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  • 151.
    Ax, Anna
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Schaal, Wesley
    Vrang, Lotta
    Samuelsson, Bertil
    Hallberg, Anders
    Karlén, Anders
    Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'2005Ingår i: Bioorganic & Medicinal Chemistry, Vol. 13, nr 3, s. 755-764Artikel i tidskrift (Refereegranskat)
  • 152.
    Ax, Anna
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Schaal, Wesley
    Vrang, Lotta
    Samuelsson, Bertil
    Hallberg, Anders
    Karlén, Anders
    Nonsymmetric cyclic sulfamide HIV-1 protease inhibitors with sidechains spanning from P2/P2' to P1/P1'Manuskript (Övrigt vetenskapligt)
  • 153.
    Axelsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Development of HIV-1 Protease Inhibitors and Palladium-Catalyzed Synthesis of Aryl Ketones and N-Allylbenzamides2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The use of palladium-catalyzed reactions to introduce new carbon-carbon bonds is a fundamental synthetic strategy that has been widely embraced due to its high chemo- and regioselectivity and functional group tolerance. In this context, Pd(0)-catalyzed aminocarbonylations using Mo(CO)6 instead of toxic and gaseous CO and with allylamine as the nucleophile were investigated. The aminocarbonylated product dominated over the Mizoroki-Heck product, and (hetero)aryl iodides, bromides and chlorides gave N-allylbenzamides in good yields.

    In this thesis improvements to an existing protocol for the Pd(II)-catalyzed synthesis of aryl ketones from five benzoic acids and a variety of nitriles are also presented. Addition of TFA improved the yields and employing THF as solvent enabled the use of solid nitriles, and the aryl ketones were isolated in good yields.

    The pandemic of HIV infection is one of the greatest public health issues of our time and approximately 35.3 million people worldwide are living with HIV. There are currently many drugs on the market targeting various parts of the viral reproduction cycle, but the problems of resistance warrant the search for new drugs. HIV-1 protease makes the virus mature into infectious particles. In this thesis a new type of HIV-1 protease inhibitor (PI) is presented, based on two of the PIs on the market, atazanavir and indinavir, but it has a tertiary alcohol, as well as a two-carbon tether between the quaternary carbon and the hydrazide β-nitrogen. A total of 25 new inhibitors were designed, synthesized and biologically evaluated, the best compound had an EC50 value of 3 nM.

    Based on this series a project aimed at synthesizing macrocycles spanning the P1-P3 area was initiated. Macrocycles often tend to have an improved affinity and metabolic profile compared to their linear analogs. Introduction of a handle in the para position of the P1 benzyl group proved difficult, despite efforts to synthesize intermediates containing either a bromo-, hydroxy-, methoxy-, silyl-group protected hydroxy- or an alkyne-group. The lactone intermediate was abandoned in favor of an alternative synthetic route and initial studies were found to be promising. This new approach requires further investigation before the target macrocycles can be synthesized. 

    Delarbeten
    1. Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up
    Öppna denna publikation i ny flik eller fönster >>Microwave-assisted, Mo(CO)(6)-mediated, palladium-catalyzed amino-carbonylation of aryl halides using allylamine: from exploration to scale-up
    2008 (Engelska)Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 49, nr 39, s. 5625-5628Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of various (hetero)aryl halides with allylamine using Mo(CO)(6) as a solid, in situ CO source, were explored. Microwave-enhanced conditions proved to be highly useful in promoting the conversions in a mere 10-20 min with various (hetero)aryl iodides, bromides and chlorides. The scale-up of a microwave-enhanced aminocarbonylation to 25 mmol scale was performed successfully. (C) 2008 Elsevier Ltd. All rights reserved.

    Nyckelord
    carbonylation, microwave, palladium, aryl chloride, scale-up
    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-104304 (URN)10.1016/j.tetlet.2008.07.053 (DOI)000259309700018 ()0040-4039 (ISBN)
    Tillgänglig från: 2009-05-28 Skapad: 2009-05-28 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles
    Öppna denna publikation i ny flik eller fönster >>An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles
    Visa övriga...
    2014 (Engelska)Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 55, nr 15, s. 2376-2380Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A palladium(II)-catalyzed decarboxylative protocol for the synthesis of aryl ketones has been developed. The addition of TFA was shown to improve the reaction yield and employing THF as solvent enabled the use of solid nitriles and in only a small excess. Using this method, five different benzoic acids reacted with a wide range of nitriles to produce 29 diverse (hetero)aryl ketone derivatives in up to 94% yield.

    Nationell ämneskategori
    Organisk kemi Teknik och teknologier
    Forskningsämne
    Teknisk fysik med inriktning mot nanoteknologi och funktionella material
    Identifikatorer
    urn:nbn:se:uu:diva-211660 (URN)10.1016/j.tetlet.2014.02.109 (DOI)000334977100012 ()
    Forskningsfinansiär
    Knut och Alice Wallenbergs Stiftelse
    Tillgänglig från: 2013-11-27 Skapad: 2013-11-27 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    3. HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells
    Öppna denna publikation i ny flik eller fönster >>HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells
    Visa övriga...
    2010 (Engelska)Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 2, s. 607-615Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-137907 (URN)10.1021/jm901165g (DOI)000273672100007 ()
    Tillgänglig från: 2010-12-17 Skapad: 2010-12-16 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
  • 154.
    Axelsson, Linda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Veron, Jean-Baptiste
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindh, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Odell, Luke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    An Improved Palladium(II)-Catalyzed Method for the Synthesis of Aryl Ketones from Aryl Carboxylic Acids and Organonitriles2014Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 55, nr 15, s. 2376-2380Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A palladium(II)-catalyzed decarboxylative protocol for the synthesis of aryl ketones has been developed. The addition of TFA was shown to improve the reaction yield and employing THF as solvent enabled the use of solid nitriles and in only a small excess. Using this method, five different benzoic acids reacted with a wide range of nitriles to produce 29 diverse (hetero)aryl ketone derivatives in up to 94% yield.

