uu.seUppsala University Publications
Change search
Refine search result
1234567 1 - 50 of 1740
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the 'Create feeds' function.
  • 1.
    AbdelRehim, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Karlen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Zhang, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Kamel, M
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hassan, M
    Enantiomer separation of underivatized tocainide and related compounds by CGC using ammonia as carrier gas1996In: JOURNAL OF MICROCOLUMN SEPARATIONS, Vol. 8, 151- p.Article in journal (Refereed)
  • 2.
    Abdel-Rehim, Mohamed
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hassan, Moustapha
    Capillary gas chromatography of trichlorophenols using ammonia as carrier gas2000In: Journal of High Resolution Chromatography, Vol. 23, 156- p.Article in journal (Refereed)
  • 3.
    Aboye, Teshome L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    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.
    Synthesis, Cyclization and Oxidative folding of backbone engineered Cyclotides2010Conference paper (Refereed)
  • 4.
    Aboye, Teshome L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gunasekera, Sunithi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bruhn, Jan G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, K. Johan
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    A Cactus-Derived Toxin-Like Cystine Knot Peptide with Selective Antimicrobial Activity2015In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 16, no 7, 1068-1077 p.Article in journal (Refereed)
    Abstract [en]

    Naturally occurring cystine knot peptides show a wide range of biological activity, and as they have inherent stability they represent potential scaffolds for peptide-based drug design and biomolecular engineering. Here we report the discovery, sequencing, chemical synthesis, three-dimensional solution structure determination and bioactivity of the first cystine knot peptide from Cactaceae (cactus) family: Ep-AMP1 from Echinopsis pachanoi. The structure of Ep-AMP1 (35 amino acids) conforms to that of the inhibitor cystine knot (or knottin) family but represents a novel diverse sequence; its activity was more than 500 times higher against bacterial than against eukaryotic cells. Rapid bactericidal action and liposome leakage implicate membrane permeabilisation as the mechanism of action. Sequence homology places Ec-AMP1 in the plant C6-type of antimicrobial peptides, but the three dimensional structure is highly similar to that of a spider neurotoxin.

  • 5.
    Aboye, Teshome Leta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Engineering of the Ultra-stable Cystine Knot Framework of Microproteins: Design, Chemical Synthesis and Structural Studies2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ultra-stable cystine knotted microproteins, in which two disulfides and their connecting backbones form a circle that is penetrated by the third disulfide bonds, have attracted high interest due to their resistance to degradation in vitro and potential for the development of peptide drugs. This thesis gives new insights into engineering of that framework of microproteins, including approaches to their chemical synthesis, backbone engineering, structural and biological evaluations.

    Synthetic and oxidative folding approaches for bracelet cyclotides, a family of cyclic cystine knotted microproteins, was developed using a model peptide, cycloviolacin O2. Following assembly of the peptide chain, protected peptide was generated by mild cleavage that was subsequently thioesterified and cyclized in solution. The cyclic peptide was oxidatively folded under optimized conditions containing co-solvent and non-ionic detergent affording native cycloviolacin O2 as a major product. To gain further insights into the heterogeneity, efficiency and kinetics of cyclotides’ oxidative folding, the intermediates that accumulate in oxidative refolding pathways of all cyclotide subfamilies: Möbius, bracelet and the hybrid cyclotides were quantitatively determined under four different folding conditions. The results were used for defining major folding pathways, which indicated that Möbius cyclotides might accumulate heterogeneous folding intermediates with one-, two- and three-disulfides, whereas bracelet tend to accumulate a homogenous intermediate with three-disulfides, depending on the buffer systems used.

    Furthermore, to probe the internal factors contributing to inefficiency of oxidative folding, as well as undesired bioactivities of bracelet cyclotides (e.g., cytotoxic activity), polymer-hybridized cyclotides were designed by replacing non-conserved residues with small isosteric polymers. The designed hybrid analogs in which hybridization involved replacement of loop 3 with isosteric polymers showed improved synthetic and oxidative folding properties. The cytoxicity of a model hybrid designed with replacement of loop 3 and 5 exhibited no cytotoxic activity at concentration of 128-fold relative to that of native peptide. Furthermore, 1D and 2D 1H NMR analysis of this hybrid showed that it had well structured fold.

