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  • 51.
    Andersson, Pher
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Schab, Szymon
    Mechanism of the Palladium-Catalyzed Elimination of Acetic Acid from Allylic Acetates1995In: Organometallics, Vol. 14, no 1, p. 1-Article in journal (Refereed)
  • 52.
    Andersson, Pher
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Schink, Hans
    Österlund, Krister
    Asymmetric Total Synthesis of (+)-Tolterodine, a New Muscarinic Receptor Antagonist, via Copper-Assisted Asymmetric Conjugate Addition of Aryl Grignard Reagents to 3-Phenyl-prop-2-enoyl-oxazolidinones1998In: J. Org. Chem., no 63, p. 8067-8070Article in journal (Refereed)
  • 53.
    Andersson, Pher
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Sharpless, K. Barry
    A Dramatic Ligand Effect on the Relative Reactive Reactivites of Substituted Alkenes with Osmium Tetroxide1993In: J. Am. Chem. Soc., no 115, p. 7047-7048Article in journal (Refereed)
  • 54. Andersson, Theresa
    et al.
    Lundquist, Martin
    Dolphin, Gunnar T.
    Enander, Karin
    Jonsson, Bengt-Harald
    Nilsson, Jonas W.
    Baltzer, Lars
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Cooperative binding of human Carbonic Anhydrase II by functionalized folded polypeptide receptors2005In: Chem. Biol., no 12, p. 1245-1252Article in journal (Refereed)
  • 55. Ankarloo, Jonas
    et al.
    Wikman, Susanne
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Escherichia coli mar and acrAB Mutants Display No Tolerance to Simple Alcohols2010In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 11, no 4, p. 1403-1412Article in journal (Refereed)
    Abstract [en]

    The inducible Mar phenotype of Escherichia coli is associated with increased tolerance to multiple hydrophobic antibiotics as well as some highly hydrophobic organic solvents such as cyclohexane, mediated mainly through the AcrAB/TolC efflux system. The influence of water miscible alcohols ethanol and 1-propanol on a Mar constitutive mutant and a mar deletion mutant of E. coli K-12, as well as the corresponding strains carrying the additional acrAB deletion, was investigated. In contrast to hydrophobic solvents, all strains were killed in exponential phase by 1-propanol and ethanol at rates comparable to the parent strain. Thus, the Mar phenotype does not protect E. coli from killing by these more polar solvents. Surprisingly, AcrAB does not contribute to an increased alcohol tolerance. In addition, sodium salicylate, at concentrations known to induce the mar operon, was unable to increase 1-propanol or ethanol tolerance. Rather, the toxicity of both solvents was increased in the presence of sodium salicylate. Collectively, the results imply that the resilience of E. coli to water miscible alcohols, in contrast to more hydrophobic solvents, does not depend upon the AcrAB/TolC efflux system, and suggests a lower limit for substrate molecular size and functionality. Implications for the application of microbiological systems in environments containing high contents of water miscible organic solvents, e. g., phage display screening, are discussed.

  • 56.
    Antoni, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Axelsson, Jan
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lindsjö, Lars
    Kero, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Granstam, Sven-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Rosengren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Vedin, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    In Vivo Visualization of Amyloid Deposits in the Heart with 11C-PIB and PET2013In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 2, p. 213-220Article in journal (Refereed)
    Abstract [en]

    Cardiac amyloidosis is a differential diagnosis in heart failure and is associated with high mortality. There is currently no noninvasive imaging test available for specific diagnosis. N-[methyl-11C]2-(4′-methylamino-phenyl)-6-hydroxybenzothiazole (11C-PIB) PET is used in the evaluation of brain amyloidosis. We evaluated the potential use of 11C-PIB PET in systemic amyloidosis affecting the heart.

    Methods:

    Patients (n = 10) diagnosed with systemic amyloidosis—including heart involvement of either monoclonal immunoglobulin light-chain (AL) or transthyretin (ATTR) type—and healthy volunteers (n = 5) were investigated with PET/CT using 11C-PIB to study cardiac amyloid deposits and with 11C-acetate to measure myocardial blood flow to study the impact of global and regional perfusion on PIB retention.

    Results:

    Myocardial 11C-PIB uptake was visually evident in all patients 15–25 min after injection and was not seen in any volunteer. A significant difference in 11C-PIB retention in the heart between patients and healthy controls was found. The data indicate that myocardial amyloid deposits in patients diagnosed with systemic amyloidosis could be visualized with 11C-PIB. No correlation between 11C-PIB retention index and myocardial blood flow as measured with 11C-acetate was found on the global level, whereas a positive correlation on the segmental level was seen in a single patient.

    Conclusion:

    11C-PIB and PET could be a method to study systemic amyloidosis of type AL and ATTR affecting the heart and should be investigated further both as a diagnostic tool and as a noninvasive method for treatment follow-up.

  • 57.
    Antoni, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
    Omura, H
    Ikemoto, M
    Moulder, R
    Watanabe, Y
    Långström, B
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Enzyme catalysed synthesis of L-(4-11C) aspartate and L-(5-11C) glutamate2001In: J. Labbelled Compd. Radiopharm.Article in journal (Other academic)
  • 58.
    Arvidsson, Per
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Frackenpohl, J
    Seebach, D
    Syntheses an CD-Spectroscopic Investigations of Longer-Chain B-Peptides: Preparation by Solid-Phase Couplings of Single Amino Acids, Dipeptides, and Tripeptides2003In: Helvetica Chemica Acta, no 86, p. 1552-1553Article in journal (Refereed)
  • 59.
    Arvidsson, Per I.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Govender, Thavendran
    Kruger, G
    Maguire, M
    Naicker, Tricia
    Application of (S,S)-Pentacycloundecane bis(4-Phenyloxazoline) as a Novel Chiral Ligand for Catalysis of the Asymmetric Diels-Alder Reaction of Cyclopentadiene with 3-Acryloyl-2-oxazolidinone2009In: South African Journal of Chemistry, ISSN 0379-4350, E-ISSN 1996-840X, Vol. 62, p. 60-U78Article in journal (Refereed)
    Abstract [en]

    The synthesis of the novel C-1 symmetric (S,S)-pentacycloundecane bis(4-phenyloxazoline) ligand 5 and its evaluation as a chiral Lewis acid catalyst in the benchmark asymmetric Diels-Alder reaction between 3-acryloyloxazolidin-2-one (6) and cyclopentadiene (7) is reported. From the various metal salts screened the anhydrous magnesium perchlorate complex emerged as the best catalyst. The endo-cycloadduct product 8 was afforded in 81% enantiomeric excess with an endo:exo ratio of 98:2. An extensive screening of various metal ions as complexing agents was performed and is also reported.

