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  • 51.
    Bodén, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Persson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Ekselius, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study2017In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, no 3, article id e1050Article in journal (Refereed)
    Abstract [en]

    The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [(11)C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [(11)C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [(11)C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [(11)C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

  • 52.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, Jan G.Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bioassay methods in natural product research and drug development: proceedings of the international symposium on Bioassay Methods in Natural Product Research and Drug Development, held at the Biomedical Centre of Uppsala University, Sweden, from 24-27 August 19971999Conference proceedings (editor) (Other academic)
  • 53.
    Boldbaatar, Delgerbat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Natl Univ Mongolia, Sch Engn & Appl Sci, Ulaanbaatar 46, Mongol Peo Rep..
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis, Structural Characterization, and Bioactivity of the Stable Peptide RCB-1 from Ricinus communis2015In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 78, no 11, p. 2545-2551Article in journal (Refereed)
    Abstract [en]

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

  • 54. Bosnyak, S.
    et al.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Widdop, E.
    Jones, S.
    Vasodepressor effect of compund 21 is via stimulation of AT2R in conscious SHR2009In: Abstracts From the 30th Annual Scientific Meeting of the High Blood Pressure Research Council of Australia, Melbourne, Australia, December 3-5, 2008: [published in Hypertension, 2009, 53, 1098-1123], American Heart Association , 2009, Vol. 53, no 6, p. 1102-Conference paper (Refereed)
  • 55.
    Braun, Katharina
    et al.
    Univ Ulm, Dept Inorgan Chem 2, D-89031 Ulm, Germany..
    Pochert, Alexander
    Univ Ulm, Dept Inorgan Chem 2, D-89031 Ulm, Germany..
    Linden, Mika
    Univ Ulm, Dept Inorgan Chem 2, D-89031 Ulm, Germany..
    Davoudi, Mina
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden..
    Schmidtchen, Artur
    Lund Univ, Dept Clin Sci, Div Dermatol & Venereol, SE-22184 Lund, Sweden.;Nanyang Technol Univ, Lee Kong Chian Sch Med, 11 Mandalay Rd, Singapore 308232, Singapore..
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Membrane interactions of mesoporous silica nanoparticles as carriers of antimicrobial peptides2016In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 475, p. 161-170Article in journal (Refereed)
    Abstract [en]

    Membrane interactions are critical for the successful use of mesoporous silica nanoparticles as delivery systems for antimicrobial peptides (AMPs). In order to elucidate these, we here investigate effects of nanoparticle charge and porosity on AMP loading and release, as well as consequences of this for membrane interactions and antimicrobial effects. Anionic mesoporous silica particles were found to incorporate considerable amounts of the cationic AMP LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (LL-37), whereas loading is much lower for non-porous or positively charged silica nanoparticles. Due to preferential pore localization, anionic mesoporous particles, but not the other particles, protect LL-37 from degradation by infection-related proteases. For anionic mesoporous nanoparticles, membrane disruption is mediated almost exclusively by peptide release. In contrast, non-porous silica particles build up a resilient LL-37 surface coating due to their higher negative surface charge, and display largely particle-mediated membrane interactions and antimicrobial effects. For positively charged mesoporous silica nanoparticles, LL-37 incorporation promotes the membrane binding and disruption displayed by the particles in the absence of peptide, but also causes toxicity against human erythrocytes. Thus, the use of mesoporous silica nanoparticles as AMP delivery systems requires consideration of membrane interactions and selectivity of both free peptide and the peptide-loaded nanoparticles, the latter critically dependent on nanoparticle properties.

  • 56.
    Buatoisi, Simon
    et al.
    Univ Paris Diderot, IAME, UMR 1137, INSERM,Sorbonne Paris Cite, Paris, France.;F Hoffmann La Roche Ltd, Roche Pharma Res & Early Dev, Pharmaceut Sci, Roche Innovat Ctr Basel, Grenzacherstr 124, CH-4070 Basel, Switzerland.;INST ROCHE, 30 Cours Ile Seguin, F-92650 Boulogne, France..
    Ueckert, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Frey, Nicolas
    F Hoffmann La Roche Ltd, Roche Pharma Res & Early Dev, Pharmaceut Sci, Roche Innovat Ctr Basel, Grenzacherstr 124, CH-4070 Basel, Switzerland..
    Retout, Sylvie
    F Hoffmann La Roche Ltd, Roche Pharma Res & Early Dev, Pharmaceut Sci, Roche Innovat Ctr Basel, Grenzacherstr 124, CH-4070 Basel, Switzerland.;INST ROCHE, 30 Cours Ile Seguin, F-92650 Boulogne, France..
    Mentre, France
    Univ Paris Diderot, IAME, UMR 1137, INSERM,Sorbonne Paris Cite, Paris, France..
    A pharmacometric extension of MCP-MOD in dose finding studies2018In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 45, no Suppl. 1, p. S106-S106Article in journal (Other academic)
  • 57.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chemistry and Biology of Cyclotides: Circular Plant Peptides Outside the Box2014In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 77, no 3, p. 724-736Article, review/survey (Refereed)
    Abstract [en]

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

  • 58.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Cyclotide-membrane interactions: defining factors of membrane binding, depletion and disruption2011In: Biochimica et Biophysica Acta - Biomembranes, ISSN 0005-2736, E-ISSN 1879-2642, Vol. 1808, no 11, p. 2665-2673Article in journal (Refereed)
    Abstract [en]

    The cyclotide family of plant-derived peptides is defined by a cyclic backbone and three disulfide bonds locked into a cyclic cystine knot. They display a diverse range of biological activities, many of which have been linked to an ability to target biological membranes. In the current work, we show that membrane binding and disrupting properties of prototypic cyclotides are dependent on lipid composition, using neutral (zwitterionic) membranes with or without cholesterol and/or anionic lipids. Cycloviolacin O2 (cyO2) caused potent membrane disruption, and showed selectivity towards anionic membranes, whereas kalata B1 and kalata B2 cyclotides were significantly less lytic towards all tested model membranes. To investigate the role of the charged amino acids of cyO2 in the membrane selectivity, these were neutralized using chemical modifications. In contrast to previous studies on the cytotoxic and antimicrobial effects of these derivatives, the Glu6 methyl ester of cyO2 was more potent than the native peptide. However, using membranes of Escherichia coil lipids gave the opposite result: the activity of the native peptide increased 50-fold. By using a combination of ellipsometry and LC-MS, we demonstrated that this unusual membrane specificity is due to native cyO2 extracting preferentially phosphatidylethanolamine-lipids from the membrane, i.e., PE-C16:0/cyC17:0 and PE-C16:0/C18:1.

