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  • 101.
    Farag, Mohamed A.
    et al.
    Cairo Univ, Pharmacognosy Dept, Coll Pharm, Kasr el Aini St,PB 11562, Cairo, Egypt..
    Ali, Sara E.
    German Univ Cairo, Fac Pharm & Biotechnol, Dept Pharmaceut Biol, PB 11835, Cairo, Egypt..
    Hodaya, Rashad H.
    Desert Res Ctr, Plant Prod Dept, PB 11714, Cairo, Egypt..
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm 32512, Egypt..
    Sultani, Haider N.
    Leibniz Inst Plant Biochem, Dept Bioorgan Chem, Weinberg 3, D-06120 Halle, Saale, Germany..
    Laub, Annegret
    Leibniz Inst Plant Biochem, Dept Bioorgan Chem, Weinberg 3, D-06120 Halle, Saale, Germany..
    Eissa, Tarek E.
    Modern Sci & Arts Univ, Coll Pharm, Pharmacognosy Dept, PB 12566, Cairo, Egypt..
    Abou-Zaid, Fouad O. F.
    Desert Res Ctr, Plant Prod Dept, PB 11714, Cairo, Egypt..
    Wessjohann, Ludger A.
    Leibniz Inst Plant Biochem, Dept Bioorgan Chem, Weinberg 3, D-06120 Halle, Saale, Germany..
    Phytochemical Profiles and Antimicrobial Activities of Allium cepa Red cv. and A. sativum Subjected to Different Drying Methods: A Comparative MS-Based Metabolomics2017Ingår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, nr 5, artikel-id 761Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Plants of the Allium genus produce sulphur compounds that give them a characteristic (alliaceous) flavour and mediate for their medicinal use. In this study, the chemical composition and antimicrobial properties of Allium cepa red cv. and A. sativum in the context of three different drying processes were assessed using metabolomics. Bulbs were dried using either microwave, air drying, or freeze drying and further subjected to chemical analysis of their composition of volatile and non-volatile metabolites. Volatiles were collected using solid phase micro-extraction (SPME) coupled to gas chromatography-mass spectrometry (GC/MS) with 42 identified volatiles including 30 sulphur compounds, four nitriles, three aromatics, and three esters. Profiling of the polar non-volatile metabolites via ultra-performance liquid chromatography coupled to high resolution MS (UPLC/MS) annotated 51 metabolites including dipeptides, flavonoids, phenolic acids, and fatty acids. Major peaks in GC/MS or UPLC/MS contributing to the discrimination between A. sativum and A. cepa red cv. were assigned to sulphur compounds and flavonoids. Whereas sulphur conjugates amounted to the major forms in A. sativum, flavonoids predominated in the chemical composition of A. cepa red cv. With regard to drying impact on Allium metabolites, notable and clear separations among specimens were revealed using principal component analysis (PCA). The PCA scores plot of the UPLC/MS dataset showed closer metabolite composition of microwave dried specimens to freeze dried ones, and distant from air dried bulbs, observed in both A. cepa and A. sativum. Compared to GC/MS, the UPLC/MS derived PCA model was more consistent and better in assessing the impact of drying on Allium metabolism. A phthalate derivative was found exclusively in a commercial garlic preparation via GC/MS, of yet unknown origin. The freeze dried samples of both Allium species exhibited stronger antimicrobial activities compared to dried specimens with A. sativum being in general more active than A. cepa red cv.

  • 102.
    Farag, Mohamed A.
    et al.
    Cairo Univ, Coll Pharm, Pharmacognosy Dept, Kasr El Aini St,PB 11562, Cairo, Egypt..
    Fekry, Mostafa I.
    Cairo Univ, Coll Pharm, Pharmacognosy Dept, Kasr El Aini St,PB 11562, Cairo, Egypt..
    Al-Hammady, Montasser A.
    Natl Inst Oceanog & Fisheries, Red Sea Branch, Hurghada 84511, Egypt..
    Khalil, Mohamed N.
    Cairo Univ, Coll Pharm, Pharmacognosy Dept, Kasr El Aini St,PB 11562, Cairo, Egypt..
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Menoufia Univ, Fac Sci, Dept Chem, Shibin Al Kawm 32512, Egypt..
    Meyer, Achim
    Leibniz Ctr Trop Marine Res, Fahrenheit Str 6, D-28359 Bremen, Germany..
    Porzel, Andrea
    Leibniz Inst Plant Biochem, Dept Bioorgan Chem, Weinberg 3, D-06120 Halle, Saale, Germany..
    Westphal, Hildegard
    Leibniz Ctr Trop Marine Res, Fahrenheit Str 6, D-28359 Bremen, Germany..
    Wessjohann, Ludger A.
    Leibniz Inst Plant Biochem, Dept Bioorgan Chem, Weinberg 3, D-06120 Halle, Saale, Germany..
    Cytotoxic Effects of Sarcophyton sp Soft Corals-Is There a Correlation to Their NMR Fingerprints?2017Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 15, nr 7, artikel-id 211Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sarcophyton sp. soft corals are rich in cembranoid diterpenes, which represent the main chemical defense of corals against their natural predators in addition to their myriad biological effects in humans. Quantitative NMR (qNMR) was applied for assessing the diterpene variation in 16 soft coral specimens in the context of their genotype, origin, and growing habitat. qNMR revealed high diterpene levels in Sarcophyton sp. compared to Sinularia and Lobophyton, with (ent)sarcophines as major components (17-100 mu g/mg) of the coral tissues. Multivariate data analysis was employed to classify samples based on the quantified level of diterpenes, and compared to the untargeted NMR approach. Results revealed that qNMR provided a stronger classification model of Sarcophyton sp. than untargeted NMR fingerprinting. Additionally, cytotoxicity of soft coral crude extracts was assessed against androgen-dependent prostate cancer cell lines (PC3) and androgen-independent colon cancer cell lines (HT-29), with IC50 values ranging from 10-60 mu g/mL. No obvious correlation between the extracts' IC50 values and their diterpene levels was found using either Spearman or Pearson correlations. This suggests that this type of bioactivity may not be easily predicted by NMR metabolomics in soft corals, or is not strongly correlated to measured diterpene levels.

  • 103.
    Felth, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Studies of Cytotoxic Compounds of Natural Origin and their Mechanisms of Action2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Cancer incidence is increasing and novel anticancer drugs with new mechanisms of action are essential for future chemotherapeutic treatment. Natural products have historically played an important role in the development of anti-cancer drugs and have potential to do so also in the future. In this thesis two classes of natural products are identified as possible drug lead candidates, and the mechanisms of their action are elucidated.

    Initially, in a screening of a compound library for cytotoxic effects in colon cancer cells, natural products with potent activity were identified. Based on their potency, and on previously reported activities in cancer cells, two main groups of compounds, cardiac glycosides (CGs) and gambogic acid (GA) analogues, were selected for further in-depth studies.

    The concentration-dependent cytotoxicity was confirmed in cell lines of different origin. Cardiac glycosides were mainly evaluated for their activity in colon cancer cells and in leukemic cells, whereas the GA analogues were studied using a resistance-based panel of ten human cancer cell lines. Using activity profiles and the ChemGPS-NP model, the compounds were compared, structurally and mechanistically, to standard chemotherapeutic drugs. The results from these analyses suggested that the CGs and the GA analogues act by mechanisms different from those of antimetabolites, alkylating agents, topoisomerase I and II inhibitors, or tubulin-active agents. By analysis of drug-induced gene expression, one GA analogue, dihydro GA, was identified as a possible inhibitor of the ubiquitin-proteasome system (UPS), and the CGs showed similarities to protein synthesis inhibitors.

    Starting from these hypotheses, we further investigated the mechanisms of actions on a molecular level. The results showed that GA and dihydro GA act as inhibitors of the 20S proteasome chymotrypsin activity, leading to accumulation of ubiquitinated proteins. The CGs were confirmed to inhibit protein synthesis in colon cancer cell lines. However, interestingly, in leukemia cell lines, it seemed that the CGs act through a different, yet unexplored, mechanism of action. The leukemic cells (pre-B and T-ALL) were particularly susceptible to the cytotoxic effects of CGs, including at concentrations that may be achievable in the clinic.