    List of papers
    1. Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Open this publication in new window or tab >>Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoi
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145716 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
    2. Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    Open this publication in new window or tab >>Ultra-stable peptide scaffolds for protein engineering-synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2
    2008 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 1, 103-113 p.Article in journal (Refereed) Published
    Abstract [en]

    The cyclic cystine knot motif, as defined by the cyclotide peptide family, is an attractive scaffold for protein engineering. To date, however, the utilisation of this scaffold has been limited by the inability to synthesise members of the most diverse and biologically active subfamily, the bracelet cyclotides. This study describes the synthesis and first direct oxidative folding of a bracelet cyclotide-cycloviolacin O2-and thus provides an efficient method for exploring the most potent cyclic cystine knot peptides. The linear chain of cycloviolacin O2 was assembled by solid-phase Fmoc peptide synthesis and cyclised by thioester-mediated native chemical ligation, and the inherent difficulties of folding bracelet cyclotides were successfully overcome in a single-step reaction. The folding pathway was characterised and was found to include predominating fully oxidised intermediates that slowly converted to the native peptide structure.

    Keyword
    cyclotides, native chemical ligation, peptides, protein folding, synthesis, thioesters
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-98767 (URN)10.1002/cbic.200700357 (DOI)000252292200017 ()18058973 (PubMedID)
    Available from: 2009-03-03 Created: 2009-03-03 Last updated: 2018-01-13Bibliographically approved
    3. An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    Open this publication in new window or tab >>An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS
    2010 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, no 3, 167-176 p.Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are mini-proteins of approximately 30 amino acid residues that have a unique structure consisting of a head-to-tail cyclized backbone and a knotted arrangement of three disulfide bonds. This unique cyclotide structure provides exceptional stability to chemical, enzymatic and thermal treatments and has been implicated as an ideal drug scaffold for the development into agricultural and biotechnological agents. In the current work, we present the first method for microwave assisted Fmoc-SPPS of cyclotides. This protocol adopts a strategy that combines optimized microwave assisted chemical reactions for Fmoc-SPPS of the peptide backbone, the cleavage of the protected peptide and the introduction of a thioester at the C-terminal carboxylic acid to obtain the head-to-tail cyclized cyclotide backbone by native chemical ligation. To exemplify the utility of this protocol in the synthesis of a wide array of different cyclotide sequences we synthesized representative members from the three cyclotide subfamilies-the Mobius kalata B1, the bracelet cycloviolacin O2 and the trypsin inhibitory MCoTI-II. In addition, a "one pot" reaction promoting both cyclization and oxidative folding of crude peptide thioester was adapted for kalata B1 and MCoTI-II.

    Keyword
    Cyclotides, Microwave chemistry, Fmoc-SPPS, Circular proteins, Cystine knot, Native chemical ligation
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-134899 (URN)10.1007/s10989-010-9221-0 (DOI)000281682600007 ()
    Available from: 2010-12-02 Created: 2010-12-02 Last updated: 2018-01-12Bibliographically approved
    4. Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Open this publication in new window or tab >>Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.
    Show others...
    2011 (English)In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, 77-86 p.Article in journal (Refereed) Published
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-139359 (URN)10.1089/ars.2010.3112 (DOI)000284572100009 ()20486762 (PubMedID)
    Available from: 2010-12-23 Created: 2010-12-23 Last updated: 2018-01-12Bibliographically approved
    5. Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    Open this publication in new window or tab >>Design, synthesis, structural and biological evaluation of backbone-engineered cyclotides
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-145719 (URN)
    Available from: 2011-02-10 Created: 2011-02-10 Last updated: 2011-05-04
  • 6.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    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.
    Design, synthesis, structural and biological evaluation of backbone-engineered cyclotidesManuscript (preprint) (Other academic)
  • 7.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    University of Queensland, Institute for Molecular Bioscience.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis and Oxidative Folding of Cyclic Cystine Knot Peptides: Towards Backbone Engineering2010In: Peptides 2010: Tales of Peptides Proceedings of the Thirty-First European Peptide Symposium / [ed] Michal Lebl, Morten Meldal, Knud J. Jensen, Thomas Høeg-Jensen, European Peptide Society , 2010, 142-143 p.Conference paper (Refereed)
  • 8.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Burman, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Roig, Marta Bajona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Interlocking disulfides in circular proteins: toward efficient oxidative folding of cyclotides.2011In: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 14, no 1, 77-86 p.Article in journal (Refereed)
    Abstract [en]

