egypt..
    Wu, Tung-Ying
    China Med Univ Hosp, Chinese Med Res & Dev Ctr, Taichung 40402, Taiwan. China Med Univ Hosp, Ctr Mol Med, Taichung 40402, Taiwan..
    Du, Ying-Chi
    Kaohsiung Med Univ, Coll Pharm, Grad Inst Nat Prod, Kaohsiung 80708, Taiwan..
    Hwang, Tsong-Long
    Chang Gung Univ Sci & Technol, Res Ctr Chinese Herbal Med, Res Ctr Ind Human Ecol, Taoyuan 33302, Taiwan.;Chang Gung Mem Hosp, Dept Anesthesiol, Taoyuan 33302, Taiwan. China Med Univ, Sch Pharm, Coll Pharm, Taichung 40402, Taiwan. China Med Univ, Res Ctr Chinese Herbal Med, Taichung 40402, Taiwan..
    Cheng, Yuan-Bin
    Kaohsiung Med Univ, Coll Pharm, Grad Inst Nat Prod, Kaohsiung 80708, Taiwan.;Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung 80708, Taiwan.;Kaohsiung Med Univ, Res Ctr Nat Prod & Drug Dev, Kaohsiung 80708, Taiwan..
    Wu, Yang-Chang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Kaohsiung Med Univ, Coll Pharm, Grad Inst Nat Prod, Kaohsiung 80708, Taiwan.;Ain Shams Univ, Fac Pharm, Dept Pharmacognosy & Nat Prod Chem, Cairo 11566, Egypt.;China Med Univ Hosp, Chinese Med Res & Dev Ctr, Taichung 40402, Taiwan. China Med Univ Hosp, Ctr Mol Med, Taichung 40402, Taiwan.;Chang Gung Univ, Grad Inst Nat Prod, Coll Med, Taoyuan 33302, Taiwan..
    Zoanthamine-Type Alkaloids from the Zoanthid Zoanthus kuroshio Collected in Taiwan and Their Effects on Inflammation2016In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 79, no 10, p. 2674-2680Article in journal (Refereed)
    Abstract [en]

    Zoanthus kuroshio is a colorful zoanthid with a fluorescent pink oral disc and brown tentacles, which dominates certain parts of the Taiwanese and Japanese coasts. This sea anemone is a rich source of biologically active alkaloids. In the current investigation, two novel halogenated zoanthamines [5 alpha-iodozoanthenamine (1) and 11 beta-chloro-11-deoxykuroshine A (2)], along with four new zoanthamines [18-epi-kuroshine A (3), 7 alpha-hydroxykuroshine E (4), 5 alpha-methoxykuroshine E (5), and 18-epi-kuroshine E (6)], and six known compounds were isolated from Z. kuroshio. Compounds 1 and 2 are the first examples of halogenated zoanthamine-type alkaloids isolated from nature. Compounds 3 and 6 are the first zoanthamine stereoisomers with a cis-junction of the A/B rings. All isolated compounds were evaluated for their anti-inflammatory activities by measuring their effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP.

  • 20.
    Huss, U
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Ringbom, T
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Perera, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Vasänge, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Screening of ubiquitous plant constituents for COX-2 inhibition with a scintillation proximity based assay2002In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 65, no 11, p. 1517-1521Article in journal (Refereed)
    Abstract [en]

    A rapid semi-homogeneous cyclooxygenase-2 (COX-2) enzymatic assay using scintillation proximity assay (SPA) technology was developed, and 49 ubiquitous plant secondary metabolites were screened for inhibition of COX-2-catalyzed prostaglandin E(2) (PGE(2)) biosynthesis. Assay conditions were optimized with respect to reaction time, amount of antibody, radiolabeled PGE(2), and SPA beads, and the kinetic parameter, K(m), was estimated. The assay was validated with two natural triterpenoids, ursolic and oleanolic acid, known to inhibit COX-2, as well as with four synthetic COX inhibitors, NS-398, rofecoxib, indomethacin, and aspirin. Plant metabolites of different biosynthetic origin representing several substance classes, including alkaloids, anthraquinones, flavonoids, phenylpropanes, steroids, and terpenes, were screened for inhibition of COX-2-catalyzed PGE(2) production. Of these 49 plant metabolites, eugenol, pyrogallol, and cinnamaldehyde (with IC(50) values of 129, 144, and 245 microM, respectively) were found to inhibit COX-2. This study showed that a COX-2-catalyzed PGE(2) assay using SPA is suitable for screening natural compounds with respect to COX-2 inhibition.

