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  • 151.
    Isaksson, Rebecka
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Lindman, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Wannberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sallander, Jessica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baraldi, Dhaniel
    Department of Pharmacology, Monash University.
    Widdop, Robert
    Department of Pharmacology, Monash University.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Åqvist, Johan
    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.
    Gising, Johan
    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.
    A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode2019In: ChemistryOpen, ISSN 2191-1363, Vol. 8, no 1, p. 114-125Article in journal (Refereed)
    Abstract [en]

    We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

  • 152.
    Jacobsson, Micael
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Structure-Based Virtual Screening: New Methods and Applications in Infectious Diseases2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A drug discovery project typically starts with a pharmacological hypothesis: that the modulation of a specific molecular biological mechanism would be beneficial in the treatment of the targeted disease. In a small-molecule project, the next step is to identify hits, i.e. molecules that can effect this modulation. These hits are subsequently expanded into hit series, which are optimised with respect to pharmacodynamic and pharmacokinetic properties, through medicinal chemistry. Finally, a drug candidate is clinically developed into a new drug. This thesis concerns the use of structure-based virtual screening in the hit identification phase of drug discovery.

    Structure-based virtual screening involves using the known 3D structure of a target protein to predict binders, through the process of docking and scoring. Docking is the prediction of potential binding poses, and scoring is the prediction of the free energy of binding from those poses. Two new methodologies, based on post-processing of scoring results, were developed and evaluated using model systems. Both methods significantly increased the enrichment of true positives. Furthermore, correlation was observed between scores and simple molecular properties, and identified as a source of false positives in structure-based virtual screening.

    Two target proteins, Mycobacterium tuberculosis ribose-5-phosphate isomerase, a potential drug target in tuberculosis, and Plasmodium falciparum spermidine synthase, a potential drug target in malaria, were subjected to docking and virtual screening. Docking of substrates and products of ribose-5-phosphate isomerase led to hypotheses on the role of individual residues in the active site. Additionally, virtual screening was used to predict 48 potential inhibitors, but none was confirmed as an inhibitor or binder to the target enzyme. For spermidine synthase, structure-based virtual screening was used to predict 32 potential active-site binders. Seven of these were confirmed to bind in the active site.

    List of papers
    1. Improving structure-based virtual screening by multivariate analysis of scoring data
    Open this publication in new window or tab >>Improving structure-based virtual screening by multivariate analysis of scoring data
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    2003 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 26, p. 5781-5789Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97599 (URN)
    Available from: 2008-10-10 Created: 2008-10-10Bibliographically approved
    2. Ligand bias of scoring functions in structure-based virtual screening
    Open this publication in new window or tab >>Ligand bias of scoring functions in structure-based virtual screening
    2006 In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 46, no 3, p. 1334-1343Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97600 (URN)
    Available from: 2008-10-10 Created: 2008-10-10Bibliographically approved
    3. Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site
    Open this publication in new window or tab >>Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site
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    2004 In: Journal of Molecular Biology, ISSN 0022-2836, Vol. 335, no 3, p. 799-809Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97601 (URN)
    Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2016-05-09Bibliographically approved
    4. Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening
    Open this publication in new window or tab >>Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening
    2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 9, p. 2777-2786Article in journal (Refereed) Published
    Abstract [en]

    Seven novel binders, binding in the active site of Plasmodium falciparum spermidine synthase, were identified by structure-based virtual screening. The binding of these compounds was experimentally verified by NMR techniques. Spermidine synthase, an enzyme involved in the polyamine pathway, has been suggested as a target for treating malaria. The virtual screening protocol combined 3D pharmacophore filtering, docking, and scoring, focusing on finding compounds predicted to form interactions mimicking those of a previously known binder. The virtual screen resulted in the selection of 28 compounds that were acquired and tested from 2.6 million starting structures. Two of the seven binders were predicted to bind in the amino substrate binding pocket. Both of these showed stronger binding upon addition of methylthioadenosine, one of the two products of the enzyme, and a known binder and inhibitor. The five other compounds were predicted to bind in the part of the active site where the other substrate, decarboxylated S-adenosylmethionine, binds. These five compounds all competed for binding with methylthioadenosine.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97602 (URN)10.1021/jm7016144 (DOI)000255500000023 ()18410081 (PubMedID)
    Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2018-01-13Bibliographically approved
  • 153.
    Jaiteh, Mariama
    et al.
    Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, CNRS and Université Paris Diderot, Paris, France .
    Taly, Antoine
    Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, CNRS and Université Paris Diderot, Paris, France .
    Henin, Jerome
    Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, CNRS and Université Paris Diderot, Paris, France .
    Evolution of Pentameric Ligand-Gated Ion Channels: Pro-Loop Receptors2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0151934Article in journal (Refereed)
    Abstract [en]

    Pentameric ligand-gated ion channels (pLGICs) are ubiquitous neurotransmitter receptors in Bilateria, with a small number of known prokaryotic homologues. Here we describe a new inventory and phylogenetic analysis of pLGIC genes across all kingdoms of life. Our main finding is a set of pLGIC genes in unicellular eukaryotes, some of which are metazoan-like Cys-loop receptors, and others devoid of Cys-loop cysteines, like their prokaryotic relatives. A number of such "Cys-less" receptors also appears in invertebrate metazoans. Together, those findings draw a new distribution of pLGICs in eukaryotes. A broader distribution of prokaryotic channels also emerges, including a major new archaeal taxon, Thaumarchaeota. More generally, pLGICs now appear nearly ubiquitous in major taxonomic groups except multicellular plants and fungi. However, pLGICs are sparsely present in unicellular taxa, suggesting a high rate of gene loss and a non-essential character, contrasting with their essential role as synaptic receptors of the bilaterian nervous system. Multiple alignments of these highly divergent sequences reveal a small number of conserved residues clustered at the interface between the extracellular and transmembrane domains. Only the "Cys-loop" proline is absolutely conserved, suggesting the more fitting name "Pro loop" for that motif, and "Pro-loop receptors" for the superfamily. The infered molecular phylogeny shows a Cys-loop and a Cys-less clade in eukaryotes, both containing metazoans and unicellular members. This suggests new hypotheses on the evolutionary history of the superfamily, such as a possible origin of the Cys-loop cysteines in an ancient unicellular eukaryote. Deeper phylogenetic relationships remain uncertain, particularly around the split between bacteria, archaea, and eukaryotes.

  • 154.
    Jaiteh, Mariama
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zeifman, Alexey
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Saarinen, Marcus
    Karolinska Inst, Dept Physiol & Pharmacol, Ctr Mol Med, SE-17177 Stockholm, Sweden.
    Svenningsson, Per
    Karolinska Inst, Dept Physiol & Pharmacol, Ctr Mol Med, SE-17177 Stockholm, Sweden.
    Brea, Jose
    Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis, USEF Screening Platform BioFarma Res Grp, Santiago De Compostela 15706, Spain.
    Loza, Maria Isabel
    Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis, USEF Screening Platform BioFarma Res Grp, Santiago De Compostela 15706, Spain.
    Carlsson, Jens
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, BMC Box 596, SE-75124 Uppsala, Sweden.
    Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson's Disease2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 12, p. 5269-5278Article in journal (Refereed)
    Abstract [en]

    Modulation of multiple biological targets with a single drug can lead to synergistic therapeutic effects and has been demonstrated to be essential for efficient treatment of CNS disorders. However, rational design of compounds that interact with several targets is very challenging. Here, we demonstrate that structure-based virtual screening can guide the discovery of multi-target ligands of unrelated proteins relevant for Parkinson's disease. A library with 5.4 million molecules was docked to crystal structures of the A(2A) adenosine receptor (A(2A)AR) and monoamine oxidase B (MAO-B). Twenty-four compounds that were among the highest ranked for both binding sites were evaluated experimentally, resulting in the discovery of four dual-target ligands. The most potent compound was an A(2A)AR antagonist with nanomolar affinity (K-i = 19 nM) and inhibited MAO-B with an IC50 of 100 nM. Optimization guided by the predicted binding modes led to the identification of a second potent dual-target scaffold. The two discovered scaffolds were shown to counteract 6-hydroxydopamine-induced neurotoxicity in dopaminergic neuronal-like SH-SY5Y cells. Structure-based screening can hence be used to identify ligands with specific polypharmacological profiles, providing new avenues for drug development against complex diseases.

  • 155.
    Jeannot, Frédéric
    et al.
    Sanofi R&D, Therapeut Area Infect Dis, 1541 Ave Marcel Merieux, F-69280 Marcy Letoile, France.
    Taillier, Thomas
    Sanofi R&D, Therapeut Area Infect Dis, 1541 Ave Marcel Merieux, F-69280 Marcy Letoile, France.
    Despeyroux, Pierre
    Sanofi R&D, Therapeut Area Infect Dis, 1541 Ave Marcel Merieux, F-69280 Marcy Letoile, France.
    Renard, Stéphane
    Sanofi R&D, Therapeut Area Infect Dis, 1541 Ave Marcel Merieux, F-69280 Marcy Letoile, France.
    Rey, Astrid
    Sanofi R&D, Therapeut Area Infect Dis, 1541 Ave Marcel Merieux, F-69280 Marcy Letoile, France.
    Mourez, Michaël
    Sanofi R&D, Therapeut Area Infect Dis, 1541 Ave Marcel Merieux, F-69280 Marcy Letoile, France.
    Poeverlein, Christoph
    Sanofi Aventis Deutschland GmbH, Integrated Drug Discovery, R&D, Ind Pk Hoechst, D-65926 Frankfurt, Germany.
    Khichane, Imène
    Sanofi R&D, Analyt Sci, LGCR, 13 Quai Jules Guesde, F-94400 Vitry Sur Seine, France.
    Perrin, Marc-Antoine
    Sanofi R&D, Analyt Sci, LGCR, 13 Quai Jules Guesde, F-94400 Vitry Sur Seine, France.
    Versluys, Stéphanie
    Evotec France, 195 Route Espagne,BP 13669, F-31036 Toulouse 1, France.
    Stavenger, Robert A.
    GlaxoSmithKline, Antibacterial DPU, 1250 Collegeville Rd, Collegeville, PA 19426 USA.
    Huang, Jianzhong
    GlaxoSmithKline, Antibacterial DPU, 1250 Collegeville Rd, Collegeville, PA 19426 USA.
    Germe, Thomas
    John Innes Ctr, Dept Biol Chem, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England.
    Maxwell, Anthony
    John Innes Ctr, Dept Biol Chem, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England.
    Cao, Sha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Huseby, Douglas L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bacqué, Eric
    Sanofi R&D, Therapeut Area Infect Dis, 1541 Ave Marcel Merieux, F-69280 Marcy Letoile, France.
    Imidazopyrazinones (IPYs): Non-Quinolone Bacterial Topoisomerase Inhibitors Showing Partial Cross-Resistance with Quinolones2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 8, p. 3565-3581Article in journal (Refereed)
    Abstract [en]

    In our quest for new antibiotics able to address the growing threat of multidrug resistant infections caused by Gram-negative bacteria, we have investigated an unprecedented series of non-quinolone bacterial topoisomerase inhibitors from the Sanofi patrimony, named IPYs for imidazopyrazinones, as part of the Innovative Medicines Initiative (IMI) European Gram Negative Antibacterial Engine (ENABLE) organization. Hybridization of these historical compounds with the quinazolinediones, a known series of topoisomerase inhibitors, led us to a novel series of tricyclic IPYs that demonstrated potential for broad spectrum activity, in vivo efficacy, and a good developability profile, although later profiling revealed a genotoxicity risk. Resistance studies revealed partial cross-resistance with fluoroquinolones (FQs) suggesting that IPYs bind to the same region of bacterial topoisomerases as FQs and interact with at least some of the keys residues involved in FQ binding.

  • 156.
    Jidheden, Claes
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Single Microgels in Core-Shell Equilibrium: A Novel Method for Limited Volume Studies2016In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 120, no 37, p. 10030-10042Article in journal (Refereed)
    Abstract [en]

    The interactions of cationic surfactant dodecyl-trimethylammonium bromide and cationic protein cytochrome c with anionic polyacrylate microgels have been investigated in microscopic liquid droplets by means of a micropipette technique at ionic strength 0.01 M and pH 8. Experiments on single microgels in solutions of limited amounts of the surfactant provide the first evidence of microgels in a stable biphasic core shell state with the surfactant partitioned to the shell. Under the same conditions, the protein is found to distribute uniformly in the microgels. Quantitative data in the form of swelling and binding isotherms are presented and compared with literature data for macrogels and with predictions of a recent gel theory. Theory is found to be in semiquantitative agreement with the experiments. The importance of polyion-mediated attractions between the protein molecules is analyzed theoretically and proposed to explain the continuous but highly cooperative binding isotherms.

  • 157.
    Johannesson, Petra
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis of Aldehyde-Functionalized Building Blocks and Their Use for the Cyclization of Peptides: Applications to Angiotensin II2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This study addresses the issue of how to convert peptides into drug-like non- peptides with retained biological activities at peptide receptors. Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Ang II) was used as a model peptide.

    Knowledge of the bioactive conformations of endogenous peptides is invaluable for the conversion of peptides into less peptidic analogues. Effectively constrained cyclic analogues, with retained pharmacological activities, may provide valuable information about the bioactive conformations of the peptide in question.

    This thesis describes the development of synthesis for a number of protected, aldehyde-functionalized building blocks for standard solid phase peptide synthesis, and their use for the preparation of cyclic peptide analogues. The effect of variations in the side-chain lengths of the building blocks, on the outcome of the cyclizations was studied. Incorporation of a building block derived from L-aspartic acid afforded bicyclization towards the C-terininal end of the peptide, while for the corresponding L-glutamic acid derived building block, N-terminal directed bicyclization was achieved. A building block derived from L-2-aminoadipic acid was exploited for monocyclization furnishing cis- and trans- vinyl sulfide bridged peptide analogues.