  • 155.
    Axén, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Andersson, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Rönnholm, Harriet
    Kortesmaa, Jarkko
    Demaegdt, Heidi
    Vauquelin, Georges
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT(4) receptor2007Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, nr 7, s. 434-444Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Angiotensin IV analogs encompassing aromatic scaffolds replacing parts of the backbone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an o-substituted aryl acetic acid derivative delivered the ligand 4, which exhibited the highest binding affinity (Ki = 1.9 nM). The high affinity of this ligand provides support to the hypothesis that angiotensin IV adopts a -turn in the C-terminal of its bioactive conformation.Ligand (4) inhibits both human IRAP and aminopeptidase N-activity and induces proliferation of adult neural stem cells at low concentrations. Furthermore, ligand 4 is degraded considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies of the (IRAP)/AT4 receptor.

  • 156.
    Axén, Andreas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Demaegdt, Heidi
    Vauquelin, Georges
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Cyclic insulin-regulated aminopeptidase (IRAP)/AT(4) receptor ligands2006Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 12, nr 11, s. 705-713Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The angiotensin IV receptor (AT(4) receptor) is the insulin-regulated aminopeptidase enzyme (IRAP, EC 3.4.11.3). This membrane-spanning enzyme belongs to the M1 family of zinc-dependent metallo-peptidases. It has been proposed that AT4 receptor ligands exert their physiological effects by binding to the active site of IRAP and thereby inhibiting the catalytic activity of the enzyme. The biological activity of a large series of linear angiotensin IV analogs was previously disclosed. Herein, the synthesis and biological evaluation of a series of angiotensin IV analogs, encompassing macrocyclic ring systems of different sizes, are presented. It is demonstrated that disulfide cyclizations of angiotensin IV can deliver ligands with high IRAP/AT4 receptor affinity. One ligand, with an 11-membered ring system (4), inhibited human IRAP and aminopeptidase N (AP-N) activity with similar potency as angiotensin IV but was considerably more stable than angiotensin IV toward enzymatic degradation. The compound provides a promising starting point for further optimization toward more drug-like derivatives. The cyclic constrained analogs allowed us to propose a tentative bioactive conformation of angiotensin IV and it seems that the peptide adopts an inverse gamma-turn at the C-terminal.

  • 157.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Bioactivity mapping of chemical property space - possible applications in natural products research2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift (Övrigt vetenskapligt)
  • 158.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Columelliaceae2016Ingår i: The Families and Genera of Vascular Plants / [ed] K. Kubitzki, J. Kadereit, and V. Bittrich, Springer, 2016, s. 141-144Kapitel i bok, del av antologi (Refereegranskat)
  • 159.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Dipsacales (Honeysuckle)2002Ingår i: Encyclopedia of Life Sciences, John Wiley & Sons , 2002Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    The plant order Dipsacales comprises about 2000 species belonging to the eight core families Adoxaceae, Caprifoliaceae, Collumelliaceae, Diervillaceae, Dipsacaceae, Linnaeceae, Morinaceae and Valerianaceae. It includes many ornamental plants such as honeysuckle and weigela.

  • 160.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Impulse Lecture: The odd fellow - Benefits of anomaly2014Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 80, nr 16, s. 1373-1374Artikel i tidskrift (Övrigt vetenskapligt)
  • 161.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Phylogeny and chemography2008Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 74, nr 9, s. SL64-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Natural compounds are evolutionary selected and pre-validated by Nature, displaying a unique diversity of chemical properties and corresponding biological activities. Of utmost importance for a rational discovery and exploration of new biologically active compounds are two aspects: one the identification and charting of the biologically relevant chemical space, the other a similar charting of the corresponding evolutionary space.

    he first key to this is the coverage of the natural products' chemical space. For this purpose we introduced ChemGPS-NP, with the aim to provide a tool for more efficient and stringent compound comparison, to identify parts of chemical space related to particular biological activities, and to track changes in chemical properties due to e.g. evolutionary traits and modifications in biosynthesis. Physical-chemical properties not directly discernible from structural data can be compared, making selection more rational when screening natural compounds and analogues.

    The second key would consequently be to explore evolutionary space by elucidating and utilising robust phylogenies for the organisms under study. From this basis reflecting the evolutionary history and hence biosynthesis development, further conclusions can be drawn.

    Based these initial attempts, the intersection of chemical and evolutionary space have been explored. With regard to e.g. compound classes such as iridoids, betalains, and sesquiterpene lactones, evolutionary patterns of changes in physical-chemical properties are observed and compared. For eight major classes of plant defence peptides analyses of structure base alignments provide arguments for rational classification. In addition, evolution of the enzyme Rubisco, have been explored with reference to major structural features.

  • 162.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Topical chemical space in relation to biological space2010Ingår i: Comprehensive Natural Products II: Chemistry and Biology / Volume 3 / [ed] L. Mander & H.-W. Lui, Oxford: Elsevier, 2010, s. 47-79Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    In this chapter, the mapping of physical–chemical descriptor space of natural products and its relation to the biological space, with emphasis on evolutionary and topical biological space, is discussed. A brief presentation of methods for phylogenetic analysis and their different advantages is followed by discussions of evolutionary implications. Examples from both unpublished and previously published studies are presented.