    Delarbeten
    1. Screening for natural compounds with anticancer activity in colon cancer cells identifies cytotoxic gambogic acid analogues
    Öppna denna publikation i ny flik eller fönster >>Screening for natural compounds with anticancer activity in colon cancer cells identifies cytotoxic gambogic acid analogues
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    gambogic acid, colon cancer, ChemGPS-NP
    Nationell ämneskategori
    Farmaceutiska vetenskaper Farmakologi och toxikologi
    Forskningsämne
    Farmakognosi; Klinisk farmakologi
    Identifikatorer
    urn:nbn:se:uu:diva-147794 (URN)
    Tillgänglig från: 2011-02-28 Skapad: 2011-02-28 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system
    Öppna denna publikation i ny flik eller fönster >>Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system
    Visa övriga...
    2013 (Engelska)Ingår i: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 31, nr 3, s. 587-598Artikel i tidskrift (Övrigt vetenskapligt) Published
    Abstract [en]

    Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.

    Nyckelord
    gambogic acid, cancer, cytotoxic, proteasome inhibition
    Nationell ämneskategori
    Farmaceutiska vetenskaper Farmakologi och toxikologi
    Forskningsämne
    Farmakognosi; Klinisk farmakologi
    Identifikatorer
    urn:nbn:se:uu:diva-147799 (URN)10.1007/s10637-012-9902-y (DOI)000318657000010 ()
    Tillgänglig från: 2011-03-02 Skapad: 2011-02-28 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    3. Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs
    Öppna denna publikation i ny flik eller fönster >>Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs
    Visa övriga...
    2009 (Engelska)Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 72, nr 11, s. 1969-1974Artikel i tidskrift (Refereegranskat) Published
    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.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmakognosi
    Identifikatorer
    urn:nbn:se:uu:diva-125009 (URN)10.1021/np900210m (DOI)000272227600010 ()19894733 (PubMedID)
    Tillgänglig från: 2010-05-07 Skapad: 2010-05-07 Senast uppdaterad: 2018-01-12
    4. Ex Vivo Activity of Cardiac Glycosides in Acute Leukaemia
    Öppna denna publikation i ny flik eller fönster >>Ex Vivo Activity of Cardiac Glycosides in Acute Leukaemia
    Visa övriga...
    2011 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 1, s. e15718-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background:

    Despite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Reports have demonstrated promising in vitro effects on different targets as well as a possible therapeutic index/selectivity in vitro and in experimental animals. Recently, however, general inhibition of protein synthesis was suggested as the main mechanism of the anti-cancerous effects of CGs. In addition, evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results.

    Principal Findings:

    In this report we identified primary B-precursor and T-ALL cells as being particularly susceptible to the cytotoxic effects of CGs. Digitoxin appeared most potent and IC50 values for several patient samples were at concentrations that may be achieved in the clinic. Significant protein synthesis inhibition at concentrations corresponding to IC50 was demonstrated in colorectal tumour cell lines moderately resistant to the cytotoxic effects of digoxin and digitoxin, but not in highly sensitive leukaemia cell lines.

    Conclusion:

    It is suggested that further investigation regarding CGs may be focused on diagnoses like T-and B-precursor ALL.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-147765 (URN)10.1371/journal.pone.0015718 (DOI)000286511200012 ()21246039 (PubMedID)
    Tillgänglig från: 2011-03-01 Skapad: 2011-02-28 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
  • 104.
    Felth, Jenny
    et al.
    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.
    Haglund, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Rosén, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    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.
    Rickardson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Screening for natural compounds with anticancer activity in colon cancer cells identifies cytotoxic gambogic acid analoguesManuskript (preprint) (Övrigt vetenskapligt)
  • 105.
    Felth, Jenny
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Lesiak-Mieczkowska, Karolina
    Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute.
    Haglund, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Linder, Stig
    Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Rickardson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gambogic acid is cytotoxic to cancer cells through inhibition of the ubiquitin-proteasome system2013Ingår i: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 31, nr 3, s. 587-598Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Gambogic acid (GA), displays cytotoxicity towards a wide variety of tumor cells and has been shown to affect many important cell-signaling pathways. In the present work, we investigated the mechanism of action of GA by analysis of drug-induced changes in gene expression profiles and identified GA and the derivative dihydro GA as possible inhibitors of the ubiquitin-proteasome system (UPS). Both GA and dihydro GA inhibited proteasome function in cells resulting in the accumulation of polyubiquitin complexes. In vitro experiments showed that both GA and dihydro GA inhibited 20S chymotrypsin activity and the inhibitory effects of GA and dihydro GA on proteasome function corresponded with apoptosis induction and cell death. In conclusion, our results show that GA and dihydro GA exert their cytotoxic activity through inhibition of the UPS, specifically by acting as inhibitors of the chymotrypsin activity of the 20S proteasome.

  • 106.
    Felth, Jenny
    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.
    Rosén, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Wickström, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Lindskog, Magnus
    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.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs2009Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 72, nr 11, s. 1969-1974Artikel i tidskrift (Refereegranskat)
    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.

  • 107. Fernandes-Cerqueira, Catia
    et al.
    Ossipova, Elena
    Gunasekera, Sunithi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Hansson, Monika
    Mathsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Catrina, Anca I.
    Sommarin, Yngve
    Klareskog, Lars
    Lundberg, Karin
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Jakobsson, Per-Johan
    Targeting of anti-citrullinated protein/peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens2015Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, artikel-id 155Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: We have previously identified endogenously citrullinated peptides derived from fibrinogen in rheumatoid arthritis (RA) synovial tissues. In this study, we have investigated the auto-antigenicity of four of those citrullinated peptides, and explored their feasibility to target anti-citrullinated protein/peptide antibodies (ACPA). Methods: The autoantigenic potential of the fibrinogen peptides was investigated by screening 927 serum samples from the Epidemiological Investigation of RA (EIRA) cohort on a peptide microarray based on the ImmunoCAP ISAC (R) system. In order to assay for ACPA blocking, two independent pools of purified ACPA were incubated with the respective targeting peptide prior to binding to cyclic citrullinated peptide (CCP) 2 using the CCPlus (R) ELISA kit. Results: Two peptides derived from the fibrinogen a chain, Arg573Cit (563-583) and Arg591Cit (580-600), referred to as Cit573 and Cit591, and two peptides from the fibrinogen beta chain, Arg72Cit (62-81) and Arg74Cit (62-81) (Cit72 and Cit74), displayed 65 %, 15 %, 35 %, and 53 % of immune reactivity among CCP2-positive RA sera, respectively. In CCP2-negative RA sera, a positive reactivity was detected in 5 % (Cit573), 6 % (Cit591), 8 % (Cit72), and 4 % (Cit74). In the competition assay, Cit573 and Cit591 peptides reduced ACPA binding to CCP2 by a maximum of 84 % and 63 % respectively. An additive effect was observed when these peptides were combined. In contrast, Cit74 and Cit72 were less effective. Cyclization of the peptide structure containing Cit573 significantly increased the blocking efficiency. Conclusions: Here we demonstrate extensive autoantibody reactivity against in vivo citrullinated fibrinogen epitopes, and further show the potential use of these peptides for antagonizing ACPA.

  • 108.
    Flodmark, Charlotte A
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bruhn, Jan G
    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.
    One-third of Swedish food plants has anti-inflammatory records2001Ingår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 6, nr 9, s. 455-456Artikel i tidskrift (Övrigt vetenskapligt)
  • 109. Frederick, Raphael
    et al.
    Bruyere, Celine
    Vancraeynest, Christelle
    Reniers, Jeremy
    Meinguet, Celine
    Pochet, Lionel
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Masereel, Bernard
    Kiss, Robert
    Wouters, Johan
    Novel Trisubstituted Harmine Derivatives with Original in Vitro Anticancer Activity2012Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, nr 14, s. 6489-6501Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To overcome the intrinsic resistance of cancer cells to apoptotic stimuli, we designed and synthesized approximately 50 novel beta-carbolines structurally related to harmine. Harmine is known for its anticancer properties and is a DYRK1A inhibitor. Of the synthesized compounds, the most active in terms of growth inhibition of five cancer cell lines are cytostatic and approximately 100 times more potent than harmine but demonstrated no DYRK1A inhibitory activity. These novel beta-carbolines display similar growth inhibitory activity in cancer cells that are sensitive and resistant to apoptotic stimuli. Using ChemGPS-NP, we found that the more active beta-carbolines are all more lipophilic and larger than the less active compounds. Lastly, on the basis of the NCI human tumor cell line anticancer drug screen and the NCI COMPARE algorithm, it appears that some of these compounds, including 5a and 5k, seem to act as protein synthesis inhibitors.