  • 21.
    Johansson, Senia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Luijendijk, Teus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    A neutrophil multitarget functional bioassay to detect anti-inflammatory natural products2002In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 65, no 1, p. 32-41Article in journal (Refereed)
    Abstract [en]

    A multitarget functional bioassay was optimized as a method for detecting substances interacting with the inflammatory process of activated neutrophil granulocytes, mainly to release elastase detected by p-nitroanilide (pNA) formation. Using this bioassay, 100 fractionated extracts of 96 plants were screened, with results presented in a manner that links recorded biological activity to phylogenetic information. The plants were selected to represent a major part of the angiosperms, with emphasis on medicinal plants, Swedish anti-inflammatory plants, and plants known to contain peptides. Of the tested extracts, 41% inhibited pNA formation more than 60%, and 3% stimulated formation. The extract of Digitalbis purpurea enhanced pNA formation, and digitoxin, the active compound, was isolated and identified. Plant extracts that exhibited potent nonselective inhibition (> 80% inhibition) were evaluated further for direct inhibition of isolated elastase and trypsin enzyme. The inhibitory effect of most tested extracts on the isolated enzyme elastase was similar to that of PAF- and fMLP-induced pNA formation. Compared to trypsin, inhibition of elastase by extracts of Rubus idaeus and Tabernaemontana dichotoma was significantly higher (80% and 99%, respectively). Inhibition of trypsin by the extract of Reseda luteola was high 97%. Orders such as Lamiales and Brassicales were shown to include a comparably high proportion of plants with inhibitory extracts.

  • 22. Kraus, Christina M
    et al.
    Neszmelyi, András
    Holly, Sándor
    Wiedemann, Beate
    Nenninger, Anneli
    Torsell, Kurt B G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wagner, Hildebert
    New acetylenes isolated from the bark of Heisteria acuminata1998In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, no 4, p. 422-427Article in journal (Refereed)
    Abstract [en]

    Five new linear acetylenic compounds, namely, pentadeca-6,8,10-triynoic acid (1), octadeca-8,10,12-triynoic acid (2), trans-pentadec-10-en-6,8-diynoic acid (3), cis-hexadec-11-en-7,9-diynoic acid (4), and cis-octadec-12-en-7,9-diynoic acid (5), were isolated from the bark of Heisteria acuminata by bioassay-guided fractionation, using cyclooxygenase (COX) and 5-lipoxygenase (5-LO) assays as models for antiinflammatory activity. The structures of compounds 1-5 were established by NMR, MS, IR, and Raman spectroscopy. These isolated compounds were found to be potent inhibitors of COX. Compounds 4 and 5 were the most potent inhibitors of 5-LO, whereas the other compounds only showed a weak inhibition at the same concentration.

  • 23.
    Lai, Kuei-Hung
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lu, Mei-Chin
    Du, Ying-Chi
    El-Shazly, Mohamed
    Wu, Tung-Ying
    Hsu, Yu-Ming
    Henz, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Yang, Juan-Cheng
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chang, Fang-Rong
    Wu, Yang-Chang
    Cytotoxic Lanostanoids from Poria cocos2016In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 79, no 11, p. 2805-2813Article in journal (Refereed)
    Abstract [en]