    The described cyclization methods have been applied to the synthesis of a number of conformationally constrained Ang II analogues, for which the pharmacological properties have been evaluated. Two of the Ang II analogues synthesized displayed high affinities and full agonist activities at the AT1 angiotensin receptor, and have proven to be useful tools in the search for the bioactive conformation of Ang II.

  • 158.
    Johansson, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hepatitis C Virus (HCV) is the leading cause of chronic liver disease worldwide as well as the primary indication for liver transplantation. More than 3% of the world’s population is chronically infected with HCV and there is an urgent need for effective therapy. NS3 protease, a viral enzyme required for propagation of HCV in humans, is a promising target for drug development in this area. This thesis addresses the design, synthesis and biochemical evaluation of new HCV NS3 protease inhibitors.

    The main objective of the thesis was the synthesis of peptide-based protease inhibitors of the bifunctional full-length NS3 enzyme (protease-helicase/NTPase). Three types of inhibitors were synthesized: i) classical serine protease inhibitors with electrophilic C-terminals, ii) product-based inhibitors with a C-terminal carboxylate group, and iii) product-based inhibitors with C-terminal carboxylic acid bioisosteres.

    The developmental work included the establishment of an improved procedure for solid-phase peptide synthesis (SPPS) in the N-to-C direction, in contrast to the C-to-N direction of classical SPPS methods. This inverse method facilitated synthesis of the peptides modified at the C-terminal.

    The potency of more than seventy newly synthesized inhibitors was assessed in an in vitro assay using the native form of the protease, i.e. the full-length NS3. The structure-activity relationship (SAR) data achieved was different from SAR data obtained from the more widely used truncated NS3 (protease domain) assay, indicating that the helicase domain of NS3 participates in the binding of the inhibitors.

    The most potent inhibitors identified in this study contained a C-terminal phenyl acyl sulfonamide moiety, i.e. a carboxylic acid bioisostere. It is concluded that the acyl sulfonamide moiety is a promising P1-P1´ spanning entity, which may have potential for use in the development of more drug-like HCV protease inhibitors.

    List of papers
    1. An Improved Procedure for N- to C-Directed (Inverse) Solid-Phase Peptide Synthesis
    Open this publication in new window or tab >>An Improved Procedure for N- to C-Directed (Inverse) Solid-Phase Peptide Synthesis
    Show others...
    2000 (English)In: Journal of combinatorial chemistry, ISSN 1520-4766, E-ISSN 1520-4774, Vol. 2, no 5, p. 496-507Article in journal (Refereed) Published
    Abstract [en]

    A method for solid-phase peptide synthesis in the N- to C-direction that delivers good coupling yields and a low degree of epimerization is reported. The optimized method involves the coupling, without preactivation, of the resin-bound C-terminal amino acid with excess amounts of amino acid tri-tert-butoxysilyl (Sil) esters, using HATU as coupling reagent and 2,4,6-trimethylpyridine (TMP, collidine) as a base. For the amino acids investigated, the degree of epimerization was typically 5%, except for Ser(t-Bu) which was more easily epimerized (ca. 20%). Five tripeptides (AA(1)-AA(2)-AA(3)) with different properties were used as representative model peptides in the development of the synthetic method: Asp-Leu-Glu, Leu-Ala-Phe, Glu-Asp-Val, Asp-Ser-Ile, and Asp-D-Glu-Leu. The study used different combinations of HATU and TBTU as activating agents, N, N-diisopropylethylamine (DIEA) and TMP as bases, DMF and dichloromethane as solvents, and cupric chloride as an epimerization suppressant. The epimerization of AA(2) in the coupling of AA(3) was further reduced in the presence of cupric chloride. However, the use of this reagent also resulted in a decrease in loading onto the resin and significant cleavage between AA(1) and AA(2). Experiments indicated that the observed suppressing effect of cupric chloride on epimerization in the present system merely seemed to be a result of a base-induced cleavage of the oxazolone system, the key intermediate in the epimerization process. Consequently, the cleavages were most pronounced in slow couplings. An improved synthesis of fully characterized amino acid tri-tert-butoxysilyl (Sil) ester hydrochloride building blocks is presented. The amino acid Sil esters were found to be stable as hydrochlorides but not as free bases. Although only a few peptides have been used in this study, we believe that the facile procedure devised herein should provide an attractive alternative for the solid-phase synthesis of short (six residues or less) C-terminally modified peptides, e.g., in library format.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-90139 (URN)10.1021/cc000022h (DOI)11029175 (PubMedID)
    Available from: 2003-02-26 Created: 2003-02-26 Last updated: 2017-12-14Bibliographically approved
    2. Inhibition of hepatitis C virus NS3 protease activity by product-based peptides is dependent on helicase domain
    Open this publication in new window or tab >>Inhibition of hepatitis C virus NS3 protease activity by product-based peptides is dependent on helicase domain
    Show others...
    2001 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 11, no 2, p. 203-206Article in journal (Refereed) Published
    National Category
    Pharmaceutical Sciences Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-51295 (URN)10.1016/S0960-894X(00)00625-9 (DOI)
    Available from: 2006-03-04 Created: 2006-03-04 Last updated: 2018-01-11Bibliographically approved
    3. Tetrapeptides as potent protease inhibitors of Hepatitis C Virus full-length NS3 (protease-helicase/NTPase)
    Open this publication in new window or tab >>Tetrapeptides as potent protease inhibitors of Hepatitis C Virus full-length NS3 (protease-helicase/NTPase)
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    2002 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 10, no 12, p. 3915-22Article in journal (Refereed) Published
    National Category
    Pharmaceutical Sciences Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-91487 (URN)10.1016/S0968-0896(02)00310-3 (DOI)
    Available from: 2004-03-16 Created: 2004-03-16 Last updated: 2018-01-13Bibliographically approved
    4. Acyl sulfonamides as potent protease inhibitors of the hepatitis C virus full-length NS3 (protease-helicase/NTPase): a comparative study of different C-terminals
    Open this publication in new window or tab >>Acyl sulfonamides as potent protease inhibitors of the hepatitis C virus full-length NS3 (protease-helicase/NTPase): a comparative study of different C-terminals
    Show others...
    2003 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 12, p. 2551-2568Article in journal (Refereed) Published
    National Category
    Pharmaceutical Sciences Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-66026 (URN)10.1016/S0968-0896(03)00179-2 (DOI)
    Available from: 2006-11-13 Created: 2006-11-13 Last updated: 2018-01-10Bibliographically approved
  • 159.
    Johansson, Senia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Studies on Cytotoxic and Neutrophil Challenging Polypeptides and Cardiac Glycosides of Plant Origin2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis examines the isolation and characterisation (biological and chemical) of polypeptides from plants. A fractionation protocol was developed and applied on 100 plant materials with the aim of isolating highly purified polypeptide fractions from small amounts of plant materials. The polypeptide fractions were analysed and evaluated for peptide content and biological activities. A multitarget functional bioassay was optimised as a method for detecting substances interacting with the inflammatory process of activated neutrophil granulocytes. In this assay, the neutrophil was challenged with an inflammatory mediator, N-formyl methionyl-leucyl-phenylalanine (fMLP), or with platelet activating factor (PAF), to induce exocytotic release of the enzyme elastase, which then was quantified by photometric determination of the product p-nitroanilide (pNA) formed from a chromogenic substrate for elastase. Of the tested extracts, 41% inhibited pNA formation more than 60%, and 3% stimulated formation.

    Phoratoxin B and four new peptides, phoratoxins C-F, were isolated from Phoradendron tomentosum. In addition, the cardiac glycoside digitoxin was isolated from Digitalis purpurea. All these substances expressed cytotoxicity and a neutrophil challenging activity.

    Phoratoxins C-F were similar to earlier described phoratoxins A and B, which belong to the group of thionins. All the peptides were evaluated for cytotoxicity in a human cell line panel. Phoratoxin C was the most potent towards the cell lines (mean IC50: 160 nM), and was therefore investigated further on tumour cells from patients. Correlation analysis of the log IC50 values indicated a mechanism of action different from clinically used archetypal cytotoxic drugs. Phoratoxin C also showed selective toxicity to the solid tumours when compared to the haematological cancer types. The phoratoxin C was 18 times more potent towards the solid tumour samples from breast cancer cells (87 nM) compared to the tested haematological malignancies.

    The structure-activity relationship concerning cytotoxicity was evaluated for digitoxin and related cardiac glycosides. Digitoxin was shown to be potent, with the average IC50 37 nM being within the therapeutic concentration used for cardiac congestion (13-45 nM). Digitoxin expressed selective toxicity towards solid tumours from patients compared to haematological malignancies.

  • 160.
    Jäverfalk-Hoyes, Emmy
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Development of Methods in CE, CE-MS and MS/MS: Applications in Pharmaceutical, Biomedical and Forensic sciences2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Capillary electrophoresis-mass spectrometry has been used successfully for the analysis of a wide range of analytes such as chiral local anaesthetics, sulphonated reactive dyes and endogenous neurotransmitters and neuropeptides.

    The partial filling technique was used in CE-MS for chiral separation of bupivacaine and ropivacaine using the non-volatile selector β-cyclodextrin. By only partially filling the capillary with selector and using capillaries coated with polyacrylamide to suppress the electroosmotic flow, introduction of the selector into the mass spectrometer was avoided. An impurity of 0.25% of the R-enantiomer of ropivacaine in the S-form could be detected.

    The partial filling technique was developed further using CE employing two different selectors in separate plugs in the capillary. This enhanced the separation efficiency and offered greater flexibility in controlling the separation.

    By using transient-isotachophoresis (tITP)-CE-MS it was possible to concentrate and detect classical neurotransmitters and neuropeptides with masses ranging from 104 Da to 1642 Da. γ -Aminopropyltriethoxysilane coated capillaries were used to minimize adsorption of the peptides onto to capillary surface. Endogenous dopamine, glutamate, γ-aminobutyric acid (GABA), acetylcholine, methionine-enkephalin and substance P 1-7 were detected in the striatum of marmoset monkey.

    Sulphonated dyes obtained from single textile fibres were analysed using CE-MS. Capillary electrophoresis was found to be a good way of removing the excess amounts of glucose present in the sample that would otherwise interfere with the electrospray ionisation.

    Automatic function switching, originally developed for use together with liquid chromatography, was found to be a great method for acquiring MS/MS data when doing infusion experiments saving both time and sample without decreasing the quality of the MS/MS data. It was also found to be a more time efficient way than using the precursor ion scanning mode on the Q-TOF to obtain precursor ion data.

  • 161.
    Kaiser, Nils-Fredrik K.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Fast Chemistry by Microwave Heating: First Descriptions of Highly Enantioselective Microwave Protocols for Metal Catalysis; First Descriptions of in-situ Gas Generation for Fast Combinatorial Microwave Chemistry2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Microwave heating was applied to different palladium-catalyzed allylic substitution reactions. The use of various nucleophiles demonstrated C-, N-, O- and S- nucleophilicity. High yields and stereopurities of the corresponding alkyls, amides, ethers and sulfones were afforded after only 30 – 120 s of heating. The sensitive stereocontrol induced by the catalyst and the catalytic activity were sustained (88 to > 99 % enantiomeric excess (ee) ) despite high temperatures (up to 215oC) and forced conditions.

    Rapid molybdenum-catalyzed allylic alkylation was undertaken utilizing microwave heating. This formerly troublesome catalysis was developed into a simple, fast and convenient protocol. The protocol was employed in a structure-activity investigation for optimizing catalytic activity. An electron-rich environment with low steric restriction around the catalyzing molybdenum improved catalytic activity as well as induced stereoselectivity (> 99 % ee).

    A new methodology was developed for performing carbon monoxide reactions without the use of gaseous carbon monoxide from an external source. Solid metal carbonyls of low toxicity were utilized for in situ liberation of carbon monoxide directly into the reaction mixture. The methodology was applied to the combinatorial microwave-assisted synthesis of a small sized substance library of amidated HIV-1 protease inhibitors.

  • 162.
    Karami, Kiomars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Electrolyte structures and ionization conditions for iontophoretic drug formulation of local anesthetics1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Iontophoresis is a modern method of drug delivery by which charged bioactive molecules (drugs) are transferred from an electrolytic reservoir into and through a tissue, normally skin, by means of a weak electric current. The drug is placed in a conductive medium, usually an aqueous solution or a hydrogel, between the "active" electrode and the skin. The circuit is completed by a second "passive" electrode and the skin. Although iontophoresis is a well-known method for transdermal delivery of drugs, basic physicochemical knowledge of this phenomenon is still lacking.

    This thesis aimed to obtain a wide understanding of electrolyte structures and ionization conditions in iontophoresis, and a firm physicochemical basis for improvement of iontophoretic drug formulation of local anesthetics. The precision conductometric technique was used mainly. Lidocaine hydrochloride (LidHCl) was selected as a model local anesthetic substance. The conductance theory of Fuoss, Hsia and Fernandez-Prini was used to interpret the experimental data, with respect to ionization and mobility of LidHCl in different solvent media. LidHCl was studied in the following solvents:, water, propylene glycol (a transdermal enhancer),aqueous propylene glycol (20 weight-% PG) and 1-octanol. To compare the ionization properties of prilocaine hydrochloride (PrilHCl) with those of LidHCl, PrilHCl was studied in the same pharmaceutical aqueous-enhancer medium. Furthermore, the molecular diffusive transport properties of the local anesthetics lidocaine-, prilocaine-,bupivacaine-, etidocaine-, mepivacaine- and ropivacaine hydrochloride in an agarose hydrogel (1 weight-% agarose) were studied.