  • 110. Fucik, Helena
    et al.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Farah, Mohamed
    Building a computerized herbal substance register for imnplementation and use in the whole world health organisation international drug monitoring programme2002Ingår i: Drug information journal, ISSN 0092-8615, E-ISSN 2164-9200, Vol. 36, nr 4, s. 839-854Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The overall aim of this project is to sort and structure the plant name material gathered by Mohamed Farah, PhD, in order to update the substance register of the international database of adverse drug reactions, the International Drug Information System (INTDIS). This database is used within the World Health Organisation (WHO) International Drug Monitoring Programme, which for more than 30 years has collected information about adverse drug reactions (ADRs). In recent years, it has become necessary to store information about herbal medicinal remedies as well as allopathic drugs. In order to create a structure that allowed for easy retrieval, a set of new herbal serial numbers have been assigned, which indicate mother plant, part, and type of extract used for each herbal substance; and the register was designed to contain records of scientific, vernacular and common name synonyms, which were identified as such. The system was built in a local PC environment and was implemented into INTDIS during the fall of 2001.

  • 111. Gerlach, Samantha L.
    et al.
    Burman, Robert
    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.
    Mondal, Debasis
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Isolation, Characterization, and Bioactivity of Cyclotides from the Micronesian Plant Psychotria leptothyrsa2010Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 73, nr 7, s. 1207-1213Artikel i tidskrift (Refereegranskat)
    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.

  • 112. Gerlach, Samantha L.
    et al.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Kaas, Quentin
    Craik, David J.
    Mondal, Debasis
    Gruber, Christian W.
    A Systematic Approach to Document Cyclotide Distribution in Plant Species from Genomic, Transcriptomic, and Peptidomic Analysis2013Ingår i: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 100, nr 5, s. 433-437Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are a large family of plant peptides characterized by their cyclic cystine knot composed of a circular backbone and three disulfide bonds that impart exceptional stability. They, and several acyclic variants, have been isolated from plants within the Rubiaceae, Violaceae, Cucurbitaceae, Fabaceae, Solanaceae, and Poaceae families. A variety of chemical and genetic approaches have been applied for the discovery and characterization of cyclotides. As investigations of cyclotide expression, distribution, and phylogeny rapidly increase, the authors have proposed the inclusion of information pertaining to plant species that have been analyzed but do not appear to express cyclotides into the CyBase database. CyBase is dedicated to providing web tools and information about cyclic peptides and proteins to the scientific community. Including detailed information about sampling and analysis parameters of plant species that have been investigated but not published elsewhere should assist in the process of selecting species for establishing new cyclotide discovery projects, as well as for detailed reanalysis using alternative technical approaches. In summary, the collection and deposition of all plant species that have been examined (whether cyclotides have been found or not) would help to impart a deeper understanding of cyclotide discovery, evolution, and physiological function.

  • 113. Gerlach, Samantha L.
    et al.
    Rathinakumar, Ramesh
    Chakravarty, Geetika
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Wimley, William C.
    Darwin, Steven P.
    Mondal, Debasis
    Anticancer and Chemosensitizing Abilities of Cycloviolacin O2 from Viola odorata and Psyle Cyclotides from Psychotria leptothyrsa2010Ingår i: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 94, nr 5, s. 617-625Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cycloviolacin O2 (CyO2), a cyclotide from Viola odorata (Violaceae) has antitumor effects and causes cell death by membrane permeabilization. In the breast cancer line, MCF-7 and its drug resistant subline MCF-7/ADR, the cytotoxic effects of CyO2 (0.2-10 mu M) were monitored in the presence and absence of doxorubicin (0.1-5 mu M) using cell proliferation assays to establish its chemosensitizing abilities. SYTOX Green assays were performed to verify membrane permeabilization and showed cellular disruption correlates with cyclo tide chemosensitization. Fluorescence microscopy studies demonstrated increased cellular internalization of doxorubicin in drug resistant cells when coexposed to CyO2. Interestingly, CyO2 did not produce significant membrane disruption in primary human brain endothelial cells, which suggested cyclo tide specificity toward induced pore formation in highly proliferating tumor cells. Furthermore, three novel cyclotides (psyle A, C and E) from Psychotria leptothyrsa (Rubiaceae) were also monitored for cytotoxic activity. The cyclotides displayed potent cytotoxicity (IC50 = 0.64->10 mu M), and coexposure to cyclotides significantly enhanced doxorubicin induced toxicity (IC50 = 0.39-0.76 mu M). This study documents several cyclotides with robust cytotoxicity that may be promising chemosensitizing agents against drug resistant breast cancer.

  • 114. Gerlach, Samantha L.
    et al.
    Yeshak, Mariamawit
    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.
    Roy, Upal
    Izadpanah, Reza
    Mondal, Debasis
    Cycloviolacin O2 (CyO2) Suppresses Productive Infection and Augments the Antiviral Efficacy of Nelfinavir in HIV-1 Infected Monocytic Cells2013Ingår i: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 100, nr 5, s. 471-479Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human immunodeficiency virus type-1 (HIV-1), the etiologic agent of acquired immune deficiency syndrome (AIDS), is a global pandemic causing millions of deaths annually. Highly active antiretroviral therapy (HAART) greatly enhances lifespan but eventually causes debilitating side effects, in part, due to their chronic administration required to suppress HIV-1 replication. If treatment is discontinued, viral suppression is lost and dormant replication-competent monocytic cell reservoirs become reactivated, leading to viral recrudescence and progression to AIDS. Therefore, novel strategies to circumvent obstacles to HIV-1 therapy are critically needed. We evaluated the potentially therapeutic effects of cycloviolacin O2 (CyO2) on cell viability (MTTassay), membrane disruption (SYTOX Green uptake), p24 production [enzyme-linked immunosorbent assays (ELISA)], and proviral integration (PCR amplification) in U1 cells; a monocytic cell model of HIV-1 latency and reactivation. We demonstrate, for the first time, that CyO2 (0.5-5.0 mu M) kills productively infected cells. Sub-toxic concentrations (< 0.5 mu M) of CyO2 disrupted plasma membranes in both latently-infected and productively-infected U1 cells and enhanced the antiviral efficacy of nelfinavir, a HIV-1 protease inhibitor (HPI). Interestingly, CyO2 also decreased virus production by activated U1 cells; however, this effect was not due to suppression of integrated provirus in U1 cells. This suggested that, in addition to the known pore-forming ability of cyclotides, a novel mode of antiviral activity may exist for CyO2. Our data indicate that CyO2 may be a promising candidate for the targeting HIV-1 reservoirs in monocytes, and their inclusion in adjuvant therapy approaches may augment the efficacy of HPIs and ultimately facilitate virus elimination.

  • 115.
    Gomaa, Mohamed N.
    et al.
    King Abdulaziz Univ, Fac Sci & Arts Khulais, Dept Biol, Khulais, Saudi Arabia..
    Soliman, Kawther
    King Abdulaziz Univ, Fac Sci & Arts Khulais, Dept Biol, Khulais, Saudi Arabia..
    Ayesh, Ahmed
    King Abdulaziz Univ, Fac Sci & Arts Khulais, Dept Biol, Khulais, Saudi Arabia..
    Abd El-Wahed, Aida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Hamza, Zeinab
    Natl Res Ctr, Food Toxins & Contaminants Dept, Marine Toxins Lab, Cairo, Egypt..
    Mansour, Hager M.
    Univ Karachi, HEJ Res Inst Chem, Int Ctr Chem Sci, Karachi 75270, Pakistan..
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden..
    Mohd Ali, Hapipah Bint
    Univ Malaya, Dept Chem, Ctr Nat Prod & Drug Discovery CENAR, Fac Sci, Kuala Lumpur 50603, Malaysia..
    El-Seedi, Hesham R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden.;Univ Malaya, Dept Chem, Ctr Nat Prod & Drug Discovery CENAR, Fac Sci, Kuala Lumpur 50603, Malaysia..
    Antibacterial effect of the red sea soft coral Sarcophyton trocheliophorum2016Ingår i: Natural Product Research, ISSN 1478-6419, E-ISSN 1478-6427, Vol. 30, nr 6, s. 729-734Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The marine soft corals Sarcophyton trocheliophorum crude extracts possessed antimicrobial activity towards pathogenic bacterial strains, i.e. Bacillus cereus, Salmonella typhi, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. Bioassay-guided fractionation indicated that the antimicrobial effect was due to the presence of terpenoid bioactive derivatives. Further biological assays of the n-hexane fractions were carried out using turbidity assay, inhibition zone assay and minimum inhibitory concentration for investigating the growth-inhibition effect towards the Gram-positive and Gram-negative bacteria. The fractions were screened and the structure of the isolated compound was justified by interpretation of the spectroscopic data, mainly mass spectrometry (GC-MS). The structure was assigned as (5S)-3-[(3E,5S)-5-hydroxy-3-hepten-6-yn-1-yl]-5-methyl-2(5H)-furanone and was effective at concentrations as low as 0.20mg/mL. The above findings, in the course of our ongoing research on marine products, may implicate that the profound anti-microbial activity of the S. trocheliophorum soft corals, inhabiting the red sea reefs, is attributed to the presence of growth-inhibiting secondary metabolites mainly terpenoids.