    Six new and 16 known lanostanoids were isolated from the sclerotia of Poria cocos. The structures of the new isolates were elucidated to be 16α-hydroxy-3-oxo-24-methyllanosta-5,7,9(11),24(31)-tetraen-21-oic acid (1), 3β,16α,29-trihydroxy-24-methyllanosta-7,9(11),24(31)-trien-21-oic acid (2), 3β,16α,30-trihydroxy-24-methyllanosta-7,9(11),24(31)-trien-21-oic acid (3), 3β-acetoxy-16α,24β-dihydroxylanosta-7,9(11),25-trien-21-oic acid (4), 3β,16α-dihydroxy-7-oxo-24-methyllanosta-8,24(31)-dien-21-oic acid (5), and 3α,16α-dihydroxy-7-oxo-24-methyllanosta-8,24(31)-dien-21-oic acid (6), based on extensive spectroscopic analyses. The absolute configuration of 4 was determined using Mosher's method. The antiproliferative activity of the isolated compounds (except 3 and 4) was evaluated against four leukemic cell lines (Molt 4, CCRF-CEM, HL 60, and K562). Dehydropachymic acid (9), dehydroeburicoic acid (12), pachymic acid (14), and lanosta-7,9(11),24-trien-21-oic acid (20) exhibited an antiproliferative effect on the CCRF-CEM cancer cell line with IC50 values of 2.7, 6.3, 4.9, and 13.1 μM, respectively. Both dehydropachymic acid (9) and dehydroeburicoic acid (12) showed antiproliferative effects against Molt 4 (IC50 13.8 and 14.3 μM) and HL 60 (IC50 7.3 and 6.0 μM) leukemic cell lines. Primary computational analysis using a chemical global positioning system for natural products (ChemGPS-NP) on the active lanostanoids from P. cocos suggested that targets other than topoisomerases may be involved in the antiproliferative activity.

  • 24.
    Larsson, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gottfries, Johan
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Expanding the ChemGPS chemical space with natural products2005In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 68, no 7, p. 985-991Article in journal (Refereed)
    Abstract [en]

    Recently various attempts have been made to increase the efficacy and precision of chemical libraries used in high-throughput screening (HTS) drug discovery approaches. One such approach is ChemGPS, which provides a defined chemical space for prescreening evaluation of chemical compound properties or virtual dereplication. In the present study, ChemGPS has been applied to a set of natural products shown to exhibit cyclooxygenase-1 and/or -2 (COX-1/2) inhibition. With the purpose of defining chemical properties and linking these to the observed mode of enzyme inhibition, this resulted in two lines of reasoning. On one hand several specific features of these compounds have been identified and discussed. Overall COX inhibition was frequently correlated with the presence of at least one ring in the structure, fragments exhibiting structural rigidity, and a relatively large molecular size. The concept "size" includes several parameters, e.g., molecular volume, weight, and number of bonds. On the other hand, and possibly even more important, was the unexpected finding that the natural products studied to a large extent fell outside the defined ChemGPS chemical space. Therefore, we also propose an expanded space for natural products: ChemGPS-NP.

  • 25.
    Larsson, Josefin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gottfries, Johan
    Muresan, Sorel
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    ChemGPS-NP: tuned for navigation in biologically relevant chemical space2007In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 70, no 5, p. 789-794Article in journal (Refereed)
    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.

  • 26.
    Noreen, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Perera, Premila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Two new isoflavones from Ceiba pentandra and their effect on cyclooxygenase-catalyzed prostaglandin biosynthesis1998In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, no 1, p. 8-12Article in journal (Refereed)
    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).

  • 27.
    Noreen, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Ringbom, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Perera, Premila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Danielson, Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Development of a radiochemical cyclooxygenase-1 and 2 in vitro assay for identification of natural products as inhibitors of prostaglandin biosynthesis1998In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, no 1, p. 2-7Article in journal (Refereed)
  • 28. Nyandoro, Stephen S
    et al.
    Munissi, Joan J E
    Gruhonjic, Amra
    Duffy, Sandra
    Pan, Fangfang
    Puttreddy, Rakesh
    Holleran, John P
    Fitzpatrick, Paul A
    Pelletier, Jerry
    Avery, Vicky M
    Rissanen, Kari
    Erdélyi, Máté
    Polyoxygenated Cyclohexenes and Other Constituents of Cleistochlamys kirkii Leaves.2017In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 80, no 1, p. 114-125Article in journal (Refereed)
    Abstract [en]