  • 163.
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Tribelaceae2016Ingår i: The Families and Genera of Vascular Plants / [ed] K. Kubitzki, J. Kadereit, and V. Bittrich, Springer, 2016, s. 377-379Kapitel i bok, del av antologi (Refereegranskat)
  • 164.
    Backlund, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Backlund, Maria
    Klum, Mattias
    Klum collection anteckningsbok2008Bok (Övrig (populärvetenskap, debatt, mm))
  • 165.
    Backlund, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Bittrich, Volker
    Adoxaceae2016Ingår i: The Families and Genera of Vascular Plants / [ed] K. Kubitzki, J. Kadereit, and V. Bittrich, Springer, 2016, s. 19-29Kapitel i bok, del av antologi (Refereegranskat)
  • 166.
    Backlund, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Buonfiglio, R.
    AstraZeneca R&D, Discovery Sci, Computat Sci, Molndal, Sweden..
    Henz, A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Vikeved, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Lai, Kuei-Hung
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Kogej, T.
    AstraZeneca R&D, Discovery Sci, Computat Sci, Molndal, Sweden..
    Charting biological activity in chemical property space using ChemGPS-NP2015Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 81, nr 16, s. 1413-1413Artikel i tidskrift (Övrigt vetenskapligt)
  • 167.
    Backlund, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Gottfries, Johan
    AstraZeneca R&D, Mölndal.
    Bohlin, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Larsson, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Chemography and Phylogeny: navigating chemical and evolutionary space2006Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 72, nr 11, s. 972-972Artikel i tidskrift (Övrigt vetenskapligt)
  • 168.
    Backlund, Anders
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Rosén, Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Larsson, Sonny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Teoribildning öppnar nya fält för naturproduktsforskning2008Ingår i: Läkemedelsvärlden, ISSN 1402-1927, nr 6, s. 31-Artikel i tidskrift (Övrig (populärvetenskap, debatt, mm))
  • 169.
    Bagge, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Chromatography of Therapeutic Peptides - Contrasting SFC and HPLC2019Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    This work is a comparison of a well-established and a novel, "green" and efficient technique to separate peptides of pharmaceutical interest. An attempt is made to derive the chromatographic retention behaviour from these techniques to a number of property descriptors derived from the linear sequence of amino acids. A set of therapeutic peptides were carefully chosen to be experimentally evaluated using in silico-based descriptor calculations. A principle component analysis was performed to assess the distribution of calculated descriptors for including peptides with variable properties. A diluent optimization study was also included to find the optimal diluent for peptides with minimal diluent effects and peak splitting phenomena. The results showed that the solvents tert-butanol and methanol performed best between 20-30 and 50 volumetric percent water as additive in SFC and HPLC, respectively. These diluents were then used for the peptides within the set to evaluate the retention and selectivity in HPLC and SFC. SFC performed well in terms of resolving power. Inparticular, SFC was able to separate Leuprolide and Triptorelin while HPLC was not. A comparison was also made in between the two stationary phases CN and XT, where a global selectivity was shown to be higher for CN.

    This work does also assess a novel method for determining solubility of analytes in supercritical fluid. The method was evaluated using the pharmaceutical compounds caffeine and aspirin and then used to determine solubility of Leu-Enkephalin in 20% (v/v%) methanol. The solubility of caffeine was determined to be 0.45 mg ml-1 in pure SF-CO2 under 140 bar pressure and 3.9 mg ml-1 for aspirin in 2.4% methanol. Both values correlated well with measurements from four acknowledged papers within this field. Leu-Enkephalin was found to have a solubility of 1.90 mg ml-1 using a solvent corresponding to the initial phase condition of the gradient used for peptide analysis in SFC. Further experimental work is required before the method can be implemented as a useful tool in preparative chromatography, however the results presented here show the compatibility of assessing biomolecules in both pure SF-CO2 and mixed with modifier. The possibility to determine solubility with additional modifier infers an important step of including and evaluating these compounds creating a solid support to subsequent large scale separation.

  • 170.
    Balgoma, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. INRA, UR1268 BIA Biopolymeres Interact Assemblages, F-44316 Nantes, France;INRA, Oniris, Laberca, F-44307 Nantes, France.
    Guitton, Yann
    INRA, Oniris, Laberca, F-44307 Nantes, France.
    Evans, Jason J.
    Univ Massachusetts, Dept Chem, Boston, MA 02125 USA.
    Le Bizec, Bruno
    INRA, Oniris, Laberca, F-44307 Nantes, France.
    Dervilly-Pinel, Gaud
    INRA, Oniris, Laberca, F-44307 Nantes, France.
    Meynier, Anne
    INRA, UR1268 BIA Biopolymeres Interact Assemblages, F-44316 Nantes, France.
    Modeling the fragmentation patterns of triacylglycerides in mass spectrometry allows the quantification of the regioisomers with a minimal number of standards2019Ingår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 1057, s. 60-69Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mass spectrometry allows the relative quantification of the regioisomers of triacylglycerides by the calibration of their fragmentation patterns. However, due to the plethora of regioisomers of triacylglycerides, calibration with every standard is not feasible. An analytical challenge in the field is the prediction of the fragmentation patterns of triacylglycerides to quantify their regioisomers. Thus, we aimed to model these fragmentation patterns to quantify the regioisomeric composition, even for those without commercially available standards. In a first step, we modeled the fragmentation patterns of the regioisomers of triacylglycerides obtained from different published datasets. We found the same qualitative trends of fragmentation beyond differences in the type of adduct in these datasets (both [M+NH4]+ and [M+H]+), and the type of instrument (orbitrap, Q-ToF, ion-trap, single quadrupole, and triple quadrupole). However, the quantitative trends of fragmentation were adduct and instrument specific. From these observations, we modeled quantitatively the common trends of fragmentation of triacylglycerides in every dataset. In a second step, we applied this methodology on a Synapt G2S Q-ToF to quantify the regioisomers of triacylglycerides in sunflower and olive oils. The results of our quantification were in good agreement with previous published quantifications of triacylglycerides, even for regioisomers that were not present in the training dataset. The species with more than two highly unsaturated fatty acids (arachidonic, eicosapentaenoic, and docosahexaenoic acids) showed a complex behavior and lower predictability of their fragmentation patterns. However, this framework presents the capacity to model this behavior when more data are available. It would be also applicable to standardize the quantification of the regioisomers of triacylglycerides in an inter-laboratory ring study.

  • 171.
    Balgoma, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hedeland, Mikael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Common Fatty Markers in Diseases with Dysregulated Lipogenesis2019Ingår i: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 30, nr 5, s. 283-285Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Recent studies have reported the upregulation of a subgroup of triacylglycerides as markers of different diseases with dysregulated lipogenesis, which means that these markers are not selective. This observation has a deep impact on their use as diagnostic tools in clinical practice (e.g., markers of risk of type 2 diabetes).

  • 172.
    Ballet, Caroline
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Correia, Mario S. P.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Conway, Louis P.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Locher, Theresa L.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Lehmann, Laura C.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Garg, Neeraj
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Kemisk biologi för biomarkörer. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Vujasinovic, Miroslav
    Karolinska Univ Hosp, Dept Digest Dis, Stockholm, Sweden.
    Deindl, Sebastian
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lohr, J. -Matthias
    Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden;Karolinska Univ Hosp, Dept Digest Dis, Stockholm, Sweden.
    Globisch, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Kemisk biologi för biomarkörer. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    New enzymatic and mass spectrometric methodology for the selective investigation of gut microbiota-derived metabolites2018Ingår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 9, nr 29, s. 6233-6239Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gut microbiota significantly impact human physiology through metabolic interaction. Selective investigation of the co-metabolism of bacteria and their human host is a challenging task and methods for their analysis are limited. One class of metabolites associated with this co-metabolism are O-sulfated compounds. Herein, we describe the development of a new enzymatic assay for the selective mass spectrometric investigation of this phase II modification class. Analysis of human urine and fecal samples resulted in the detection of 206 sulfated metabolites, which is three times more than reported in the Human Metabolome Database. We confirmed the chemical structure of 36 sulfated metabolites including unknown and commonly reported microbiota-derived sulfated metabolites using synthesized internal standards and mass spectrometric fragmentation experiments. Our findings demonstrate that enzymatic sample pre-treatment combined with state-of-the-art metabolomics analysis represents a new and efficient strategy for the discovery of unknown microbiota-derived metabolites in human samples. Our described approach can be adapted for the targeted investigation of other metabolite classes as well as the discovery of biomarkers for diseases affected by microbiota.