  • 59. Burrows, Jeremy
    et al.
    Huerta, Fernando
    Lake, Fredrik
    Pedersen, Torben
    Rein, Tobias
    Rotticci, Didier
    Staaf, Karin
    Yngve, Ulrika.
    Preparation of imidazolyl-pyrimidine derivatives as GSK3 inhibitors.2008Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Title compds. I [R1 = sulfamoyl, carbamoyl or -R5-R6 and N linked (un)substituted 4- to 7-membered satd. ring which optionally contains an addnl. N, O or S; R5 = O, C(O), C(O)O, C(O)NH, etc., R6 = (un)substituted alkyl, carbocyclyl or heterocyclyl; at least one of X1, X2, X3 and X4 = N, the other three independently = N or C(R9), wherein R9 = H, halo, CN, OH, NH2, alkyl or alkoxy; provided that not more than two of X1, X2, X3 or X4 = N; R2 = halo or CN; R3 = Me, (un)substituted 3-tetrahydropyranyl or 4-tetrahydropyranyl; R4 = H, halo, CN or (un)substituted alkyl], and their pharmaceutically acceptable salts, are prepd. and disclosed as glycogen synthase kinase 3 (GSK3) inhibitors. Thus, e.g., II was prepd. by amidation of 3,5-dichloro-2-pyridinecarboxylic acid with piperidine followed by coupling reaction with 5-fluoro-4-[2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine, which was prepd. starting from 5-methyl-4-aminoisoxazole and tetrahydro-2H-pyran-4-one in 5 steps. All the exemplar compds. were evaluated for their GSK3 inhibitory activity in GSK3 inhibition assays with typical Ki values ranging from 0.001 to 10,000 nM. For instance, II exhibited a Ki value of 7 nM. As inhibitors of GSK3, I should prove useful in treatment and prevention of GSK3 assocd. diseases including Alzheimer's disease. [on SciFinder(R)]

  • 60.
    Bäckbro, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Löwgren, Seved
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Österlund, Katrin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Atepo, Johnson
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Unge, Torsten
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hulten, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bonham, Nicholas M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Karlen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unexpected binding mode of a cyclic sulfamide HIV-1 protease inhibitor1997In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 40, no 6, p. 898-902Article in journal (Refereed)
    Abstract [en]

    Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1‘ positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 Å resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1‘ and P2‘ side chains were transposed.

  • 61.
    Carbajales, Carlos
    et al.
    Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Azuaje, Jhonny
    Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Oliveira, Ana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Loza, Maria I.
    Univ Santiago de Compostela, Drug Screening Platform Biofarma Res Grp, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain..
    Brea, Jose
    Univ Santiago de Compostela, Drug Screening Platform Biofarma Res Grp, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain..
    Cadavid, Maria I.
    Univ Santiago de Compostela, Drug Screening Platform Biofarma Res Grp, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain..
    Masaguer, Christian F.
    Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Garcia-Mera, Xerardo
    Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Sotelo, Eddy
    Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Enantiospecific Recognition at the A(2B) Adenosine Receptor by Alkyl 2-Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates2017In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 8, p. 3372-3382Article in journal (Refereed)
    Abstract [en]

    A novel family of structurally simple, potent, and selective nonxanthine A(2B)AR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(+/-)16b, K-i = 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A(2B)AR, with the (S)-16b enantiomer retaining all the affinity (K-i = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A(2B) adenosine receptor and opens new possibilities in ligand design for this receptor.

  • 62.
    Carlsson, Daniel O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Hua, Kai
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Forsgren, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Aspirin stability in anionically charged crystalline nanocellulose2013Conference paper (Refereed)
  • 63.
    Carlsson, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Non-aquoeus capillary electrophoretic separation of enantiomeric amines with (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid as chiral counter ion2001In: Journal of Chromatography A, ISSN 0021-9673, Vol. 922, no 1-2, p. 303-311Article in journal (Refereed)
    Abstract [en]

    (2)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid [(2)-DIKGA] has been introduced as a chiral counter ion innon-aqueous capillary electrophoresis. High enantioresolutions (R $3) were obtained for amines, e.g., pronethalol, labetalol Sand bambuterol. Methanol containing NaOH and (2)-DIKGA was used as the background electrolyte. The counter ionconcentration and the nature of the injection medium were found to affect the chiral separation. Covalent coating of thefused-silica capillary reduced the electro-osmotic flow resulting in improved enantioresolutions.

  • 64.
    Caroli, Antonia
    et al.
    Department of Physics, Sapienza Universita ̀ di Roma, P.le Aldo Moro 5, 00185, Roma, Italy.
    Ballante, Flavio
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Wickersham, Richard B
    Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States; Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy .
    Corelli, Federico
    Dipartimento Farmaco Chimico Tecnologico, Universita ̀ degli Studi di Siena, via A. Moro, I-53100 Siena, Italy.
    Ragno, Rino
    Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
    Hsp90 inhibitors, part 2: combining ligand-based and structure-based approaches for virtual screening application.2014In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 54, no 3, p. 970-7Article in journal (Refereed)
    Abstract [en]

    Hsp90 continues to be an important target for pharmaceutical discovery. In this project, virtual screening (VS) for novel Hsp90 inhibitors was performed using a combination of Autodock and Surflex-Sim (LB) scoring functions with the predictive ability of 3-D QSAR models, previously generated with the 3-D QSAutogrid/R procedure. Extensive validation of both structure-based (SB) and ligand-based (LB), through realignments and cross-alignments, allowed the definition of LB and SB alignment rules. The mixed LB/SB protocol was applied to virtually screen potential Hsp90 inhibitors from the NCI Diversity Set composed of 1785 compounds. A selected ensemble of 80 compounds were biologically tested. Among these molecules, preliminary data yielded four derivatives exhibiting IC50 values ranging between 18 and 63 μM as hits for a subsequent medicinal chemistry optimization procedure.

  • 65.
    Channar, Pervaiz Ali
    et al.
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Saeed, Aamer
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Larik, Fayaz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Batool, Bakhtawar
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan.
    Kalsoom, Saima
    Int Islamic Univ, SA CIRBS, Islamabad, Pakistan.
    Hasan, M. M.
    PIEAS, Islamabad, Pakistan.
    Erben, Mauricio F.
    UNLP, CONICET, Fac Ciencias Exactas, CEQUINOR,CCT La Plata,Dept Quim, CC 962, RA-1900 La Plata, Buenos Aires, Argentina.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Ali, Musrat
    Quaid I Azam Univ, Dept Biol Sci, Islamabad 45320, Pakistan.
    Ashraf, Zaman
    Allama Iqbal Open Univ, Dept Chem, Islamabad 44000, Pakistan.
    Synthesis of aryl pyrazole via Suzuki coupling reaction, in vitro mushroom tyrosinase enzyme inhibition assay and in silico comparative molecular docking analysis with Kojic acid2018In: Bioorganic chemistry (Print), ISSN 0045-2068, Vol. 79, p. 293-300Article in journal (Refereed)
    Abstract [en]

    Aryl pyrazoles are well recognized class of heterocyclic compounds found in several commercially available drugs. Owing to their significance in medicinal chemistry, in this current account we have synthesized a series of suitably substituted aryl pyrazole by employing Suzuki cross-coupling reaction. All compounds were evaluated for inhibition of mushroom tyrosinase enzyme both in vitro and in silico. Compound 3f (IC50 = 1.568 +/- 0.01 mu M) showed relatively better potential compared to reference kojic acid (IC50 = 16.051 +/- 1.27 mu M). A comparative docking studies showed that compound 3f have maximum binding affinity against mushroom tyrosinase (PDBID: 2Y9X) with binding energy value (-6.90 kcal/mol) as compared to Kojic acid. The 4-methoxy group in compound 3f shows 100% interaction with Cu. Compound 3f displayed hydrogen binding interaction with His61 and His94 at distance of 1.71 and 1.74 angstrom which might be responsible for higher activity compared to Kojic acid.