    Thirteen new metabolites, including the polyoxygenated cyclohexene derivatives cleistodiendiol (1), cleistodienol B (3), cleistenechlorohydrins A (4) and B (5), cleistenediols A-F (6-11), cleistenonal (12), and the butenolide cleistanolate (13), 2,5-dihydroxybenzyl benzoate (cleistophenolide, 14), and eight known compounds (2, 15-21) were isolated from a MeOH extract of the leaves of Cleistochlamys kirkii. The purified metabolites were identified by NMR spectroscopic and mass spectrometric analyses, whereas the absolute configurations of compounds 1, 17, and 19 were established by single-crystal X-ray diffraction. The configuration of the exocyclic double bond of compound 2 was revised based on comparison of its NMR spectroscopic features and optical rotation to those of 1, for which the configuration was determined by X-ray diffraction. Observation of the co-occurrence of cyclohexenoids and heptenolides in C. kirkii is of biogenetic and chemotaxonomic significance. Some of the isolated compounds showed activity against Plasmodium falciparum (3D7, Dd2), with IC50 values of 0.2-40 μM, and against HEK293 mammalian cells (IC50 2.7-3.6 μM). While the crude extract was inactive at 100 μg/mL against the MDA-MB-231 triple-negative breast cancer cell line, some of its isolated constituents demonstrated cytotoxic activity with IC50 values ranging from 0.03-8.2 μM. Compound 1 showed the most potent antiplasmodial (IC50 0.2 μM) and cytotoxic (IC50 0.03 μM, MDA-MB-231 cell line) activities. None of the compounds investigated exhibited translational inhibitory activity in vitro at 20 μM.

  • 29. Nyandoro, Stephen S
    et al.
    Munissi, Joan J E
    Kombo, Msim
    Mgina, Clarence A
    Pan, Fangfang
    Gruhonjic, Amra
    Fitzpatrick, Paul
    Lu, Yu
    Wang, Bin
    Rissanen, Kari
    Erdelyi, Mate
    Flavonoids from Erythrina schliebenii.2017In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 80, no 2, p. 377-383Article in journal (Refereed)
    Abstract [en]

    Prenylated and O-methylflavonoids including one new pterocarpan (1), three new isoflavones (2-4), and nineteen known natural products (5-23) were isolated and identified from the root, stem bark, and leaf extracts of Erythrina schliebenii. The crude extracts and their constituents were evaluated for antitubercular activity against Mycobacterium tuberculosis (H37Rv strain), showing MICs of 32-64 μg mL-1 and 36.9-101.8 μM, respectively. Evaluation of their toxicity against the aggressive human breast cancer cell line MDA-MB-231 indicated EC50 values of 13.0-290.6 μM (pure compounds) and 38.3 to >100 μg mL-1 (crude extracts).

  • 30. Nyandoro, Stephen S
    et al.
    Ndanu, Joseph
    Munissi, Joan J E
    Gruhonjic, Amra
    Fitzpatrick, Paul A
    Landberg, Göran
    Lu, Yu
    Wang, Bin
    Pan, Fangfang
    Rissanen, Kari
    Erdelyi, Mate
    N-Cinnamoyltetraketide Derivatives from the Leaves of Toussaintia orientalis.2015In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 78, no 8, p. 2045-2050Article in journal (Refereed)
    Abstract [en]

    Seven N-cinnamoyltetraketides (1-7), including the new Z-toussaintine E (2), toussaintine F (6), and toussaintine G (7), were isolated from the methanol extract of the leaves of Toussaintia orientalis using column chromatography and HPLC. The configurations of E-toussaintine E (1) and toussaintines A (3) and D (5) are revised based on single-crystal X-ray diffraction data from racemic crystals. Both the crude methanol extract and the isolated constituents exhibit antimycobacterial activities (MIC 83.3-107.7 μM) against the H37Rv strain of Mycobacterium tuberculosis. Compounds 1, 3, 4, and 5 are cytotoxic (ED50 15.3-105.7 μM) against the MDA-MB-231 triple negative aggressive breast cancer cell line.

  • 31.
    Ogundaini, Abiodun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Farah, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Perera, Premila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Samuelsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Isolation of two new antiinflammatory biflavanoids from Sarcophyte piriei1996In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 59, no 6, p. 587-590Article in journal (Refereed)
    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.