  • 60.
    Arvidsson, Per
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Ryder, N
    Weiss, M
    Gross, G
    Kretz, O
    Woessner, R
    Seebach, D
    Antibiotic and Hemolytic Activity of a B2/B3 Peptide Capable of Folding into a 12/10-Helical Secondary Structure2003In: ChemBioChem, no 4, p. 1345-1347Article in journal (Refereed)
  • 61.
    Arvidsson, Per
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Organisk kemi.
    Ryder, Neil S.
    Weiss, H. Markus
    Hook, David F.
    Escalante, Jaime
    Seebach, Dieter
    Exploring the Antibacterial and Hemolytic Activity of Shorter- and Longer-Chain B-, a,B-, and y-Peptides, and of B-Peptides from B2-3-Aza- and B3-2-Methylidene-amino Acids Bearing Proteinogenic Side Chains - A Survey2005In: Chemistry & Biodiversity, Vol. 2, p. 401-420Article in journal (Refereed)
    Abstract [en]

    The antibacterial activities of 31 different b-, mixed a/B-, and y-peptides, as well as of B-peptides derived from B2-3-aza- and B3-2-methylidene-amino acids were assayed against six pathogens (Enterococcus faecails, STaphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa), and the results were compared with literature data. The interaction of these peptides with mammalian cells, as modeled by measuring the hemolysis of human erythrocytes, was also investigated. In addition to those peptides designed to fold into amphiphilic helical conformations with positive charges on one face of the helix, one new peptide with hemolytic activity was detected within the sample set. Moreover, it was demontrated that neither cationic peptides used for membrane translocation (B3-oligoarginines), nor mixeda/B- or y-peptides with somatostatin-mimicking activities display unwanted hemolytic activity.

  • 62.
    Ausmees, Nora
    et al.
    Swedish University of Agricultural Sciences, SLU, Department of Microbiology.
    Jonsson, Hans
    Swedish University of Agricultural Sciences, SLU, Department of Microbiology.
    Höglund, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Ljunggren, Hans
    Swedish University of Agricultural Sciences, SLU, Department of Microbiology.
    Lindberg, Martin
    Swedish University of Agricultural Sciences, SLU, Department of Microbiology.
    Structural and putative regulatory genes involved in cellulose synthesis in Rhizobium leguminosarum bv. trifolii1999In: Microbiology, ISSN 1350-0872, E-ISSN 1465-2080, Vol. 145, p. 1253-1262Article in journal (Refereed)
    Abstract [en]

    Six genes involved in cellulose synthesis in Rhizobium leguminosarum bv. trifolii were identified using Tn5 mutagenesis. Four of them displayed homology to the previously cloned and sequenced Agrobacterium tumefaciens cellulose genes celA, celB, celC and celE. These genes are organized similarly in R. leguminosarum bv. trifolii. In addition, there were strong indications that two tandemly located genes, celR1 and celR2, probably organized as one operon, are involved in the regulation of cellulose synthesis. The deduced amino acid sequences of these genes displayed a high degree of similarity to the Caulobacter crescentus DivK and PleD proteins that belong to the family of two-component response regulators. This is to our knowledge the first report of genes involved in the regulation of cellulose synthesis. Results from attachment assays and electron microscopic studies indicated that cellulose synthesis in R. leguminosarum bv. trifolii is induced upon close contact with plant roots during the attachment process.

  • 63. Bacskay, Ivett
    et al.
    Takatsy, Aniko
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Vegvari, Akos
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Elfwing, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology, Centre for Surface Biotechnology.
    Balllagi-Pordany, Andras
    Kilar, Ferenc
    Hjertén, Stellan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Universal method for synthesis of artificial gel antibodies by the imprinting approach combined with a unique electrophoresis technique for detection of minute structural differences of proteins, viruses, and cells (bacteria). III: Gel antibodies against cells (bacteria)2006In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 27, no 23, p. 4682-4687Article in journal (Refereed)
    Abstract [en]

    Artificial antibodies in the form of gel granules were synthesized from the monomers acrylamide and N,N'-methylenebisacrylamide by the imprinting method in the presence of Echerichia coli bacteria as template. The electrophoretic migration velocities of the gel antibodies (i) saturated with the antigen (Escherichia coli MRE-600), (ii) freed of the antigen, and (iii) resaturated with bacteria, were determinated by electrophoresis in a rotating narrow-bore tube of 245 mm length and the 2.5 and 9.6 mm inner and outer diameters, respectively. Removal of bacteria from the gel antibodies was made by treatment with enzymes, followed by washing with SDS and buffer. Gel granules becoming charged by adsorption of bacteria move in an electrical field. We obtained a significant selectivity of gel antibodies for E coli MRE-600, since the granules did not interact with Lactococcus lactis; and when E coli BL21 bacteria were added to the gels selective for E coli MRE-600, a significant difference in the migration rate of the complexes formed with the two strains was observed indicating the ability of differentiation between the two strains. The gel antibodies can be used repeatedly. The new imprinting method for the synthesis of artificial gel antibodies against bioparticles described herein, and the classical electrophoretic analysis technique employed, thus represent - when combined - a new approach to distinguish between different types and strains of bacteria. The application area can certainly be extended to cover other classes of cells.

  • 64. Balogh, Larissa M.
    et al.
    Le Trong, Isolde
    Kripps, A
    Tars, Kaspars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Stenkamp, E
    Mannervik, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Atkins, William M.
    Structural Analysis of a Glutathione Transferase A1-1 Mutant Tailored for High Catalytic Efficiency with Toxic Alkenals2009In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 32, p. 7698-7704Article in journal (Refereed)
    Abstract [en]

    The specificity of human glutathione transferase (GST) A1-1 is drastically altered to favor alkenal substrates in the GIMFhelix mutant designed to mimic first-sphere interactions utilized by GSTA4-4. This redesign serves as a model for improving our understanding of the structural determinants that contribute to the distinct specificities of alpha class GSTs. Herein we report the first crystal structures of GIMFhelix, both in complex with GSH and in apo form at 1.98 and 2.38 angstrom resolution. In contrast to the preorganized hydrophobic binding pocket that accommodates alkenals in GSTA4-4, GSTA1-1 includes a dynamic alpha 9 helix that undergoes a ligand-dependent localization to complete the active site. Comparisons of the GIMFhelix structures with previously reported structures show a striking similarity with the GSTA4-4 active site obtained within an essentially GSTA1-1 scaffold and reveal the 0 helix assumes a similar localized structure regardless of active site occupancy in a manner resembling that of GSTA4-4. However, Are cannot fully account for all the structural elements important in GSTA4-4 within the mutant's active site. The contribution of Phe10 to the Tyr212-Phe10-Phe220 network prevents complete C-terminal Closure and demonstrates that the presence of Phe10 within the context of a GSTA4-4-like active site may ultimately hinder Phe220, a key C-terminal residue, from effectively contributing to the active site. In total, these results illustrate the remaining structural differences presumably reflected in the previously reported catalytic efficiencies of GIMFhelix and GSTA4-4 and emphasize the F10P mutation as being necessary to completely accomplish the transformation to a highly specific GST from the more promiscuous GSTA1-1 enzyme.