    The results indicate that, for the solvents studied, LidHCl has the highest ionic mobility in aqueous propylene glycol; u(LidH+) = 1.35 mm2 V-1 min-1. No measurable difference in ionization properties and ionic mobility between LidHCl and PrilHCl in aqueous propylene glycol was observed. Within the concentration range investigated in this solvent, more than 98% of both LidHCl and PrilHCl are in ionized form (LidH+ and PrilH+). Of the six local anesthetics studied by diffusion measurements in agarose hydrogel (1 weight-% agarose) as medium, LidHCl and PrilHCl have the highest diffusion coefficients; D(lido) = 7.79 · 10-6 and D(prilo) = 7.76  · 10-6 cm2/s.

    From a pharmaceutical point of view, it might be interesting to study the possibility of combining lidocaine- and prilocaine hydrochloride in an aqueous-enhancer medium as an iontophoretic drug formulation of local anesthetics.

  • 163.
    Karlsson, Christoffer
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Blom, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Johansson, Miranda
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Jansson, Anna M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Scifo, Enzo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Karlén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Govender, Thavendran
    Catalysis and Peptide Research Unit, University of KwaZulu Natal, South Africa.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
    Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding2015In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 9, p. 2612-2621Article in journal (Refereed)
    Abstract [en]

    Incorporation of an artificial amino acid 2 with a stilbene chromophore into peptidomimetics with three to nine amino acids yields phototriggerable candidates for inhibition of the binding between the R1 and R2 subunits of the M. tuberculosis ribonucleotide reductase (RNR). Interstrand hydrogen bond probability was used as a guideline for predicting conformational preferences of the photoisomers. Binding of these inhibitors has been rationalized by docking studies with the R1 unit. Significant differences in binding of the photoisomers were observed. For the shorter peptidomimetics, stronger binding of the Z isomer might indicate hydrophobic interactions between the stilbene chromophore and the binding site.

  • 164.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hanrieder, Jörg
    Imaging mass spectrometry in drug development and toxicology2017In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, no 6, p. 2283-2294Article, review/survey (Refereed)
    Abstract [en]

    During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general.

  • 165.
    Karlsson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Sweden; Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, USA.
    Michno, Wojciech
    Ransome, Yusuf
    Hanrieder, Jörg
    MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure.2017In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1865, no 7, p. 740-746Article in journal (Refereed)
    Abstract [en]

    The environmental toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative diseases. We have previously shown that neonatal exposure to BMAA results in dose-dependent cognitive impairments, proteomic alterations and progressive neurodegeneration in the hippocampus of adult rats. A high BMAA dose (460mg/kg) also induced intracellular fibril formation, increased protein ubiquitination and enrichment of proteins important for lipid transport and metabolism. The aim of this study was therefore to elucidate the role of neuronal lipids in BMAA-induced neurodegeneration. By using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we characterized the spatial lipid profile in the hippocampus of six month-old rats that were treated neonatally (postnatal days 9-10) with 460mg/kg BMAA. Multivariate statistical analysis revealed long-term changes in distinct ganglioside species (GM, GD, GT) in the dentate gyrus. These changes could be a consequence of direct effects on ganglioside biosynthesis through the b-series (GM3-GD3-GD2-GD1b-GT1b) and may be linked to astrogliosis. Complementary immunohistochemistry experiments towards GFAP and S100β further verified the role of increased astrocyte activity in BMAA-induced brain damage. This highlights the potential of imaging MS for probing chemical changes associated with neuropathological mechanisms in situ. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.

  • 166.
    Kennedy, Amanda
    et al.
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Ballante, Flavio
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Johansson, Johan
    Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Milligan, Graeme
    Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow.
    Sundström, Linda
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Nordqvist, Anneli
    Cardiovascular Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.
    Carlsson, Jens
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling2018In: ACS Pharmacology & Translational Science, ISSN 2575-9108, Vol. 1, no 2, p. 119-133Article in journal (Refereed)
    Abstract [en]

    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor that is activated by proteolytic cleavage of its N-terminus. The unmasked N-terminal peptide then binds to the transmembrane bundle, leading to activation of intracellular signaling pathways associated with inflammation and cancer. Recently determined crystal structures have revealed binding sites of PAR2 antagonists, but the binding mode of the peptide agonist remains unknown. In order to generate a model of PAR2 in complex with peptide SLIGKV, corresponding to the trypsin-exposed tethered ligand, the orthosteric binding site was probed by iterative combinations of receptor mutagenesis, agonist ligand modifications and data-driven structural modeling. Flexible-receptor docking identified a conserved binding mode for agonists related to the endogenous ligand that was consistent with the experimental data and allowed synthesis of a novel peptide (1-benzyl-1H[1,2,3]triazole-4-yl-LIGKV) with higher functional potency than SLIGKV. The final model may be used to understand the structural basis of PAR2 activation and in virtual screens to identify novel PAR2 agonist and competitive antagonists. The combined experimental and computational approach to characterize agonist binding to PAR2 can be extended to study the many other G protein-coupled receptors that recognize peptides or proteins.

  • 167.
    Khan, T. M.
    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.
    Roy, D.
    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.
    Structure and Activity Relationship of the Echinochloa Crus-Galli Antimicrobial Peptide 12014In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 20, p. S278-S279Article in journal (Other academic)
  • 168.
    Kirkpatrick, Christine L.
    et al.
    Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA..
    Broberg, Christopher A.
    Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA..
    McCool, Elijah N.
    Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA..
    Lee, Woo Jean
    Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA..
    Chao, Alex
    Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA..
    McConnell, Evan W.
    Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA..
    Pritchard, David A.
    Univ North Carolina Chapel Hill, Dept Biostat, Chapel Hill, NC USA..
    Hebert, Michael
    Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA..
    Fleeman, Renee
    Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL USA..
    Adams, Jessie
    Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL USA..
    Jamil, Amer
    Univ Agr Faisalabad, Dept Biochem, Faisalabad, Pakistan..
    Madera, Laurence
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
    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.
    Liu, Yufeng
    Univ North Carolina Chapel Hill, Dept Biostat, Dept Genet, Dept Stat & Operat Res, Chapel Hill, NC USA.;Univ North Carolina Chapel Hill, Carolina Ctr Genome Sci, Chapel Hill, NC USA..
    Hoskin, David W.
    Dalhousie Univ, Dept Pathol, Halifax, NS, Canada..
    Shaw, Lindsey N.
    Univ S Florida, Dept Cell Biol Microbiol & Mol Biol, Tampa, FL USA..
    Hicks, Leslie M.
    Univ North Carolina Chapel Hill, Dept Chem, Chapel Hill, NC USA..
    The "PepSAVI-MS" Pipeline for Natural Product Bioactive Peptide Discovery2017In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 89, no 2, p. 1194-1201Article in journal (Refereed)
    Abstract [en]

    The recent increase in extensively drug-resistant bacterial pathogens and the associated increase of morbidity and mortality demonstrate the immediate need for new antibiotic backbones with novel mechanisms of action. Here, we report the development of the PepSAVI-MS pipeline for bioactive peptide discovery. This highly versatile platform employs mass spectrometry and statistics to identify bioactive peptide targets from complex biological samples. We validate the use of this platform through the successful identification of known bioactive peptides from a botanical species, Viola odorata. Using this pipeline, we have widened the known antimicrobial spectrum for V. odorata cyclotides, including antibacterial activity of cycloviolacin O2 against A. baumannii. We further demonstrate the broad applicability of the platform through the identification of novel anticancer activities for cycloviolacins by their cytotoxicity against ovarian, breast, and prostate cancer cell lines.

  • 169.
    Lagerlund, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Design and Synthesis of Novel Glutamine Synthetase Inhibitors and Development of Palladium(0)-Catalyzed Aminocarbonylation2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tuberculosis (TB) is a major infectious disease, killing about 2 million people annually throughout the world. Today's TB treatment is a lengthy procedure involving a combination of antibiotics. No new TB drug has been introduced onto the market in the past 40 years, and the emergence of multi- and extensively drug-resistant TB calls for new drugs. Finding new drug targets is important and one such target is the Mycobacterium tuberculosis enzyme glutamine synthetase (GS), which catalyses the formation of glutamine from glutamic acid. In this work, novel GS inhibitors and new Pd(0)-catalyzed methods have been developed.

    A microwave-enhanced Pd(0)-catalyzed α-arylation reaction was developed using water as solvent, and a phenylglycine scaffold was identified using structure-based design. A series of α-arylated phenylglycine derivates was produced at moderate to good yields. Some of these were biologically evaluated against GS.

    A novel scaffold, 3-amino-imidazo[1,2-a]pyridine, was identified by high-throughput screening directed towards GS. This type of compound could be easily produced via a Ugi-type, microwave-promoted multi-component reaction in 20 min. The scaffold was investigated by changing one substituent at a time, and in an experimental design where 8 factors were varied in the same design. Several potent inhibitors were identified; amongst them the most potent inhibitor to date (IC50 = 0.38 µM). Two discrete structure-activity relationships were established, and one of the inhibitors was co-crystallized.

    The first general aminocarbonylation of aryl chlorides and the first aminocarbonylation of alkenyl phosphates were developed. Alkenyl chlorides, bromides and triflates were investigated in the same transformation utilizing Mo(CO)6 as a solid carbon monoxide source. Two different Pd(0)-based catalytic systems were developed. A wide variety of aryl chlorides and amines could be transformed into the corresponding amides with good yields. The alkenyl substrates produced low to good yields.

    List of papers
    1. Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase
    Open this publication in new window or tab >>Microwave-enhanced alpha-arylation of a protected glycine in water: evaluation of 3-phenylglycine derivatives as inhibitors of the tuberculosis enzyme, glutamine synthetase
    Show others...
    2007 (English)In: Combinatorial chemistry & high throughput screening, ISSN 1386-2073, E-ISSN 1875-5402, Vol. 10, no 9, p. 783-789Article in journal (Refereed) Published
    Abstract [en]

    A microwave-enhanced, palladium-catalyzed protocol for the alpha-arylation of a protected glycine in neat water is described. This reaction proceeds rapidly, under non-inert conditions, to afford a range of phenylglycine derivatives in moderate to good yields. Based on this arylation, a number of aryl L-methionine-SR-sulfoximine (MSO) analogues were prepared and evaluated for their Mycobacterium tuberculosis glutamine synthetase (TB-GS) inhibitory activity.

    Keywords
    arylation, glutamine synthetase, microwave, palladium, tuberculosis, water
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-16614 (URN)10.2174/138620707783018478 (DOI)000253584600005 ()18478959 (PubMedID)
    Available from: 2008-06-05 Created: 2008-06-05 Last updated: 2018-01-12Bibliographically approved
    2. Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
    Open this publication in new window or tab >>Functionalized 3-amino-imidazo[1,2-a]pyridines: A novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors
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    2009 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 19, no 16, p. 4790-4793Article in journal (Refereed) Published
    Abstract [en]

    3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated. Compound 4n was found to be the most potent inhibitor (IC50 = 0.38 ± 0.02 μM). This compound was significantly more potent than the known inhibitors, L-methionine-SR-sulfoximine and phosphinothricin.

    Keywords
    Mycobacterium tuberculosis, Glutamine synthetase inhibitors, Microwave, 3-Aminoimidazo[1, 2-a]pyridine
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-100360 (URN)10.1016/j.bmcl.2009.06.045 (DOI)000268358800057 ()19560924 (PubMedID)
    Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2018-01-13Bibliographically approved
    3. Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
    Open this publication in new window or tab >>Synthesis, biological evaluation and X-ray crystallographic studies of imidazo[1,2-a]-pyridine based Mycobacterium tuberculosis glutamine synthetase inhibitors
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    2012 (English)In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 3, no 5, p. 620-626Article in journal (Refereed) Published
    Abstract [en]

    Based on an imidazo[1,2-a]pyridine hit from a high-throughput screen directed at the M. tuberculosis enzyme glutamine synthetase, a hit expansion was performed by synthesizing a series of analogs. A set of 16 molecules was first synthesized according to a statistical molecular design approach. One potent inhibitor was identified (IC50 = 3.0 µM), which led to the synthesis of 17 additional imidazo[1,2-a]pyridines in a follow-up study. Among these, several inhibitors were identified showing single digit micromolar potency. An X-ray structure of one of these revealed the binding mode of this class of inhibitors in the ATP-binding site, and allowed us to rationalize some of the structure-activity relationships observed.

    National Category
    Medicinal Chemistry Medical and Health Sciences
    Research subject
    Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-100359 (URN)10.1039/c2md00310d (DOI)000304387300013 ()
    Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2018-01-13Bibliographically approved
    4. Microwave-promoted aminocarbonylations of aryl chlorides using Mo(CO)(6) as a solid carbon monoxide source.
    Open this publication in new window or tab >>Microwave-promoted aminocarbonylations of aryl chlorides using Mo(CO)(6) as a solid carbon monoxide source.
    2005 (English)In: J Comb Chem, ISSN 1520-4766, Vol. 8, no 1, p. 4-6Article in journal (Refereed) Published
    Keywords
    Benzamides/*chemical synthesis/chemistry, Benzene Derivatives/*chemistry, Carbon Monoxide/*chemistry, Catalysis, Combinatorial Chemistry Techniques, Hydrocarbons; Chlorinated/*chemistry, Microwaves, Molecular Structure, Molybdenum/*chemistry, Palladium/chemistry, Research Support; Non-U.S. Gov't
    Identifiers
    urn:nbn:se:uu:diva-75624 (URN)16398545 (PubMedID)
    Available from: 2006-02-13 Created: 2006-02-13 Last updated: 2011-01-11
    5. Aminocarbonylations of Alkenyl Phosphates, Chlorides, Bromides and Triflates with Mo(CO)6 as a Solid CO source
    Open this publication in new window or tab >>Aminocarbonylations of Alkenyl Phosphates, Chlorides, Bromides and Triflates with Mo(CO)6 as a Solid CO source
    2009 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 65, no 36, p. 7646-7652Article in journal (Refereed) Published
    Abstract [en]

    Palladium-catalyzed aminocarbonylations of alkenyl chlorides, bromides, and triflates were investigated using Mo(CO)6 as a solid carbon monoxide source. The reactions afforded moderate to good yields producing a wide variety of acrylamides after 20 minutes of microwave irradiation. In addition, the aminocarbonylation reaction was, for the first time, expanded to include alkenyl phosphates as starting materials.