    Cyclotides are ultrastable plant proteins characterized by the presence of a cyclic amide backbone and three disulfide bonds that form a cystine knot. Because of their extreme stability, there has been significant interest in developing these molecules as a drug design scaffold. For this potential to be realized, efficient methods for the synthesis and oxidative folding of cyclotides need to be developed, yet we currently have only a basic understanding of the folding mechanism and the factors influencing this process. In this study, we determine the major factors influencing oxidative folding of the different subfamilies of cyclotides. The folding of all the cyclotides examined was heavily influenced by the concentration of redox reagents, with the folding rate and final yield of the native isomer greatly enhanced by high concentrations of oxidized glutathione. Addition of hydrophobic solvents to the buffer also enhanced the folding rates and appeared to alter the folding pathway. Significant deamidation and isoaspartate formation were seen when oxidation conditions were conducive to slow folding. The identification of factors that influence the folding and degradation pathways of cyclotides will facilitate the development of folding screens and optimized conditions for producing cyclotides and grafted analogs as stable peptide-based therapeutics.

  • 9.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Clark, Richard. J.
    University of Queensland, Institute for Molecular Bioscience.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Goransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O2.2008In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 74, no 9, 1158-1158 p.Article in journal (Refereed)
  • 10.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Clark, Richard J.
    University of Queensland, Institute for Molecular Bioscience.
    Craik, David J.
    University of Queensland, Institute for Molecular Bioscience.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Synthesis and folding of the circular cystine knotted cyclotide cycloviolacin O22008In: Peptides 2008: Chemistry of Peptides in Life Science Technology and MedicineProceedings of The Thirtieth European Peptide Symposium / [ed] Hilkka Lankinen, The Finnish Peptide Society and The European Peptide Society , 2008, 280-281 p.Conference paper (Refereed)
  • 11.
    Aboye, Teshome Leta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Rosengren, Johan
    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.
    Bruhn, G. Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Discovery, synthesis, and structural determination of a toxine-like disulfide-rich peptide from the cactus Trichoserus pachanoiManuscript (preprint) (Other academic)
  • 12.
    Acuna, UM
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Atha, DE
    Ma, J
    Nee, MH
    Kennelly, EJ
    Antioxidant capacities of ten edible North American plants.2002In: Phytother Res, Vol. 16, 63- p.Article in journal (Refereed)
  • 13.
    Adeyemi, Ahmed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Bergman, Joakim
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Branalt, Jonas
    AstraZeneca, Dept Med Chem Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor2017In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, 947-955 p.Article in journal (Refereed)
    Abstract [en]

    A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.

  • 14.
    Aftab, Obaid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Engskog, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Elmsjö, Albert
    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.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    NMR spectroscopy based metabolic profiling of drug induced changes in vitro can discriminate between pharmacological classes2014In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 54, no 11, 3251-3258 p.Article in journal (Refereed)
    Abstract [en]

    Drug induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances as well as to support drug repurposing, i.e. identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the “Connectivity Map” (CMap). The potential of similar exercises at the metabolite level is, however, still largely unexplored. Only recently the first high throughput metabolomic assay pilot study was published, involving screening of metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here we report results from a separately developed metabolic profiling assay, which leverages 1H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of most tested drugs according to their respective pharmacological class. A more advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (three metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this kind of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement.