  • 66.
    Chen, Xiaomei
    et al.
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Keep, Richard F.
    Univ Michigan Hlth Syst, Dept Neurosurg, Ann Arbor, MI USA..
    Liang, Yan
    Univ Michigan, Coll Pharm, Dept Clin Pharm, 428 Church St, Ann Arbor, MI 48109 USA..
    Zhu, Hao-Jie
    Univ Michigan, Coll Pharm, Dept Clin Pharm, 428 Church St, Ann Arbor, MI 48109 USA..
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hu, Yongjun
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Smith, David E.
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study2017In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 131, p. 89-97Article in journal (Refereed)
    Abstract [en]

    Peptide transporter 2 (PEPT2) is a high-affinity low-capacity transporter belonging to the proton-coupled oligopeptide transporter family. Although many aspects of PEPT2 structure-function are known, including its localization in choroid plexus and neurons, its regional activity in brain, especially extracellular fluid (ECF), is uncertain. In this study, the pharmacokinetics and regional brain distribution of cefadroxil, a beta-lactam antibiotic and PEN 2 substrate, were investigated in wildtype and Pept2 null mice using in vivo intracerebral microdialysis. Cefadroxil was infused intravenously over 4 h at 0.15 mg/min/kg, and samples obtained from plasma, brain ECF, cerebrospinal fluid (CSF) and brain tissue. A permeability surface area experiment was also performed in which 0.15 mg/min/kg cefadroxil was infused intravenously for 10 min, and samples obtained from plasma and brain tissues. Our results showed that PEPT2 ablation significantly increased the brain ECF and CSF levels of cefadroxil (2- to 2.5-fold). In contrast, there were no significant differences between wildtype and Pept2 null mice in the amount of cefadroxil in brain cells. The unbound volume of distribution of cefadroxil in brain was 60% lower in Pept2 null mice indicating an uptake function for PEPT2 in brain cells. Finally, PEPT2 did not affect the influx clearance of cefadroxil, thereby, ruling out differences between the two genotypes in drug entry across the blood-brain barriers. These findings demonstrate, for the first time, the impact of PEPT2 on brain ECF as well as the known role of PEPT2 in removing peptide-like drugs, such as cefadroxil, from the CSF to blood.

  • 67.
    Chinthakindi, Praveen Kumar
    et al.
    University of KwaZulu Natal, Durban, South Africa.
    Thota, Niranjan
    University of KwaZulu Natal, Durban, South Africa.
    Govender, Thavendran
    University of KwaZulu Natal, Durban, South Africa.
    Kruger, Hendrik G.
    University of KwaZulu Natal, Durban, South Africa.
    Arvidsson, Per I.
    University of KwaZulu Natal, Durban, South Africa; Karolinska Institutet, Stockholm, Swede.
    Sulfonimidamides in Medicinal and Agricultural Chemistry2017In: Angewandte Chemie International Edition, Vol. 56, p. 4100-4109Article in journal (Refereed)
    Abstract [en]

    The synthesis and evaluation of structural analogues and isosteres are of central importance in medicinal and agricultural chemistry. The sulfonamide functional group represents one of the most important amide isosteres in contemporary drug design, and about 500 such compounds have overcome both the pharmacological and regulatory hurdles that precede studies in humans. The mono aza analogues of sulfonamides, that is, sulfonimidamides, are rapidly gaining popularity as a novel functional group among synthetic chemists involved in the design of biologically active compounds for both pharmaceutical and agrochemical applications. Herein, we review these recent developments to showcase the promise of this functional group.

  • 68. Chofor, Rene
    et al.
    Sooriyaarachchi, Sanjeewani
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Risseeuw, Martijn D. P.
    Bergfors, Terese
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pouyez, Jenny
    Johny, Chinchu
    Haymond, Amanda
    Everaert, Annelien
    Dowd, Cynthia S.
    Maes, Louis
    Coenye, Tom
    Alex, Alexander
    Couch, Robin D.
    Jones, T. Alwyn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wouters, Johan
    Mowbray, Sherry L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Van Calenbergh, Serge
    Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase2015In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 58, no 7, p. 2988-3001Article in journal (Refereed)
    Abstract [en]

    Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the beta-position of the hydroxamate analogue of 2. While direct addition of a beta-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the longer compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamates methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.

  • 69.
    Chow, Shiao Y.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of N-Sulfonyl Amidines and Acyl Sulfonyl Ureas from Sulfonyl Azides, Carbon Monoxide, and Amides2017In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, no 5, p. 2515-2522Article in journal (Refereed)
    Abstract [en]

    A Pd-catalyzed and ligand-free carbonylation/cycloaddition/decarboxylation cascade synthesis of sulfonyl amidines from sulfonyl azides and substituted amides at low CO pressure is reported. The reaction proceeds via an initial Pd-catalyzed carbonylative generation of sulfonyl isocyanates from sulfonyl azides, followed by a [2 + 2] cycloaddition with amides and subsequent decarboxylation, which liberates the desired sulfonyl amidines, generating N-2 and CO2 as the only reaction byproducts. Using this simple protocol, a diverse range of sulfonyl amidines was obtained in moderate to excellent yields. In addition, the reaction can also be directed through a more conventional amidocarbonylation pathway by employing N-monosubstituted amide nucleophiles to afford acyl sulfonyl ureas in good yields.

  • 70.
    Chow, Shiao Y.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Low-Pressure Radical C-11-Aminocarbonylation of Alkyl Iodides through Thermal Initiation2016In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 36, p. 5980-5989Article in journal (Refereed)
    Abstract [en]

    A radical C-11-aminocarbonylation protocol characterized by excellent substrate compatibility was developed to transform alkyl iodides into C-11-labelled amides, including the 11-HSD1 inhibitor [carbonyl-C-11]adamantan-1-yl(piperidin-1-yl)methanone. This protocol serves as a complementary extension of palladium-mediated C-11-aminocarbonylation, which is limited to the preparation of C-11-labelled compounds lacking beta-hydrogen atoms. The use of AIBN as a radical initiator and a low-pressure xenon-[C-11]CO delivery unit represents a simple and convenient alternative to previous radical C-11-carbonylation methodologies burdened with the need for a proprietary high pressure reactor connected to a light source.

  • 71.
    Coenen, Heinz H.
    et al.
    Forschungszentrum Julich, Julich, Germany..
    Gee, Antony D.
    Kings Coll London, London, England..
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY 11973 USA..
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan..
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea..
    Mach, Robert H.
    Univ Penn, Philadelphia, PA 19104 USA..
    Mindt, Thomas L.
    Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria..
    Pike, Victor W.
    NIMH, Bethesda, MD 20892 USA..
    Windhorst, Albert D.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands..
    Letter to the Editor: International Consensus Radiochemistry Nomenclature Guidelines2018In: Current Radiopharmaceuticals, ISSN 1874-4710, E-ISSN 1874-4729, Vol. 11, no 1, p. 73-75Article in journal (Other academic)
  • 72.
    Coenen, Heinz H.
    et al.
    Res Ctr Julich, Julich, Germany..
    Gee, Antony D.
    Kings Coll London, London, England..
    Adam, Michael
    TRIUMF, Vancouver, BC, Canada..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Cutler, Cathy S.
    Brookhaven Natl Lab, Upton, NY 11973 USA..
    Fujibayashi, Yasuhisa
    Keio Univ, Tokyo, Japan..
    Jeong, Jae Min
    Seoul Natl Univ, Seoul, South Korea..
    Mach, Robert H.
    Univ Penn, Philadelphia, PA 19104 USA..
    Mindt, Thomas L.
    Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria..
    Pike, Victor W.
    NIMH, Bethesda, MD 20892 USA..
    Windhorst, Albert D.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands..
    Open letter to journal editors on: International consensus radiochemistry nomenclature guidelines2018In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 61, no 4, p. 402-404Article in journal (Other academic)
  • 73.
    Correia, Mário S. P.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Chemical Biology for Biomarker Discovery.
    Ballet, Caroline
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Chemical Biology for Biomarker Discovery.
    Meistermann, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Conway, Louis P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Chemical Biology for Biomarker Discovery.
    Globisch, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Chemical Biology for Biomarker Discovery. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comprehensive kinetic and substrate specificity analysis of an arylsulfatase from Helix pomatia using mass spectrometry2019In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 27, no 6, p. 955-962Article in journal (Refereed)
    Abstract [en]

    Sulfatases hydrolyze sulfated metabolites to their corresponding alcohols and are present in all domains of life. These enzymes have found major application in metabolic investigation of drugs, doping control analysis and recently in metabolomics. Interest in sulfatases has increased due to a link between metabolic processes involving sulfated metabolites and pathophysiological conditions in humans. Herein, we present the first comprehensive substrate specificity and kinetic analysis of the most commonly used aryl sulfatases extracted from the snail Helix pomatia. In the past, this enzyme has been used in the form of a crude mixture of enzymes, however, recently we have purified this sulfatase for a new application in metabolomics-driven discovery of sulfated metabolites. To evaluate the substrate specificity of this promiscuous sulfatase, we have synthesized a series of new sulfated metabolites of diverse structure and employed a mass spectrometric assay for kinetic substrate hydrolysis evaluation. Our analysis of the purified enzyme revealed that the sulfatase has a strong preference for metabolites with a bi- or tricyclic aromatic scaffold and to a lesser extent for monocyclic aromatic phenols. This metabolite library and mass spectrometric method can be applied for the characterization of other sulfatases from humans and gut microbiota to investigate their involvement in disease development.