  • 173.
    Barclay, K.H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    A liquid chromatography-tandem mass spectrometry method for the trace analysis of diazepam and nordiazepam in environmental water samples. A comprehensive study of storage conditions and identification of an unknown compound.Manuskript (preprint) (Övrigt vetenskapligt)
  • 174.
    Barclay, Victoria K. H.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk farmaceutisk kemi.
    Tyrefors, Niklas L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk farmaceutisk kemi.
    Johansson, I. Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk farmaceutisk kemi.
    Pettersson, Curt E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Analytisk farmaceutisk kemi.
    Acidic transformation of nordiazepam can affect recovery estimate during trace analysis of diazepam and nordiazepam in environmental water samples by liquid chromatography-tandem mass spectrometry2019Ingår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 411, nr 17, s. 3919-3928Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, a special interest was focused on the stability of diazepam and nordiazepam in aqueous samples at acidic and neutral pH. The aim of the study was to isolate and illustrate one of the many possible sources of error that can be encountered when developing and validating analytical methods. This can be of particular importance when developing multi-analyte methods where there is limited time to scrutinize the behavior of each analyte. A method was developed for the analysis of the benzodiazepines diazepam and nordiazepam in treated wastewater. The samples were extracted by solid phase extraction, using SPEC C18AR cartridges, and analyzed by the use of liquid chromatography, with a C18 stationary phase, coupled to tandem mass spectrometry. Environmental water samples are often acidified during storage to reduce the microbial degradation of the target compounds and to preserve the sample. In some cases, the samples are acidified before extraction. In this study, it was found that a chemical equilibrium between nordiazepam and a transformation product could cause inaccurately high extraction recovery values when the samples were stored at low sample pH. The stability of nordiazepam was shown to be low at pH3. Within 12days, 20% of the initial concentration of nordiazepam was transformed. Interestingly, the transformed nordiazepam was shown to be regenerated and reformed to nordiazepam during sample handling. At a sample pH of 7, diazepam and nordiazepam were stable for 12days. It was concluded that great care must be taken when acidifying water samples containing nordiazepam during storage or extraction. The storage and the extraction should be conducted at neutral pH if no internal standard is used to compensate for degradation and conversion of nordiazepam. The developed method was validated in treated wastewater and applied for the quantification of diazepam and nordiazepam in treated wastewater samples.

  • 175.
    Barclay, Victoria K. H.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Tyrefors, Niklas L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Johansson, I. Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Trace analysis of fluoxetine and its metabolite norfluoxetine: Part I: Development of a chiral liquid chromatography-tandem mass spectrometry method for wastewater samples2011Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, nr 33, s. 5587-5596Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An enantioselective method for the determination of fluoxetine (a selective serotonin reuptake inhibitor) and its pharmacologically active metabolite norfluoxetine has been developed for raw and treated wastewater samples. The stable isotope-labeled fluoxetine and norfluoxetine were used in an extended way for extraction recovery calculations at trace level concentrations in wastewater. Wastewater samples were enriched by solid phase extraction (SPE) with Evolute CX-50 extraction cartridges. The obtained extraction recoveries ranged between 65 and 82% in raw and treated wastewater at a trace level concentration of 50 pM (15-16 ng L(-1)). The target compounds were identified by the use of chiral liquid chromatography tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring (SRM) mode. The enantiomers were successfully resolved on a chiral alpha(1)-acid glycoprotein column (chiral AGP) with acetonitrile and 10 mM ammonium acetate buffer at pH 4.4 (3/97, v/v) as the mobile phase. The effects of pH, amount of organic modifier and buffer concentration in the mobile phase were investigated on the enantiomeric resolution (R(s)) of the target compounds. Enantiomeric R(s)-values above 2.0 (1.03 RSD%, n = 3) were achieved for the enantiomers of fluoxetine and norfluoxetine in all mobile phases investigated. The method was validated by assessing parameters such as cross-contamination and carryover during SPE and during LC analysis. Cross-talk effects were examined during the detection of the analytes in SRM mode. In addition, the isotopic purity of fluoxetine-d(5) and norfluoxetine-d(5) were assessed to exclude the possibility of self-contamination. The interassay precision of the chromatographic separation was excellent, with relative standard deviations (RSD) equal to or lower than 0.56 and 0.81% in raw and treated wastewaters, respectively. The method detection and quantification limits (respectively, MDL and MQL) were determined by the use of fluoxetine-d5 and norfluoxetine-d5. The MQL for the single enantiomers ranged from 12 to 14 pM (3.6-4.3 ng L(-1)) in raw wastewater and from 3 to 4 pM (0.9-1 ng L(-1)) in treated wastewater. The developed method has been employed for the quantification of (R)-fluoxetine, (S)-fluoxetine and the enantiomers of norfluoxetine in raw and treated wastewater samples to be presented in Part II of this study.