  • 65. Balogh, Larissa M.
    et al.
    Le Trong, Isolde
    Kripps, Kimberly A.
    Shireman, Laura M.
    Stenkamp, Ronald E.
    Zhang, Wei
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Mannervik, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Atkins, William M.
    Substrate Specificity Combined with Stereopromiscuity in Glutathione Transferase A4-4-Dependent Metabolism of 4-Hydroxynonenal2010In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 49, no 7, p. 1541-1548Article in journal (Refereed)
    Abstract [en]

    Conjugation to glutathione (GSH) by glutathione transferase A4-4 (GSTA4-4) is a major route of elimination for the lipid peroxidation product 4-hydroxynonenal (HNE), a toxic compound that contributes to numerous diseases. Both enantiomers of HNE are presumed to be toxic, and GSTA4-4 has negligible stereoselectivity toward them, despite its high catalytic chemospecificity for alkenals. In contrast to the highly flexible, and substrate promiscuous, GSTA1-1 isoform that has poor catalytic efficiency with HNE, GSTA4-4 has been postulated to be a rigid template that is preorganized for HNE metabolism. However, the combination of high substrate chemoselectivity and low substrate stereoselectivity is intriguing. The mechanism by which GSTA4-4 achieves this combination is important, because it must metabolize both enantiomers of HNE to efficiently detoxify the biologically formed mixture. The crystal structures of GSTA4-4 and ail engineered variant of GSTA1-1 with high catalytic efficiency toward HNE, cocrystallized with a GSH-HNE conjugate analogue, demonstrate that GSTA4-4 undergoes no enantiospecific induced fit; instead, the active site residue Arg15 is ideally located to interact with the 4-hydroxyl group of either HNE enantiomer. The results reveal an evolutionary strategy for achieving biologically useful stereopromiscuity toward a toxic racemate, concomitant with high catalytic efficiency and substrate specificity toward ail endogenously formed toxin.

  • 66.
    Baltzer, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry.
    Crossing borders to bind proteins-a new concept in protein recognition based on the conjugation of small organic molecules or short peptides to polypeptides from a designed set2011In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 400, no 6, p. 1653-1664Article, review/survey (Refereed)
    Abstract [en]

    A new concept for protein recognition and binding is highlighted. The conjugation of small organic molecules or short peptides to polypeptides from a designed set provides binder molecules that bind proteins with high affinities, and with selectivities that are equal to those of antibodies. The small organic molecules or peptides need to bind the protein targets but only with modest affinities and selectivities, because conjugation to the polypeptides results in molecules with dramatically improved binder performance. The polypeptides are selected from a set of only sixteen sequences designed to bind, in principle, any protein. The small number of polypeptides used to prepare high-affinity binders contrasts sharply with the huge libraries used in binder technologies based on selection or immunization. Also, unlike antibodies and engineered proteins, the polypeptides have unordered three-dimensional structures and adapt to the proteins to which they bind. Binder molecules for the C-reactive protein, human carbonic anhydrase II, acetylcholine esterase, thymidine kinase 1, phosphorylated proteins, the D-dimer, and a number of antibodies are used as examples to demonstrate that affinities are achieved that are higher than those of the small molecules or peptides by as much as four orders of magnitude. Evaluation by pull-down experiments and ELISA-based tests in human serum show selectivities to be equal to those of antibodies. Small organic molecules and peptides are readily available from pools of endogenous ligands, enzyme substrates, inhibitors or products, from screened small molecule libraries, from phage display, and from mRNA display. The technology is an alternative to established binder concepts for applications in drug development, diagnostics, medical imaging, and protein separation.

  • 67.
    Baltzer, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Polypeptide Conjugate Binders for Protein Recognition2007In: Topics in current chemistry, ISSN 0340-1022, E-ISSN 1436-5049, Vol. 277, p. 89-106Article, review/survey (Refereed)
    Abstract [en]

    A new class of hybrid molecules for protein recognition is presented, where polypeptides are covalently linked to small organic molecules to form polypeptide conjugates that bind proteins with high affinity and selectivity. To illustrate the concept, a binder for human carbonic anhydrase 11 with a dissociation constant of 4 nM is described. The affinity of the polypeptide conjugate arises from cooperativity in binding between a benzenesulfonamide residue, with a dissociation constant of 1.5 mu M, and the polypeptide scaffold with a dissociation constant of < 1 mM. The combination of a ligand with moderate affinity for a target protein with a polypeptide relaxes considerably the need for high affinity on the part of the polypeptide, and thus the need for structural complexity and preorganization. At the same time, the requirement for high affinity on the part of ligand is relaxed. As a consequence, the time for development of robust, high affinity, selective binder is shortened. The chemical approach to protein recognition provides well-defined molecular entities that are conveniently handled, stored and site-specifically functionalized.

  • 68.
    Baltzer, Lars
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    DeGrado, W. F.
    Engineering and design: Expanding the protein world2004In: Editorial overview Current Opinion of Structural Biology, Vol. 14, p. 455-457Article, review/survey (Other (popular scientific, debate etc.))
  • 69.
    Baltzer, Lars
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Klinman, J.P.
    Hynes, J.T.
    Limbach, H-H.
    Acid base catalysis in designed polypeptides2006In: Handbook of Hydrogen Transfer, Wiley , 2006Chapter in book (Refereed)
  • 70.
    Barletta, Julien
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    [11C]Carbon Monoxide in Rhodium-/Palladium-Mediated Carbonylation Reactions2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Methods for the 11C-labeling of carbonyl compounds applicable in the preparation of radiotracers for Positron Emission Tomography (PET) are described. To this end [11C]carbon monoxide at low concentration was used in transition metal- mediated reactions.

    Stille couplings were employed in the synthesis of [carbonyl-11C]ketones from methyl and aryl halides with [11C]carbon monoxide. The synthesized [carbonyl-11C]ketones were obtained from the corresponding organostannanes with analytical radiochemical yields up to 98%.

    A number of synthetic routes were designed using [11C]carbon monoxide and rhodium complexes. Nitrene intermediates were generated from azides and reacted via a rhodium-mediated carbonylation reaction as a general synthetic route to [carbonyl-11C]isocyanates, versatile precursors. [carbonyl-11C]Isocyanate reacted via nucleophilic attack of an amine to form N,N’-diphenyl[11C]urea in 82% analytical radiochemical yield, ethyl phenyl[11C]carbamate was synthesized by the same route, using ethanol as the nucleophile, in 70% radiochemical yield. [11C]Isocyanate was also able to react in a [2+3] cycloaddition with ethylene oxide to form 3-phenyl[carbonyl-11C]oxazolidin-2-one in over 80% analytical radiochemical yield. This method was applied to the synthesis of a potential efflux system tracer [11C]hydroxyurea in 38% isolated radiochemical yield and the derivative 1-hydroxy-3-phenyl[11C]urea in 35% isolated radiochemical yield. Carbene intermediates, generated from diazo compounds, were reacted with [11C]carbon monoxide in the rhodium-mediated synthesis of [carbonyl-11C]ketenes. [carbonyl-11C]Ketene intermediates were utilised in the synthesis of diethyl[carbonyl-11C]malonate, from ethyl diazoacetate and ethanol. The product was obtained with a 20% isolated radiochemical yield. Alkylation of diethyl[carbonyl-11C]malonate, with ethyliodide and tetrabutylammonium fluoride, was successfully accomplished and diethyl diethyl[carbonyl-11C]malonate was synthesized in 50% analytical radiochemical yield. Several (carbonyl-13C)compounds were also synthesized using the described methods as a way of characterizing the position of the label using 13C-NMR.