  • 74.
    Craik, David J.
    et al.
    Univ Queensland, Inst Mol Biosci, Div Chem & Struct Biol, Brisbane, Qld 4072, Australia..
    Shim, Youn Young
    Univ Saskatchewan, Coll Agr & Bioresources, Dept Plant Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada.;Prairie Tide Chem Inc, 102 Melville St, Saskatoon, SK S7J 0R1 5A8, Canada.;Jinan Univ, Dept Food Sci & Engn, Guangdong Saskatchewan Oilseed Joint Lab, 601 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Moss, Gerard P.
    Queen Mary Univ London, Sch Biol & Chem Sci, Mile End Rd, London E1 4NS, England..
    Tan, Ninghua
    China Pharmaceut Univ, Sch Tradit Chinese Med, 639 Longmian Ave, Nanjing 211198, Jiangsu, Peoples R China..
    Jadhav, Pramodkumar D.
    Univ Saskatchewan, Coll Agr & Bioresources, Dept Plant Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada..
    Shen, Jianheng
    Univ Saskatchewan, Coll Agr & Bioresources, Dept Plant Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada..
    Reaney, Martin J. T.
    Univ Saskatchewan, Coll Agr & Bioresources, Dept Plant Sci, 51 Campus Dr, Saskatoon, SK S7N 5A8, Canada.;Prairie Tide Chem Inc, 102 Melville St, Saskatoon, SK S7J 0R1 5A8, Canada.;Jinan Univ, Dept Food Sci & Engn, Guangdong Saskatchewan Oilseed Joint Lab, 601 Huangpu Ave West, Guangzhou 510632, Guangdong, Peoples R China..
    Nomenclature of homodetic cyclic peptides produced from ribosomal precursors: An IUPAC task group interim report2016In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 106, no 6, p. 917-924Article in journal (Refereed)
    Abstract [en]

    In 2015, an International Union of Pure and Applied Chemistry (IUPAC) Task Group was formed to develop nomenclature recommendations for homodetic cyclic peptides produced from ribosomal precursors. Delegates of the 2015 International Conference on Circular Proteins (ICCP) were presented with the strengths and weaknesses of four published approaches to homodetic cyclic peptide nomenclature, and a summary of the ensuing discussion is presented here. This interim report presents a potentially novel suggestion-the use of Cahn-Ingold-Prelog rules to specify amino acid priority in homodetic peptides for consistent numbering. Indeed, this might be the first extension of the Cahn-Ingold-Prelog rules in five decades. The authors invite interested parties to contact the corresponding author with suggestions for the improvement of the proposed nomenclature; these ideas will be discussed and considered for inclusion in the final report.

  • 75.
    Czapla-Masztafiak, Joanna
    et al.
    Polish Acad Sci, Inst Nucl Phys, PL-31342 Krakow, Poland.;PSI, CH-5232 Villigen, Switzerland..
    Nogueira, Juan J.
    Univ Vienna, Inst Theoret Chem, Fac Chem, Wahringer Str 17, A-1090 Vienna, Austria..
    Lipiec, Ewelina
    Polish Acad Sci, Inst Nucl Phys, PL-31342 Krakow, Poland.;Swiss Fed Inst Technol, Vladimir Prelog Weg 1-5-10, CH-8093 Zurich, Switzerland..
    Kwiatek, Wojciech M.
    Polish Acad Sci, Inst Nucl Phys, PL-31342 Krakow, Poland..
    Wood, Bayden R.
    Monash Univ, Sch Chem, Ctr Biospectroscopy, Victoria 3800, Australia..
    Deacon, Glen B.
    Monash Univ, Sch Chem, Fac Sci, Clayton, Vic 3800, Australia..
    Kayser, Yves
    PSI, CH-5232 Villigen, Switzerland..
    Fernandes, Daniel L. A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Pavliuk, Mariia V.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry.
    Szlachetko, Jakub
    PSI, CH-5232 Villigen, Switzerland.;Jan Kochanowski Univ Humanities & Sci, Inst Phys, Swietokrzyska 15 St, PL-25406 Kielce, Poland..
    Gonzalez, Leticia
    Univ Vienna, Inst Theoret Chem, Fac Chem, Wahringer Str 17, A-1090 Vienna, Austria..
    Sá, Jacinto
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Physical Chemistry. Polish Acad Sci, Inst Phys Chem, Ul Kasprzaka 44-52, PL-01224 Warsaw, Poland..
    Direct Determination of Metal Complexes' Interaction with DNA by Atomic Telemetry and Multiscale Molecular Dynamics2017In: Journal of Physical Chemistry Letters, ISSN 1948-7185, E-ISSN 1948-7185, Vol. 8, no 4, p. 805-811Article in journal (Refereed)
    Abstract [en]

    The lack of molecular mechanistic understanding of the interaction between metal complexes and biomolecules hampers their potential medical use. Herein we present a robust procedure combining resonant X-ray emission spectroscopy and multiscale molecular dynamics simulations, which allows for straightforward elucidation of the precise interaction mechanism at the atomic level. The report unveils an unforeseen hydrolysis process and DNA binding of [Pt{N(p-HC6F4)CH2}(2)py(2)] (Pt103), which showed potential cytotoxic activity in the past. Pt103 preferentially coordinates to adjacent adenine sites, instead of guanine sites as in cisplatin, because of its hydrogen bond ability. Comparison with previous research on cisplatin suggests that selective binding to guanine or adenine may be achieved by controlling the acidity of the compound.

  • 76.
    Dahl, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Åkerblom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Effects on protease inhibition by modifying of helicase residues in hepatitis C virus nonstructural protein 32007In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 274, no 22, p. 5979-5986Article in journal (Refereed)
    Abstract [en]

    This study of the full-length bifunctional nonstructural protein 3 from hepatitis C virus (HCV) has revealed that residues in the helicase domain affect the inhibition of the protease. Two residues (Q526 and H528), apparently located in the interface between the S2 and S4 binding pockets of the substrate binding site of the protease, were selected for modification, and three enzyme variants (Q526A, H528A and H528S) were expressed, purified and characterized. The substitutions resulted in indistinguishable Km values and slightly lower kcat values compared to the wild-type. The Ki values for a series of structurally diverse protease inhibitors were affected by the substitutions, with increases or decreases up to 10-fold. The inhibition profiles for H528A and H528S were different, confirming that not only did the removal of the imidazole side chain have an effect, but also that minor differences in the nature of the introduced side chain influenced the characteristics of the enzyme. These results indicate that residues in the helicase domain of nonstructural protein 3 can influence the protease, supporting our hypothesis that full-length hepatitis C virus nonstructural protein 3 should be used for protease inhibitor optimization and characterization. Furthermore, the data suggest that inhibitors can be designed to interact with residues in the helicase domain, potentially leading to more potent and selective compounds.