  • 176.
    Barclay, Victoria K H
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Tyrefors, Niklas L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Johansson, I Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Trace analysis of fluoxetine and its metabolite norfluoxetine. Part II: Enantioselective quantification and studies of matrix effects in raw and treated wastewater by solid phase extraction and liquid chromatography-tandem mass spectrometry2012Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1227, s. 105-114Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The isotope-labeled compounds fluoxetine-d5 and norfluoxetine-d5 were used to study matrix effects caused by co-eluting compounds originating from raw and treated wastewater samples, collected in Uppsala, Sweden. The matrix effects were investigated by the determination of matrix factors (MF) and by a post-column infusion method. The matrix factors were determined to be 38–47% and 71–86% for the enantiomers of norfluoxetine-d5 and fluoxetine-d5, respectively. The influence of matrix effects when quantifying the enantiomers of the active pharmaceutical ingredient and the metabolite in wastewater samples with LC–MS/MS is discussed and methods to overcome the problem are presented. The enantiomeric concentrations of fluoxetine and its human metabolite norfluoxetine, quantified by a one-point calibration method, were 12–52 pM (3.5–16 ng L−1) in raw wastewater and 4–48 pM (1.2–15 ng L−1) in treated wastewater. Furthermore, the calculated enantiomeric fractions (EF) of the substances were found to be between 0.68 and 0.71 in both matrices. Neither the EF values for fluoxetine nor those for norfluoxetine were significantly different in the raw wastewater compared to the treated wastewater. Interestingly, the concentration of (S)-fluoxetine was found to be higher than the concentration of (R)-fluoxetine in both raw and treated wastewater. These results are different from other results presented in the literature, which shows that the relative concentrations of the enantiomers of a chiral active pharmaceutical ingredient might be significantly different in wastewater samples from different treatment systems. We report, for the first time, the concentrations of the enantiomers of norfluoxetine in wastewater samples. The concentrations of (S)-norfluoxetine were found to be higher than the concentration of (R)-norfluoxetine in the raw as well as in the treated wastewater samples.

  • 177.
    Barclay, Victoria K.H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Development of LC-MS/MS Methods for the Analysis of Chiral and Achiral Pharmaceuticals and Metabolites in Aqueous Environmental Matrices2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis describes the development of liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the trace analysis of active pharmaceutical ingredients (APIs) and their metabolites in aqueous environmental matrices. The research was focused on the development of chiral LC-MS/MS methods for the analysis of fluoxetine and metoprolol, as well as their chiral metabolites in environmental water samples. A method was also developed for the achiral compounds, diazepam and nordiazepam.

    The LC-MS/MS methods were validated by the use of the isotope-labeled compounds. As these isotope-labeled compounds were not found in the wastewater samples, the validation could be assessed at trace level concentrations in the actual matrices in which the analytes were detected.

    The analytes were extracted from the water samples using solid phase extraction methods. Different types of solid phase extraction sorbents were evaluated. Fluoxetine and norfluoxetine were extracted through the use of a mixed mode polymeric based extraction sorbent. A hydrophilic and lipophilic balanced sorbent was employed for the simultaneous extraction of metoprolol and its metabolites, the base α-hydroxymetoprolol and the acidic metabolite deaminated metoprolol. Moreover, silica based C18 extraction discs were applied for the sample preparation of diazepam and nordiazepam.

    The chromatographic separations were conducted in reversed phase LC with MS compatible mobile phases. The enantiomers of fluoxetine and norfluoxetine were simultaneously separated using the chiral stationary phase (CSP), α1-acid glycoprotein (AGP). The Chiral AGP column was also applied for the separation of the enantiomers of deaminated metoprolol. For the simultaneous separation of the metoprolol enantiomers and the four stereoisomers of α-hydroxymetoprolol, the cellobiohydrolase (CBH) protein based CSP was used. An octadecyl silica based LC column was applied for the separation of diazepam and nordiazepam.

    The analytes were detected by the use of tandem quadrupole mass spectrometry operating in selective reactive monitoring mode. High resolution MS, employing a quadrupole time-of-flight (QqTOF) mass analyzer, was utilized for the identification of an unknown compound in wastewater samples.

    The APIs and their metabolites, as well as their respective enantiomers, were quantified in raw and treated wastewater from Uppsala, Sweden along with surface water from the River Fyris in Uppsala.

    Delarbeten
    1. Trace analysis of fluoxetine and its metabolite norfluoxetine: Part I: Development of a chiral liquid chromatography-tandem mass spectrometry method for wastewater samples
    Öppna denna publikation i ny flik eller fönster >>Trace analysis of fluoxetine and its metabolite norfluoxetine: Part I: Development of a chiral liquid chromatography-tandem mass spectrometry method for wastewater samples
    2011 (Engelska)Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1218, nr 33, s. 5587-5596Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    An enantioselective method for the determination of fluoxetine (a selective serotonin reuptake inhibitor) and its pharmacologically active metabolite norfluoxetine has been developed for raw and treated wastewater samples. The stable isotope-labeled fluoxetine and norfluoxetine were used in an extended way for extraction recovery calculations at trace level concentrations in wastewater. Wastewater samples were enriched by solid phase extraction (SPE) with Evolute CX-50 extraction cartridges. The obtained extraction recoveries ranged between 65 and 82% in raw and treated wastewater at a trace level concentration of 50 pM (15-16 ng L(-1)). The target compounds were identified by the use of chiral liquid chromatography tandem mass spectrometry (LC-MS/MS) in selected reaction monitoring (SRM) mode. The enantiomers were successfully resolved on a chiral alpha(1)-acid glycoprotein column (chiral AGP) with acetonitrile and 10 mM ammonium acetate buffer at pH 4.4 (3/97, v/v) as the mobile phase. The effects of pH, amount of organic modifier and buffer concentration in the mobile phase were investigated on the enantiomeric resolution (R(s)) of the target compounds. Enantiomeric R(s)-values above 2.0 (1.03 RSD%, n = 3) were achieved for the enantiomers of fluoxetine and norfluoxetine in all mobile phases investigated. The method was validated by assessing parameters such as cross-contamination and carryover during SPE and during LC analysis. Cross-talk effects were examined during the detection of the analytes in SRM mode. In addition, the isotopic purity of fluoxetine-d(5) and norfluoxetine-d(5) were assessed to exclude the possibility of self-contamination. The interassay precision of the chromatographic separation was excellent, with relative standard deviations (RSD) equal to or lower than 0.56 and 0.81% in raw and treated wastewaters, respectively. The method detection and quantification limits (respectively, MDL and MQL) were determined by the use of fluoxetine-d5 and norfluoxetine-d5. The MQL for the single enantiomers ranged from 12 to 14 pM (3.6-4.3 ng L(-1)) in raw wastewater and from 3 to 4 pM (0.9-1 ng L(-1)) in treated wastewater. The developed method has been employed for the quantification of (R)-fluoxetine, (S)-fluoxetine and the enantiomers of norfluoxetine in raw and treated wastewater samples to be presented in Part II of this study.