    Keywords
    Carbonylation, Microwave, Vinyl halides, Vinyl phosphates, Vinyl triflates, Alkenyl electrophiles, Palladium, Enolizable ketones
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-100358 (URN)10.1016/j.tet.2009.06.101 (DOI)000269340000043 ()
    Available from: 2009-03-31 Created: 2009-03-31 Last updated: 2018-01-13Bibliographically approved
  • 170.
    Lai, Kuei-Hung
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Studies on anti-leukemic terpenoids from medicinal mushrooms and marine sponges with ChemGPS-NP-based targets investigation of lead compounds2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis investigates the anti-leukemic activity of terpenoids isolated from medicinal mushrooms and marine sponges, as well as their possible targets and mechanisms of action.

    In the first section, we focused on studying the triterpenoidal components of three triterpenoid-enriched medicinal mushrooms Antrodia cinnamomea, Ganoderma lucidum, and Poria cocos, which have been used in folk medicine for centuries and also developed into several contemporary marketed products. We isolated the major and characteristic triterpenoids from these mushrooms, together with six new lanostanoids (II-1II-6). The anti-leukemic activity of the isolates was evaluated in vitro using MTT proliferative assay and seven of them exhibited potential anti-leukemic effect. The active lead compounds were further subjected to computational analyses utilizing the ChemGPS-NP tool. We established a database for the anti-leukemic relevant chemical space of triterpenoids isolated from these three medicinal mushrooms, which could be used as a reference database for further research on anti-leukemic triterpenoids. Our results indicated that the anti-leukemic effect of the active lead compounds was mediated not only through topoisomerases inhibition but also through inhibiting DNA polymerases.

    The second and third sections focused on isolation of anti-leukemic sesterterpenoids from sponges. The investigation of Carteriospongia sp. led to the isolation of two new scalarane-type sesterterpenoids (III-1 and III-2) and one known tetraprenyltoluquinol-related metabolite (III-3). All isolates exhibit an apoptotic mechanism of action against Molt 4 cells, found to be mediated through the disruption of the mitochondrial membrane potential (MMP) and inhibition of topoisomerase IIα expression. Detailed investigation of the apoptotic mechanism of action using molecular docking analysis revealed that compound III-1 might target Hsp90 protein. The apoptotic-inducing effect of III-3 was supported by in vivo experiment by suppressing the volume of xenograft tumor growth (47.58%) compared with the control.

    In the final section of this thesis we studied manoalide and its derivatives, sesterterpenoids isolated from the sponge Luffariella sp.. Manoalide has been studied as a potential anti-inflammatory agent for the last thirty years with more than 200 publications and 40 patents. However, the configurations at positions 24 and 25 were never revealed. In the current study, ten manoalide-type sesterterpenoids (IV-1IV-10) were isolated from Luffariella sp. and their stereoisomers at positions 24 and 25 were identified and separated for the first time. The configuration at positions 24 and 25 showed to have a significant effect on the anti-leukemic activity of manoalide derivatives, with the 24R,25S-isomer exhibiting the most potent anti-leukemic activity. The apoptotic mechanism of action of compound IV-7 against Molt 4 cells was investigated, and the compound was found to trigger MMP disruption and intracellular reactive oxygen species (ROS) generation. Compound IV-7 also inhibited activity against both human topoisomerases, I and II. The in vivo experiment further supported the anti-leukemic effect of IV-7 with a 66.11% tumor volume suppression compared to the control.

    List of papers
    1. Cytotoxic Lanostanoids from Poria cocos
    Open this publication in new window or tab >>Cytotoxic Lanostanoids from Poria cocos
    Show others...
    2016 (English)In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 79, no 11, p. 2805-2813Article in journal (Refereed) Published
    Abstract [en]

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

    National Category
    Biochemistry and Molecular Biology Medicinal Chemistry Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-317526 (URN)10.1021/acs.jnatprod.6b00575 (DOI)000394410600006 ()27808511 (PubMedID)
    Note

    De 2 första författarna delar förstaförfattarskapet.

    Available from: 2017-03-15 Created: 2017-03-15 Last updated: 2018-01-13Bibliographically approved
    2. Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90
    Open this publication in new window or tab >>Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90
    Show others...
    2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36170Article in journal (Refereed) Published
    Abstract [en]

    Two new scalarane sesterterpenoids, 12 beta-(3'beta-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12 beta-(3'beta-hydroxypentanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (2), along with one known tetraprenyltoluquinol-related metabolite (3), were isolated from the sponge Carteriospongia sp. In leukemia Molt 4 cells, 1 at 0.0625 mu g/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than 2 and 3. The isolates inhibited topoisomerase II alpha expression. The apoptotic-inducing effect of 3 was supported by the in vivo experiment through suppressing the volume of xenograft tumor growth (47.58%) compared with the control. Compound 1 apoptotic mechanism of action in Molt 4 cells was further elucidated through inducing ROS generation, calcium release and ER stress. Using the molecular docking analysis, 1 exhibited more binding affinity to N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. The expression of Hsp90 client proteins, Akt, p70(S6k), NF kappa B, Raf-1, p-GSK3 beta, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF1 and HSF1 were suppressed by the use of 1. However, the expression of Hsp70, acetylated tubulin, and activated caspase 3 were induced after 1 treatment. Our results suggested that the proapoptotic effect of the isolates is mediated through the inhibition of Hsp90 and topoisomerase activities.

    National Category
    Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-308635 (URN)10.1038/srep36170 (DOI)000386462100001 ()27796344 (PubMedID)
    Available from: 2016-11-30 Created: 2016-11-29 Last updated: 2018-01-13Bibliographically approved
    3. ChemGPS-NP study on antileukemic triterpenoids from widely-used medicinal mushrooms in Asia
    Open this publication in new window or tab >>ChemGPS-NP study on antileukemic triterpenoids from widely-used medicinal mushrooms in Asia
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medicinal Chemistry Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-317552 (URN)
    Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2018-01-13
    4. Separation and identification on stereoisomers of manoalide derivatives and their configuration-depending antileukemic effects in vitro and in vivo
    Open this publication in new window or tab >>Separation and identification on stereoisomers of manoalide derivatives and their configuration-depending antileukemic effects in vitro and in vivo
    (English)Manuscript (preprint) (Other academic)
    National Category
    Pharmacology and Toxicology Cell and Molecular Biology Pharmaceutical Sciences Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-317553 (URN)
    Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2018-01-13
  • 171.
    Lai, Kuei-Hung
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    ChemGPS-NP study on antileukemic triterpenoids from widely-used medicinal mushrooms in AsiaManuscript (preprint) (Other academic)
  • 172.
    Lai, Kuei-Hung
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Separation and identification on stereoisomers of manoalide derivatives and their configuration-depending antileukemic effects in vitro and in vivoManuscript (preprint) (Other academic)
  • 173.
    Lai, Kuei-Hung
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Lu, Mei-Chin
    Du, Ying-Chi
    El-Shazly, Mohamed
    Wu, Tung-Ying
    Hsu, Yu-Ming
    Henz, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Yang, Juan-Cheng
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chang, Fang-Rong
    Wu, Yang-Chang
    Cytotoxic Lanostanoids from Poria cocos2016In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 79, no 11, p. 2805-2813Article in journal (Refereed)
    Abstract [en]

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

  • 174.
    Larhed, Mats
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    NONPEPTIDE AT2 RECEPTOR AGONISTS2016In: Medicinal Chemistry Reviews, ISSN 978-0-9962932-3-5Article, book review (Refereed)
  • 175.
    Larik, Fayaz Ali
    et al.
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Saeed, Aamer
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Shahzad, Danish
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Faisal, Muhammad
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Mehfooz, Haroon
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Channar, Pervaiz Ali
    Quaid I Azam Univ, Dept Chem, Islamabad 45320, Pakistan..
    Synthetic approaches towards the multi target drug spironolactone and its potent analogues/derivatives2017In: Steroids, ISSN 0039-128X, E-ISSN 1878-5867, Vol. 118, p. 76-92Article, review/survey (Refereed)
    Abstract [en]

    Spironolactone is a well-known multi-target drug and is specifically used for the treatment of high blood pressure and heart failure. It is also used for the treatment of edema, cirrhosis of the liver, malignant, pediatric, nephrosis and primary hyperaldosteronism. Spironolactone in association with thiazide diuretics treats hypertension and in association with furosemide treats bronchopulmonary dyspepsia. The therapeutic mechanism of action of spironolactone involves binding to intracellular mineralocorticoids receptors (MRs) in kidney epithelial cells, thereby inhibiting the binding of aldosterone. Since its first synthesis in 1957 there are several synthetic approaches have been reported throughout the years, Synthetic community has devoted efforts to improve the synthesis of spironolactone and to synthesize its analogues and derivatives. This review aims to provide comprehensive insight for the synthetic endeavors devoted towards the synthesis of a versatile drug spironolactone and its analogues/derivatives.

  • 176. Lauer, Dilyara
    et al.
    Slavic, Svetlana
    Sommerfeld, Manuela
    Thoene-Reineke, Christa
    Sharkovska, Yuliya
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Dahlof, Bjorn
    Kintscher, Ulrich
    Unger, Thomas
    Steckelings, Ulrike Muscha
    Kaschina, Elena
    Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor beta 1 in the Rat Heart2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 63, no 3, p. E60-E67Article in journal (Refereed)
  • 177.
    Lee, Jin-Ching
    et al.
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung 807, Taiwan.;Kaohsiung Med Univ, Dept Biotechnol, Coll Life Sci, Kaohsiung 807, Taiwan.;Kaohsiung Med Univ, Res Ctr Nat Prod & Drug Dev, Kaohsiung 807, Taiwan..
    Chang, Fang-Rong
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung 807, Taiwan.;Natl Sun Yat Sen Univ, Dept Marine Biotechnol & Resources, Kaohsiung 804, Taiwan.;Kaohsiung Med Univ Hosp, Ctr Canc, Kaohsiung 807, Taiwan..
    Chen, Shu-Rong
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung 807, Taiwan..
    Wu, Yu-Hsuan
    Natl Cheng Kung Univ, Inst Basic Med Sci, Coll Med, Tainan 701, Taiwan.;Natl Cheng Kung Univ, Coll Med, Ctr Infect Dis & Signaling Res, Tainan 701, Taiwan..
    Hu, Hao-Chun
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung 807, Taiwan..
    Wu, Yang-Chang
    China Med Univ, Sch Pharm, Coll Pharm, Taichung 404, Taiwan.;China Med Univ Hosp, Chinese Med Res & Dev Ctr, Taichung 404, Taiwan.;China Med Univ Hosp, Ctr Mol Med, Taichung 404, Taiwan.;China Med Univ, Res Ctr Chinese Herbal Med, Taichung 404, Taiwan..
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Cheng, Yuan-Bin
    Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung 807, Taiwan.;Kaohsiung Med Univ, Res Ctr Nat Prod & Drug Dev, Kaohsiung 807, Taiwan.;Kaohsiung Med Univ, Ctr Infect Dis & Canc Res, Kaohsiung 807, Taiwan..
    Anti-Dengue Virus Constituents from Formosan Zoanthid Palythoa mutuki2016In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, no 8, article id 151Article in journal (Refereed)
    Abstract [en]

    A new marine ecdysteroid with an alpha-hydroxy group attaching at C-4 instead of attaching at C-2 and C-3, named palythone A (1), together with eight known compounds (2-9) were obtained from the ethanolic extract of the Formosan zoanthid Palythoa mutuki. The structures of those compounds were mainly determined by NMR spectroscopic data analyses. The absolute configuration of 1 was further confirmed by comparing experimental and calculated circular dichroism (CD) spectra. Anti-dengue virus 2 activity and cytotoxicity of five isolated compounds were evaluated using virus infectious system and [3-(4,5-dimethylthiazol-2-yl)5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays, respectively. As a result, peridinin (9) exhibited strong antiviral activity (IC50 = 4.50 +/- 0.46 mu g/mL), which is better than that of the positive control, 2'CMC. It is the first carotene-like substance possessing anti-dengue virus activity. In addition, the structural diversity and bioactivity of the isolates were compared by using a ChemGPS-NP computational analysis. The ChemGPS-NP data suggested natural products with anti-dengue virus activity locate closely in the chemical space.

  • 178. Leuzy, Antoine
    et al.
    Rodriguez-Vieitez, Elena
    Saint-Aubert, Laure
    Chiotis, Konstantinos
    Almkvist, Ove
    Savitcheva, Irina
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Department of Medical Physics, Uppsala University Hospital, Uppsala, Sweden.
    Wall, Anders
    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 Pharmacy, Department of Medicinal Chemistry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Nordberg, Agneta
    Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer's disease.2018In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 14, no 5, p. 652-663Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Cross-sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single positron emission tomography study can provide both functional and molecular information.

    METHODS: We included 16 patients with Alzheimer's disease who completed follow-up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed-effects models and annual percentage change maps were used to examine longitudinal change.

    RESULTS: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317.

    DISCUSSION: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity.