    List of papers
    1. Synthesis of 11C-labelled N,N’-diphenylurea and ethyl phenylcarbamate by rhodium-promoted carbonylation reaction via [11C]-isocyanatobenzene using phenyl azide and [11C]carbon monoxide
    Open this publication in new window or tab >>Synthesis of 11C-labelled N,N’-diphenylurea and ethyl phenylcarbamate by rhodium-promoted carbonylation reaction via [11C]-isocyanatobenzene using phenyl azide and [11C]carbon monoxide
    Show others...
    2004 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 2, no 21, p. 3063-3066Article in journal (Refereed) Published
    Abstract [en]

    The reaction with phenyl azide and [11C]carbon monoxide to give N,N'-diphenyl[11C]urea and ethyl phenyl[11C]carbamate has been studied with the aim of development of a new methodology for carbonylation using [11C]carbon monoxide with high specific radioactivity. The synthesis of 11C-labelled N,N'-diphenylurea from phenyl azide and [11C]carbon monoxide, with 1,2-bis(diphenylphosphino)ethane-bound Rh(I) complex at 120 degrees C at a pressure of 35 MPa in the presence of aniline was accomplished in 82% trapping efficiency and 82% conversion yield. This approach was also useful for the synthesis of ethyl phenyl[11C]carbamate with lithium ethoxide as a nucleophilic reagent giving 90% trapping efficiency and 76% conversion yield. These reactions can be considered to proceed via a [11C]isocyanate or a [11C]isocyanate-coordinated Rh complex to give the corresponding 11C-products. This protocol provides the chemical basis for the synthesis of [11C]urea and [11C]carbamate derived from [11C]isocyanates.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-94170 (URN)10.1039/B409294E (DOI)15505707 (PubMedID)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    2. Palladium-mediated 11C-carbonylative cross coupling of alkyl / aryl iodides with organostannanes. An efficient synthesis of un-symmetrical alkyl - aryl [carbonyl-11C]ketones
    Open this publication in new window or tab >>Palladium-mediated 11C-carbonylative cross coupling of alkyl / aryl iodides with organostannanes. An efficient synthesis of un-symmetrical alkyl - aryl [carbonyl-11C]ketones
    2005 In: Eur.J. Org. Chem., p. 2374-2378Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94171 (URN)
    Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
    3. Synthesis of [11C-carbonyl]hydroxyureas by a rhodium-mediated carbonylation reaction using [11C]carbon monoxide
    Open this publication in new window or tab >>Synthesis of [11C-carbonyl]hydroxyureas by a rhodium-mediated carbonylation reaction using [11C]carbon monoxide
    2006 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 5, p. 429-436Article in journal (Refereed) Published
    Abstract [en]

    [11C]Hydroxyurea has been successfully labelled using [11C]carbon monoxide at low concentration. The decay-corrected radiochemical yield was 38±3%, and the trapping efficiency of [11C]carbon monoxide in the order of 90±5%. This synthesis was performed by a rhodium-mediated carbonylation reaction starting with azidotrimethylsilane and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]2) and 1,2-bis(diphenylphosphino)ethane (dppe). (13C)Hydroxyurea was synthesized using this method and the position of the labelling was confirmed by 13C-NMR. In order to perform accurate LC–MS identification, the derivative 1-hydroxy-3-phenyl[11C]urea was synthesized in a 35±4% decay-corrected radiochemical yield. After 13 µA h bombardment and 21 min synthesis, 1.6 GBq of pure 1-hydroxy-3-phenyl[11C]urea was collected starting from 6.75 GBq of [11C]carbon monoxide and the specific radioactivity of this compound was in the order of 686 GBq/µmol (3.47 nmol total mass). [11C]Hydroxyurea could be used in conjunction with PET to evaluate the uptake of this anticancer agent into tumour tissue in individual patients.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-94172 (URN)10.1002/jlcr.1062 (DOI)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    4. Synthesis of diethyl [carbonyl-C-11]malonate from [C-11]carbon monoxide by rhodium-promoted carbonylation and its application as a reaction intermediate
    Open this publication in new window or tab >>Synthesis of diethyl [carbonyl-C-11]malonate from [C-11]carbon monoxide by rhodium-promoted carbonylation and its application as a reaction intermediate
    2006 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 9, p. 801-809Article in journal (Refereed) Published
    Abstract [en]

    Rhodium-mediated carbonylation reaction was applied to synthesize diethyl [carbonyl-C-11]malonate using [C-11]carbon monoxide at low concentration. The synthesis was performed starting with ethyl diazoacetate, ethanol and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(l) dimer ([Rh(cod)Cl](2)) and 1,2-bis(diphenylphosphino)ethane (dppe), and the reaction is assumed to proceed via a ketene intermediate. The isolated radiochemical yield was 20% (75% analytical radiochemical yield) and the trapping efficiency of [C-11]carbon monoxide in the order of 85%. The specific radioactivity of this compound was measured at 127 GBq/mu mol (7.28 nmol total mass) after 8 mu Ah bombardment and 35 min synthesis. The corresponding C-13-labelled compound was synthesized using (C-13)carbon monoxide to confirm the position of the carbonyl-labelled atom by C-13-NMR. Diethyl [carbonyl-C-11]malonate was further used in subsequent alkylation step using ethyl iodide and tetrabutylammonium fluoride to obtain diethyl diethyl [carbonyl-C-11]malonate in 50% analytical radiochemical yield.

    Keywords
    diethyl [carbonyl-C-11]malonate, [C-11]carbon monoxide, rhodium-mediated carbonylation reaction, ketene
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94173 (URN)10.1002/jlcr.1098 (DOI)000240473200005 ()
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    5. Synthesis of [11C]oxazolidinone via rhodium-mediated carbon-yaltion reaction using [11C]carbon monoxide and [11C]isocyanate intermediate
    Open this publication in new window or tab >>Synthesis of [11C]oxazolidinone via rhodium-mediated carbon-yaltion reaction using [11C]carbon monoxide and [11C]isocyanate intermediate
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94174 (URN)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2010-01-13Bibliographically approved
  • 71.
    Barletta, Julien
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry and Organic Chemistry.
    Karimi, Farhad
    Doi, Hisashi
    Långström, Bengt
    Synthesis of [11C]oxazolidinone via rhodium-mediated carbon-yaltion reaction using [11C]carbon monoxide and [11C]isocyanate intermediateManuscript (Other academic)
  • 72.
    Barletta, Julien
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Karimi, Farhad
    Doi, Hisashi
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Synthesis of diethyl [carbonyl-C-11]malonate from [C-11]carbon monoxide by rhodium-promoted carbonylation and its application as a reaction intermediate2006In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 9, p. 801-809Article in journal (Refereed)
    Abstract [en]

    Rhodium-mediated carbonylation reaction was applied to synthesize diethyl [carbonyl-C-11]malonate using [C-11]carbon monoxide at low concentration. The synthesis was performed starting with ethyl diazoacetate, ethanol and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(l) dimer ([Rh(cod)Cl](2)) and 1,2-bis(diphenylphosphino)ethane (dppe), and the reaction is assumed to proceed via a ketene intermediate. The isolated radiochemical yield was 20% (75% analytical radiochemical yield) and the trapping efficiency of [C-11]carbon monoxide in the order of 85%. The specific radioactivity of this compound was measured at 127 GBq/mu mol (7.28 nmol total mass) after 8 mu Ah bombardment and 35 min synthesis. The corresponding C-13-labelled compound was synthesized using (C-13)carbon monoxide to confirm the position of the carbonyl-labelled atom by C-13-NMR. Diethyl [carbonyl-C-11]malonate was further used in subsequent alkylation step using ethyl iodide and tetrabutylammonium fluoride to obtain diethyl diethyl [carbonyl-C-11]malonate in 50% analytical radiochemical yield.