    Nyckelord
    Wastewater, Solid phase extraction, Fluoxetine, Norfluoxetine, Isotope-labeled compounds, Chiral LC-MS/MS
    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-158308 (URN)10.1016/j.chroma.2011.06.024 (DOI)000294031700004 ()
    Tillgänglig från: 2011-09-06 Skapad: 2011-09-06 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    2. Trace analysis of fluoxetine and its metabolite norfluoxetine. Part II: Enantioselective quantification and studies of matrix effects in raw and treated wastewater by solid phase extraction and liquid chromatography-tandem mass spectrometry
    Öppna denna publikation i ny flik eller fönster >>Trace analysis of fluoxetine and its metabolite norfluoxetine. Part II: Enantioselective quantification and studies of matrix effects in raw and treated wastewater by solid phase extraction and liquid chromatography-tandem mass spectrometry
    2012 (Engelska)Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1227, s. 105-114Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The isotope-labeled compounds fluoxetine-d5 and norfluoxetine-d5 were used to study matrix effects caused by co-eluting compounds originating from raw and treated wastewater samples, collected in Uppsala, Sweden. The matrix effects were investigated by the determination of matrix factors (MF) and by a post-column infusion method. The matrix factors were determined to be 38–47% and 71–86% for the enantiomers of norfluoxetine-d5 and fluoxetine-d5, respectively. The influence of matrix effects when quantifying the enantiomers of the active pharmaceutical ingredient and the metabolite in wastewater samples with LC–MS/MS is discussed and methods to overcome the problem are presented. The enantiomeric concentrations of fluoxetine and its human metabolite norfluoxetine, quantified by a one-point calibration method, were 12–52 pM (3.5–16 ng L−1) in raw wastewater and 4–48 pM (1.2–15 ng L−1) in treated wastewater. Furthermore, the calculated enantiomeric fractions (EF) of the substances were found to be between 0.68 and 0.71 in both matrices. Neither the EF values for fluoxetine nor those for norfluoxetine were significantly different in the raw wastewater compared to the treated wastewater. Interestingly, the concentration of (S)-fluoxetine was found to be higher than the concentration of (R)-fluoxetine in both raw and treated wastewater. These results are different from other results presented in the literature, which shows that the relative concentrations of the enantiomers of a chiral active pharmaceutical ingredient might be significantly different in wastewater samples from different treatment systems. We report, for the first time, the concentrations of the enantiomers of norfluoxetine in wastewater samples. The concentrations of (S)-norfluoxetine were found to be higher than the concentration of (R)-norfluoxetine in the raw as well as in the treated wastewater samples.

    Nationell ämneskategori
    Analytisk kemi Farmaceutiska vetenskaper Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-170511 (URN)10.1016/j.chroma.2011.12.084 (DOI)000301563700013 ()22265784 (PubMedID)
    Tillgänglig från: 2012-03-12 Skapad: 2012-03-12 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    3. Chiral analysis of metoprolol and two of its metabolites, alpha‑hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry
    Öppna denna publikation i ny flik eller fönster >>Chiral analysis of metoprolol and two of its metabolites, alpha‑hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry
    2012 (Engelska)Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1269, nr SI, s. 208-217Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    A LC–MS/MS method for the chiral separation of metoprolol and two of its main metabolites, α-hydroxymetoprolol (α-OH-Met) and deaminated metoprolol (COOH-Met), in environmental water samples has been developed. The target bases, metoprolol and α-OH-Met, as well as the acidic metabolite (COOH-Met) were extracted from water samples by a solid phase extraction method employing Oasis HLB cartridges. The extraction recoveries were ≥73% for all compounds in surface water. Four different types of chiral stationary phases were investigated for the separation of the eight stereoisomers of metoprolol and its metabolites, Chiralcel OD-H, Chirobiotic V, Chiral AGP and Chiral CBH. In the final method, the enantiomers of metoprolol and four stereoisomers of α-OH-Met were separated using Chiral CBH, the enantiomers of COOH-Met were separated employing Chiral AGP. The analytes were detected in SRM mode by triple quadrupole mass spectrometry. The method was applied for the chiral analysis of the analytes in treated wastewater samples from Uppsala, Sweden. The enantiomers and diastereoisomers of α-OH-Met were detected and analyzed in the samples. The concentrations of the three first eluting stereoisomers of α-OH-Met were between 54 and 61 pM. Interestingly, the last eluting stereoisomer was found to be present at a concentration of 151 pM at the same sampling occasion. This is, to the best of the authors’ knowledge, the first time the stereoisomers of α-OH-Met have been detected in wastewater samples. The enantiomers of metoprolol were determined to be 1.77 and 1.86 nM in the same matrix. The enantiomers of COOH-Met were not detected above the method detection limit (42 pM) in treated wastewater samples. The developed LC–MS/MS methods were validated in wastewater samples.

    Nationell ämneskategori
    Farmaceutiska vetenskaper Analytisk kemi
    Forskningsämne
    Analytisk farmaceutisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-171547 (URN)10.1016/j.chroma.2012.09.090 (DOI)000312475300016 ()
    Tillgänglig från: 2012-03-21 Skapad: 2012-03-21 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    4. A liquid chromatography-tandem mass spectrometry method for the trace analysis of diazepam and nordiazepam in environmental water samples. A comprehensive study of storage conditions and identification of an unknown compound.
    Öppna denna publikation i ny flik eller fönster >>A liquid chromatography-tandem mass spectrometry method for the trace analysis of diazepam and nordiazepam in environmental water samples. A comprehensive study of storage conditions and identification of an unknown compound.
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Farmaceutiska vetenskaper Analytisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-171548 (URN)
    Tillgänglig från: 2012-03-21 Skapad: 2012-03-21 Senast uppdaterad: 2018-01-12
  • 178.
    Barclay, Victoria K.H.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Tyrefors, Niklas L.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Johansson, I. Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Pettersson, Curt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Chiral analysis of metoprolol and two of its metabolites, alpha‑hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry2012Ingår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1269, nr SI, s. 208-217Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A LC–MS/MS method for the chiral separation of metoprolol and two of its main metabolites, α-hydroxymetoprolol (α-OH-Met) and deaminated metoprolol (COOH-Met), in environmental water samples has been developed. The target bases, metoprolol and α-OH-Met, as well as the acidic metabolite (COOH-Met) were extracted from water samples by a solid phase extraction method employing Oasis HLB cartridges. The extraction recoveries were ≥73% for all compounds in surface water. Four different types of chiral stationary phases were investigated for the separation of the eight stereoisomers of metoprolol and its metabolites, Chiralcel OD-H, Chirobiotic V, Chiral AGP and Chiral CBH. In the final method, the enantiomers of metoprolol and four stereoisomers of α-OH-Met were separated using Chiral CBH, the enantiomers of COOH-Met were separated employing Chiral AGP. The analytes were detected in SRM mode by triple quadrupole mass spectrometry. The method was applied for the chiral analysis of the analytes in treated wastewater samples from Uppsala, Sweden. The enantiomers and diastereoisomers of α-OH-Met were detected and analyzed in the samples. The concentrations of the three first eluting stereoisomers of α-OH-Met were between 54 and 61 pM. Interestingly, the last eluting stereoisomer was found to be present at a concentration of 151 pM at the same sampling occasion. This is, to the best of the authors’ knowledge, the first time the stereoisomers of α-OH-Met have been detected in wastewater samples. The enantiomers of metoprolol were determined to be 1.77 and 1.86 nM in the same matrix. The enantiomers of COOH-Met were not detected above the method detection limit (42 pM) in treated wastewater samples. The developed LC–MS/MS methods were validated in wastewater samples.