  • 179.
    Lindgren, Cecilia
    et al.
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden.
    Tyagi, Mohit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Viljanen, Johan V.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Toms, Johannes
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Ge, Changrong
    Karolinska Inst, Med Inflammat Res, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden.
    Zhang, Naru
    Karolinska Inst, Med Inflammat Res, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden;Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China.
    Holmdahl, Rikard
    Karolinska Inst, Med Inflammat Res, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden;Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Guangdong, Peoples R China.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Linusson, Anna
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden.
    Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 11, p. 4774-4790Article in journal (Refereed)
    Abstract [en]

    Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CI1259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CI1259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CI1259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CI1259-273, together with the positioning of the galactose moiety of CI1259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CI1259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.

  • 180.
    Lindh, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Palladium(II)-Catalyzed Coupling Reactions2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Sustainable chemical processes are becoming increasingly important in all fields of synthetic chemistry. Catalysis can play an important role in developing environmentally benign chemical processes, and transition metals have an important role to play in the area of green chemistry. In particular, palladium(II) catalysis includes many key features for successful green chemistry methods, as demonstrated by a number of eco-friendly oxidation reactions catalyzed by palladium(II).

    The aim of the work presented in this thesis was to develop novel and greener palladium(II)-catalyzed coupling reactions. In striving to achieve this aim, the first open-vessel, room-temperature palladium(II)-catalyzed oxidative Heck reaction, using oxygen from the air as the reoxidant of palladium, was developed.

    In a further investigation of the palladium(II)-catalyzed oxidative Heck reaction, base-free conditions for the transformation were identified and suitable conditions for microwave-assisted oxidative Heck reactions were established.

    A convenient and low-cost palladium(II)-catalyzed method for the synthesis of styrene derivatives, by coupling arylboranes with vinyl acetate, was developed. The reaction mechanism was studied using ESI-MS, which enabled the detection of cationic palladium intermediates in ongoing productive reactions, and a plausible catalytic cycle was proposed.

    In an attempt to make the oxidative Heck and the styrene synthesis reactions more attractive from an industrial point of view, conditions for continuous flow synthesis were identified. The results were generally good and rapid synthesis of the desired products was obtained.

    The first palladium(II)-catalyzed C–P bond-forming Hirao-type reaction, employing arylboranes instead of the commonly used aryl halides, was developed. An ESI-MS study was performed, and a plausible catalytic pathway was suggested.

    Finally, a novel method for synthesizing aryl ketones from benzoic acids and nitriles, via palladium(II)-catalyzed decarboxylation of the benzoic acids, was established. Further, the reaction mechanism was studied by ESI-MS and a plausible catalytic route presented.

    List of papers
    1. Open-air oxidative Heck reactions at room temperature
    Open this publication in new window or tab >>Open-air oxidative Heck reactions at room temperature
    2006 (English)In: Green Chemistry, ISSN 1463-9262, E-ISSN 1463-9270, Vol. 8, no 4, p. 338-343Article in journal (Refereed) Published
    Abstract [en]

    Palladium(II)-catalyzed oxidative Heck arylation reactions proceed at room temperature with atmospheric air as the sole reoxidant. Using arylboronic acids as arylating agents and inexpensive 2,9-dimethyl-1,10-phenanthroline as the supporting ligand, efficient vinylic substitution reactions were obtained both with electron-poor and electron-rich olefins on a 1–50 mmol scale.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94792 (URN)10.1039/B517152K (DOI)
    Available from: 2006-09-14 Created: 2006-09-14 Last updated: 2017-12-14Bibliographically approved
    2. Efficient palladium(II) catalysis under air. Base-free oxidative heck reactions at room temperature or with microwave heating
    Open this publication in new window or tab >>Efficient palladium(II) catalysis under air. Base-free oxidative heck reactions at room temperature or with microwave heating
    Show others...
    2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 21, p. 7957-7962Article in journal (Refereed) Published
    Abstract [en]

    Scope and limitations of the base-free oxidative Heck reaction with arylboronic acids have been explored. Under our conditions, the dmphen−palladium(II)-catalyzed arylation proceeded with air or p-benzoquinone as reoxidants of palladium(0). We found that ambient temperature and mild aerobic conditions allow for the use of substrates sensitive to palladium(II)-catalyzed oxidation. Oxidative Heck couplings, employing different arylboronic acids, were smoothly and regioselectively conducted with both electron-rich and electron-poor olefins, providing high yields even with disubstituted butyl methacrylate, sensitive acrolein, and a vinylboronate ester. Controlled microwave processing was used to reduce reaction times from hours to minutes both in small scale and in 50 mmol scale batch processes.

    Keywords
    Acrylates/*chemistry, Aerobiosis, Benzene Derivatives/*chemistry, Boronic Acids/*chemistry, Catalysis, Chemistry; Organic/*methods, Heat, Microwaves, Oxidation-Reduction, Palladium/*chemistry, Temperature
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-16615 (URN)10.1021/jo701434s (DOI)000249986500019 ()17887706 (PubMedID)
    Available from: 2008-05-29 Created: 2008-05-29 Last updated: 2018-01-12Bibliographically approved
    3. Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
    Open this publication in new window or tab >>Synthesis of styrenes by palladium(II)-catalyzed vinylation of arylboronic acids and aryltrifluoroborates by using vinyl acetate
    Show others...
    2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 18, p. 4630-4636Article in journal (Refereed) Published
    Abstract [en]

    Reactions of aromatic and heteroaromatic boronic acids or aryltrifluoroborate salts with vinyl acetate in the presence of a palladium(II) catalyst give the corresponding styrenes in good yields. This Heck reaction proceeds with microwave heating in less than 30 min at 140 degrees C in the absence of base and tolerates a variety of substituents. No palladium reoxidant is needed and the vinylation is performed under non-inert conditions. Mass spectrometry (electrospray ionization mass spectrometry (ESIMS) and tandem mass spectrometry   (MS/MS)) was used to identify cationic palladium-containing complexes in ongoing reactions. The key intermediates that have been detected, together with experiments that used deuterated vinyl acetate, support the existence of catalytically active palladium hydride species, and that it is the arylation of ethylene, not vinyl acetate, which   generates the styrene product. The mechanism of the reaction is discussed in terms of the palladium(II) intermediates mentioned above.

    Keywords
    Heck reaction, mass spectrometry, mechanistic studies, palladium, styrene
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-102918 (URN)10.1002/chem.200802744 (DOI)000265955200018 ()19274694 (PubMedID)
    Available from: 2009-05-13 Created: 2009-05-12 Last updated: 2017-12-13Bibliographically approved
    4. Continuous Flow Palladium(II): Catalyzed Oxidative Heck Reactions with Arylboronic Acids
    Open this publication in new window or tab >>Continuous Flow Palladium(II): Catalyzed Oxidative Heck Reactions with Arylboronic Acids
    2010 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 12, p. 2270-2274Article in journal (Refereed) Published
    Abstract [en]

    Palladium(II)-catalyzed oxidative Heck reactions were investigated under continuous flow conditions. Selective, fast and convenient protocols for the coupling of arylboronic acids with electron-rich and electron-poor olefins were developed by using a commercially available flow reactor.

    Keywords
    Continuous flow, cross-coupling, Boron, Palladium, homogeneous catalysis, organic-synthesis, base-free, coupling reactions, room-temperature, bond formation, efficient, catalysis, palladium, air, perspective
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-130028 (URN)10.1002/ejoc.201000063 (DOI)000277332500004 ()
    Available from: 2010-08-27 Created: 2010-08-27 Last updated: 2017-12-12Bibliographically approved
    5. Microwave-promoted palladium(II)-catalyzed C-P bond formation by using arylboronic acids or aryltrifluoroborates.
    Open this publication in new window or tab >>Microwave-promoted palladium(II)-catalyzed C-P bond formation by using arylboronic acids or aryltrifluoroborates.
    Show others...
    2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 47, p. 13069-13074Article in journal (Refereed) Published
    Abstract [en]

    The first Pd-II-catalyzed P arylation has been performed by using palladium acetate, the rigid bidentate ligand dmphen (dmphen=2,9-dimethyl-1,10-phenanthroline), and without the addition of base or acid. Couplings of arylboronic acids or aryl trifluoroborates with H-phosphonate dialkyl esters were conducted in 30 min with controlled microwave (MW) heating under non-inert conditions. Aryl phosphites were also synthesized at room temperature with atmospheric air as the sole reoxidant. The arylated phosphonates were isolated in 44-90% yields. The excellent chemoselectivity of the method was illustrated in the synthesis of a Mycobacterium tuberculosis glutamine synthetase (MTB-GS) inhibitor. Online ESIMS was used to detect cationic palladium species in ongoing reactions directly, and a catalytic cycle has been proposed based on these results.

    Place, publisher, year, edition, pages
    Weinheim: Wiley-VCH Verlag GmbH, 2009
    Keywords
    Boronic acids, microwave chemistry, palladium, P arylation, trifluoroborates
    National Category
    Analytical Chemistry
    Research subject
    Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-113919 (URN)10.1002/chem.200901473 (DOI)000273697100021 ()19856344 (PubMedID)
    Available from: 2010-02-04 Created: 2010-02-04 Last updated: 2017-12-12Bibliographically approved
    6.
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  • 181.
    Lindh, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Modelling in Drug Discovery: Application of Structure-Based Drug Design, Conformal Prediction and Evaluation of Virtual Screening2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Structure-based drug design and virtual screening are areas of computational medicinal chemistry that use 3D models of target proteins. It is important to develop better methods in this field with the aim of increasing the speed and quality of early stage drug discovery.

    The first part of this thesis focuses on the application of structure-based drug design in the search for inhibitors for the protein 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), one of the enzymes in the DOXP/MEP synthetic pathway. This pathway is found in many bacteria (such as Mycobacterium tuberculosis) and in the parasite Plasmodium falciparum.

    In order to evaluate and improve current virtual screening methods, a benchmarking data set was constructed using publically available high-throughput screening data. The exercise highlighted a number of problems with current data sets as well as with the use of publically available high-throughput screening data. We hope this work will help guide further development of well designed benchmarking data sets for virtual screening methods.

    Conformal prediction is a new method in the computer-aided drug design toolbox that gives the prediction range at a specified level of confidence for each compound. To demonstrate the versatility and applicability of this method we derived models of skin permeability using two different machine learning methods; random forest and support vector machines.

    List of papers
    1. Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
    Open this publication in new window or tab >>Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
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    2011 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 14, p. 4964-4976Article in journal (Refereed) Published
    Abstract [en]

    The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 mu M on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 mu g/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

    National Category
    Biochemistry and Molecular Biology Other Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-156614 (URN)10.1021/jm2000085 (DOI)000292892300003 ()21678907 (PubMedID)
    Available from: 2011-08-07 Created: 2011-08-04 Last updated: 2018-01-12Bibliographically approved
    2. Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: An attempt to improve the activity against Mycobacterium tuberculosis
    Open this publication in new window or tab >>Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: An attempt to improve the activity against Mycobacterium tuberculosis
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    2011 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 21, no 18, p. 5403-5407Article in journal (Refereed) Published
    Abstract [en]

    Two series of FR900098/fosmidomycin analogs were synthesized and evaluated for MtDXR inhibition and Mycobacterium tuberculosis whole-cell activity. The design rationale of these compounds involved the exchange of either the phosphonic acid or the hydroxamic acid part for alternative acidic and metal-coordinating functionalities. The best inhibitors provided IC(50) values in the micromolar range, with a best value of 41 mu M.

    Keywords
    Tuberculosis, DXR, Enzyme inhibitor, Fosmidomycin, FR900098
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-158288 (URN)10.1016/j.bmcl.2011.07.005 (DOI)000294051800057 ()
    Available from: 2011-09-07 Created: 2011-09-06 Last updated: 2017-12-08
    3. DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
    Open this publication in new window or tab >>DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
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    2013 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 15, p. 6190-6199Article in journal (Refereed) Published
    Abstract [en]

    The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway producing the universally essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the cramped substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites. A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC50 of 40 nM.

    Keywords
    Mycobacterium tuberculosis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, DXR
    National Category
    Structural Biology
    Research subject
    Biology with specialization in Structural Biology; Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-196616 (URN)10.1021/jm4006498 (DOI)000323082400015 ()
    Funder
    Swedish Foundation for Strategic Research Swedish Research Council
    Note

    De tre (3) första författarna delar förstaförfattarskapet.

    Available from: 2013-03-11 Created: 2013-03-11 Last updated: 2017-12-06Bibliographically approved
    4. Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
    Open this publication in new window or tab >>Toward a Benchmarking Data Set Able to Evaluate Ligand- and Structure-based Virtual Screening Using Public HTS Data
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    2015 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, Vol. 55, no 2, p. 343-353Article in journal (Refereed) Published
    Abstract [en]

    Virtual screening has the potential to accelerate and reduce costs of probe development and drug discovery. To develop and benchmark virtual screening methods, validation data sets are commonly used. Over the years, such data sets have been constructed to overcome the problems of analogue bias and artificial enrichment. With the rapid growth of public domain databases containing high-throughput screening data, such as the PubChem BioAssay database, there is an increased possibility to use such data for validation. In this study, we identify PubChem data sets suitable for validation of both structure- and ligand-based virtual screening methods. To achieve this, high-throughput screening data for which a crystal structure of the bioassay target was available in the PDB were identified. Thereafter, the data sets were inspected to identify structures and data suitable for use in validation studies. In this work, we present seven data sets (MMP13, DUSP3, PTPN22, EPHX2, CTDSP1, MAPK10, and CDK5) compiled using this method. In the seven data sets, the number of active compounds varies between 19 and 369 and the number of inactive compounds between 59 405 and 337 634. This gives a higher ratio of the number of inactive to active compounds than what is found in most benchmark data sets. We have also evaluated the screening performance using docking and 3D shape similarity with default settings. To characterize the data sets, we used physicochemical similarity and 2D fingerprint searches. We envision that these data sets can be a useful complement to current data sets used for method evaluation.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2015
    National Category
    Structural Biology Pharmaceutical Chemistry
    Research subject
    Chemistry with specialization in Bioorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-248018 (URN)10.1021/ci5005465 (DOI)000349943100014 ()25564966 (PubMedID)
    Available from: 2015-03-26 Created: 2015-03-26 Last updated: 2018-03-05Bibliographically approved
    5. Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework
    Open this publication in new window or tab >>Predicting the Rate of Skin Penetration Using an Aggregated Conformal Prediction Framework
    2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 5, p. 1571-1576Article in journal (Refereed) Published
    Abstract [en]

    Skin serves as a drug administration route, and skin permeability of chemicals is of significant interest in the pharmaceutical and cosmetic industries. An aggregated conformal prediction (ACP) framework was used to build models, for predicting the permeation rate (log K-p) of chemical compounds through human skin. The conformal prediction method gives as an output the prediction range at a given level of confidence for each compound, which enables the user to make a more informed decision when, for example, suggesting the next compound to prepare, Predictive models were built using;both the random forest and the support vector machine methods and were based on experimentally derived permeability data on 211 diverse compounds. The derived models were of similar predictive quality as compared to earlier published models but have the extra advantage of not only presenting a single predicted value for each, compound but also a reliable, individually assigned prediction range. The models use calculated descriptors and can quickly predict the skin permeation rate of new compounds.