  • 73.
    Barletta, Julien
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Karimi, Farhad
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Synthesis of [11C-carbonyl]hydroxyureas by a rhodium-mediated carbonylation reaction using [11C]carbon monoxide2006In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 5, p. 429-436Article in journal (Refereed)
    Abstract [en]

    [11C]Hydroxyurea has been successfully labelled using [11C]carbon monoxide at low concentration. The decay-corrected radiochemical yield was 38±3%, and the trapping efficiency of [11C]carbon monoxide in the order of 90±5%. This synthesis was performed by a rhodium-mediated carbonylation reaction starting with azidotrimethylsilane and the rhodium complex being made in situ by chloro(1,5-cyclooctadiene)rhodium(I) dimer ([Rh(cod)Cl]2) and 1,2-bis(diphenylphosphino)ethane (dppe). (13C)Hydroxyurea was synthesized using this method and the position of the labelling was confirmed by 13C-NMR. In order to perform accurate LC–MS identification, the derivative 1-hydroxy-3-phenyl[11C]urea was synthesized in a 35±4% decay-corrected radiochemical yield. After 13 µA h bombardment and 21 min synthesis, 1.6 GBq of pure 1-hydroxy-3-phenyl[11C]urea was collected starting from 6.75 GBq of [11C]carbon monoxide and the specific radioactivity of this compound was in the order of 686 GBq/µmol (3.47 nmol total mass). [11C]Hydroxyurea could be used in conjunction with PET to evaluate the uptake of this anticancer agent into tumour tissue in individual patients.

  • 74.
    Barman, Jharna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Targeting RNA by the Antisense Approach and a Close Look at RNA Cleavage Reaction2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis summarizes the results of studies on two aspects of nucleic acids. Chemically modified antisense oligonucleotides (AONs) have been evaluated with regards to their suitability for mRNA targeting in an antisense approach (Paper I – III). The chemically modified nucleotidic units 2'-O-Me-T, 2'-O-MOE-T, oxetane-T, LNA-T, azetidine-T, aza-ENA-T, carbocyclic-ENA-T and carbocyclic-LNA-T were incorporated into 15-mer AONs and targeted against a 15-mer RNA chosen from the coding region of SV-40 large T antigen. The comparative study showed that a single modified nucleotide in the AON with North-East locked sugar (oxetane-T and azetidine-T) lowered the affinity for the complementary RNA whereas North locked sugars (LNA-T, aza-ENA-T, carbocyclic-ENA-T, and carbocyclic-LNA-T) significantly improved the affinity. A comparative RNase H digestion study showed that modifications of the same type (North-East type or North type) in different sequences gave rise to similar cleavage patterns. Determination of the Michaelis-Menten parameters by kinetic experiments showed that the modified AONs recruit RNase H resulting in enhanced turnover numbers (kcat) although with weaker enzyme-substrate binding (1/Km) compared to the unmodified AON. The modified AONs were also evaluated with regards to resistance towards snake venom phosphodiesterase and human serum to estimate their stability toward exonucleases. The aza-ENA-T and carbocyclic-ENA-T modified AONs showed improved stability compared to all other modified AONs. In general, the modified AONs with North type nucleotides (except LNA-T) were found to be superior to the North-East type as they showed improved target affinity, comparable RNase H recruitment capability and improved exonuclease stability.

    The second aspect studied in this thesis is based on physicochemical studies of short RNA molecules utilizing NMR based pH titration and alkaline hydrolysis reactions (Paper IV – V). The NMR based (1H and 31P) pH titration studies revealed the effect of guaninyl ion formation, propagated electrostatically through a single stranded chain in a sequence dependent manner. The non-identical electronic character of the internucleotidic phosphodiesters was further verified by alkaline hydrolysis experiments. The internucleotidic phosphodiesters, which were influenced by guaninyl ion formation, were hydrolyzed at a faster rate than those sequences where such guaninyl ion formation was prevented by replacing G with N1-Me-G.

    List of papers
    1. Comparison of the RNase H Cleavage Kinetics and Blood Serum Stability of the North-Conformationally Constrained and 2‘-Alkoxy Modified Oligonucleotides
    Open this publication in new window or tab >>Comparison of the RNase H Cleavage Kinetics and Blood Serum Stability of the North-Conformationally Constrained and 2‘-Alkoxy Modified Oligonucleotides
    2007 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 19, p. 5635-5646Article in journal (Refereed) Published
    Abstract [en]

    The RNase H cleavage potential of the RNA strand basepaired with the complementary antisense oligonucleotides (AONs) containing NorthEast conformationally constrained 1‘,2‘-methylene-bridged (azetidine-T and oxetane-T) nucleosides, North-constrained 2‘,4‘-ethylene-bridged (aza-ENA-T) nucleoside, and 2‘-alkoxy modified nucleosides (2‘-O-Me-T and 2‘-O-MOE-T modifications) have been evaluated and compared under identical conditions. When compared to the native AON, the aza-ENA-T modified AON/RNA hybrid duplexes showed an increase of melting temperature (ΔTm = 2.5−4 °C per modification), depending on the positions of the modified residues. The azetidine-T modified AONs showed a drop of 4−5.5 °C per modification with respect to the native AON/RNA hybrid, whereas the isosequential oxetane-T modified counterpart, showed a drop of 5−6 °C per modification. The 2‘-O-Me-T and 2‘-O-MOE-T modifications, on the other hand, showed an increased of Tm by 0.5 °C per modification in their AON/RNA hybrids. All of the partially modified AON/RNA hybrid duplexes were found to be good substrates for the RNase H mediated cleavage. The Km and Vmax values obtained from the RNA concentration-dependent kinetics of RNase H promoted cleavage reaction for all AON/RNA duplexes with identical modification site were compared with those of the reference native AON/RNA hybrid duplex. The catalytic activities (Kcat) of RNase H were found to be greater (1.4−2.6-fold) for all modified AON/RNA hybrids compared to those for the native AON/RNA duplex. However, the RNase H binding affinity (1/Km) showed a decrease (1.7−8.3-fold) for all modified AON/RNA hybrids. This resulted in less effective (1.1−3.2-fold) enzyme activity (Kcat/Km) for all modified AON/RNA duplexes with respect to the native counterpart. A stretch of five to seven nucleotides in the RNA strand (from the site of modifications in the complementary modified AON strand) was found to be resistant to RNase H digestion (giving a footprint) in the modified AON/RNA duplex. Thus, (i) the AON modification with azetidine-T created a resistant region of five to six nucleotides, (ii) modification with 2‘-O-Me-T created a resistant stretch of six nucleotides, (iii) modification with aza-ENA-T created a resistant region of five to seven nucleotide residues, whereas (iv) modification with 2‘-O-MOE-T created a resistant stretch of seven nucleotide residues. This shows the variable effect of the microstructure perturbation in the modified AON/RNA heteroduplex depending upon the chemical nature as well as the site of modifications in the AON strand. On the other hand, the enhanced blood serum as well as the 3‘-exonuclease stability (using snake venom phosphodiesterase, SVPDE) showed the effect of the tight conformational constraint in the AON with aza-ENA-T modifications in that the 3‘-exonuclease preferentially hydrolyzed the 3‘-phosphodiester bond one nucleotide away (n + 1) from the modification site (n) compared to all other modified AONs, which were 3‘-exonuclease cleaved at the 3‘-phosphodiester of the modification site (n). The aza-ENA-T modification in the AONs made the 5‘-residual oligonucleotides (including the n + 1 nucleotide) highly resistant in the blood serum (remaining after 48 h) compared to the native AON (fully degraded in 2 h). On the other hand, the 5‘-residual oligonucleotides (including the n nucleotide) in azetidine-T, 2‘-O-Me-T, and 2‘-O-MOE-T modified AONs were more stable compared to that of the native counterpart but more easily degradable than that of aza-ENA-T containing AONs.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96312 (URN)10.1021/bi0620205 (DOI)000246283600002 ()17411072 (PubMedID)
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14
    2. Conformationally Constrained 2'-N,4'-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides
    Open this publication in new window or tab >>Conformationally Constrained 2'-N,4'-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides
    Show others...
    2006 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 47, p. 15173-15187Article in journal (Refereed) Published
    Abstract [en]