  • 116.
    Goransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Cyclotides: circular plant peptides for protein engineering2008Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 74, nr 9, s. 904-905Artikel i tidskrift (Refereegranskat)
  • 117. Gruber, Christian W
    et al.
    Elliott, Alysha G
    Ireland, David C
    Delprete, Piero G
    Dessein, Steven
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Trabi, Manuela
    Wang, Conan K
    Kinghorn, Andrew B
    Robbrecht, Elmar
    Craik, David J
    Distribution and evolution of circular miniproteins in flowering plants2008Ingår i: The Plant Cell, ISSN 1040-4651, E-ISSN 1532-298X, Vol. 20, nr 9, s. 2471-2483Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are disulfide-rich miniproteins with the unique structural features of a circular backbone and knotted arrangement of three conserved disulfide bonds. Cyclotides have been found only in two plant families: in every analyzed species of the violet family (Violaceae) and in few species of the coffee family (Rubiaceae). In this study, we analyzed >200 Rubiaceae species and confirmed the presence of cyclotides in 22 species. Additionally, we analyzed >140 species in related plant families to Rubiaceae and Violaceae and report the occurrence of cyclotides in the Apocynaceae. We further report new cyclotide sequences that provide insights into the mechanistic basis of cyclotide evolution. On the basis of the phylogeny of cyclotide-bearing plants and the analysis of cyclotide precursor gene sequences, we hypothesize that cyclotide evolution occurred independently in various plant families after the divergence of Asterids and Rosids ( approximately 125 million years ago). This is strongly supported by recent findings on the in planta biosynthesis of cyclotides, which involves the serendipitous recruitment of ubiquitous proteolytic enzymes for cyclization. We further predict that the number of cyclotides within the Rubiaceae may exceed tens of thousands, potentially making cyclotides one of the largest protein families in the plant kingdom.

  • 118.
    Gunasekera, Sunithi
    et al.
    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.
    Madian, Walid A.
    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.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Making Ends Meet: Microwave-Accelerated Synthesis of Cyclic and Disulfide Rich Proteins Via In Situ Thioesterification and Native Chemical Ligation2013Ingår i: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 19, nr 1- SI, s. 43-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The development of synthetic methodologies for cyclic peptides is driven by the discovery of cyclic peptide drug scaffolds such as the plant-derived cyclotides, sunflower trypsin inhibitor 1 (SFTI-1) and the development of cyclized conotoxins. Currently, the native chemical ligation reaction between an N-terminal cysteine and C-terminal thioester group remains the most robust method to obtain a head-to-tail cyclized peptide. Peptidyl thioesters are effectively generated by Boc SPPS. However, their generation is challenging using Fmoc SPPS because thioester linkers are not stable to repeated piperidine exposure during deprotection. Herein we describe a Fmoc-based protocol for synthesizing cyclic peptides adapted for microwave assisted solid phase peptide synthesis. The protocol relies on the linker Di-Fmoc-3,4-diaminobenzoic acid, and we demonstrate the use of Gly, Ser, Arg and Ile as C-terminal amino acids (using HBTU and HATU as coupling reagents). Following synthesis, an N-acylurea moiety is generated at the C-terminal of the peptide; the resin bound acylurea peptide is then deprotected and cleaved from the resin. The fully deprotected peptide undergoes thiolysis in aqueous buffer, generating the thioester in situ. Ultimately, the head-to-tail cyclized peptide is obtained via native chemical ligation. Two naturally occurring cyclic peptides, the prototypical Mobius cyclotide kalata B1 and SFTI-1 were synthesized efficiently, avoiding potential branching at the diamino linker, using the optimized protocol. In addition, we demonstrate the possibility to use the approach for the synthesis of long and synthetically challenging linear sequences, by the ligation of two truncated fragments of a 50-residue long plant defensin.

  • 119.
    Gunasekera, Sunithi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Fernandes-Cerqueira, C.
    Karolinska Inst, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Eriksson, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Jakobsson, P-J
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Anti-Citrullinated Peptide Antibody Inhibitors Based On Sunflower Trypsin Inhibitor-1 Scaffold For Potential Anti-Rheumatoid Arthritis Activity2016Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 22, nr S2, s. S170-S170Artikel i tidskrift (Övrigt vetenskapligt)
  • 120.
    Gunasekera, Sunithi
    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.
    Fmoc-SPPS based synthesis of bioactive cyclic peptides via N-acylurea intermediates2012Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 18, nr suppl 1, s. S182-S182Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The plant cyclotides form the largest family of cyclic peptides(1). They contain a signature motif referred to as the cyclic cystine knot, which is derived from the cyclic backbone and three inter-knotted disulfide bonds. Intriguingly, cyclotides can be boiled, treated with chemicals or enzymes without disrupting their overall fold. Thus, they are sometimes labeled as ultra-stable proteins. In addition, cyclotides are tolerant to mutations, and as a scaffold they can successfully accommodate foreign bioactive epitopes of variable sequences(2). Cyclotides share many of these properties with another disulfide containing cyclic plant peptide, the sunflower trypsin inhibitor 1 (SFTI-1)(3). Emerging evidence indicates that cyclotides and SFTI-1 are valuable not only as peptide stabilizing scaffolds; in combination with their cell penetrating properties, these disulfide rich cyclic peptides have significance as intracellular drug carriers. Although both peptides are genetically encoded, studies to ascertain the exact mechanisms of their biosynthesis are currently on going. Thus, the synthesis of cyclotides and SFTI-1 are currently restricted to chemical means. We have recently adapted a Fmoc-SPPS method for cyclic peptide synthesis, via N-acylurea intermediates with the assistance of microwave irradiation.

    This method is a safe and convenient alternative to Boc-SPPS and has the ability to be automated conveniently. Using this method, parent scaffolds as well as several cyclotide and SFTI-1 analogues with potential antimicrobial and matrix metalloprotease activities were synthesized. With the rising interest in the cyclization concept as a tool to impart stability on unstable peptides, the cyclic peptide synthesis method adapted herein is anticipated to have numerous applications.

    1. Burman, R.; Gunasekera, S.; Stromstedt, A.; Rosengren, J.; Goransson, U. J. Biol. Chem. 2012 (in press)

    2. Gunasekera, S.; Foley, F. M.; Clark, R. J.; Sando, L.; Fabri, L. J.; Craik, D. J.; Daly, N. L. J. Med. Chem. 2008, 51, 7697.

    3. Chan, L. Y.; Gunasekera, S.; Henriques, S. T.; Worth, N. F.; Le, S. J.; Clark, R. J.; Campbell, J. H.; Craik, D. J.; Daly, N. L. Blood 2011, 118, 6709.