  • 15.
    Afzelius, L
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Masimirembwa, CM
    Karlen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Andersson, TB
    Zamora, I
    Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors2002In: JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, Vol. 16, 443- p.Article in journal (Refereed)
  • 16. Afzelius, L
    et al.
    Zamora, I
    Ridderstrom, M
    Andersson, TB
    Karlen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Masimirembwa, CM
    Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homologymodeling, and three-dimensional quantitative structure-activityrelationship analysis.2001In: Mol Pharmacol, Vol. 59, 909- p.Article in journal (Refereed)
  • 17.
    Afzelius, Lovisa
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Computational Modelling of Structures and Ligands of CYP2C92004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    CYP2C9 is one of our major drug metabolising enzymes and belongs to the cytochrome P450 (CYP) super family. The aim of this thesis was to gain an understanding of the quantitative structure–activity relationships (QSAR) of CYP2C9 substrates and inhibitors. This information will be useful in predicting drug metabolism and the potential for drug–drug interactions. To achieve this, a well characterised data set of structurally diverse, competitive CYP2C9 inhibitors was identified in our laboratory. Several computational methodologies, many based on GRID molecular interaction fields, were applied or developed in order to handle issues such as compound alignment and bioactive conformer selection. First, a traditional 3D QSAR was carried out in GOLPE, generating a predictive model. In this model the selection of a bioactive conformer and alignment was based on docking in a homology model of CYP2C9. Secondly, we introduced the concept of alignment independent descriptors from ALMOND. These descriptors were used to generate quantitatively and qualitatively predictive models. We subsequently derived conformation independent descriptors from molecular interaction fields calculated in FlexGRID. This enabled the derivation of 3D QSAR models without taking into account the selection of an alignment or a bioactive conformer. A subsequent programming effort enabled the conversion of this model back to 3D aligned pharmacophores. Similar alignment independent descriptors were also used in the development of the software MetaSite® that predicts the site of metabolism for CYP2C9 ligands. Finally, as crystal information on this isoform emerged, the performance of molecular dynamics simulations and homology models and the flexibility of the protein were evaluated using statistical analyses.

    These modelling efforts have resulted in detailed knowledge of the structural characteristics in ligand interactions with the cytochrome P450 2C9 isoform.

    List of papers
    1. Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
    Open this publication in new window or tab >>Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis
    Show others...
    2001 In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, 909 - 919 p.Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91425 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    2. Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
    Open this publication in new window or tab >>Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
    Show others...
    2002 In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, 443 - 458 p.Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91426 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    3. Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    Open this publication in new window or tab >>Predicting Drug Metabolism: A Site of Metabolism Tool Applied to the Cytochrome P450 CYP2C9.
    2003 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 12, 2313-2324 p.Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91427 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    4. A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
    Open this publication in new window or tab >>A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.
    Show others...
    2004 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91428 (URN)
    Available from: 2004-02-27 Created: 2004-02-27Bibliographically approved
    5. Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
    Open this publication in new window or tab >>Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91429 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
    6. Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
    Open this publication in new window or tab >>Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91430 (URN)
    Available from: 2004-02-27 Created: 2004-02-27 Last updated: 2010-01-13Bibliographically approved
  • 18.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Fontaine, Fabien
    Karlén, Anders
    Andersson, Tommy B.
    Masimirembwa, Collen
    Pastor, Manuel
    Zamora, Ismael
    Virtual receptor site (VRS) derivation for competitive CYP2C9 inhibitors: - a novel approach for structurally diverse compounds.Manuscript (Other academic)
  • 19.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Masimirembwa, Collen
    Karlén, Anders
    Andersson, Tommy B.
    Zamora, Ismael
    Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.2002In: Journal of Computer-Aided Molecular Design, ISSN 0920-654, Vol. 16, 443 - 458 p.Article in journal (Refereed)
  • 20.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. OrgFarmKemi.
    Raubacher, Florian
    Karlen, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Department of Pharmacy. OrgFarmKemi.
    Jørgensen, Flemming Steen
    Andersson, Tommy B
    Masimirembwa, Collen M
    Zamora, Ismael
    Structural analysis of CYP2C9 and CYP2C5 and an evaluation of commonly used molecular modeling techniques.2004In: Drug Metab Dispos, ISSN 0090-9556, Vol. 32, no 11, 1218-29 p.Article in journal (Refereed)
  • 21.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Raubacher, Florian
    Karlén, Anders
    Jørgensen, Flemming S.
    Andersson, Tommy B.
    Masimirembwa, Collen
    Zamora, Ismael
    Structural analysis of CYP2C9 and CYP2C5 and critical assessment of molecular modelling techniques.Manuscript (Other academic)
  • 22.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Zamora, Ismael
    Masimirembwa, Collen
    Karlén, Anders
    Andersson, Tommy B.
    Mecucci, Silvio
    Baroni, Massimo
    Cruciani, Gabriele
    A Conformer and Alignment independent model to predict structurally diverse competitive CYP2C9 inhibitors.2004In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. Web Release Date: 13-JanArticle in journal (Refereed)
  • 23.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. OrgFarmKemi.
    Zamora, Ismael
    Masimirembwa, Collen M
    Karlen, Anders
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Andersson, Tommy B
    Mecucci, Silvio
    Baroni, Massimo
    Cruciani, Gabriele
    Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors.2004In: J Med Chem, ISSN 0022-2623, Vol. 47, no 4, 907-14 p.Article in journal (Refereed)
  • 24.
    Afzelius, Lovisa
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Zamora, Ismael
    Ridderström, Marianne
    Andersson, Tommy B.
    Karlén, Anders
    Masimirembwa, Collen
    Competitive CYP2C9 Inhibitors: Enzyme inhibition Studies, Protein Homology Modelling, and Three-Dimensional Quantitative Structure Activity Relationship Analysis2001In: Molecular Pharmacology, ISSN 0026-895, Vol. 59, 909 - 919 p.Article in journal (Refereed)
  • 25.
    Agalo, Faith
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Synthesis of Insulin-Regulated Aminopeptidase (IRAP) inhibitors2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The need for alternative cognitive enhancers has risen due to the fact that clinical trial results of the drugs currently approved for treating these disorders have not been satisfactory.