  • 179.
    Barlow, Nicholas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia.
    Vanga, Sudarsana Reddy
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Burns, Peta
    Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Åqvist, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Gutiérrez-de-Terán, Hugo
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi. Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, BMC, SE-751 24 Uppsala, Sweden.
    Chai, Siew Yeen
    Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
    Thompson, Philip E
    Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia.
    Macrocyclic Peptidomimetics as Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (∆G) and relative binding free energies (∆∆G) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.

  • 180. Barta, Pavel
    et al.
    Malmberg, Jennie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Melicharova, Ludmila
    Strandgård, John
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Laznicek, Milan
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Protein interactions with HER-family receptors can have different characteristics depending on the hosting cell line2012Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 40, nr 5, s. 1677-1682Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cell lines are common model systems in the development of therapeutic proteins and in the research on cellular functions and dysfunctions. In this field, the protein interaction assay is a frequently used tool for assessing the adequacy of a protein for diagnostic and therapeutic purposes. In this study, we investigated the extent to which the interaction characteristics depend on the choice of cell line for HER-family receptors. The interaction characteristics of two therapeutic antibodies (trastuzumab and cetuximab) and one Affibody molecule (ZHER2:342), interacting with the intended receptor were characterized with high precision using an automated real-time interaction method, in different cell lines (HaCaT, A431, HEP-G2, SKOV3, PC3, DU-145). Clear differences in binding affinity and kinetics, up to one order of magnitude, were found for the interaction of the same protein binding to the same receptor on different cells for all three proteins. For HER-family receptors, it is therefore important to refer to the measured affinity for a protein-receptor interaction together with the hosting cell line. The ability to accurately measure affinity and kinetics of a protein-receptor interaction on cell lines of different origins may increase the understanding of underlying receptor biology, and impact the selection of candidates in the development of therapeutic or diagnostic agents.

  • 181.
    Basic, Almedina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Insulin Amyloid Formation: Effects of additives and environmental factors encountered during production scale HPLC purification2016Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Insulin is a peptide hormone that regulates blood sugar levels and is used to treat diabetes. In acidic buffers, high temperature, and at high concentration, insulin aggregates to form insoluble amyloid fibrils. This is problematic in industrial production of insulin, where aggregation during HPLC purification results in clogged columns and reduced separation capacity. Insulin amyloid formation has mainly been studied at low pH (~2); the influence of protein concentration, organic modifiers, and excess surfaces and particles at intermediate (~4) or neutral pH is less clear, albeit highly relevant to understand insulin fibrillation in industrial production settings. To address this, Thioflavin-T (ThT) fluorescence was used to study insulin fibrillation under different experimental conditions in vitro.Moreover, insulin solubility and thermodynamic stability was determined across a range of relevant solution pH using spectroscopic techniques, including circular dichroism. The main conclusions of this work are that insulin aggregation is faster at low and neutral pH, whereas aggregation is slower in the intermediate range between pH 4 and 6. Further, increasing amounts of ethanol or isopropanol has a retarding effect on fibril formation at concentrations up to 30% (v/v). Presence of hydrophobic silica particles enhance insulin fibrillation, which explains the observations of this adverse reaction during HPLC purifications. Also, this work concludes that the stability of insulins secondary structure is unaffected by pH.

    This project has given insight into how insulin aggregation could be avoided and has thereby enabled further work for new ideas on how clogged columns could be restored by dissolving insulin aggregates.

  • 182.
    Bass, Tarek Z.
    et al.
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Frejd, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, SE-17163 Solna, Sweden.
    Löfblom, John
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ståhl, Stefan
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    In vivo evaluation of a novel format of a bivalent HER3-targeting and albumin- binding therapeutic affibody construct2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 43118Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Overexpression of human epidermal growth factor receptor 3 (HER3) is involved in resistance to several therapies for malignant tumours. Currently, several anti-HER3 monoclonal antibodies are under clinical development. We introduce an alternative approach to HER3-targeted therapy based on engineered scaffold proteins, i.e. affibody molecules. We designed a small construct (22.5 kDa, denoted 3A3), consisting of two high-affinity anti-HER3 affibody molecules flanking an albumin-binding domain ABD, which was introduced for prolonged residence in circulation. In vitro, 3A3 efficiently inhibited growth of HER3-expressing BxPC-3 cells. Biodistribution in mice was measured using 3A3 that was site-specifically labelled with In-111 via a DOTA chelator. The residence time of In-111-DOTA-3A3 in blood was extended when compared with the monomeric affibody molecule. In-111-DOTA-3A3 accumulated specifically in HER3-expressing BxPC-3 xenografts in mice. However, In-111-DOTA-3A3 cleared more rapidly from blood than a size-matched control construct In-111-DOTA-TAT, most likely due to sequestering of 3A3 by mErbB3, the murine counterpart of HER3. Repeated dosing and increase of injected protein dose decreased uptake of In-111-DOTA-3A3 in mErbB3-expressing tissues. Encouragingly, growth of BxPC-3 xenografts in mice was delayed in an experimental (pilot-scale) therapy study using 3A3. We conclude that the 3A3 affibody format seems promising for treatment of HER3-overexpressing tumours.