  • 77.
    Dahl, Kenneth
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Nordeman, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    11C-Acetylation of Amines with [11C]Methyl Iodide with Bis(cyclopentadienyldicarbonyliron) as the CO Source2017In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 38, p. 5785-5788Article in journal (Refereed)
    Abstract [en]

    We describe herein a novel approach for the direct 11C-acetylation of amines. The carbonylative protocol is palladium-mediated, uses bis(cyclopentadienyldicarbonyliron) as the CO source, and [11C]methyl iodide or [11C]methyl iodide-D3 as a radioactive precursor. A set of functionalized primary and secondary amines was 11C-labelled in radiochemical yields ranging from 7–85 %. The potential use of this method for positron emission tomography radiotracer production was additionally demonstrated by the radiosynthesis of [11C]lacosamide, [11C]melatonine, and [11C]acecainide in 44–55 % RCY.

  • 78. Dahlström, Mia
    et al.
    Sjögren, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jonsson, Per R.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lindh, Liselott
    Arnebrant, Thomas
    Pinori, Emiliano
    Elwing, Hans
    Berglin, Mattias
    Affinity states of biocides determine bioavailability and release rates in marine paints2015In: Biofouling (Print), ISSN 0892-7014, E-ISSN 1029-2454, Vol. 31, no 2, p. 201-210Article in journal (Refereed)
    Abstract [en]

    A challenge for the next generation marine antifouling (AF) paints is to deliver minimum amounts of biocides to the environment. The candidate AF compound medetomidine is here shown to be released at very low concentrations, ie ng ml(-1) day(-1). Moreover, the release rate of medetomidine differs substantially depending on the formulation of the paint, while inhibition of barnacle settlement is independent of release to the ambient water, ie the paint with the lowest release rate was the most effective in impeding barnacle colonisation. This highlights the critical role of chemical interactions between biocide, paint carrier and the solid/aqueous interface for release rate and AF performance. The results are discussed in the light of differential affinity states of the biocide, predicting AF activity in terms of a high surface affinity and preserved bioavailability. This may offer a general framework for the design of low-release paint systems using biocides for protection against biofouling on marine surfaces.

  • 79.
    Datta, Gopal K.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Heck Reactions with Aryl Chlorides: Studies of Regio- and Stereoselectivity2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(t-Bu)3-liberating salt [(t-Bu)3PH]BF4. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent.

    For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(t-Bu)3PH]BF4 as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of para-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(t-Bu)3 ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol.

    Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(t-Bu)3-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing para-cyano substituent under cationic conditions increased the preparative usefulness of the methodology.

    Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de).

    Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.

    List of papers
    1. A Rapid Microwave Protocol for Heck Vinylation of Aryl Chlorides under Air
    Open this publication in new window or tab >>A Rapid Microwave Protocol for Heck Vinylation of Aryl Chlorides under Air
    2003 (English)In: Molecular Diversity, ISSN 1381-1991, Vol. 7, no 2-4, p. 107-114Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97432 (URN)
    Available from: 2008-08-27 Created: 2008-08-27 Last updated: 2013-07-04Bibliographically approved
    2. Selective Terminal Heck Arylation of Vinyl Ethers with Aryl Chlorides: A Combined Experimental-Computational Approach Including Synthesis of Betaxolol
    Open this publication in new window or tab >>Selective Terminal Heck Arylation of Vinyl Ethers with Aryl Chlorides: A Combined Experimental-Computational Approach Including Synthesis of Betaxolol
    2006 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 71, no 10, p. 3896-3903Article in journal (Refereed) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97433 (URN)
    Available from: 2008-08-27 Created: 2008-08-27 Last updated: 2013-07-04Bibliographically approved
    3. High Stereoselectivity in Chelation-Controlled Intermolecular Heck Reactions with Aryl Chlorides, Vinyl Chlorides and Vinyl Triflates
    Open this publication in new window or tab >>High Stereoselectivity in Chelation-Controlled Intermolecular Heck Reactions with Aryl Chlorides, Vinyl Chlorides and Vinyl Triflates
    2008 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 6, no 4, p. 674-676Article in journal (Refereed) Published
    Abstract [en]

    Highly stereoselective chelation-controlled Pd(0)-catalyzed beta-arylations and beta-vinylations of a five-membered chiral, pyrrolidine-based vinyl ether were achieved using aryl- and vinyl chlorides as substrates, yielding quaternary 2-aryl/vinyl-2-methyl cyclopentanones in 89-96% ee under neutral reaction conditions.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97434 (URN)10.1039/b719131f (DOI)000253014900005 ()18264566 (PubMedID)
    Available from: 2008-08-27 Created: 2008-08-27 Last updated: 2018-01-13Bibliographically approved
    4. Enantiopure 2-Aryl-2-Methyl Cyclopentanones by an Asymmetric Chelation-Controlled Heck Reaction Using Aryl Bromides: Increased Preparative Scope and Effect of Ring Size on Reactivity and Selectivity
    Open this publication in new window or tab >>Enantiopure 2-Aryl-2-Methyl Cyclopentanones by an Asymmetric Chelation-Controlled Heck Reaction Using Aryl Bromides: Increased Preparative Scope and Effect of Ring Size on Reactivity and Selectivity
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    2008 (English)In: Tetrahedron: asymmetry, ISSN 0957-4166, E-ISSN 1362-511X, Vol. 19, no 9, p. 1120-1126Article in journal (Refereed) Published
    Abstract [en]

    Quaternary 2-aryl-2-methyl cyclopentanones were obtained in 85–94% ee via Pd(0)-catalyzed chelation-controlled asymmetric arylation of a cyclopentenyl ether with aryl bromides and subsequent hydrolysis. Two new cyclohexenyl ethers were synthesized and evaluated as Heck substrates with both aryl iodides and bromides under different reaction conditions. Arylations of the six-membered vinyl ether 1-methyl-2-(S)-(cyclohex-1-enyloxymethyl)-pyrrolidine with aryl bromides were achieved with t-Bu3P-promoted palladium catalysis using either classical or microwave heating. Isolated Heck products were also obtained in high diastereoselectivities (94–98% de).

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97435 (URN)10.1016/j.tetasy.2008.04.004 (DOI)000256935800012 ()
    Available from: 2008-08-27 Created: 2008-08-27 Last updated: 2018-01-13Bibliographically approved
  • 80.
    De Rosa, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Syntheses of new tuberculosis inhibitors promoted by microwave irradiation2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 181-191Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis (TB) represents a major public health problem. The growing number of (extensively) multi-drug resistance cases indicates that there is an urgent need for discovery of new anti-TB entities, addressed towards new and specific targets, and continuous development of fast and efficient synthetic strategies to access them easily. Microwave-assisted chemistry is well suited for small-scale laboratory synthetic work, allowing full control of reaction conditions, such as temperature, pressure, and time. Microwave-assisted high-speed organic synthesis is especially useful in the lead optimization phase of drug discovery. To illustrate the advantages of modern microwave heating technology, we herein describe applications and approaches that have been useful for the synthesis of new drug-like anti-TB compounds.

  • 81.
    De Rosa, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Unge, Johan
    Motwani, Hitesh V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Rosenquist, Asa
    Vrang, Lotta
    Wallberg, Hans
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Synthesis of P1 '-Functionalized Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol2014In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 15, p. 6444-6457Article in journal (Refereed)
    Abstract [en]

    Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the para position of the benzyl group in the P1' side with (hetero)aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1-P3 macro-cyclization, 14- and 15-membered macrocyclic Pis were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound 101, with a 2-thiazoly1 group in the P1' position, was the most potent PI of this new series (K-1 2.2 nM, EC50 0.2 mu M). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed.