  • 121.
    Gunasekera, Sunithi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Muhammad, Taj
    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.
    Backbone-Cyclized Peptide Dimers Derived from Human Cathelicidin Peptide LL-37 Mediate Potent Antimicrobial Activity2014Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 20, s. S270-S271Artikel i tidskrift (Övrigt vetenskapligt)
  • 122.
    Gunasekera, Sunithi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Park, SungKyu
    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.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Strategies for macrocyclic cyclotide synthesis2010Ingår i: Posters 001-067: Synthetic Chemistry of Amino Acids and Peptides: [Published in: Journal of Peptide Science, 16: 48–206], 2010, Vol. 16, nr S2, s. 65-65Konferensbidrag (Övrigt vetenskapligt)
  • 123.
    Göransson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Broussalis, Adriana M
    Claeson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Expression of Viola cyclotides by liquid chromatography-mass spectrometry and tandem mass spectrometry sequencing of intercysteine loops after introduction of charges and cleavage sites by aminoethylation2003Ingår i: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 318, nr 1, s. 107-117Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The expression of cyclotides—macrocyclic plant peptides—was profiled in six violets, Viola cotyledon, V. biflora, V. arvensis,V. tricolor, V. riviniana, and V. odorata, by LC-MS. All were found to express notably complex mixtures, with single speciescontaining >50 cyclotides. To facilitate their sequencing by MS-MS, an analytical strategy is presented involving aminoethylation ofcysteines. This overcomes a number of problems intimately associated with the cyclotide core structure—that is, their joined N and Ctermini, disulfide knot, and low or clustered content of positively charged amino acids and enzymatic cleavage sites. As a result,charges as well as cleavage sites are introduced at the most conserved part of their sequence, the cysteines. Combined with trypticdigestion, all intercysteine loops are then of suitable size and charge for MS-MS sequencing. The utility of this strategy is shown bythe sequencing of two novel cyclotides isolated from V. cotyledon; vico A (cyclo-(AESCVYIPCFTGIAGCSCKNKVCYYNGSIPC)) and vico B(cyclo-(AESCVYIPCITGIAGCSCKNKVCYYNGSIPC)); their complete sequence could be determined bynanospray MS-MS. The strategy for converting conserved cysteines to enzymatic cleavage sites might also benefit the study of otherpeptides and proteins displaying similar structural problems for MS analysis.

  • 124.
    Göransson, Ulf
    et al.
    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.
    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.
    Rosengren, K. Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Circular Proteins from Plants and Fungi2012Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, nr 32, s. 27001-27006Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Circular proteins, defined as head-to-tail cyclized polypeptides originating from ribosomal synthesis, represent a novel class of natural products attracting increasing interest. From a scientific point of view, these compounds raise questions of where and why they occur in nature and how they are formed. From a rational point of view, these proteins and their structural concept may be exploited for crop protection and novel pharmaceuticals. Here, we review the current knowledge of three protein families: cyclotides and circular sunflower trypsin inhibitors from the kingdom of plants and the Amanita toxins from fungi. A particular emphasis is placed on their biological origin, structure, and activity. In addition, the opportunity for discovery of novel circular proteins and recent insights into their mechanism of action are discussed.

  • 125.
    Göransson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Craik, David J
    Disulfide mapping of the cyclotide kalata B1: Chemical proof of the cystic cystine knot motif2003Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 278, nr 48, s. 48188-48196Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cyclotides are a recently discovered family of plant proteins that have the fascinating structural feature of a continuous cyclic backbone and, putatively, a knotted arrangement of their three conserved disulfide bonds. We here show definite chemical proof of the I-IV, II-V, III-VI knotted disulfide connectivity of the prototypic cyclotide kalata B1. This has been achieved by a new approach for disulfide analysis, involving partial reduction and stepwise alkylation including introduction of charges and enzymatic cleavage sites by aminoethylation of cysteines. The approach overcomes the intrinsic difficulties for disulfide mapping of cyclotides, i.e. the cyclic amide backbone, lack of cleavage sites between cysteines, and a low or clustered content of basic amino acids, and allowed a direct determination of the disulfide bonds in kalata B1 using analysis by mass spectrometry. The established disulfide connectivity is unequivocally shown to be cystine knotted by a topological analysis. This is the first direct chemical determination of disulfides in native cyclotides and unambiguously confirms the unique cyclic cystine knot motif.

  • 126.
    Göransson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Herrmann, Anders
    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.
    Haugaard-Jonsson, M
    Rosengren, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    The Conserved Glu in the Cyclotide Cycloviolacin O2 Has a Key Structural Role2009Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 10, nr 14, s. 2354-2360Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are a large family of plant peptides that are characterised by a head-to-tail circular backbone and three disulfide bonds that are arranged in a cystine knot. This unique structural feature, which is referred to as a cyclic cystine knot, gives the cyclotides remarkable stability against chemical and biological degradation. In addition to their natural function as insecticides for plant defence, the cyclotides have a range of bioactivities with pharmaceutical relevance, including cytotoxicity against cancer cell lines. A glutamic acid residue, aside from the invariable disulfide array, is the most conserved feature throughout the cyclotide family, and it has recently been shown to be crucial for biological activity. Here we have used solution-state NMR spectroscopy to determine the three-dimensional structures of the potent cytotoxic cyclotide cycloviolacin O2, and an inactive analogue in which this conserved glutamic acid has been methylated. The structures of the peptides show that the glutamic acid has a key structural role in coordinating a set of hydrogen bonds in native cycloviolacin O2; this interaction is disrupted in the methylated analogue. The proposed mechanism of action of cyclotides is membrane disruption and these results suggest that the glutamic acid is linked to cyclotide function by stabilising the structure to allow efficient aggregation in membranes, rather than in a direct interaction with a target receptor.

  • 127.
    Göransson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Luijendijk, Teus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Johansson, Senia
    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.
    Claeson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Seven novel macrocyclic polypeptides from Viola arvensis1999Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 62, nr 2, s. 283-286Artikel i tidskrift (Refereegranskat)
    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.

  • 128.
    Göransson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Malik, Sohaib
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Slazak, Blazej
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. W.SZAFER INSTITUTE OF BOTANY OF THE POLISH ACADEMY OF SCIENCES.
    Cyclotides in the Violaceae2015Ingår i: Plant Cyclotides / [ed] Craik, David J., Academic Press , 2015, Vol. 76, s. 15-49Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Abstract It has been 20 years since the cyclic cystine-knotted compounds, called cyclotides, tied our knot with the violets. This chapter, above all, is a lucid summary of the twists, turns, knots, and rings in the relationship that followed. The chapter begins by giving an account of how a little known scientific article facilitated the discovery of cyclotides in Violaceae, how it captured our imagination, and how it was realized that the discovery of a series of cyclotides was within a touching distance. The processes of extraction, isolation, and characterization as well as chemical synthesis of cyclotides used in our laboratory have been described, and in doing so, the solvents, materials, conditions, instrumentation, and techniques involved have been pointed out. An introduction to Violaceae and a description of these plants in diverse cultural settings for various therapeutic purposes is provided. A section follows it on the discovery of cycloviolacin O2 from Viola odorata as a potent antimicrobial peptide, and how its interaction with bacteria in terms of mechanism of action and resistance development was investigated. It is followed by a reflection on how the recent innovations in biotechnology and bioinformatics have helped out along the way: the use of novel strategies for cyclization and the use of transcriptomics data in the discovery of new cyclotides. Finally, the question about biological role of cyclotides in Violaceae has been asked, and an attempt to answer this question has been presented.

  • 129.
    Göransson, Ulf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Svangård, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Claeson, Per
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Novel strategies for isolation and characterization of cyclotides: the discovery of bioactive macrocyclic plant polypeptides in the Violaceae2004Ingår i: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 5, nr 5, s. 317-29Artikel i tidskrift (Refereegranskat)
  • 130. Hajrezaie, Maryam
    et al.
    Salehen, NurAin
    Karimian, Hamed
    Zahedifard, Maryam
    Shams, Keivan
    Al Batran, Rami
    Majid, Nazia Abdul
    Khalifa, Shaden A. M.
    Ali, Hapipah Mohd
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Abdulla, Mahmood Ameen
    Biochanin A Gastroprotective Effects in Ethanol-Induced Gastric Mucosal Ulceration in Rats2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 3, artikel-id e0121529Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Biochanin A notable bioactive compound which is found in so many traditional medicinal plant. In vivo study was conducted to assess the protective effect of biochanin A on the gastric wall of Spraguedawley rats' stomachs. Methodology The experimental set included different animal groups. Specifically, four groups with gastric mucosal lesions were receiving either a) Ulcer control group treated with absolute ethanol (5 ml/kg), b) 20 mg/kg of omeprazole as reference group, c) 25 of biochanin A, d) 50 mg/kg of biochanin A. Histopathological sectioning followed by immunohistochemistry staining were undertaken to evaluate the influence of the different treatments on gastric wall mucosal layer. The gastric secretions were collected in the form of homogenate and exposed to superoxide dismutase (SOD) and nitric oxide enzyme (NO) and the level of malondialdehyde (MDA) and protein content were measured. Ulceration and patchy haemorrhage were clearly observed by light microscopy. The morphology of the gastric wall as confirmed by immunohistochemistry and fluorescent microscopic observations, exhibited sever deformity with notable thickness, oedematous and complete loss of the mucosal coverage however the biochanin-pretreated animals, similar to the omeprazole-pretreated animals, showed less damage compared to the ulcer control group. Moreover, up-regulation of Hsp70 protein and down-regulation of Bax protein were detected in the biochanin A pre-treated groups and the gastric glandular mucosa was positively stained with Periodic Acid Schiff (PAS) staining and the Leucocytes infiltration was commonly seen. Biochanin A displayed a great increase in SOD and NO levels and decreased the release of MDA. Conclusions This gastroprotective effect of biochanin A could be attributed to the enhancement of cellular metabolic cycles perceived as an increase in the SOD, NO activity, and decrease in the level of MDA, and also decrease in level of Bax expression and increase the Hsp70 expression level.