    IRAP has become a possible drug target for treating cognitive impairment brought about by Alzheimer’s disease, head trauma or cerebral ischemia, among others. This came after the revelation that Angiotensin IV enhances memory and learning. Angiotensin IV, the endogenous ligand of IRAP has been structurally modified with the aim of producing potent IRAP inhibitors. However, the peptidic nature of these inhibitors restricts their use; they are not likely to cross the blood brain barrier.

    Other strategies for generating IRAP inhibitors have been through structure-based design and receptor based virtual screening. These drug-like molecules have exhibited positive results in animal studies.

    IRAP inhibitors have been identified via a HTS of 10500 low-molecular weight compounds to give the hit based on a spirooxindole dihydroquinazolinone scaffold, with an IC50 value of 1.5 µM. In this project, some analogues to this hit compound have successfully been synthesized using a known method, whereas others have been synthesized after additional method development.

    The application of the developed method was found to be limited, because poor yield was obtained when a compound with an electron withdrawing substituent on the aniline was synthesized. As a result of this, modification of this method may be required or new methods may have to be developed to synthesize these types of analogues.

    Inhibition capability of 5 new spirooxindole dihydroquinazolinones was tested through a biochemical assay. Compound 6e emerged as the most potent inhibitor in the series, with an IC50 value of 0.2 µM. This compound will now serve as a lead compound and should be used as a starting point for future optimization in order to generate more potent IRAP inhibitors.

     

  • 26.
    Ahlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Remediation of diclofenac in a non-sterile bioreactor using the white rot fungus Trametes versicolor2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    From an environmental perspective, it is interesting to assess new methods for efficient removal of drugs from wastewater. The purpose of this project was to assess the possibility of using the white rot fungus Trametes versicolor  to degrade diclofenac in a lab scale bioreactor. Two methods for quantitative analysis of diclofenac were developed, using GC-MS and UHPLC-Q-TOF (C18-column). Both methods were partly validated, with regard to sensitivity, linearity, accuracy and precision, which highlighted the superiority of UHPLC-Q-TOF over GC-MS. Two HILIC columns were also assessed, but proved unsuitable for quantitative analysis of diclofenac under the used conditions. The fungal mycelia were immobilized on plastic carriers in a nutrient solution. In initial E-flask experiments, 10 mg/L diclofenac was added to an active culture and a heat-killed control of T. versicolor . Samples were analyzed, and the results from the active culture indicated a 98% removal of diclofenac after 48 hours. The lab scale bioreactor was used in a semi-continuous mode with the influent containing 10 mg/L diclofenac. Samples were collected from the effluent to monitor the concentration over 7 days. The results showed a decline in concentration to a stable level of approximately 2 mg/L. The initial experiments showed that most of the removal (85%) was due to sorption of diclofenac, but a clear difference was seen between the active and heat-killed culture. It was impossible to conclude from the bioreactor experiment if the observed removal was due to sorption or to a combination of sorption and enzymatic remediation.