  • 82.
    Diwakarla, Shanti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vanga, Sudarsana Reddy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Khan, Yasmin Shamsudin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ng, Leelee
    Monash Univ, Dept Physiol, Biomed Discovery Inst, Clayton, Vic 3800, Australia..
    Pham, Vi
    Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
    Lundback, Thomas
    Karolinska Inst, Chem Biol Consortium Sweden, Sci Life Lab, Div Translat Med & Chem Biol,Dept Med Biochem & B, S-17177 Solna, Sweden..
    Jenmalm-Jensen, Annika
    Karolinska Inst, Chem Biol Consortium Sweden, Sci Life Lab, Div Translat Med & Chem Biol,Dept Med Biochem & B, S-17177 Solna, Sweden..
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zelleroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Engen, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Chai, Siew Yeen
    Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures2016In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 10, p. 1383-1392Article in journal (Refereed)
    Abstract [en]

    The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of TRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors:A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

  • 83.
    Doak, Bradley C.
    et al.
    Monash Univ, Dept Med Chem, MIPS, 381 Royal Parade, Parkville, Vic 3052, Australia.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Cyclophilin Succumbs to a Macrocyclic Chameleon2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 21, p. 9469-9472Article in journal (Refereed)
    Abstract [en]

    Targets that have large and groove-shaped binding sites, such as cyclophilin, are difficult to drug with small molecules. Macrocycles of natural product origin can be ideal starting points for such targets as illustrated by the transformation of sanglifehrin A into an orally bioavailable potential candidate drug. Optimization benefits from development of convergent, modular synthetic routes in combination with structure and property based methods for lead optimization.

  • 84.
    Doak, Bradley C
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Zheng, Jie
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Dobritzsch, Doreen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets.2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 6, p. 2312-2327Article in journal (Refereed)
    Abstract [en]

    To improve discovery of drugs for difficult targets, the opportunities of chemical space beyond the rule of 5 (bRo5) were examined by retrospective analysis of a comprehensive set of structures for complexes between drugs and clinical candidates and their targets. The analysis illustrates the potential of compounds far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.

  • 85.
    Elmsjö, Albert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Engskog, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Erngren, Ida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Selectivity evaluation using the co-feature ratio in LC/MS metabolomics: comparison of HILIC stationary phases’ performance for the analysis of plasma, urine and cell extracts.Manuscript (preprint) (Other academic)
  • 86.
    Elversson, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Millqvist-Fureby, Anna
    Aqueous two-phase systems as a formulation concept for spray-dried protein2005In: International Journal of Pharmaceutics, Vol. 294, no 1-2, p. 73-87Article in journal (Refereed)
    Abstract [en]

    This study investigates to what extent an aqueous two-phase system (ATPS) can encapsulate and protect the secondary structure of a protein during spray drying. The ATPSs contained polyvinyl alcohol (PVA) and dextran solutions, in different proportions. A model protein, bovine serum albumin (BSA) and, in some experiments, trehalose were added to the ATPS prior to spray drying. Electron spectroscopy for chemical analysis (ESCA), differential scanning calorimetry (DSC), UV spectrophotometry, size exclusion high-performance liquid chromatography (SEC-HPLC) and Fourier transform infrared spectroscopy (FTIR) were used for analysis of solid and reconstituted samples. The anticipated function of the ATPS was to improve the stability of the protein by preventing interactions with the air–liquid interface during drying and by improving the encapsulation of the protein in the dried powder. BSA was found to preferentially partition to the dextran phase and in the absence of PVA, BSA dominated the powder surface. In samples containing PVA, the polymer mainly covered the powder surface, even though the dextran-rich phase was continuous, thus preventing protein surface interactions and providing improved encapsulation. However, PVA was found to cause partial loss of the native structure of BSA although the protein was well encapsulated during spray drying.

  • 87.
    Elversson, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Millqvist-Fureby, Anna
    In situ coating: an approach for particle modification and encapsulation of proteins during spray-drying2006In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 323, no 1-2, p. 52-63Article in journal (Refereed)
    Abstract [en]

    In this paper, we present a method for in situ coating of individual protein particles in a respirable size. The aim of the coating was to influence the particle/powder properties, and to reduce or prevent surface-induced conformational changes of the protein, during spray-drying, which was the method used for simultaneously preparing and coating particles. The investigated formulations included bovine serum albumin (BSA), trehalose and either of the two non-ionic polymers, hydroxypropyl methylcellulose (HPMC) and poly(ethylene oxide)–poly(propylene oxide) triblock co-polymer (Poloxamer 188). Complete protein coating as measured by electron spectroscopy for chemical analysis (ESCA) was achieved at a polymer concentration of approximately 1% of the total solids weight, and could be predicted from the dynamic surface tension at the air/water interface, as measured by the pendant drop method. Further, particle properties such as: size, dissolution time, powder flowability, and apparent particle density, as measured by gas pycnometry, were affected by the type and concentration of the polymer. In addition, the particle surface morphology could possibly be correlated to the surface elasticity of the droplet surface during drying. Moreover, an extensive investigation (Fourier transform infrared spectroscopy, circular dichroism and size exclusion chromatography) of the structural effects of protein encapsulated in a polymeric coating suggested that in situ coating provide particulate formulations with preserved native conformation and with a high stability during rehydration.

  • 88.
    Elversson, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Millqvist-Fureby, Anna
    Particle size and density in spray drying: effects of carbohydrate properties2005In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, no 9, p. 2049-2060Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to examine some fundamental aspects of the particle formation during spray drying, related to particle size and density. Particles were prepared in a laboratory spray dryer from carbohydrates with different solubility and crystallization propensity, such as lactose, mannitol, and sucrose/dextran 4:1. The feed concentrations ranged from 1% w/w to saturated and the size of droplets and particles were measured by laser diffraction. Particles were also characterized by various microscopy techniques (i.e., scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and light microscopy), differential scanning calorimetry (DSC), gas adsorption, and gas pycnometry. As demonstrated larger particles could be obtained by either increasing the droplet size during atomization; increasing the concentration of the feed solution; or decreasing the solubility of the solute. The apparent particle density, measured by gas pycnometry, was found negatively correlated to the feed concentration. Due to the nonlinear relationship between the feed concentration and the particle size, it was concluded that higher solids load would cause an increase in the effective particle density and that the reduction in the apparent particle density was a result of a gradually less permeable particle surface. Further, the crystallization propensity of the carbohydrate influenced the particle formation and resulted in either hollow or porous particles.

  • 89.
    Elversson, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Millqvist-Fureby, Anna
    Alderhorn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Elofsson, Ulla
    Droplet and particle size relationship and shell thickness of inhalable lactose particles during spray drying2003In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 92, no 4, p. 900-910Article in journal (Refereed)
    Abstract [en]

    To find means of controlling the size and density of particles intended for inhalation the relationship between droplet and particle size during spray drying was investigated. Lactose solutions were atomized with a two-fluid nozzle and dried in a laboratory spray drier. The effects of nozzle orifice diameter, atomization airflow and feed concentration on droplet and particle size were examined. Mass median diameter of both droplets and particles were analyzed with laser diffraction. In addition, scanning electron microscopy and transmission electron microscopy were used for studies of particle shape and morphology. It was demonstrated that nozzle orifice diameter and airflow, but not feed concentration controlled the droplet size during atomization. Increasing droplet size increased particle size but the effect was also influenced by feed concentration. Particles from solutions of a low concentration (1% w/w) were smaller than those from higher concentrations (5-20% w/w). This may be partly explained by lower yields at higher feed concentrations, but may also be related to differences in drying rate. Spray-dried lactose solutions formed hollow particles, and it was suggested that the shell thickness of the particles increased with increasing feed concentration.