  • 131.
    Hallböök, Helene
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Felth, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Eriksson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Fryknäs, Mårten
    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.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Ex Vivo Activity of Cardiac Glycosides in Acute Leukaemia2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 1, s. e15718-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:

    Despite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Reports have demonstrated promising in vitro effects on different targets as well as a possible therapeutic index/selectivity in vitro and in experimental animals. Recently, however, general inhibition of protein synthesis was suggested as the main mechanism of the anti-cancerous effects of CGs. In addition, evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results.

    Principal Findings:

    In this report we identified primary B-precursor and T-ALL cells as being particularly susceptible to the cytotoxic effects of CGs. Digitoxin appeared most potent and IC50 values for several patient samples were at concentrations that may be achieved in the clinic. Significant protein synthesis inhibition at concentrations corresponding to IC50 was demonstrated in colorectal tumour cell lines moderately resistant to the cytotoxic effects of digoxin and digitoxin, but not in highly sensitive leukaemia cell lines.

    Conclusion:

    It is suggested that further investigation regarding CGs may be focused on diagnoses like T-and B-precursor ALL.

  • 132. Hamidi, H. M.
    et al.
    Cardenas, Paco
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Systematisk biologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Thacker, R. W.
    Diversification and Correlated Trait Evolution in Astrophorid Sponges (Porifera: Demospongiae)2015Ingår i: Integrative and Comparative Biology, ISSN 1540-7063, E-ISSN 1557-7023, Vol. 55, nr S1, s. E269-E269Artikel i tidskrift (Övrigt vetenskapligt)
  • 133.
    Han, Xiao
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för ytbioteknik med Centrum för ytbioteknik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Pathmasiri, Wimal
    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.
    Janson, Jan-Christer
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för ytbioteknik med Centrum för ytbioteknik. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Isolation of high purity 1-[2′,4′-dihydroxy-3′,5′-di-(3″-methylbut-2″-enyl)-6′-methoxy] phenylethanone from Acronychia pedunculata (L.) Miq. by high-speed counter-current chromatography2004Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1022, nr 1-2, s. 213-216Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Following an initial clean-up step on silica, high-speed counter-current chromatography (HSCCC) was used to purify an aryl ketone, 1-[2′,4′-dihydroxy-3′,5′-di-(3″-methylbut-2″-enyl)-6′-methoxy] phenylethanone from an extract of the stem bark of the shrub Acronychia pedunculata. The two-phase solvent system used was composed of n-heptane–ethyl acetate–methanol–water at an optimized volume ratio of 4:1:4:1 (v/v/v/v). Target compound (58.1 mg) with a purity of 98.9% was obtained after HSCCC of 183.5 mg sample with a purity of 35.7% recovered after the silica clean-up step. Identification of the target compound was performed by 1H NMR, 13C NMR, two-dimensional NMR and LC–electrospray ionization MS.

  • 134.
    Hassan, Saadia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Laryea, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Mahteme, Haile
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Felth, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Fayad, Walid
    Linder, Stig
    Rickardson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Graf, Wilhelm
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Pålman, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Novel activity of acriflavine against colorectal cancer tumor cells2011Ingår i: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 102, nr 12, s. 2206-2213Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.

  • 135.
    Hedner, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Bioactive Compounds in the Chemical Defence of Marine Sponges: Structure-Activity Relationships and Pharmacological Targets2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Marine invertebrates, in particular sponges, represent a source of a wide range of secondary metabolites, many of which have been attributed various defensive capabilities against environmental stress factors. In this thesis sponge-derived low-molecular peptide-like compounds and associated analogs are investigated for bioactivity and pharmacological targets.

    The compound bromobenzisoxazolone barettin (cyclo[(6-bromo-8-(6-bromo-benzioxazol -3(1H)-one)-8-hydroxy)tryptophan)]arginine) was isolated from the sponge Geodia barretti and its ability to inhibit larval settlement of the barnacle Balanus improvisus was determined. With an EC50 value of 15 nM, this compound’s antifouling effect was higher than those of the previously reported brominated dipeptides from Geodia barretti, i.e., barettin and 8,9-dihydrobarettin; moreover, this antifouling effect was demonstrated to be reversible. However, the compound lacked affinity for 5-HT1-7 receptors, whereas barettin possessed specific affinity to 5-HT2A, 5-HT2C and 5-HT4, while 8,9-dihydrobarettin interacted with 5-HT4. In an attempt to evaluate structure-activity relationships synthesized analogs with barettin and dipodazine scaffolds were investigated for antifouling activity. The analog benso[g]dipodazine, with an EC50 value of 34 nM, displayed the highest settlement inhibition.

    The studies of the structure-activity relationships of sponge-derived compounds were extended to cover analogs of agelasines and agelasimines originally isolated from sponges of the genus Agelas. Synthesized (+)-agelasine D and two structurally close analogs were investigated for cytotoxic and antibacterial activity. The profound cytotoxicity and broad spectrum antibacterial activity found prompted a further investigation of structure-activity relationships in 42 agelasine and agelasimine analogs and several characteristics that increased bioactivity were identified.

    In conclusion this work has produced new results regarding the potent bioactivity of compounds derived from the sponges Geodia barretti and Agelas spp. and increased SAR knowledge of the fouling inhibition, cytotoxicity and antimicrobial activity of these compounds.

    Delarbeten
    1. Antifouling activity of a dibrominated cyclopeptide from the marine sponge Geodia barretti
    Öppna denna publikation i ny flik eller fönster >>Antifouling activity of a dibrominated cyclopeptide from the marine sponge Geodia barretti
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    2008 (Engelska)Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 71, nr 3, s. 330-333Artikel i tidskrift (Refereegranskat) Published
    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.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-96228 (URN)10.1021/np0705209 (DOI)000254544900007 ()18271554 (PubMedID)
    Tillgänglig från: 2007-09-27 Skapad: 2007-09-27 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    2. Antifouling activity of synthesized peptide analogs of the sponge metabolite barettin
    Öppna denna publikation i ny flik eller fönster >>Antifouling activity of synthesized peptide analogs of the sponge metabolite barettin
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    2006 (Engelska)Ingår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 27, nr 9, s. 2058-2064Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Barettin (cyclo [(6-bromo-8-en-tryptophan) arginine]), a diketopiperazine isolated from the marine sponge Geodia barretti, is a potent inhibitor of barnacle larvae settlement with an EC50-value of 0.9 mu M. In the present study, 14 analogs of barettin and its structural congener dipodazine were synthezised and tested for their ability to inhibit larval settlement. Two of the analogs have an intact barettin skeleton. The remaining analogs have a dipodazine skeleton (a diketopiperazine where arginine is replaced with glycine). Six of the tested synthetic analogs displayed significant settlement inhibition with the most potent inhibitor being benzo[g]dipodazine, which displayed even stronger activity than barettin (EC50-value 0.034 mu M). The effect of benzo[g]dipodazine was also shown to be readily reversible, when cyprids were transferred to filtered seawater (FSW).

    Nyckelord
    barettin, dipodazine, marine sponges, Geodia barretti, synthesis, cyprid settlement
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-94327 (URN)10.1016/j.peptides.2006.03.027 (DOI)000240379800002 ()16781016 (PubMedID)
    Tillgänglig från: 2006-04-19 Skapad: 2006-04-19 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    3. Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands
    Öppna denna publikation i ny flik eller fönster >>Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands
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    2006 (Engelska)Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 69, nr 10, s. 1421-1424Artikel i tidskrift (Refereegranskat) Published
    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.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-94328 (URN)10.1021/np0601760 (DOI)000241562700009 ()17067154 (PubMedID)
    Tillgänglig från: 2006-04-19 Skapad: 2006-04-19 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    4. (+)-Agelasine D: improved synthesis and evaluation of antibacterial and cytotoxic activities
    Öppna denna publikation i ny flik eller fönster >>(+)-Agelasine D: improved synthesis and evaluation of antibacterial and cytotoxic activities
    Visa övriga...
    2006 Ingår i: Journal of Natural Products, Vol. 69, nr 3, s. 381-286Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-96231 (URN)
    Tillgänglig från: 2007-09-27 Skapad: 2007-09-27Bibliografiskt granskad
    5. Antimicrobial and cytotoxic activity of agelasine and agelasimine analogs
    Öppna denna publikation i ny flik eller fönster >>Antimicrobial and cytotoxic activity of agelasine and agelasimine analogs
    Visa övriga...
    2007 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, nr 12, s. 4016-4037Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Agelasine and agelasimine derivatives with substantially less complicated terpenoid side chains compared to the naturally occurring compounds have been synthesized and their ability to inhibit growth of microorganisms and cancer cells has been studied. Compounds with excellent activity against cancer cell lines (MIC ca. 1 μM for the most potent compounds), including a drug resistant renal cell line, have been identified. Most compounds studied also exhibited broad spectrum antimicrobial activity including activity against Mycobacterium tuberculosis.