    Keywords
    conformal prediction, skin penetration nonconformist, Scikit Learn, random forest, Support vector machines
    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-323448 (URN)10.1021/acs.molpharmaceut.7b00007 (DOI)000400633300024 ()28335598 (PubMedID)
    Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-01-13Bibliographically approved
  • 182. Lindhe, Örjan
    et al.
    Almqvist, Per
    Kågedal, Matts
    Gustavsson, Sven-Åke
    Bergström, Mats
    Nilsson, Dag
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Autoradiographic mapping of 5-HT1B/1D binding sites in the Rhesus monkey brain using [carbonyl-11C]zolmitriptan2011In: International Journal of Molecular Imaging, ISSN 2090-1712, E-ISSN 2090-1720Article in journal (Refereed)
    Abstract [en]

    Zolmitriptan is a serotonin 5-HT1B/1D receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [11C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [11C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [11C]zolmitriptan as a radioligand. In saturation studies, [11C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95–5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT1 receptor antagonists, [11C]zolmitriptan binding was blocked by selective 5-HT1B and 5-HT1D ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT1A receptor antagonist.

  • 183.
    Lindman, Susanna
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Design and synthesis of -turn peptidomimetics: Applications to angiotensin II2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This study addresses the issue of how to convert peptides into drug-like non-peptides while retaining the biological activity at peptide receptors. Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe, Ang II) was used as a model peptide.

    Small bioactive peptides are in most cases conformationally flexible molecules. Rigidified peptide analogues or peptidomimetic scaffolds can be introduced into the peptide, to enforce a particular backbone conformation, and thereby locate the side-chains at defined positions in space. The conformationally constrained analogues are of considerable value in determining biologically active conformation(s) of the studied peptide. The strategy applied in this thesis includes identification of non-pharmacophoric amino acid residues, rigidification, conformational analysis and incorporation of turn mimicking scaffolds in

    Ang II. Several side-chain cyclized (disulfide and methylendithioether) Ang II analogues have been synthesized. The binding studies of the rigidified analogues demonstrated that the compounds designed for the AT1-receptor had affinity for both receptor subtypes, while the compounds designed for the AT2-receptor displayed high selectivity only for this receptor subtype. Conformational evaluation revealed that several of the cyclized Ang II analogues most probably adopt a γ-turn like conformation around Tyr-4 while interacting with the

    Ang II receptor. Based on this hypothesis, three different γ-turn mimetics replacing amino acid residues 3-5 were designed, synthesized and incorporated into Ang II. One of the synthesized pseudopeptides, incorporating an azepine-containing γ-turn mimetic, exerted high binding affinity and agonistic activity. These results strongly support the theory that Ang II adopts a γ-turn like conformation when activating the AT1 receptor. The other Ang II analogues, incorporating bicyclic and aromatic γ-turn mimetics, did not display any binding to the AT1 receptor.

  • 184.
    Linkuviene, Vaida
    et al.
    Vilnius Univ, Inst Biotechnol, Dept Biothermodynam & Drug Design, Sauletekio 7, LT-10257 Vilnius, Lithuania.
    Talibov, Vladimir O
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Matulis, Daumantas
    Vilnius Univ, Inst Biotechnol, Dept Biothermodynam & Drug Design, Sauletekio 7, LT-10257 Vilnius, Lithuania.
    Introduction of Intrinsic Kinetics of Protein-Ligand Interactions and Their Implications for Drug Design2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 6, p. 2292-2302Article in journal (Refereed)
    Abstract [en]

    Structure kinetic relationship analyses and identification of dominating interactions for optimization of lead compounds should ideally be based on intrinsic rate constants instead of the more easily accessible observed kinetic constants, which also account for binding linked reactions. The intrinsic rate constants for sulfonamide inhibitors and pharmacologically relevant isoforms of carbonic anhydrase were determined by a novel surface plasmon resonance (SPR) biosensor-based approach, using chemodynamic analysis of binding-linked pH-dependent effects. The observed association rates (k(a)(obs)) were pH-dependent and correlated with the fraction of deprotonated inhibitor and protonated zinc-bound water molecule. The intrinsic association rate constants (k(a)(intr)) were pH independent and higher than k(a)(obs). By contrast, the observed and intrinsic dissociation rate constants were identical and pH-independent, demonstrating that the observed association and dissociation mechanisms are inherently different. A model accounting for the differences between intrinsic and observed rate constants was developed, useful also for other interactions with binding-linked protonation reactions.

  • 185.
    Linnanen, Tero
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
    Serotonergic aporphine derivatives: Synthesis and structure-activity relationships2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Novel series of well-characterized and stereochemically pure 11-substituted (R)-aporphine derivatives have been prepared and their interaction with serotonin 5-HT7 and 5-HT1A receptors and dopamine D2A and D1 receptors have been studied. Efficient palladium catalyzed reactions were utilized for the diastereoselective synthesis of atropisomers as well as for the synthesis of several of the other (R)-aporphine derivatives. A number of 11-arylated (R)-aporphines displayed high affinity for 5-HT7 and 5-HT1A receptors and derivatives with selectivity for either 5-HT7 or 5-HT1A receptors were obtained by chosing the proper substituents on the 11-phenyl ring. Simultaneous substitution of the 2' and 6' positions of (R)-11-phenylaporphine afforded derivatives, including some atropisomers, with increased 5-HT7 selectivity and several of these analogues were characterized as selective 5-HT7 receptor antagonists. Introduction of substituents in the other positions of the 11-phenyl group resulted in derivatives with selectivity for 5-HT1A receptors.

    In addition, new series of novel pentacyclic (R)-aporphines were synthesized either by the introduction of a methylene group between carbon atoms C1 and C11 in the (R)-aporphine skeleton or by ring expansion reactions of (R)-1,11-carbonylaporphine. These series of derivatives afforded the possibility to introduce substituents/functional groups below, above and in the plane of the ring system thereby allowing for structural extensions into previously unexplored areas of receptor binding sites. Compounds with various affinities for the serotonin and dopamine receptors were obtained and novel 5-HT7 receptor antagonists were identified.

    The identification of selective serotonin 5-HT7 receptor antagonists is of particular interest since only a few putatively selective 5-HT7 receptor antagonistic ligands have been reported.

  • 186. Llona-Minguez, Sabin
    et al.
    Höglund, Andreas
    Ghassemian, Artin
    Desroses, Matthieu
    Calderon-Montano, Jose Manuel
    Moron, Estefania Burgos
    Valerie, Nicholas C. K.
    Wiita, Elisee
    Almlöf, Ingrid
    Koolmeister, Tobias
    Mateus, André
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Cazares-Körner, Cindy
    Sanjiv, Kumar
    Homan, Evert
    Loseva, Olga
    Baranczewski, Pawel
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Darabi, Masoud
    Mehdizadeh, Amir
    Fayezi, Shabnam
    Jemth, Ann-Sofie
    Berglund, Ulrika Warpman
    Sigmundsson, Kristmundur
    Lundbäck, Thomas
    Jensen, Annika Jenmalm
    Artursson, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Scobie, Martin
    Helleday, Thomas
    Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors2017In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 10, p. 4279-4292Article in journal (Refereed)
    Abstract [en]

    The dCTP pyrophosphatase 1 (dCTPase) is a nucleotide pool "housekeeping" enzyme responsible for the catabolism of canonical and noncanonical nucleoside triphosphates (dNTPs) and has been associated with cancer progression and cancer cell sternness. We have identified a series of piperazin-1-ylpyridazines as a new class of potent dCTPase inhibitors. Lead compounds increase dCTPase thermal and protease stability, display outstanding selectivity over related enzymes and synergize with a cytidine analogue against leukemic cells. This new class of dCTPase inhibitors lays the first stone toward the development of drug-like probes for the dCTPase enzyme.

  • 187.
    Lodén, Henrik
    et al.
    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.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Amini, Ahmad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Quantitative determination of salbutamol in tablets by multiple-injection capillary zone electrophoresis2008In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1207, no 1-2, p. 181-185Article in journal (Refereed)
    Abstract [en]

    A multiple-injection capillary zone electrophoresis (MICZE) method has been developed for the assay of salbutamol in Ventoline Depot tablets (GlaxoSmithKline). In the developed method, seven sample sets, each consisting of three samples, were sequentially injected into the capillary and analyzed within a single run. This enabled a total of twenty-one sequential injections, i.e., six standards and fifteen samples, containing salbutamol and the injection marker oxprenolol. The injected sample plugs were separated by plugs of background electrolyte, through application of a short-term voltage (30 kV) over the capillary for different time periods, i.e., tPE1 and tPE2. The samples in each set were isolated from each other by partial electrophoresis for 2.35 min (tPE1), while the sample sets were separated for 10.50 min (tPE2). After the final injection, all the applied samples were subjected to electrophoresis for a time period corresponding to that in conventional single-injection CZE. The method was validated regarding linearity, accuracy, precision and robustness before it was applied to the determination of salbutamol in 15 tablets of Ventoline Depot with a labeled content of 8 mg salbutamol. The average salbutamol content was determined to 7.8 mg (±0.3 mg) from simultaneous analyses of the 15 different tablets.

  • 188. MacGregor, Kylie A
    et al.
    Abdel-Hamid, Mohammed K
    Odell, Luke R
    Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
    Chau, Ngoc
    Whiting, Ainslie
    Robinson, Phillip J
    McCluskey, Adam
    Development of quinone analogues as dynamin GTPase inhibitors2014In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 85, p. 191-206Article in journal (Refereed)
    Abstract [en]

    Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.

  • 189. Maldonado, Matias Funes
    et al.
    Sehgelmeble, Fernando
    Bjarnemark, Fanny
    Svensson, Mats
    Ahman, Jens
    Arvidsson, Per I.
    Synthesis and arylation of unprotected sulfonimidamides2012In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 68, no 36, p. 7456-7462Article in journal (Refereed)
  • 190.
    Malm, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Farnegardh, Mathias
    Grover, Gary J
    Ladenson, Paul W
    Thyroid Hormone Antagonists: Potential Medical Applications and Structure Activity Relationships2009In: Current Medicinal Chemistry, ISSN 0929-8673, E-ISSN 1875-533X, Vol. 16, no 25, p. 3258-3266Article, review/survey (Refereed)
    Abstract [en]

    Thyroid hormone receptors (TRs) exert profound effects on development, metabolism, and multiple specific organ functions. Principally by regulating crucial genes in a variety of tissues, the thyroid hormones, 3,5,3'-triiodo-L-thyronine (L-T-3, 1) and 3,5,3',5'-tetraiodo-L-thyronine (L-T-4, 2), influence basal calorigenesis and oxygen consumption, cardiac rate and contractility, lipid metabolism, bone structure and strength, and central nervous system functions critical for normal mentation and mood. Elevated levels of circulating and tissue 1 and/or 2 result in the thyrotoxic clinical state, manifested by weight loss despite increased caloric intake; heat intolerance due to increased calorigenesis; cardiac tachyarrhythmias, systolic hypertension, and heart failure; skeletal muscle weakness; and a spectrum of neuropsychiatric symptoms ranging from anxiety to delirium and psychosis. The current standard treatments of endogenous hyperthyroidism causing thyrotoxicosis reduce the overproduction of thyroid hormones by pharmacologically inhibiting their synthesis or release (e.g., with thionamides or lithium, respectively), or by ablating thyroid tissue surgically or with radioiodine. TR-antagonists could hypothetically have significant clinical use in treating thyrotoxic states if they were capable of promptly and completely restoring euthyroid levels of thyroid-specific gene activity. No TR alpha-selective ligands have been prepared up to this date, ligands that potentially would further ameliorate the problem with cardiac disease connected with hyperthyroidism and maybe cardiac arrhythmia. Despite its significant potential use, no TR-antagonist has reached clinical application. Design of TR-antagonists ligands has been based on the attachment of a large extension group at the 5-prime position of 1 or other structurally related analogues. This extension is believed to distort folding of the C-terminal helix ( helix 12) to the body of the ligand binding domain (LBD), which normally forms a coactivator site. Examples of synthetic TR antagonists based on this extension strategy are reviewed, as well as other strategies to achieve functional TR-antagonism.