  • 32.
    Ringbom, Therese
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Huss, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Stenholm, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Flock, S
    Skattebol, L
    Perera, Premila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Cox-2 inhibitory effects of naturally occurring and modified fatty acids2001In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 64, no 6, p. 745-749Article in journal (Refereed)
    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.

  • 33.
    Ringbom, Therese
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Segura, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Noreen, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Perera, Premila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Ursolic acid from Plantago major, a selective inhibitor of cyclooxygenase-2 catalyzed prostaglandin biosynthesis1998In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 61, no 10, p. 1212-1215Article in journal (Refereed)
    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.

  • 34.
    Sjögren, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Johnson, Ann-Louise
    Dahlström, Mia
    Andersson, Rolf
    Bergman, Jan
    Jonsson, Per R
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Antifouling Activity of Brominated Cyclopeptides from the Marine Sponge Geodia barretti2004In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 67, no 3, p. 368-372Article in journal (Refereed)
    Abstract [en]

    In this work, we show the potent antifouling effects of two compounds, barettin (cyclo[(6-bromo-8-entryptophan)arginine]) (1), isolated as a Z/E mixture (87/13), and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) (2), isolated from the marine sponge Geodia barretti. The compounds were isolated guided by their ability to inhibit the settlement of cyprid larvae of the barnacle Balanusimprovisus, and their structures were determined by means of mass spectrometry, NMR, and quantitative amino acid analysis. The activities of these brominated diketopiperazine-like cyclic dipeptides are in the range of antifouling agents in use today, as shown by their EC(50) values of 0.9 and 7.9 microM, respectively. However, contrary to today's antifouling agents, the effects of barettin and 8,9-dihydrobarettin are nontoxic and reversible. A small set of synthetic analogues, including l-arginine, l-tryptophan, 5-bromo-d,l-tryptophan, 6-bromo-d,l-tryptophan, and 6-fluoro-d,l-tryptophan, were tested for possible structure-activity relationships. None of these compounds showed any effect at a concentration of 10 microM. We hypothesize that the isolated compounds are part of the sponge's chemical defense to deter fouling organisms. This theory is supported by the fact that barettin is found in water exposed to living specimens of G. barretti in concentrations that completely inhibit barnacles from settling.

  • 35.
    Sjögren, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Johnson, Ann-Louise
    Dahlström, Mia
    Andersson, Rolf
    Bergman, Jan
    Jonsson, Per R
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Antifouling activity of brominated cyclopeptides from the marine sponge Geodia barretti2004In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 67, no 3, p. 368-372Article in journal (Refereed)
    Abstract [en]

    In this work, we show the potent antifouling effects of two compounds, barettin (cyclo[(6-bromo-8-entryptophan)arginine]) (1), isolated as a Z/E mixture (87/13), and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) (2), isolated from the marine sponge Geodia barretti. The compounds were isolated guided by their ability to inhibit the settlement of cyprid larvae of the barnacle Balanusimprovisus, and their structures were determined by means of mass spectrometry, NMR, and quantitative amino acid analysis. The activities of these brominated diketopiperazine-like cyclic dipeptides are in the range of antifouling agents in use today, as shown by their EC(50) values of 0.9 and 7.9 microM, respectively. However, contrary to today's antifouling agents, the effects of barettin and 8,9-dihydrobarettin are nontoxic and reversible. A small set of synthetic analogues, including l-arginine, l-tryptophan, 5-bromo-d,l-tryptophan, 6-bromo-d,l-tryptophan, and 6-fluoro-d,l-tryptophan, were tested for possible structure-activity relationships. None of these compounds showed any effect at a concentration of 10 microM. We hypothesize that the isolated compounds are part of the sponge's chemical defense to deter fouling organisms. This theory is supported by the fact that barettin is found in water exposed to living specimens of G. barretti in concentrations that completely inhibit barnacles from settling.