  • 90.
    Engen, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Axelsson, Hanna
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden..
    Konda, Vivek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Dahllund, Leif
    Sci Life Lab Stockholm, Drug Discovery & Dev Platform, Solna, Sweden..
    Otrocka, Magdalena
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden..
    Sigmundsson, Kristmundur
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden.;Duke NUS Med Sch, Program Cardiovasc & Metab Disorders, Singapore, Singapore..
    Nikolaou, Alexandros
    Vrije Univ Brussel, Dept Mol & Biochem Pharmacol, Brussels, Belgium.;Ctr Genom Regulat, Barcelona, Spain..
    Vauquelin, Georges
    Vrije Univ Brussel, Dept Mol & Biochem Pharmacol, Brussels, Belgium..
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jenmalm Jensen, Annika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden..
    Lundback, Thomas
    Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab Stockholm,Chem Biol Consortium Swede, Tomtebodavagen 23A, S-17165 Solna, Sweden..
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Identification of Drug-Like Inhibitors of Insulin-Regulated Aminopeptidase Through Small-Molecule Screening2016In: Assay and drug development technologies, ISSN 1540-658X, E-ISSN 1557-8127, Vol. 14, no 3, p. 180-193Article in journal (Refereed)
    Abstract [en]

    Intracerebroventricular injection of angiotensin IV, a ligand of insulin-regulated aminopeptidase (IRAP), has been shown to improve cognitive functions in several animal models. Consequently, IRAP is considered a potential target for treatment of cognitive disorders. To identify nonpeptidic IRAP inhibitors, we adapted an established enzymatic assay based on membrane preparations from Chinese hamster ovary cells and a synthetic peptide-like substrate for high-throughput screening purposes. The 384-well microplate-based absorbance assay was used to screen a diverse set of 10,500 compounds for their inhibitory capacity of IRAP. The assay performance was robust with Z-values ranging from 0.81 to 0.91, and the screen resulted in 23 compounds that displayed greater than 60% inhibition at a compound concentration of 10M. After hit confirmation experiments, purity analysis, and promiscuity investigations, three structurally different compounds were considered particularly interesting as starting points for the development of small-molecule-based IRAP inhibitors. After resynthesis, all three compounds confirmed low M activity and were shown to be rapidly reversible. Additional characterization included activity in a fluorescence-based orthogonal assay and in the presence of a nonionic detergent and a reducing agent, respectively. Importantly, the characterized compounds also showed inhibition of the human ortholog, prompting our further interest in these novel IRAP inhibitors.

  • 91.
    Engen, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundback, Thomas
    Wannberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jenmalm-Jensen, Annika
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nonresonant microwave heated continuous flow synthesis in medicinal chemistry2014In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Article in journal (Other academic)
  • 92.
    Engen, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Wannberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lundbäck, Thomas
    Jenmalm-Jensen, Annika
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Microwave Heated Flow Synthesis of Spiro-oxindole Dihydroquinazolinone Based IRAP Inhibitors2014In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 18, no 11, p. 1582-1588Article in journal (Refereed)
    Abstract [en]

    A fast and convenient synthetic route towards spiro-oxindole dihydroquinazolinones as novel and drug-like insulin-regulated aminopeptidase (IRAP) inhibitors is reported. The synthesis is performed using a MW heated continuous flow system employing 200 mm X 3 mm i MW absorbing silicon carbide (SiC) or MW transparent borosilicate tubular reactors. A three-component MW-flow reaction to build up the spiro compounds (9 examples, 4087% yield), using the SiC reactor, as well as a SuzukiMiyaura cross-coupling reaction (71%), employing the borosilicate reactor, are presented with residence times down to 168 s. The continuous MW-flow routes provide a smooth and scalable synthetic methodology towards this class of IRAP inhibitors.

  • 93.
    Enlund, Anna Maria
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Capillary electroseparations in pharmaceutical analysis of basic drugs and related substances2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Capillary electroseparation methods are exciting new techniques with very broad application areas and vast potential in pharmaceutical and biomedical analysis.

    To improve the limit of detection (LOD) capillary zone electrophoresis (CZE) has been combined with isotachophoretic (ITP) preconcentration in a single capillary. Using the ITP-CZE combination the LOD can be improved at least 100-fold. Laser-induced fluorescence (LIF) detection is more sensitive and more selective than the most common detection technique, UV, and the intensity and focusing capability of LIF fits well with the small dimensions in CZE. The total sensitivity enhancement attained for a new acetylcholinesterase inhibitor, NXX-066, by using ITP-CZE-LIF was more than 5500-fold compared to CZE-UV.

    Capillary electrochromatography (CEC) combines the high separation efficiency of CZE with the vast possibilities to improve selectivity of HPLC. We have examined different ways to solve the problem of extensively tailing peaks and studied the influence of the mobile phase composition on the electrochromatographic performance for a number of tricyclic antidepressants and related quaternary ammonium compounds. (1) Adding aliphatic amines to the mobile phase in reversed phase CEC. The effect on the chromatographic performance was coupled to the hydrophobicity of the additive and the amine of our choice was dimethyloctylamine. (2) Silica-based cation exchangers with different pore sizes. The large-pore materials promoted pore flow, but this had no positive influence on the performance. The small-pore (highest surface area) particles gave the best selectivity. (3) Designing special continuous beds. As the bed is covalently attached to the capillary wall, problems related to retaining frits are avoided. The stationary phase most suitable for our analytes had a molar ratio of 1:80 between the functional ligands, vinyl sulphonic acid and isopropyl groups, respectively. The LOD was lowered 26000-fold by dissolving the sample in a low-conducting medium.

  • 94.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Roy, Tamal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Sawadjoon, Supaporn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Bachmann, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Selvaraju, Ram
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Eriksson, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Synthesis and initial preclinical evaluation of the CRTH2 antagonist [C-11] MK-72462019In: Journal of Labelled Compounds and Pharmaceuticals, WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA , 2019, Vol. 62, p. S544-S545Conference paper (Refereed)
  • 95.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Roy, Tamal
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sawadjoon, Supaporn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bachmann, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sköld, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Selvaraju, Ramkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Odell, Luke R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass2019In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 71, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.

    Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.

    Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.

    Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.

  • 96.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Van Kooij, Rolph
    Schuit, Robert C.
    Froklage, Femke E.
    Reijneveld, Jaap C.
    Hendrikse, N. Harry
    Windhorst, Albert D.
    Synthesis of [3-N-11C-methyl]temozolomide via in situ activation of 3-N-hydroxymethyl temozolomide and alkylation with [11C]methyl iodide2015In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, no 3, p. 122-126Article in journal (Refereed)
    Abstract [en]

    Temozolomide is a chemotherapeutic drug that is mainly used in the treatment of primary glioblastoma multiforme and recurrent high-grade glioma. Here, we report an efficient good manufacturing practice compliant method for the synthesis of [3-N-11C-methyl]temozolomide from 3-N-hydroxymethyl temozolomide that cleaves off formaldehyde in situ and becomes activated towards alkylation with [11C]methyl iodide. The labelling method was developed for an on-going patient study in which the predictive value of [3-N-11C-methyl]temozolomide and positron emission tomography on the outcome of temozolomide treatment is being investigated. The precursor was reacted with [11C]methyl iodide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in acetonitrile, heated at stepwise increasing temperature. Purification by semipreparative HPLC with pharmaceutical grade eluent and filtration gave approximately 10 mL sterile product solution ready for injection containing 1.55 ± 0.38 GBq (n = 5), the specific activity was 88 ± 25 GBq/μmol and the radiochemical purity was 98.5 ± 1.9%.13C-NMR spectroscopy confirmed the labelled position after colabelling with 11C and 13C.

  • 97.
    Eriksson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Åberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Selvaraju, Ram K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Strategy to develop a MAO-A-resistant 5-hydroxy-L-[beta-C-11]tryptophan isotopologue based on deuterium kinetic isotope effects2014In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 4, no 1, article id 62Article in journal (Refereed)
    Abstract [en]

    Background

    The serotonin precursor 5-hydroxy-L-[β-11C]tryptophan ([11C]HTP) is in clinical use for localization of neuroendocrine tumors and has been suggested as a proxy marker for pancreatic islet cells. However, degradation by monoamine oxidase-A (MAO-A) reduces retention and the contrast to non-endocrine tissue.