  • 183.
    Behrends, Malte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sävmarker, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sjöberg, Per J. R.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Microwave-Assisted Palladium(II)-Catalyzed Synthesis of Aryl Ketones from Aryl Sulfinates and Direct ESI-MS Studies Thereof2011Ingår i: ACS Catalysis, ISSN 2155-5435, Vol. 1, nr 11, s. 1455-1459Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A fast palladium(II)-catalyzed and microwave-promoted procedure using 6-methyl-2,2'-bipyridyl as ligand to synthesize aryl ketones from aryl sulfinates and nitriles is described. More importantly, the first detailed investigation of the reaction mechanism using direct ESI-MS studies is reported.

  • 184.
    Behrends, Malte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wallinder, Charlotta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Wieckowska, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Guimond, Marie-Odile
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Gallo-Payet, Nicole
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    N-Aryl Isoleucine Derivatives as Angiotensin II AT(2) Receptor Ligands2014Ingår i: ChemistryOpen, ISSN 2191-1363, Vol. 3, nr 2, s. 65-75Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A novel series of ligands for the recombinant human AT(2) receptor has been synthesized utilizing a fast and efficient palladium-catalyzed procedure for aminocarbonylation as the key reaction. Molybdenum hexacarbonyl [Mo(CO)(6)] was employed as the carbon monoxide source, and controlled microwave heating was applied. The prepared N-aryl isoleucine derivatives, encompassing a variety of amide groups attached to the aromatic system, exhibit binding affinities at best with K-i values in the low micromolar range versus the recombinant human AT(2) receptor. Some of the new nonpeptidic isoleucine derivatives may serve as starting points for further structural optimization. The presented data emphasize the importance of using human receptors in drug discovery programs.

  • 185.
    Beijersten, I
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Westerlund, D
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Capillary zone electrophoresis and micellar electrokinetic chromatography, with taurodeoxycholate as micellar agent, of protein kinase A peptide substrates1996Ingår i: ELECTROPHORESIS, Vol. 17, s. 161-Artikel i tidskrift (Refereegranskat)
  • 186.
    Bekiroglu, Somer
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Myrberg, Olle
    Ostman, Kristina
    Ek, Marianne
    Arvidsson, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Rundlöf, Torgny
    Hakkarainen, Birgit
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för analytisk farmaceutisk kemi.
    Validation of a quantitative NMR method for suspected counterfeit products exemplified on determination of benzethonium chloride in grapefruit seed extracts2008Ingår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 47, nr 4-5, s. 958-961Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A H-1-nuclear magnetic resonance (NMR) spectroscopy method for quantitative determination of benzethonium chloride (BTC) as a constituent of grapefruit seed extract was developed. The method was validated, assessing its specificity, linearity, range, and precision, as well as accuracy, limit of quantification and robustness. The method includes quantification using an internal reference standard, 1,3,5-trimethoxybenzene, and regarded as simple, rapid, and easy to implement. A commercial grapefruit seed extract was studied and the experiments were performed on spectrometers operating at two different fields, 300 and 600 MHz for proton frequencies, the former with a broad band (BB) probe and the latter equipped with both a BB probe and a CryoProbe (TM). The concentration average for the product sample was 78.0, 77.8 and 78.4 mg/ml using the 300 BB probe, the 600 MHz BB probe and CryoProbe (TM), respectively. The standard deviation and relative standard deviation (R.S.D., in parenthesis) for the average concentrations was 0.2 (0.3%), 0.3 (0.4%) and 0.3 mg/ml (0.4%), respectively.

  • 187. Belda, O
    et al.
    Kaiser, NF
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Bremberg, U
    Larhed, M
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hallberg, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Moberg, C
    Highly stereo- and regioselective allylations catalyzed by Mo-pyridylamidecomplexes: electronic and steric effects of the ligand2000Ingår i: J Org Chem, Vol. 65, s. 5868-Artikel i tidskrift (Refereegranskat)
  • 188.
    Belfrage, Anna Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors: Targeting Different Genotypes and Drug-Resistant Variants2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Since the first approved hepatitis C virus (HCV) NS3 protease inhibitors in 2011, numerous direct acting antivirals (DAAs) have reached late stages of clinical trials. Today, several combination therapies, based on different DAAs, with or without the need of pegylated interferon-α injection, are available for chronic HCV infections. The chemical foundation of the approved and late-stage HCV NS3 protease inhibitors is markedly similar. This could partly explain the cross-resistance that have emerged under the pressure of NS3 protease inhibitors. The first-generation NS3 protease inhibitors were developed to efficiently inhibit genotype 1 of the virus and were less potent against other genotypes.

    The main focus in this thesis was to design and synthesize a new class of 2(1H)-pyrazinone based HCV NS3 protease inhibitors, structurally dissimilar to the inhibitors evaluated in clinical trials or approved, potentially with a unique resistance profile and with a broad genotypic coverage. Successive modifications were performed around the pyrazinone core structure to clarify the structure-activity relationship; a P3 urea capping group was found valuable for inhibitory potency, as were elongated R6 residues possibly directed towards the S2 pocket. Dissimilar to previously developed inhibitors, the P1’ aryl acyl sulfonamide was not essential for inhibition as shown by equally good inhibitory potency for P1’ truncated inhibitors. In vitro pharmacokinetic (PK) evaluations disclosed a marked influence from the R6 moiety on the overall drug-properties and biochemical evaluation of the inhibitors against drug resistant enzyme variants showed retained inhibitory potency as compared to the wild-type enzyme. Initial evaluation against genotype 3a displayed micro-molar potencies. Lead optimization, with respect to improved PK properties, were also performed on an advanced class of HCV NS3 protease inhibitors, containing a P2 quinazoline substituent in combination with a macro-cyclic proline urea scaffold with nano-molar cell based activities.

    Moreover, an efficient Pd-catalyzed C-N urea arylation protocol, enabling high yielding introductions of advanced urea substituents to the C3 position of the pyrazinone, and a Pd-catalyzed carbonylation procedure, to obtain acyl sulfinamides, were developed. These methods can be generally applicable in the synthesis of bioactive compounds containing peptidomimetic scaffolds and carboxylic acid bioisosteres.

    Delarbeten
    1. Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents
    Öppna denna publikation i ny flik eller fönster >>Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: Exploration of P2 quinazoline substituents