  • 191.
    Mao, Guanzhong
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Chen, Tien-Hao
    Ohio State Univ, Dept Chem & Biochem, Ctr RNA Biol, Columbus, OH 43210 USA..
    Srivastava, Abhishek S.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology. AstraZeneca R&D, Discovery Sci, Cambridge Sci Pk, Cambridge CB4 0WG, England..
    Kosek, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Biswas, Pradip K.
    Ohio State Univ, Dept Chem & Biochem, Ctr RNA Biol, Columbus, OH 43210 USA..
    Gopalan, Venkat
    Ohio State Univ, Dept Chem & Biochem, Ctr RNA Biol, Columbus, OH 43210 USA..
    Kirsebom, Leif A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Cleavage of Model Substrates by Arabidopsis thaliana PRORP1 Reveals New Insights into Its Substrate Requirements2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160246Article in journal (Refereed)
    Abstract [en]

    Two broad classes of RNase P trim the 5' leader of precursor tRNAs (pre-tRNAs): ribonucleoprotein (RNP)- and proteinaceous (PRORP)-variants. These two RNase P types, which use different scaffolds for catalysis, reflect independent evolutionary paths. While the catalytic RNA-based RNP form is present in all three domains of life, the PRORP family is restricted to eukaryotes. To obtain insights on substrate recognition by PRORPs, we examined the 5' processing ability of recombinant Arabidopsis thaliana PRORP1 (AtPRORP1) using a panel of pre-tRNA(Ser) variants and model hairpin-loop derivatives (pATSer type) that consist of the acceptor-T-stem stack and the T-/D-loop. Our data indicate the importance of the identity of N-1 (the residue immediately 5' to the cleavage site) and the N-1: N+73 base pair for cleavage rate and site selection of pre-tRNA(Ser) and pATSer. The nucleobase preferences that we observed mirror the frequency of occurrence in the complete suite of organellar pre-tRNAs in eight algae/plants that we analyzed. The importance of the T-/D-loop in pre-tRNA(Ser) for tight binding to AtPRORP1 is indicated by the 200-fold weaker binding of pATSer compared to pre-tRNA(Ser), while the essentiality of the T-loop for cleavage is reflected by the near-complete loss of activity when a GAAA-tetraloop replaced the T-loop in pATSer. Substituting the 2'-OH at N-1 with 2'-H also resulted in no detectable cleavage, hinting at the possible role of this 2'-OH in coordinating Mg2+ ions critical for catalysis. Collectively, our results indicate similarities but also key differences in substrate recognition by the bacterial RNase P RNP and AtPRORP1: while both forms exploit the acceptor-T-stem stack and the elbow region in the pre-tRNA, the RNP form appears to require more recognition determinants for cleavage-site selection.

  • 192.
    Marshall, Garland R
    et al.
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States..
    Ballante, Flavio
    Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States..
    Limiting Assumptions in the Design of Peptidomimetics2017In: Drug development research (Print), ISSN 0272-4391, E-ISSN 1098-2299, Vol. 78, no 6, p. 245-267Article, review/survey (Refereed)
    Abstract [en]

    Limiting the flexibility of organic compounds to enhance their affinity and selectivity for targeting a macromolecule involved in molecular recognition has become a well-developed paradigm in medicinal chemistry. While the role of reverse-turn motifs as peptidomimetics has received the most attention, β-sheets and helices are also important motifs for protein/protein interactions. The more complicated problem of mimicking the interacting surface of noncontiguous epitopes will not be considered in this review. This limited overview focuses on efforts to use amino acid synthons as secondary-structure mimetics as well as providing examples of peptidomimetic design focused on nonpeptide synthetic chemistry in contrast. In particular, the rationale of optimal design criteria for mimicry and the many naïve violations of those criteria made in its pursuit are emphasized.

  • 193. McCarthy, Claudia A.
    et al.
    Vinh, Antony
    Miller, Alyson A.
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Callaway, Jennifer K.
    Widdop, Robert E.
    Direct Angiotensin AT2 Receptor Stimulation Using a Novel AT2 Receptor Agonist, Compound 21, Evokes Neuroprotection in Conscious Hypertensive Rats2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e95762-Article in journal (Refereed)
    Abstract [en]

    Background: In this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents. Methods and Results: Spontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury. Conclusion: These results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development.

  • 194. McEwen, I.
    et al.
    Arvidsson, T.
    Medical Products Agency, Uppsala, Sweden..
    Feasibility studies. The use of NMR spectrometry as a possible substitute of or complement to several analytical tests in pharmacopoeia monographs2012In: Pharmeuropa bio & scientific notes, ISSN 2075-2164, Vol. 2012, p. 87-102Article in journal (Refereed)
    Abstract [en]

    NMR spectrometry has many analytical applications; for instance, the identification of known substances; the structure elucidation of unknown ones; the quantifi cation of APIs, impurities, solvent and water; kinetic studies, stereochemistry determinations, and the analyses of complex mixtures as in metabonomics. NMR spectrometry has the potential to substitute or complement existing analyses that are performed on APIs. In this work, 4 different NMR analyses were done on 2 APIs: fluvastatin sodium and benzalkonium chloride with good results.

  • 195.
    Melander, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eriksson, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Jansson, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Improved method for quantitative analysis of the cyclotide kalata B1 in plasma and brain homogenate2016In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 106, no 6, p. 910-916Article in journal (Refereed)
    Abstract [en]

    This study provides a new method for quantifying the cyclotide kalata B1 in both plasma and brain homogenate. Cyclotides are ultra-stable peptides with three disulfide bonds that are interesting from a drug development perspective as they can be used as scaffolds. In this study we describe a new validated LC-MS/MS method with high sensitivity and specificity for kalata B1. The limit of quantification was 2 ng/mL in plasma and 5 ng/gmL in brain homogenate. The method was linear in the range 2-10,000 ng/mL for plasma and 5-2000 ng/g for brain. Liquid Chromatographic separation was performed on a HyPurity C18 column, 50 3 4.6 mm, 3 mm particle size. The method had inter-and intra-day precision and accuracy levels <15% and 12% respectively. Applying the method to in vivo plasma samples and brain homogenate samples from equilibrium dialysis yielded satisfying results and was able to describe the plasma pharmacokinetics and brain tissue binding of kalata B1. The described method is quick, reproducible and well suited to quantifying kalata B1 in biological matrices.

  • 196.
    Merclin, Nadia
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Electrochemical Methods for Drug Characterisation and Transdermal Delivery: Capillary Zone Electrophoresis, Conductometry, and Iontophoresis2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis concerns the development and utilisation of techniques for characterisation and transdermal delivery of various systems for pharmaceutical applications.

    The degree of dissociation of drug molecules and the mobilities of the different species formed are essential factors affecting the rate of drug delivery by iontophoresis. Hence, determination of drug mobility parameters and equilibrium constants are important for the development of iontophoretic systems. With capillary zone electrophoresis using a partial filling technique and methyl-β-cyclodextrin as chiral selector, the enantiomers of orciprenaline were separated. The association constants between the enantiomers of the drug and the selector were also evaluated. Precision conductometry studies were performed for the hydrochloride salts of lidocaine and 5-aminolevulinic acid in aqueous propylene glycol and water as media, respectively.

    Iontophoresis is a technique for drug delivery where charged molecules are transported into and through skin by application of a weak direct electrical current. The drugs 5-aminolevulinic acid and its methyl ester were used as model compounds and incorporated in two different drug delivery vehicles, a sponge phase and carbopol gel. The bicontinuous structure of the sponge phase, constituted of monoolein and a mixture of propylene glycol and water, makes it interesting for use in iontophoretic delivery, since ions can move more or less freely in the aqueous as well as in the lipid domains. Furthermore, all three components are known for their penetration enhancing abilities. Hydrogels like carbopol gels are interesting media with respect to iontophoretic studies, since devices for iontophoresis often utilize hydrogels as contact interfaces between the skin and the electrodes. The results indicate that the transport achieved iontophoretically using the gel (1 % active substance) was comparable with the passive delivery of clinically used formulations (16 % - 20 % active substance).

    List of papers
    1. Determination of association constants between enantiomers of orciprenaline and methyl-β-cyclodextrin as chiral selector by capillary zone electrophoresis using a partial filling technique
    Open this publication in new window or tab >>Determination of association constants between enantiomers of orciprenaline and methyl-β-cyclodextrin as chiral selector by capillary zone electrophoresis using a partial filling technique
    1999 In: Electrophoresis, Vol. 20, p. 180-188Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91063 (URN)
    Available from: 2003-11-14 Created: 2003-11-14Bibliographically approved
    2. On iontophoretic delivery enhancement: Electrical conductance and transport properties of lidocaine hydrochloride in aqueous propylene glycol
    Open this publication in new window or tab >>On iontophoretic delivery enhancement: Electrical conductance and transport properties of lidocaine hydrochloride in aqueous propylene glycol
    2000 In: International Journal of Pharmaceutics, Vol. 201, p. 121-124Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91064 (URN)
    Available from: 2003-11-14 Created: 2003-11-14Bibliographically approved
    3. Improvements of conductivity measurements of electrolyte solutions using a new conductometric cell design
    Open this publication in new window or tab >>Improvements of conductivity measurements of electrolyte solutions using a new conductometric cell design
    2002 In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 29, p. 61-67Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91065 (URN)
    Available from: 2003-11-14 Created: 2003-11-14Bibliographically approved
    4. Transport properties and association behaviour of the zwitterionic drug 5-aminolevulinic acid in water. A precision conductometric study.
    Open this publication in new window or tab >>Transport properties and association behaviour of the zwitterionic drug 5-aminolevulinic acid in water. A precision conductometric study.
    In: European Journal of Pharmaceutical SciencesArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91066 (URN)
    Available from: 2003-11-14 Created: 2003-11-14Bibliographically approved
    5. Iontophoretic and passive delivery of 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA) by means of a lipid sponge phase
    Open this publication in new window or tab >>Iontophoretic and passive delivery of 5-aminolevulinic acid (ALA) and its methyl ester (m-ALA) by means of a lipid sponge phase
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91067 (URN)
    Available from: 2003-11-14 Created: 2003-11-14 Last updated: 2010-01-13Bibliographically approved
    6. Iontophoretic delivery of 5-aminolevulinic acid and its methyl ester using carbopol gel as drug vehicle
    Open this publication in new window or tab >>Iontophoretic delivery of 5-aminolevulinic acid and its methyl ester using carbopol gel as drug vehicle
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91068 (URN)
    Available from: 2003-11-14 Created: 2003-11-14 Last updated: 2010-01-13Bibliographically approved
  • 197.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University.
    Prostate cancer theranostics using GRPR antagonist RM262019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The malignant transformation of cells is often associated with an alteration of their molecular phenotype, resulting in overexpression of several cell surface proteins. Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are examples of such pro-teins that are expressed at a high density in prostate cancer. GRPR is primarily expressed in earlier stages of prostate cancer and tends to decrease with disease progression. This expression pattern indicates that GRPR could be a promising target for imaging and treatment of oligometa-static prostate cancer, an early step in prostate cancer progression characterized by limited meta-static spread. In contrast, the expression of PSMA increases with cancer progression and is significantly upregulated as tumors dedifferentiate into higher grade, in androgen-insensitive and metastatic lesions.

    This thesis is based on five original articles (papers I-V) and focuses on the preclinical de-velopment of radiotracers for imaging and treatment of prostate cancer. The work can be divided into three distinct parts: (1) the development and optimization of GRPR-antagonist RM26 for high contrast PET and SPECT imaging of oligometastatic prostate cancer (papers I-III), (2) the preclinical evaluation of 177Lu-labeled RM26 as a potential candidate for peptide receptor radionuclide therapy (PRRT) in GRPR-expressing tumors, alone or in combination with anti-HER2 antibody trastuzumab (paper IV), and (3) the development of a bispecific heterodimer targeting both PSMA and GRPR in prostate cancer (paper V).

    We have demonstrated that the in vitro and in vivo properties of GRPR antagonist RM26 are strongly influenced by the choice of chelator-radionuclide complex and that long-lived radionuclides are desirable for high-contrast imaging. Furthermore, our data indicate that 55Co-NOTA-PEG2-RM26 has remarkable potential for next-day high-contrast PET imaging of GRPR-expressing tumors. Experimental PRRT using 177Lu-DOTAGA-PEG2-RM26 resulted in a pronounced inhibition of tumor growth and a significantly longer median survival. Interestingly, survival was further improved when trastuzumab was co-injected with 177Lu-DOTAGA-PEG2-RM26. These data indicate that blocking HER2 with trastuzumab decreased the repairing ability of irradiated cells. Finally, we developed a heterodimer (NOTA-DUPA-RM26) for imaging GRPR and PSMA expression in prostate cancer shortly after administration.

    In conclusion, we have successfully developed and preclinically evaluated radioconjugates for GRPR-directed theranostics in oligometastatic prostate cancer using the bombesin antagonistic analog RM26.

    List of papers
    1. The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM26
    Open this publication in new window or tab >>The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM26
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    2015 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 42, no 5, p. 446-454Article in journal (Refereed) Published
    Abstract [en]

    Introduction

    Overexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to NOTA via a PEG2 spacer (NOTA-PEG2-RM26) labeled with 68Ga, 111In and Al18F. 68Ga-labeled NOTA-PEG2-RM26 showed high tumor-to-organ ratios.

    Methods

    The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of 68Ga-labeled PEG2-RM26 was studied in vitro and in vivo.

    Results

    All conjugates were labeled with generator-produced 68Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC50 values of natGa-X-PEG2-RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 ± 0.2, 3.0 ± 0.3, 2.9 ± 0.3 and 10.0 ± 0.6 nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [68Ga]Ga-NOTA-PEG2-RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40 ± 1.04 %ID/g at 2 h p.i.) and the tumor-to-organ ratios (25 ± 3, 157 ± 23 and 39 ± 4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs.

    Conclusions

    Chelators had a clear influence on the biodistribution and targeting properties of 68Ga-labeled antagonistic BN analogs. Positively charged [68Ga]Ga-NOTA-PEG2-RM26 provided a low kidney radioactivity uptake, high affinity, high tumor uptake and high image contrast.