    The 2'-deoxy-2'-N,4'-C-ethylene-bridged thymidine (aza-ENA-T) has been synthesized using a key cyclization step involving 2'-ara-trifluoromethylsufonyl-4'-cyanomethylene 11 to give a pair of 3',5'-bis-OBn- protected diastereomerically pure aza-ENA-Ts (12a and 12b) with the fused piperidino skeleton in the chair conformation, whereas the pentofuranosyl moiety is locked in the North-type conformation (7 < P < 27 degrees, 44 degrees < phi(m) < 52 degrees). The origin of the chirality of two diastereomerically pure aza-ENA-Ts was found to be due to the endocyclic chiral 2'-nitrogen, which has axial N-H in 12b and equatorial N-H in 12a. The latter is thermodynamically preferred, while the former is kinetically preferred with E-a 25.4 kcal mol(-1), which is thus far the highest observed inversion barrier at pyramidal N-H in the bicyclic amines. The 5'-O-DMTr-aza-ENA-T-3'-phosphoramidite was employed for solid-phase synthesis to give four different singly modified 15-mer antisense oligonucleotides (AONs). Their AON/RNA duplexes showed a T m increase of 2.5-4 degrees C per modification, depending upon the modification site in the AON. The relative rates of the RNase H1 cleavage of the aza-ENA-T-modified AON/RNA heteroduplexes were very comparable to that of the native counterpart, but the RNA cleavage sites of the modified AON/RNA were found to be very different. The aza-ENA-T modifications also made the AONs very resistant to 3' degradation (stable over 48 h) in the blood serum compared to the unmodified AON (fully degraded in 4 h). Thus, the aza-ENA-T modification in the AON fulfilled three important antisense criteria, compared to the native: (i) improved RNA target affinity, (ii) comparable RNase H cleavage rate, and (iii) higher blood serum stability.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-96272 (URN)10.1021/ja0634977 (DOI)000242216100046 ()17117869 (PubMedID)
    Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14
    3. Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies
    Open this publication in new window or tab >>Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies
    Show others...
    2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 26, p. 8362-8379Article in journal (Refereed) Published
    Abstract [en]

    Two unusual reactions involving the 5-hexenyl or the 6-heptenyl radical cyclization of a distant double bond at C4' and the radical center at C2' of the ribofuranose ring of thymidine have been used as key steps to synthesize North-type conformationally constrained cis-fused bicyclic five-membered and six-membered carbocyclic analogues of LNA (carbocyclic-LNA-T) and ENA (carbocyclic-ENA-T) in high yields. Their structures have been confirmed unambiguously by long range iH-13C NMR correlation (HMBC), TOCSY, COSY, and NOE experiments. The carbocyclic-LNA-T and carbocyclic-ENA-T were subsequently incorporated into the antisense oligonucleotides (AONs) to show that they enhance the Tm of the modified AON/RNA heteroduplexes by 3.5-5 °C and 1.5 °C/modification for carbocyclic-LNA-T and carbocyclic-ENA-T, respectively. Whereas the relative RNase H cleavage rates with carbocyclic-LNA-T, carbocyclic-ENA-T, aza-ENA-T, and LNA-T modified AON/RNA duplexes were found to be very similar to that of the native counterpart, irrespective of the type and the site modification in the AON strand, a single incorporation of carbocyclic-LNA and carbocyclic-ENA into AONs leads to very much more enhanced nuclease stability in the blood serum (stable >48 h) as compared to that of the native (fully degraded <3 h) and the LNA-modified AONs (fully degraded <9 h) and aza-ENA (≈85% stable in 48 h). Clearly, remarkably enhanced lifetimes of these carbocyclic-modified AONs in the blood serum may produce the highly desired pharmacokinetic properties because of their unique stability and consequently a net reduction of the required dosage. This unique quality as well as their efficient use as the AON in the RNase H-promoted cleavage of the target RNA makes our carbocyclic-LNA and carbocyclic-ENA modifications excellent candidates as potential antisense therapeutic agents.

    National Category
    Biological Sciences Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96273 (URN)10.1021/ja071106y (DOI)000247563700050 ()17552524 (PubMedID)
    Available from: 2007-10-16 Created: 2007-10-16 Last updated: 2017-12-14Bibliographically approved
    4. Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
    Open this publication in new window or tab >>Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
    Show others...
    2004 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 126, no 28, p. 8674-8681Article in journal (Refereed) Published
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-96321 (URN)10.1021/ja048484c (DOI)
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14Bibliographically approved
    5. Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds
    Open this publication in new window or tab >>Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds
    Show others...
    2006 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 5, p. 928-941Article in journal (Refereed) Published
    Abstract [en]