  • 27. Ahlström, Katarina
    et al.
    Biber, Björn
    Åberg, Anna-Maja
    Abrahamsson, Pernilla
    Johansson, Göran
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Waldenström, Anders
    Haney, Michael F.
    Exogenous carbon monoxide does not affect cell membrane energy availability assessed by sarcolemmal calcium fluxes during myocardial ischaemia-reperfusion in the pig2011In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 28, no 5, 356-362 p.Article in journal (Refereed)
    Abstract [en]

    Carbon monoxide is thought to be cytoprotective and may hold therapeutic promise for mitigating ischaemic injury. The purpose of this study was to test low-dose carbon monoxide for protective effects in a porcine model of acute myocardial ischaemia and reperfusion. In acute open-thorax experiments in anaesthetised pigs, pretreatment with low-dose carbon monoxide (5% increase in carboxyhaemoglobin) was conducted for 120 min before localised ischaemia (45 min) and reperfusion (60 min) was performed using a coronary snare. Metabolic and injury markers were collected by microdialysis sampling in the ventricular wall. Recovery of radio-marked calcium delivered locally by microperfusate was measured to assess carbon monoxide treatment effects during ischaemia/reperfusion on the intracellular calcium pool. Coronary occlusion and ischaemia/reperfusion were analysed for 16 animals (eight in each group). Changes in glucose, lactate and pyruvate from the ischaemic area were observed during ischaemia and reperfusion interventions, though there was no difference between carbon monoxide-treated and control groups during ischaemia or reperfusion. Similar results were observed for glycerol and microdialysate Ca-45(2+) recovery. These findings show that a relatively low and clinically relevant dose of carbon monoxide did not seem to provide acute protection as indicated by metabolic, energy-related and injury markers in a porcine myocardial ischaemia/reperfusion experimental model. We conclude that protective effects of carbon monoxide related to ischaemia/reperfusion either require higher doses of carbon monoxide or occur later after reperfusion than the immediate time frame studied here. More study is needed to characterise the mechanism and time frame of carbon monoxide-related cytoprotection.

  • 28.
    Ahlsén, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Hultén, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Shuman, Cynthia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Poliakov, Anton
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Lindgren, Maria T.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Resistance profiles of cyclic and linear inhibitors of HIV-1 protease2002In: Antiviral Chemistry & Chemotherapy, ISSN 0956-3202, E-ISSN 2040-2066, Vol. 13, no 1, 27-37 p.Article in journal (Refereed)
    Abstract [en]

    Resistance to anti-HIV protease drugs is a major problem in the design of AIDS drugs with long-term efficacy. To identify structural features associated with a certain resistance profile, the inhibitory properties of a series of symmetric and asymmetric cyclic sulfamide, cyclic urea and linear transition-state analogue inhibitors of HIV-1 protease were investigated using wild-type and mutant enzyme. To allow a detailed structure-inhibition analysis, enzyme with single, double, triple and quadruple combinations of G48V, V82A, 184V and L90M substitutions was used. Kinetic analysis of the mutants revealed that catalytic efficiency was 1-30% of that for the wild-type enzyme, a consequence of reduced kcat in all cases and an increased KM for all mutants except for the G48V enzyme. The overall structure-inhibitory profiles of the cyclic compounds were similar, and the inhibition of the V82A, 184V and G48V/L90M mutants were less efficient than of the wild-type enzyme. The greatest increase in Ki was generally observed for the 184V mutant and least for the G48V/L90M mutant, and additional combinations of mutations did not result in improved inhibition profiles for the cyclic compounds. An extended analysis of additional mutants, and including a set of linear compounds, showed that the profile was unique for each compound, and did not reveal any general structural features associated with a certain inhibition profile. The effects of structural modifications in the inhibitors, or of mutations, were not additive and they differed depending on their context. The results demonstrate the difficulties in predicting resistance, even for closely related compounds, and designing compounds with improved resistance profiles.