    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-232120 (URN)10.1016/j.nucmedbio.2014.12.009 (DOI)000353369000005 ()25684649 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2014-09-12 Created: 2014-09-12 Last updated: 2019-07-17Bibliographically approved
    2. Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26.
    Open this publication in new window or tab >>Selection of optimal chelator improves the contrast of GRPR imaging using bombesin analogue RM26.
    Show others...
    2016 (English)In: International journal of oncology, ISSN 1791-2423, Vol. 48, no 5, p. 2124-2134Article in journal (Refereed) Published
    Abstract [en]

    Bombesin (BN) analogs bind with high affinity to gastrin-releasing peptide receptors (GRPRs) that are up-regulated in prostate cancer and can be used for the visualization of prostate cancer. The aim of this study was to investigate the influence of radionuclide-chelator complexes on the biodistribution pattern of the 111In-labeled bombesin antagonist PEG2-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (PEG2-RM26) and to identify an optimal construct for SPECT imaging. A series of RM26 analogs N-terminally conjugated with NOTA, NODAGA, DOTA and DOTAGA via a PEG2 spacer were radiolabeled with 111In and evaluated both in vitro and in vivo. The conjugates were successfully labeled with 111In with 100% purity and retained binding specificity to GRPR and high stability. The cellular processing of all compounds was characterized by slow internalization. The IC50 values were in the low nanomolar range, with lower IC50 values for positively charged natIn-NOTA-PEG2-RM26 (2.6±0.1 nM) and higher values for negatively charged natIn-DOTAGA-PEG2-RM26 (4.8±0.5 nM). The kinetic binding studies showed KD values in the picomolar range that followed the same pattern as the IC50 data. The biodistribution of all compounds was studied in BALB/c nu/nu mice bearing PC-3 prostate cancer xenografts. Tumor targeting and biodistribution studies displayed rapid clearance of radioactivity from the blood and normal organs via kidney excretion. All conjugates showed similar uptake in tumors at 4 h p.i. The radioactivity accumulation in GRPR-expressing organs was significantly lower for DOTA- and DOTAGA-containing constructs compared to those containing NOTA and NODAGA. 111In-NOTA-PEG2-RM26 with a positively charged complex showed the highest initial uptake and the slowest clearance of radioactivity from the liver. At 4 h p.i., DOTA- and DOTAGA-coupled analogs showed significantly higher tumor-to-organ ratios compared to NOTA- and NODAGA-containing variants. The NODAGA conjugate demonstrated the best retention of radioactivity in tumors, and, at 24 h p.i., had the highest contrast to blood, muscle and bones.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-281358 (URN)10.3892/ijo.2016.3429 (DOI)000372568600037 ()26983776 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2016-03-23 Created: 2016-03-23 Last updated: 2019-07-17Bibliographically approved
    3. High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM26
    Open this publication in new window or tab >>High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM26
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    2017 (English)In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, article id UNSP 6873684Article in journal (Refereed) Published
    Abstract [en]

    High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a Co-55-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with Co-57 and Co-55, stability, binding specificity, and in vitro and in vivo characteristics of Co-57-NOTA-PEG(2)-RM26 were studied. NOTA-PEG(2)-RM26 was successfully radiolabeled with Co-57 and Co-55 with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. Co-57-NOTA-PEG(2)-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG(2)-RM26 translated into high contrast preclinical PET/CT (using Co-55) and SPECT/CT (using Co-57) images of PC-3 xenografts. The initial biological results suggest that Co-55-NOTA-PEG(2)-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.

    Keywords
    Positron-Emission-Tomography, Receptor-Positive Tumors, In-Vivo Evaluation, Radiolabeled Peptides, Analog; Agonists, Visualization, Proteins, Affinity, Therapy.
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-334114 (URN)10.1155/2017/6873684 (DOI)000408099300001 ()
    Funder
    Swedish Cancer Society, CAN2014/474; CAN2015/350Swedish Research Council, 2015-02509; 2015-02353Knut and Alice Wallenberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
    Available from: 2017-11-24 Created: 2017-11-24 Last updated: 2019-07-17Bibliographically approved
    4. Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177Lu-DOTAGA-PEG2-RM26
    Open this publication in new window or tab >>Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177Lu-DOTAGA-PEG2-RM26
    Show others...
    2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Article in journal (Refereed) Published
    Abstract [en]

    Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclidetherapy (TRT). We optimized the bombesin-derived GRPR-antagonist PEG2-RM26 for labeling with 177Lu and further determinedthe effect of treatment with 177Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in amurine model. The PEG2-RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-chelatorconjugates were labeled with 177Lu and characterized in vitro and in vivo. A preclinical therapeutic study was performed in PC-3xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA-PEG2-RM26, (C) 177LuDOTAGA-PEG2-RM26, (D) trastuzumab or (E) 177Lu-DOTAGA-PEG2-RM26 in combination with trastuzumab. 177Lu-DOTAGA-PEG2-RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% ofradioligand remained when coinjected with phosphoramidon), high affinity to GRPR (KD = 0.4 0.2 nM), and favorablebiodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177Lu-DOTAGAPEG2-RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorterthan for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantlyimproved survival. No treatment-related toxicity was observed. In conclusion, based on in vitro and in vivo characterization ofthe four 177Lu-labeled PEG2-RM26 analogs, we concluded that 177Lu-DOTAGA-PEG2-RM26 was the most promising analog forTRT. Radiotherapy using 177Lu-DOTAGA-PEG2-RM26 effectively inhibited tumor growth in vivo in a murine prostate cancermodel. Anti-HER2 therapy additionally improved survival.

    Keywords
    radionuclide therapy, GRPR, HER2, prostate cancer, lutetium-177
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-389561 (URN)10.1002/ijc.32401 (DOI)
    Available from: 2019-07-17 Created: 2019-07-17 Last updated: 2019-08-16Bibliographically approved
    5. Bispecific GRPR-antagonistic anti-PSMA/GRPR heterodimer for PET and SPECT diagnostic imaging of prostate cancer
    Open this publication in new window or tab >>Bispecific GRPR-antagonistic anti-PSMA/GRPR heterodimer for PET and SPECT diagnostic imaging of prostate cancer
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Prostate specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are wellvalidated molecular targets that are overexpressed in most prostate cancers (PCa). Given thecomplexity and heterogeneity of PCa, targeting both receptors using bispecific radiotracers couldimprove the diagnostic accuracy and therapeutic outcome. The aim of this study was to develop aPSMA/GRPR-targeting bispecific heterodimer for SPECT and PET diagnostic imaging of PCa.Bispecific anti-GRPR/PSMA dimer NOTA-DUPA-RM26 was produced using a combination of solidphase and manual peptide synthesis. The heterodimer was successfully labeled with111In for SPECTand 68Ga for PET with radiochemical yields exceeding 99% for 111In and 98% for 68Ga. Theradiolabeled heterodimers demonstrated high label stability and retained binding specificity to PSMAand GRPR when tested using PC3-PIP cell line expressing both PSMA and GRPR. IC50 values fornatIn-NOTA-DUPA-RM26 were 4±1 nM towards GRPR and 350±240 nM towards PSMA. Cellularprocessing assay revealed a low degree of internalization for 111In-NOTA-DUPA-RM26. In vivobinding specificity tests in PC3-PIP xenografted mice 1 h pi of 111In-NOTA-DUPA-RM26demonstrated partially blockable tumor uptake when co-injected with excess of either PSMA- orGRPR-targeting agents. A pronounced blocking effect was observed for 111In and 68Ga-labeledheterodimer when co-injected simultaneously with excess of PSMA- and GRPR-targeting agents 1 hpi. Biodistribution was studied 1, 3 and 24 h pi for 111In-NOTA-DUPA-RM26, and 1 and 3 h pi for68Ga-NOTA-DUPA-RM26 and revealed a fast clearance of radioprobes from blood and normal organsvia renal excretion. Tumor uptake exceeded the uptake in all normal organs including excretory organsfor both 111In and 68Ga-labeled heterodimers 1 h pi. 68Ga-NOTA-DUPA-RM26 had a significantlylower tumor uptake (8±2%ID/g) compared to 111In-NOTA-DUPA-RM26 (12±2%ID/g), but a two-foldhigher uptake in liver 1h pi. The faster clearance of radioactivity from normal tissues compared totumor lead to an overall increase in tumor-to-organ ratios for both 111In and 68Ga-labeled heterodimers3 h pi. At 24 h pi, tumor-to-organ ratios decreased for 111In-NOTA-DUPA-RM26. MicroPET/CT andmicroSPECT/CT scans confirmed the ex vivo data and suggested that anti-GRPR/PSMA heterodimerNOTA-DUPA-RM26 labeled with galium-68 (for PET) and indium-111 (for SPECT) is a suitablecandidate for imaging of GRPR and PSMA expression in PCa shortly after administration.

    Keywords
    PSMA, GRPR, molecular imaging, prostate cancer
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-389562 (URN)
    Available from: 2019-07-17 Created: 2019-07-17 Last updated: 2019-08-15Bibliographically approved
  • 198. Morgan, Jessica
    et al.
    Lam, Hanh
    Delgado, jocelyn
    Luu, Justin
    Mohammadi, Sina
    Isberg, Ralph
    Wang, Helen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Auerbuch, Victoria
    An experimental pipeline for initial characterization of bacterial type III secretion system inhibitor mode of action using enteropathogenic Yersinia2018In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, article id 404Article in journal (Refereed)
    Abstract [en]

    Dozens of Gram negative pathogens use one or more type III secretion systems (T3SS) to disarm host defenses or occupy a beneficial niche during infection of a host organism. While the T3SS represents an attractive drug target and dozens of compounds with T3SS inhibitory activity have been identified, few T3SS inhibitors have been validated and mode of action determined. One issue is the lack of standardized orthogonal assays following high throughput screening. Using a training set of commercially available compounds previously shown to possess T3SS inhibitory activity, we demonstrate the utility of an experiment pipeline comprised of six distinct assays to assess the stages of type III secretion impacted: T3SS gene copy number, T3SS gene expression, T3SS basal body and needle assembly, secretion of cargo through the T3SS, and translocation of T3SS effector proteins into host cells. We used enteropathogenic Yersinia as the workhorse T3SS-expressing model organisms for this experimental pipeline, as Yersinia is sensitive to all T3SS inhibitors we tested, including those active against other T3SS-expressing pathogens. We find that this experimental pipeline is capable of rapidly distinguishing between T3SS inhibitors that interrupt the process of type III secretion at different points in T3SS assembly and function. For example, our data suggests that Compound 3, a malic diamide, blocks either activity of the assembled T3SS or alters the structure of the T3SS in a way that blocks T3SS cargo secretion but not antibody recognition of the T3SS needle. In contrast, our data predicts that Compound 4, a haloid-containing sulfonamidobenzamide, disrupts T3SS needle subunit secretion or assembly. Furthermore, we suggest that misregulation of copy number control of the pYV virulence plasmid, which encodes the Yersinia T3SS, should be considered as a possible mode of action for compounds with T3SS inhibitory activity against Yersinia.

  • 199.
    Moustafa, Moustafa Sherief
    et al.
    Univ Kuwait, Dept Chem, Fac Sci, POB 5969, Safat 13060, Kuwait.
    Al-Mousawi, Saleh Mohammed
    Univ Kuwait, Dept Chem, Fac Sci, POB 5969, Safat 13060, Kuwait.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Univ Karachi, Res Inst Chem, ICCBS, Karachi 75270, Pakistan;Menoufia Univ, Chem Dept, Fac Sci, Menoufia, Egypt.
    Elnagdi, Mohamed Hilmy
    Cairo Univ, Dept Chem, Fac Sci, POB 12613, Giza, Egypt.
    Chemistry of Heterocyclic Five and Six Membered Enamino Nitriles and Enamino Esters2018In: Mini-Reviews in medical chemistry, ISSN 1389-5575, E-ISSN 1875-5607, Vol. 18, no 12, p. 992-1007Article, review/survey (Refereed)
    Abstract [en]

    Progress in the chemistry of cyclic enamino-nitriles based on the advanced synthetic methodologies is reported. Due to the recent accomplishment, it becomes possible to reactivate these molecules toward electrophiles, nucleophiles and as electron rich dienes in 2+3 dipolar additions and in 4+2 cycloadditions reactions. Synthesizing the poly functionalized 4H-pyrans and their fused derivatives is a fascinating field with a multitude of biological implications such as antitumor, cardiotonic, hepatoprotective, antihypertensive, antibronchitis, as well antifungal activity. This work was conducted with particular emphasis on reviewing the work done on the cyclic enamines since 1990 up till now in order to highlight in more details the synthetic pathways, interactions and the biological activities, Furthermore; we referred to the recent original data of our group contributions within this field.

  • 200.
    Mowbray, Sherry L
    et al.
    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.
    Kathiravan, Muthu K
    Pandey, Abhishek A
    Odell, Luke R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Inhibition of Glutamine Synthetase: A Potential Drug Target in Mycobacterium tuberculosis2014In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, no 9, p. 13161-13176Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. Globally, tuberculosis is second only to AIDS in mortality and the disease is responsible for over 1.3 million deaths each year. The impractically long treatment schedules (generally 6-9 months) and unpleasant side effects of the current drugs often lead to poor patient compliance, which in turn has resulted in the emergence of multi-, extensively- and totally-drug resistant strains. The development of new classes of anti-tuberculosis drugs and new drug targets is of global importance, since attacking the bacterium using multiple strategies provides the best means to prevent resistance. This review presents an overview of the various strategies and compounds utilized to inhibit glutamine synthetase, a promising target for the development of drugs for TB therapy.

1234567 151 - 200 of 358
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