    Methods

    A synthesis method was developed for 5-hydroxy-L-[β-11C2H]tryptophan ([11C]DHTP), an isotopologue of [11C]HTP, labeled with 11C and 2H at the β-position adjacent to the carbon involved in MAO-A decarboxylation. MAO-A-mediated degradation of [11C]DHTP was evaluated and compared to non-deuterated [11C]HTP.

    Results

    [11C]DHTP was synthesized with a radiochemical purity of >98%, radioactivity of 620 ± 190 MBq, and deuterium (2H or 2H2) incorporation at the β-position of 22% ±5%. Retention and resistance to MAO-A-mediated degradation of [11C]DHTP were increased in cells but not in non-human primate pancreas.

    Conclusions

    Partial deuteration of the β-position yields improved resistance to MAO-A-mediated degradation in vitro but not in vivo.

  • 98.
    Ersmark, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Design and Synthesis of Malarial Aspartic Protease Inhibitors2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Malaria is one of the major public health problems in the world. Approximately 500 million people are afflicted and almost 3 million people die from the disease each year. Of the four causative species Plasmodium falciparum is the most lethal. Due to the rapid spread of parasite resistance there is an urgent need for new antimalarial drugs with novel mechanisms of action. Several promising targets for drug intervention have been revealed.

    This thesis addresses the parasitic aspartic proteases termed plasmepsins (Plm), which are considered crucial to the hemoglobin catabolism essential for parasite survival. The overall aim was to identify inhibitors of the P. falciparum Plm I, II, and IV. More specific objectives were to attain activity against P. falciparum in infected erythrocytes and selectivity versus the most homologous human aspartic protease cathepsin D (Cat D). To guide the design process the linear interaction energy (LIE) method was employed in combination with molecular dynamics.

    Initial investigations of the stereochemical requirements for inhibition resulted in identification of an L-mannitol derived scaffold encompassing a 1,2-dihydroxyethylene transition state isostere with affinity for Plm II. Further modifications of this scaffold provided inhibitors of all three target plasmepsins (Plm I, II, and IV). Apart from the stereochemical analysis three major kinds of manipulation were explored: a) P1/P1′ and P2/P2′ side chain alterations, b) replacement of amide bonds by diacylhydrazine, 1,3,4-oxadiazole, and 1,2,4-triazole, and c) macrocyclization. Several inhibitors of Plm I and II with Ki values below 10 nM were discovered and one Plm IV selective inhibitor comprising two oxadiazole rings was found which represents the most potent non-peptide Plm IV inhibitor (Ki = 35 nM) reported to date. Some of the identified plasmepsin inhibitors demonstrated significant activity against P. falciparum in infected erythrocytes and all inhibitors showed a considerable selectivity for the plasmepsins over the human Cat D.

    List of papers
    1. C2-Symmetric Inhibitors of Plasmodium falciparum Plasmepsin II: Synthesis and Theoretical Predictions
    Open this publication in new window or tab >>C2-Symmetric Inhibitors of Plasmodium falciparum Plasmepsin II: Synthesis and Theoretical Predictions
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    2003 In: Bioorganic and Medicinal Chemistry, Vol. 22, no 17, p. 3723-3733Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92733 (URN)
    Available from: 2005-03-23 Created: 2005-03-23Bibliographically approved
    2. Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity
    Open this publication in new window or tab >>Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity
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    2004 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, no 1, p. 110-22Article in journal (Refereed) Published
    Keywords
    Amides/*chemical synthesis/chemistry/pharmacology, Animals, Aspartic Endopeptidases/*antagonists & inhibitors/chemistry, Cathepsin D/*antagonists & inhibitors, Cells; Cultured, Computer Simulation, Erythrocytes/parasitology, Ethylenes/*chemistry, Humans, Models; Molecular, Molecular Conformation, Plasmodium falciparum/drug effects/*enzymology, Protein Binding, Research Support; Non-U.S. Gov't, Stereoisomerism, Structure-Activity Relationship, Thermodynamics
    National Category
    Pharmaceutical Sciences Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-72743 (URN)10.1021/jm030933g (DOI)14695825 (PubMedID)
    Available from: 2005-05-27 Created: 2005-05-27 Last updated: 2018-01-14Bibliographically approved
    3. Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations
    Open this publication in new window or tab >>Synthesis of Malarial Plasmepsin Inhibitors and Prediction of Binding Modes by Molecular Dynamics Simulations
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    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-92735 (URN)
    Available from: 2005-03-23 Created: 2005-03-23Bibliographically approved
    4. Macrocyclic Inhibitors of the Malarial Aspartic Proteases Plasmepsin I, II, and IV
    Open this publication in new window or tab >>Macrocyclic Inhibitors of the Malarial Aspartic Proteases Plasmepsin I, II, and IV
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92736 (URN)
    Available from: 2005-03-23 Created: 2005-03-23 Last updated: 2010-01-13Bibliographically approved
  • 99.
    Ersmark, Karolina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Nervall, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Hamelink, Elizabeth
    Janka, Linda K.
    Clemente, Jose C.
    Dunn, Ben M.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Samuelsson, Bertil
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry, Organic Chemistry I. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Macrocyclic inhibitors of the malarial aspartic proteases plasmepsin I, II, and IV2006In: Biorganic & Medicinal Chemistry, no 14, p. 2197-2208Article in journal (Refereed)
  • 100.
    Evertsson, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Molecular dynamics and aggregation behaviour in aqueous polymer-drug model systems1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pharmaceutical formulations often contain polymers used as binders, swelling agents, etc., to give the formulation mechanical stability or specific drug release features. Many drug substances, as well as polymers, are amphiphilic which will give an associative polymer-drug interaction, affecting the dissolution rate and drug release. This thesis focuses on the molecular dynamics of model nonionic polymer-anionic drug complexesformed in aqueous solution. Two low molecular weight amphiphiles with different surface activities are used; the surfactant sodium dodecyl sulfate (SDS) and the sodium salt of ibuprofen. The polymers studied are a set of cellulose ethers of different hydrophobicity, with special emphasis on ethyl(hydroxyethyl)cellulose (EHEC).

    Fluorescence probe techniques and nuclear magnetic resonance (NMR) are the main methods used. The molecular dynamics of the EHEC/SDS system is strongly composition dependent. Mixed EHEC/SDS micelles with low SDS aggregation numbers and a high relative content of EHEC is more than three times as rigid as mixed micelles with a high relative content of SDS, as monitored by the fluorescent probe 1,3-di(1-pyrenyl)propane(P3P) and 1H NMR transverse relaxation.

    The microviscosities as monitored by P3P of a set of ten cellulose ethers with different hydrophobicity, interacting with SDS, are compared. A correlation between the microviscosity and the polymer-SDS interaction energy, as qualitatively estimated from the SDS concentration at onset of polymer-SDS association, is found. This correlation is further described by principal component analysis for a subset of six EHEC samples. The microviscosity of mixed polymer-SDS micelles as monitored by P3P is found to be a valuable parameter for the characterization of polymer samples, and can be used to predict the surface tension of the polymer.

    The interaction between EHEC and the sodium salt of ibuprofen resembles the normally accepted model for polymer-surfactant interaction, but is more complex. Fluorescence probe- and pulsed gradient spin echo self diffusion NMR- (PGSE-NMR) measurements indicate that premicellar aggregates of ibuprofen adsorb onto EHEC below the onset of cooperative adsorption with respect to the ibuprofen concentration. The thesis shows theimportance of detailed knowledge of the molecular dynamics for design of controlled release preparations.

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