  • 36.
    Sjögren, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jonsson, Per R.
    Dahlström, Mia
    Lundälv, Tomas
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Two Brominated Cyclic Dipeptides Released by the Coldwater Marine Sponge Geodia barretti Act in Synergy As Chemical Defense2011In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 74, no 3, p. 449-454Article in journal (Refereed)
    Abstract [en]

    The current work shows that two structurally similar cyclodipeptides, barettin (1) and 8,9-dihydrobarettin (2), produced by the coldwater marine sponge Geodia barretti Bowerbank act in synergy to deter larvae of surface settlers and may also be involved in defense against grazers. Previously, 1 and 2 were demonstrated to bind specifically to serotonergic 5-HT receptors. It may be suggested that chemical defense in G. barretti involves a synergistic action where one of the molecular targets is a 5-HT receptor. A mixture of 1 and 2 lowered the EC50 of larval settlement as compared to the calculated theoretical additive effect of the two compounds. Moreover, an in situ sampling at 120 m depth using a remotely operated vehicle revealed that the sponge releases these two compounds to the ambient water. Thus, it is suggested that the synergistic action of 1 and 2 may benefit the sponge by reducing the expenditure of continuous production and release of its chemical defense substances. Furthermore, a synergistic action between structurally closely related compounds produced by the same bioenzymatic machinery ought to be the most energy effective for the organism and, thus, is more common than synergy between structurally indistinct compounds.

  • 37.
    Svangård, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lövborg, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes2007In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 70, no 4, p. 643-647Article in journal (Refereed)
    Abstract [en]

    In recent years, the cyclotides have emerged as the largest family of naturally cyclized proteins. Cyclotides display potent cytotoxic activity that varies with the structure of the proteins, and combined with their unique structure, they represent novel cytotoxic agents. However, their mechanism of action is yet unknown. In this work we show that disruption of cell membranes plays a crucial role in the cytotoxic effect of the cyclotide cycloviolacin O2 (1), which has been isolated from Viola odorata. Cell viability and morphology studies on the human lymphoma cell line U-937 GTB showed that cells exposed to 1 displayed disintegrated cell membranes within 5 min. Functional studies on calcein-loaded HeLa cells and on liposomes showed rapid concentration-dependent release of their respective internal contents. The present results show that cyclotides have specific membrane-disrupting activity.

  • 38.
    Svangård, Erika
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hocaoglu, Zozan
    Gullbo, Joachim
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Rolf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Claeson, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bohlin, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Cytotoxic cyclotides from Viola tricolor2004In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 67, no 2, p. 144-7Article in journal (Refereed)
    Abstract [en]

    A crude fraction of Viola tricolor rich in small lipophilic proteins was prepared and subjected to fractionation guided by bioactivity, using RP-HPLC and a fluorometric cytotoxicity assay. Two human cancer cell lines, U-937 GTB (lymphoma) and RPMI-8226/s (myeloma), were used in this study. The most potent compounds isolated, that is, the compounds showing the lowest IC(50) values, were shown to be three small proteins: vitri A (IC(50) = 0.6 microM and IC(50) = 1 microM, respectively), varv A (IC(50) = 6 microM and IC(50) = 3 microM, respectively), and varv E (IC(50) = 4 microM in both cell lines). Their sequences, determined by automated Edman degradation, quantitative amino acid analysis, and mass spectrometry, were cyclo-GESCVWIPCITSAIGCSCKSKVCYRNGIPC (vitri A), cyclo-GETCVGGTCNTPGCSCSWPVCTRNGLPVC (varv A), and cyclo-GETCVGGTCNTPGCSCSWPVCTRNGLPIC (varv E), of which vitri A is described for the first time. Each forms a head-to-tail cyclic backbone, with six cysteine residues being involved in three disulfide bonds, characteristic of the family of small proteins called the cyclotides. This is the first report on cyclotides from the species V. tricolor and the first report on the sequence of the cytotoxic cyclotide vitri A.