    Nyckelord
    Antimicrobial agent, Anti-cancer agent, Adenine derivative, Natural product
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-96232 (URN)10.1016/j.bmc.2007.03.086 (DOI)000246870400007 ()17442577 (PubMedID)
    Tillgänglig från: 2007-09-27 Skapad: 2007-09-27 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
  • 136.
    Hedner, Erik
    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.
    Frändberg, Per-Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för biologisk beroendeforskning.
    Johansson, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för biologisk beroendeforskning.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Dahlström, Mia
    Jonsson, Per R.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för biologisk beroendeforskning.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands2006Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 69, nr 10, s. 1421-1424Artikel i tidskrift (Refereegranskat)
    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.

  • 137.
    Hedner, Erik
    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.
    Hodzic, Said
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Andersson, Rolf
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Jonsson, Per R.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Antifouling activity of a dibrominated cyclopeptide from the marine sponge Geodia barretti2008Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 71, nr 3, s. 330-333Artikel i tidskrift (Refereegranskat)
    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.

  • 138.
    Hellinger, Roland
    et al.
    Med Univ Vienna, Ctr Physiol & Fharmacol, Vienna, Austria.;Univ Nat Resources & Life Sci BOKU, Dept Agobiotechnol, Ctr Analyt Chem, Vienna, Austria..
    Thell, Kathrin
    Med Univ Vienna, Ctr Physiol & Fharmacol, Vienna, Austria..
    Vasileva, Mina
    Med Univ Vienna, Ctr Physiol & Fharmacol, Vienna, Austria..
    Muhammad, Taj
    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.
    Kuemmel, Daniel
    Univ Osnabruck, Sch Biol Chem, Osnabruck, Germany..
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Uppsala Univ, Dept Med Chem, Div Pharmacognosy, Uppsala, Sweden..
    Becker, Christian W.
    Univ Vienna, Inst Biol Chem, Dept Chem, Vienna, Austria..
    Gruber, Christian W.
    Med Univ Vienna, Ctr Physiol & Fharmacol, Vienna, Austria.;Univ Queensland, Fac Med, Sch Biomed Sci, St Lucia, Qld, Australia..
    Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins2017Ingår i: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 5, artikel-id 73Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Target deconvolution is one of the most challenging tasks in drug discovery, but a key step in drug development. In contrast to small molecules, there is a lack of validated and robust methodologies for target elucidation of peptides. In particular, it is difficult to apply these methods to cyclic and cysteine-stabilized peptides since they exhibit reduced amenability to chemical modification and affinity capture; however, such ribosomally synthesized and post-translationally modified peptide natural products are rich sources of promising drug candidates. For example, plant-derived circular peptides called cyclotides have recently attracted much attention due to their immunosuppressive effects and oral activity in the treatment of multiple sclerosis in mice, but their molecular target has hitherto not been reported. In this study, a chemical proteomics approach using photo-affinity crosslinking was developed to determine a target for the circular peptide [T20K]kalata B1. Using this prototypic nature-derived peptide enabled the identification of a possible functional modulation of 14-3-3 proteins. This biochemical interaction was validated via competition pull down assays as well as a cellular reporter assay indicating an effect on 14-3-3-dependent transcriptional activity. As proof of concept, the presented approach may be applicable for target elucidation of various cyclic peptides and mini-proteins, in particular cyclotides, which represent a promising class of molecules in drug discovery and development.

  • 139.
    Henz, A.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Leibniz Univ Hannover, Inst Pflanzengenet, D-30419 Hannover, Germany..
    Debener, T.
    Leibniz Univ Hannover, Inst Pflanzengenet, D-30419 Hannover, Germany..
    Linde, M.
    Leibniz Univ Hannover, Inst Pflanzengenet, D-30419 Hannover, Germany..
    Identification of major stable QTLs for flower color in roses2015Ingår i: Molecular breeding, ISSN 1380-3743, E-ISSN 1572-9788, Vol. 35, nr 10, artikel-id 190Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Flower color is one of the most important traits of ornamental roses. Anthocyanins are the major secondary metabolites responsible for the red and pink colors found among rose cultivars. Color varies depending on the combination of particular anthocyanins, their co-factors and their concentrations. Several genetic investigations have indicated that variation in flower color is dependent on monogenic factors and quantitative trait loci (QTL). Here, we analyze quantitative variation of total anthocyanins in diploid rose progeny. We demonstrate that the environment produces relatively small effects; the main causes of variation in anthocyanin content are the genetic differences between individuals. Two major QTLs were detected in all six tested environments. Four additional QTLs were found only in a subset of the environments. Some of the QTLs either co-segregate or are located close to the map positions of known structural genes of the anthocyanin biosynthesis pathway or transcriptional regulators of anthocyanin biosynthesis. This information might be used to characterize tetraploid parental genotypes for their potential to pass on higher anthocyanin contents to their progeny.

  • 140.
    Herrmann, Anders
    et al.
    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.
    Mylne, Joshua S.
    Karlsson, Gustav
    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.
    Craik, David
    Clark, Richard
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    The alpine violet, Viola biflora, is a rich source of novel cyclotides with potent cytotoxic cytotoxicity2008Ingår i: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 69, nr 4, s. 939-952Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The cyclotides are currently the largest known family of head-to-tail cyclic proteins. The complex structure of these small plant proteins, which consist of approximately 30 amino acid residues, contains both a circular peptide backbone and a cystine knot, the combination of which produces the cyclic cystine knot motif. To date, cyclotides have been found in plants from the Rubiaceae, Violaceace and Cucurbitaceae families, and are believed to be part of the host defence system. In addition to their insecticidal effect, cyclotides have also been shown to be cytotoxic, anti-HIV, antimicrobial and haemolytic agents. In this study, we show that the alpine violet Viola biflora (Violaceae) is a rich source of cyclotides. The sequences of 11 cyclotides, vibi A-K, were determined by isolation and MS/MS sequencing of proteins and screening of a cDNA library of V. biflora in parallel. For the cDNA screening, a degenerate primer against a conserved (AAFALPA) motif in the cyclotide precursor ER signal sequence yielded a series of predicted cyclotide sequences that were correlated to those of the isolated proteins. There was an apparent discrepancy between the results of the two strategies as only one of the isolated proteins could be identified as a cDNA clone. Finally, to correlate amino acid sequence to cytotoxic potency, vibi D, E, G and H were analysed using a fluorometric microculture cytotoxicity assay using a lymphoma cell line. The IC50-values of the bracelet cyclotides vibi E, G and H ranged between 0.96 and 5.0 mu M while the Mobius cyclotide vibi D was not cytotoxic at 30 mu M.

  • 141.
    Herrmann, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Svangård, E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Claeson, Per
    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.
    Göransson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Key role of glutamic acid for the cytotoxic activity of the cyclotide cycloviolacin O22006Ingår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 63, nr 2, s. 235-245Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are cyclic plant proteins with potent cytotoxic effects. Here we systematically probed the importance of surface-exposed charged amino acid residues of the cyclotide cycloviolacin O2, using a strategy involving chemical modifications. We show that the single glutamic acid plays a key role for the cytotoxicity: methylation of this residue produced a 48-fold decrease in potency. Virtually no change in potency was observed when masking the single arginine residue using 1,2-cyclohexanedione, while acetylation of the two lysine residues reduced the potency 3-fold. The derivative with modifications at both arginine and lysine residues showed a 7-fold loss of potency. In addition, we show that the activity is dependent on an intact disulfide network and that the short sequences between the six cysteine residues, that is, the backbone loops, are devoid of cytotoxic activity.