    We here show that the electronic properties and the chemical reactivities of the internucleotidic phosphates in the heptameric ssRNAs are dissimilar in a sequence-specific manner because of their non-identical microenvironments, in contrast with the corresponding isosequential ssDNAs. This has been evidenced by monitoring the delta H8(G) shifts upon pH-dependent ionization (pK(a1)) of the central 9-guaninyl (G) to the 9-guanylate ion (G(-)), and its electrostatic effect on each of the internucleotidic phosphate anions, as measured from the resultant delta P-31 shifts (pKa(2)) in the isosequential heptameric ssRNAs vis-`a-vis ssDNAs: [d/r( 5'-Cp(1)Ap(2)Q(1)p(3)Gp(4)Q(2)p(5)Ap(6)C-3'): Q(1) = Q(2) = A (5a/5b) or C (8a/8b), Q(1) = A, Q(2) = C (6a/6b), Q(1) = C, Q(2) = A (7a/7b)]. These oligos with single ionizable G in the centre are chosen because of the fact that the pseudoaromatic character of G can be easily modulated in a pH-dependent manner by its transformation to G(-) (the 2'-OH to 2-O- ionization effect is not detectable below pH 11.6 as evident from the N1-Me-G analog), thereby modulating/titrating the nature of the electrostatic interactions of G to G- with the phosphates, which therefore constitute simple models to interrogate how the variable pseudoaromatic characters of nucleobases under different sequence context (J. Am. Chem. Soc., 2004, 126, 8674-8681) can actually influence the reactivity of the internucleotide phosphates as a result of modulation of sequence context-specific electrostatic interactions. In order to better understand the impact of the electrostatic effect of the G to G- on the tunability of the electronic character of internucleotidic phosphates in the heptameric ssRNAs 5b, 6b, 7b and 8b, we have also performed their alkaline hydrolysis at pH 12.5 at 20 degrees C, and have identified the preferences of the cleavage sites at various phosphates, which are p(2), p(3) and p(4) (Fig. 3). The results of these alkaline hydrolysis studies have been compared with the hydrolysis of analogous N1-Me-G heptameric ssRNA sequences 5c, 7c and 8c under identical conditions in order to establish the role of the electrostatic effect of the 9-guanylate ion (and the 2'-OH to 2-O- ionization) on the internucleotidic phosphate. It turned out that the relative alkaline hydrolysis rate at those particular phosphates ( p2, p3 and p(4)) in the N1-Me-G heptamers was reduced from 16-78% compared to those in the native counterparts [Fig. 4, and ESI 2 (Fig. S11)]. Thus, these physico-chemical studies have shown that those p2, p3 and p4 phosphates in the native heptameric RNAs, which show pK(a2) as well as more deshielding ( owing to weaker P-31 screening) in the alkaline pH compared to those at the neutral pH, are more prone to the alkaline hydrolysis because of their relatively enhanced electrophilic character resulting from weaker P-31 screening. This screening effect originates as a result of the systematic charge repulsion effect between the electron cloud in the outermost orbitals of phosphorus and the central guanylate ion, leading to delocalization of the phosphorus pp charge into its d pi orbitals. It is thus likely that, just as in the non-enzymatic hydrolysis, the enzymatic hydrolysis of a specific phosphate in RNA by general base-catalyss in RNA-cleaving proteins (RNase A, RNA phosphodiesterase or nuclease) can potentially be electrostatically influenced by tuning the transient charge on the nucleobase in the steric proximity or as a result of specific sequence context owing to nearest-neighbor interactions.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-96322 (URN)10.1039/B516733G (DOI)000235992700023 ()
    Available from: 2007-10-18 Created: 2007-10-18 Last updated: 2017-12-14Bibliographically approved
  • 75.
    Barman, Jharna
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Acharya, Sandipta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Zhou, Chuanzheng
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Chatterjee, Subhrangsu
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Engström, Åke
    Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Chattopadhyaya, Jyoti
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Chemistry, Department of Biochemistry and Organic Chemistry, Biochemistry.
    Non-identical electronic characters of the internucleotidic phosphates in RNA modulate the chemical reactivity of the phosphodiester bonds.2006In: Org Biomol Chem, ISSN 1477-0520, Vol. 4, no 5, p. 928-41Article in journal (Refereed)
  • 76. Beauseigneur, Alice
    et al.
    Ericsson, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Renaud, Philippe
    Schenk, Kurt
    B-Alkylcatecholborane-Mediated Tandem Radical Conjugated Addition-Aldol Cyclization2009In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 11, no 16, p. 3778-3781Article in journal (Refereed)
    Abstract [en]

    A one-pot procedure involving radical conjugate addition of B-alkylcatecholboranes to enones followed by intramolecular aldol reaction is reported. Application to the stereoselective synthesis of monocyclic and bicyclic products with up to four contiguous stereogenic centers is presented.

  • 77. Bedekar, Ashutosh V.
    et al.
    Andersson, Pher
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    A New Class of Bis-Oxazoline Ligands for the Cu-Catalysed Asymmetric Cyclopropanation of Olefins1996In: Tetrahedron Letters, Vol. 37, no 23, p. 4073-4076Article in journal (Refereed)
  • 78. Bedekar, Ashutosh V.
    et al.
    Koroleva, Elise B.
    Andersson, Pher
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Investigation of the Effects of the Structure and Chelate Size of Bis-oxazoline Ligands in the Asymmetric Copper-Catalyzed Cyclopropanation of Olefins: Design of a New Class of Ligands1997In: J. Org. Chem., no 62, p. 2518-2526Article in journal (Refereed)
  • 79. Beletskaya, I.P
    et al.
    Bregadze, V.I.
    Ivushkin, V.A.
    Petrovskii, P.V.
    Sivaev, I.B.
    Sjöberg, Stefan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry. Department of Biochemistry and Organic Chemistry, Organic Chemistry II. Organisk kemi.
    Zhigareva, G.B.
    New B-substituted derivatives of m-carborane, p-carborane, and cobalt bis(1,2-decarbollide) anion2004In: J. Organomet. Chem., no 689, p. 2920-Article in journal (Refereed)
  • 80.
    Bergman, Jan
    et al.
    Department of Organic Chemistry, CNT, Novum Research Park, S-141 52 Huddinge Sweden.
    Venemalm, Lennart
    Department of Organic Chemistry, Royal Institute of Technology, 8-100 44 Stockholm Sweden.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Synthesis of cyclopent[b]indolones1990In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 46, no 17, p. 6067-6084Article in journal (Refereed)
    Abstract [en]

    A number of cyclopent[b]indol-1-ones as well as -3-ones have been synthesized, using a new methodology involving intramolecular ring closure of α,β-unsaturated acylindoles. In some cases 1,2,3,4-tetrahydrocarbazol-4-ones were obtained. This methodology was used in the syntheses of the indole alkaloid yuehchukene and the carbazole alkaloid analogue demethoxycarbazomycin B.

  • 81.
    Bergson, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry II.
    Linderberg, Jan
    Is a Proposed Reaction Mechanism Free from Unnecessary Assumptions?: Occam's Razor Applied in a Mathematical Way To Complex First-Order Reaction Systems2008In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, no 112, p. 4235-4240Article in journal (Refereed)
    Abstract [en]

    Following Occam's principle, a proposed reaction mechanism should not contain assumptions about the existence of reactive intermediates and reaction paths that are unnecessary for a full description and interpretation of the available facts. A mechanism refers, in this paper, to a proposed reaction scheme or network that represents the reactions supposed to be going on in a complex reaction system with observable species as well as unobservable reactive intermediates. The scope is limited here to (pseudo) first-order reactions and the steady-state approximation is invoked in order to relate unknown mechanistic rate constants to experimentally determined ones, and, when available, theoretically calculated quantities. When the resulting, nonlinear system of equations admits a unique solution within a physically reasonable domain, it is concluded that the reaction mechanism fulfills Occam's principle. Otherwise, there are many or no solutions. No subjective or qualitative arguments enter the procedure and the outcome is not negotiable.