  • 39. Trabi, Manuela
    et al.
    Svangård, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Herrmann, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Claeson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Variations in cyclotide expression in viola species2004In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 67, no 5, p. 806-10Article in journal (Refereed)
  • 40. Wang, Conan K L
    et al.
    Colgrave, Michelle L
    Gustafson, Kirk R
    Ireland, David C
    Goransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J
    Anti-HIV cyclotides from the Chinese medicinal herb Viola yedoensis2008In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 71, no 1, p. 47-52Article in journal (Refereed)
    Abstract [en]

    Cyclotides are macrocyclic plant peptides characterized by a knotted arrangement of three disulfide bonds. They display a range of interesting bioactivities, including anti-HIV and insecticidal activities. More than 100 different cyclotides have been isolated from two phylogenetically distant plant families, the Rubiaceae and Violaceae. In this study we have characterized the cyclotides from Viola yedoensis, an important Chinese herb from the Violaceae family that has been reported to contain potential anti-HIV agents. From V. yedoensis five new and three known cyclotides were identified and shown to have anti-HIV activity. The most active of these is cycloviolacin Y5, which is one of the most potent of all cyclotides tested so far using in vitro XTT-based anti-HIV assays. Cycloviolacin Y5 is the most hydrophobic of the cyclotides from V. yedoensis. We show that there is a positive correlation between the hydrophobicity and the anti-HIV activity of the new cyclotides and that this trend tracks with their ability to disrupt membranes, as judged from hemolytic assays on human erythrocytes.

  • 41.
    Yeshak, Mariamawit Y
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Asres, Kaleab
    Addis Ababa University.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Cyclotides from an Extreme Habitat: Characterization of Cyclic Peptides from Viola abyssinica of the Ethiopian Highlands2011In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 74, no 4, p. 727-731Article in journal (Refereed)
    Abstract [en]

    As part of ongoing explorations of the structural diversity of cyclotides, the cyclotide content of a native violet of the East African highlands, Viola abyssinica (which grows at altitudes up to 3400 m), was studied. Six new cyclotides, vaby A-E (1-5) and varv E (6), were isolated and characterized by employing HPLC and MS techniques and quantitative amino acid analysis. Cyclotides 1-5 were found to have new sequences, and 1-3 have a further novel feature in their sequences, an alanine moiety in loop 2. Two of the cyclotides (1 and 4) also exhibited cytotoxic properties in a flourometric microculture cytotoxicity assay. The findings corroborate the hypothesis that investigating the cyclotide contents of violets growing in diverse environments is a promising approach for extending our knowledge of both the structural and biological diversity of cyclotides.

  • 42. Yu, Bao-Zhu
    et al.
    Kaimal, Rajani
    Bai, Shi
    El Sayed, Khalid A.
    Tatulian, Suren A.
    Apitz, Rafael J.
    Jain, Mahendra K.
    Deng, Ruitang
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Molecular Evolution.
    Effect of Guggulsterone and Cembranoids of Commiphora mukul on Pancreatic Phospholipase A(2): Role in Hypocholesterolemia2009In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 72, no 1, p. 24-28Article in journal (Refereed)
    Abstract [en]

    Guggulsterone (7) and cembranoids (8-12) from Commiphora mukul stem bark resin guggul were shown to be specific modulators of two independent sites that are also modulated by bile salts (1-6) to control cholesterol absorption and catabolism. Guggulsterone (7) antagonized the chenodeoxycholic acid (3)-activated nuclear farnesoid X receptor (FXR), which regulates cholesterol metabolism in the liver. The cembranoids did not show a noticeable effect on FXR, but lowered the cholate (I)-activated rate of human pancreatic 113 phospholipase A2 (hPLA2), which controls gastrointestinal absorption of fat and cholesterol. Analysis of the data using a kinetic model has suggested an allosteric mechanism for the rate increase of hPLA2 by cholate and also for the rate-lowering effect by certain bile salts or cembranoids on the cholate-activated hPLA2 hydrolysis of phosphatidylcholine vesicles. The allosteric inhibition of PLA2 by certain bile salts and cembranoids showed some structural specificity. Biophysical studies also showed specific interaction of the bile salts with the interface-bound cholate-activated PLA2. Since cholesterol homeostasis in mammals is regulated by FXR in the liver for metabolism and by PLA2 in the intestine for absorption, modulation of PLA2 and FXR by bile acids and selected guggul components suggests novel possibilities for hypolipidemic and hypocholesterolemic therapies.

1 - 42 of 42
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