  • 142.
    Herrmann, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Svangård, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    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.
    Bohlin, Lars
    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.
    Key role of glutamic acid for the cytotoxic activity of the cyclotide cycloviolacin O22006Ingår i: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 63, nr 2, s. 235-245Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclotides are cyclic plant proteins with potent cytotoxic effects. Here we systematically probed the importance of surface-exposed charged amino acid residues of the cyclotide cycloviolacin O2, using a strategy involving chemical modifications. We show that the single glutamic acid plays a key role for the cytotoxicity: methylation of this residue produced a 48-fold decrease in potency. Virtually no change in potency was observed when masking the single arginine residue using 1,2-cyclohexanedione, while acetylation of the two lysine residues reduced the potency 3-fold. The derivative with modifications at both arginine and lysine residues showed a 7-fold loss of potency. In addition, we show that the activity is dependent on an intact disulfide network and that the short sequences between the six cysteine residues, that is, the backbone loops, are devoid of cytotoxic activity.

  • 143. Hirt, Robert P.
    et al.
    Alsmark, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Embley, T. Martin
    Lateral gene transfers and the origins of the eukaryote proteome: a view from microbial parasites2015Ingår i: Current Opinion in Microbiology, ISSN 1369-5274, E-ISSN 1879-0364, Vol. 23, s. 155-162Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Our knowledge of the extent and functional impact of lateral gene transfer (LGT) from prokaryotes to eukaryotes, outside of endosymbiosis, is still rather limited. Here we review the recent literature, focusing mainly on microbial parasites, indicating that LGT from diverse prokaryotes has played a significant role in the evolution of a number of lineages, and by extension throughout eukaryotic evolution. As might be expected, taxonomic biases for donor prokaryotes indicate that shared habitat is a major factor driving transfers. The LGTs identified predominantly affect enzymes from metabolic pathways, but over a third of LGT are genes for putative proteins of unknown function. Finally, we discuss the difficulties in analysing LOT among eukaryotes and suggest that high-throughput methodologies integrating different approaches are needed to achieve a more global understanding of the importance of LGT in eukaryotic evolution.

  • 144. Holmstedt, Bo
    et al.
    Bruhn, Jan G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Ethnopharmacology: a challenge1983Ingår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 8, nr 3, s. 251-256Artikel i tidskrift (Refereegranskat)
  • 145.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. 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 Inflammation2016Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 79, nr 10, s. 2674-2680Artikel i tidskrift (Refereegranskat)
    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.

  • 146.
    Huss, U
    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.
    Perera, P
    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.
    Vasänge, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Screening of ubiquitous plant constituents for COX-2 inhibition with a scintillation proximity based assay2002Ingår i: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 65, nr 11, s. 1517-1521Artikel i tidskrift (Refereegranskat)
    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.

  • 147.
    Hussein, Juma
    et al.
    Systematisk biologi, Systematic Biology.
    Chi, Celestine N.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Tibell Savić, Sanja
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Systematisk biologi.
    Tibuhwa, Donatha
    University of Dar es Salaam, Department of molecular Biology and Biotechnology.
    Jacobsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Rosengren, Johan
    Wedén, Christina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolution, genomik och systematik, Systematisk botanik. 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. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Cysteine-rich peptide from the gigantic edible mushroom Kusaghiporia usambarensis (Laetiporaceae)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Cysteine-rich peptides are produced by various organisms across all kingdoms and have triggered an interest in isolation of molecules for novel drug development. In this study, we report a novel cysteine-rich peptide, kusaghitide, isolated from the gigantic medicinal mushroom Kusaghiporia usambarensis. It is highly expressed in the K. usambarensis transcriptome and it is the most abundant compound in the methanol-water extract. The 54 amino acid residue long peptide was isolated through aqueous methanol 50% and a sample was reduced, alkylated and cleaved enzymatically. De novo sequencing was done by LC-MS/MS and obtained sequences were used for mining the transcriptome to search for the complete gene. The peptide was recombinantly expressed in One Shot BL21 Star Escherichia coli using lysogenic broth and minimal media. Its 3D NMR structure was determined using 2D and 3D NMR. Three hypothetical protein sequences similar to kusaghitide originate from Laetiporus sulphureusWolfiporia cocos and Sparassis crispa with per cent similarity of 76% and 58% and 53% respectively and were found by BLAST search in the NCBI database. Kusaghitide did not inhibit the growth of either Escherichia coli or Staphylococcus aureus. This is first report of a peptide from K. usambarensis in Laetiporaceae.

  • 148.
    Hussein, Juma
    et al.
    Systematisk biologi, Systematic Biology.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Tibuhwa, Donatha
    University of Dar es Salaam, Department of molecular Biology and Biotechnology.
    Tibell Savić, Sanja
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Systematisk biologi.
    Wedén, Christina
    Göransson, Ulf
    Chemical composition of the medicinal mushroom Kusaghiporia usambarensisManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The mushroom Kusaghiporia usambarensis was recently described as a new species and the single member of a new genus. It appears endemic to Tanzania. The mushroom forms large, conspicuous fruiting bodies with an unusually high radial growth rate and an observed ability to attract insects. The mushroom is used by the local community both for food and in traditional medicine. In order to gain insight into both basic biology and the traditional use of this mushroom, we here report the first analyses of its chemical composition. A dichloromethane extract was prepared from the dried fruiting body and analysed by nuclear magnetic resonance and gas chromatography coupled to mass spectrometry. This extract of medium polar chemical constituents of Kusaghiporia usambarensis showed a high content of phenolic compounds and esters. The main elements were phenols, which account for ~22%, and esters ~20 %). These two groups of compounds may explain formerly reported antioxidant activity and traditional medicinal use of the mushroom. Revealing the chemistry also shed light on K. usambarensi as a sought-after delicacy: presence of 1-octen-3-one, octanal, 3-octen-2-one contribute to its fruity, cheesy and chicken flavour.

  • 149. Ibewuike, Joseph C
    et al.
    Ogungbamila, Francis O
    Ogundaini, Abiodun O
    Okeke, Irukaku N
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Antiinflammatory and antibacterial activities of C-methylflavonols from Piliostigma thonningii1997Ingår i: Phytotherapy Research, ISSN 0951-418X, E-ISSN 1099-1573, Vol. 11, nr 4, s. 281-284Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Newly described C-methylflavonols, 6,8-di-C-methylquercetin 3-methyl ether, 6-C-methylquercetin 3,7-dimethyl ether, 6,8-di-C-methylquercetin 3,7-dimethyl ether together with the known compounds quercetin, quercitrin, 6-C-methylquercetin 1-methyl ether, 6-C-methylquercetin 3,7,3'-trimethyl ether, 6,8-di-C-methylkaempferoI 3-methyl ether and 6,8-di-C-methylkaempferol 3,7-dimethyl ether isolated from the leaves of Piliostigma thonningii, were tested for their ability to inhibit prostaglandin synthesis in vitro and antibacterial activity against Staph, aureus, The influence of the B ring 3',4' diol group on the activity of C-methylflavonols in the inhibition of prostaglandin synthesis differ from that observed for a series of flavonoids without C-methyl groups, The antibacterial activity in the series mirror those of methylated antimicrobial flavonoids, The traditional uses of the plant in infections and inflammatory conditions were rationalized on the basis of the activities of these compounds.

  • 150.
    Ibewuike, Jospeh C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Ogundaini, Abiodun O
    Ogungbamila, Francis O
    Martin, Marie-Thérese
    Gallard, Jean-Francois
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Païs, Mary
    Piliostigmin, a 2-phenoxychromone, and C-methylflavonols from Piliostigma thonningii1996Ingår i: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 43, nr 3, s. 687-690Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Piliostigmin, a 2-phenoxychromone, and three C-methylflavonols, 6,8-di-C-methylquercetin 3-methyl ether, 6-C-methylquercetin 3,7-dimethyl ether and 6,8-di-C-methylquercetin 3,7-dimethyl ether, were isolated from the leaves of Piliostigma thonningii, together with the known compounds quercetin, quercitrin, 6-C-methylquercetin S-methyl ether, 6-C-methylquercetin 3,7,3'-trimethyl ether, 6,8-di-C-methyllraempferol 3-methyl ether and 6,8-di-C-methyllraempferol 3,7-dimethyl ether. The structures of the new compounds were established by spectral methods, especially 2D NMR. Complete C-13 assignments using HMBC experiments are reported for the four latter C-methylflavonols.

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