  • 82. Bergström, M
    et al.
    Lu, L
    Marquez, M
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Catechol-O-Methyltransferase Inhibition Increases the Uptake of 11C-3-(3,4-Dihydroxyphenyl)-L-Alanine in the Rat PancreasRead1996In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 31, no 12, p. 1216-1222Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The objective of the present investigation was to evaluate the uptake and metabolism of 3-(3,4-dihydroxyphenyl-L-alanine) (L-DOPA) in the rat pancreas.

    METHODS:

    The procedure included intravenous injection of the positron-emitting radiotracer L-[beta-11C] DOPA (DOP) into unanaesthetized male Sprague-Dawley rats and evaluation of uptake of radioactivity in organs in animals only given the tracer and in animals given therapeutic doses of three different catechol-O-methyltransferase (COMT) inhibitors, OR-486, OR-611, or Ro 41-0960. Selected pancreati were homogenized, and the chemical form bearing the radioactivity was analysed with high-performance liquid chromatography (HPLC).

    RESULTS:

    The main finding was that the tracer uptake in the pancreas increased fourfold when the rats were pretreated with COMT inhibitors. Half maximum effect of OR-486 was found at a dose of 0.2 mg/kg. HPLC analysis showed that with COMT inhibitor, the radioactivity in the pancreas consisted of 90% DOPAC. When administering MAO-A and COMT inhibitor together, the pancreas radioactivity corresponded to dopamine. Also in the pig pancreas a significant increase of DOP was observed after COMT inhibition.

    CONCLUSIONS:

    This study has shown a high turnover of L-DOPA in the rat pancreas, which can be modulated to give enhanced levels of DOPAC or dopamine by COMT and MAO inhibition.

  • 83. Bergström, Mats
    et al.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindner, K J
    Bjurling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    In vivo demonstration of enzyme activity in endocrine pancreatic tumors: decarboxylation of carbon-11-DOPA to carbon-11-dopamine1996In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 37, no 1, p. 32-37Article in journal (Refereed)
    Abstract [en]

    METHODS:

    We used PET to characterize the uptake and decarboxylation of 11C-L-DOPA in vivo in two patients with endocrine pancreatic tumors: one glucagonoma and one gastrinoma.

    RESULTS:

    With L-DOPA labeled with 11C in the beta position, in which the radioactive label follows the molecule through decarboxylation to dopamine, significant uptake was observed in the tumors. With L-DOPA labeled in the carboxyl group, in which the label is rapidly eliminated from the tissue as 11CO2 if decarboxylation takes place, an almost complete lack of uptake is noted.

    CONCLUSION:

    This study shows that, using selective position labeling, an in vivo action of enzymatic activity can be observed with PET and that significant decarboxylation occurs in the tested endocrine pancreatic tumors. Also, marked retention of radioactivity occurs after treatment with somatostatin analogs. It is hypothesized that this is a reflection of a reduction of exocytosis which is induced by this treatment.

  • 84. Bergström, Mats
    et al.
    Lu, Li
    Marquez, M
    Fasth, K.J.
    Bjurling, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Watanabe, Y
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Modulation of organ uptake of 11C-labelled L-DOPA1997In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 24, no 1, p. 15-19Article in journal (Refereed)
    Abstract [en]

    The present study was undertaken to investigate if pretreatment with pharmacological agents could change the organ uptake of 11C-labelled L-DOPA, and especially if the urinary excretion could be decreased. L-[beta-11C]DOPA was injected IV into unanesthetized Sprague-Dawley rats. After 20 min the rats were decapitated and organs taken out for radioactivity measurements. The uptake in the organs was investigated in animals only given the tracer, and in animals pretreated with drugs such as decarboxylase inhibitors carbidopa and benserazide as well as the monoamine oxidase inhibitors deprenyl, clorgyline, and the COMT inhibitor OR-486. A marked decrease in the urinary radioactivity was observed after carbidopa and benserazide administration. HPLC analysis revealed that under native conditions the major part of urinary radioactivity existed as dopamine, which was eliminated by the decarboxylase inhibitors. After pretreatment with the COMT inhibitor OR-486, the radioactivity uptake in the pancreas increased fourfold as compared to non-treated animals. HPLC analysis showed that this correlated with a marked increase in radiolabelled DOPAC. In the other organs and with the other drugs, only small effects were observed. With L-[beta-11C]fluoroDOPA as a tracer, similar results were observed although the increase in the pancreas by OR-486 had a lower magnitude. These studies suggest that it might be possible to improve the diagnostic ratio of L-[beta-11C]DOPA or L-[18F]fluoroDOPA in whole-body PET studies by pretreating the patient with decarboxylase inhibitor for reducing the urinary excretion and potentially increase the target organ uptake by COMT inhibition.

  • 85.
    Bergström, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Yates, Roger
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Kågedal, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Blood-brain barrier penetration of zolmitriptan--modelling of positron emission tomography data2006In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 33, no 1, p. 75-91Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography (PET) with the drug radiolabelled allows a direct measurement of brain or other organ kinetics, information which can be essential in drug development. Usually, however, a PET-tracer is administered intravenously (i.v.), whereas the therapeutic drug is mostly given orally or by a different route to the PET-tracer. In such cases, a recalculation is needed to make the PET data representative for the alternative administration route. To investigate the blood-brain barrier penetration of a drug (zolmitriptan) using dynamic PET and by PK modelling quantify the brain concentration of the drug after the nasal administration of a therapeutic dose. [11C]Zolmitriptan at tracer dose was administered as a short i.v. infusion and the brain tissue and venous blood kinetics of [11C]zolmitriptan was measured by PET in 7 healthy volunteers. One PET study was performed before and one 30 min after the administration of 5 mg zolmitriptan as nasal spray. At each of the instances, the brain radioactivity concentration after subtraction of the vascular component was determined up to 90 min after administration and compared to venous plasma radioactivity concentration after correction for radiolabelled metabolites. Convolution methods were used to describe the relationship between arterial and venous tracer concentrations, respectively between brain and arterial tracer concentration. Finally, the impulse response functions derived from the PET studies were applied on plasma PK data to estimate the brain zolmitriptan concentration after a nasal administration of a therapeutic dose. The studies shows that the PET data on brain kinetics could well be described as the convolution of venous tracer kinetics with an impulse response including terms for arterial-to-venous plasma and arterial-to-brain impulse responses. Application of the PET derived impulse responses on the plasma PK from nasal administration demonstrated that brain PK of zolmitriptan increased with time, achieving about 0.5 mg/ml at 30 min and close to a maximum of 1.5 mg/ml after 2 hr. A significant brain concentration was observed already after 5 min. The data support the notation of a rapid brain availability of zolmitriptan after nasal administration.

  • 86.
    Berner, Simon
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Biela, Sarah
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Ledung, Greger
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I.
    Bäckvall, Jan-E.
    Puglia, Carla
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Oscarsson, Sven
    Activity boost of a bio