  • 29. Ahmed, A. Ahmed
    et al.
    El-Seedi, Hesham R.
    Mahmoud, Ahmed A.
    El-Douski, Abd El-Aziz A.
    Zeid, Ibrahim F.
    Bohlin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Eudesmane derivatives from Laggera crispata and Pluchea carolonesis1998In: Phytochemistry, ISSN 0031-9422, E-ISSN 1873-3700, Vol. 49, no 8, 2421-2424 p.Article in journal (Refereed)
    Abstract [en]

    Investigation of the aerial parts of Laggera crispata and Pluchea carolonesis afforded in addition to several known compounds, three new eudesmane derivatives, 3β,4α-dihydroxy-7-epi-eudesm-11(13)-ene, 3α-(2′,3′-dihydroxy-2′-methylbutanoyl)-4,11-dihydroxy-6,7-dehydroeudesman-8-one and 3α-(3′-chloro-2′-hydroxy-2′-methylbutanoyl)cuauhtemone. The structures were elucidated by spectroscopic methods

  • 30.
    Ahnfelt, Nils-Otto
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of History of Science and Ideas, History of Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fors, Hjalmar
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of History of Science and Ideas, History of Science. Hagströmer Library, Karolinska Institutet, Stockholm.
    Making Early Modern Medicine: Reproducing Swedish Bitters2016In: Ambix, ISSN 0002-6980, E-ISSN 1745-8234, Vol. 63, no 2, 162-183 p.Article in journal (Refereed)
    Abstract [en]

    Historians of science and medicine have rarely applied themselves to reproducing the experiments and practices of medicine and pharmacy. This paper delineates our efforts to reproduce "Swedish Bitters," an early modern composite medicine in wide European use from the 1730s to the present. In its original formulation, it was made from seven medicinal simples: aloe, rhubarb, saffron, myrrh, gentian, zedoary and agarikon. These were mixed in alcohol together with some theriac, a composite medicine of classical origin. The paper delineates the compositional history of Swedish Bitters and the medical rationale underlying its composition. It also describes how we go about to reproduce the medicine in a laboratory using early modern pharmaceutical methods, and analyse it using contemporary methods of pharmaceutical chemistry. Our aim is twofold: first, to show how reproducing medicines may provide a path towards a deeper understanding of the role of sensual and practical knowledge in the wider context of early modern medical culture; and second, how it may yield interesting results from the point of view of contemporary pharmaceutical science.

  • 31.
    Akerblom, EB
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Six new photolabile linkers for solid phase synthesis. 2. Coupling ofvarious building blocks and photolytic cleavage.1998In: Mol Divers, Vol. 4, 53- p.Article in journal (Refereed)
  • 32. Alder, JT
    et al.
    Johansson, AM
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Strange, PG
    The relative binding affinities of a series of 2-(dipropylamino)tetralins at the human 5-HT1A receptor expressed in CHO cells2000In: Br. J. Pharmacol., Vol. 129, 242- p.Article in journal (Refereed)
  • 33. Alhalaweh, Amjad
    et al.
    Sokolowski, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Rodriguez-Hornedo, Nair
    Velaga, Sitaram P.
    Solubility Behavior and Solution Chemistry of Indomethacin Cocrystals in Organic Solvents2011In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 11, no 9, 3923-3929 p.Article in journal (Refereed)
    Abstract [en]

    The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacin-saccharin (IND-SAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of IND-SAC cocrystals was compared with that of indomethacin-nicotinamide (IND-NIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of IND-SAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of IND-SAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The IND-NIC cocrystals were more soluble than the IND-SAC cocrystals in all the solvents studied. The eutectic constants predicted both the solubility and the stability of the cocrystals. Understanding the solubility behavior and solution chemistry of cocrystals has important implications for the screening, scale-up, and formulation development of this solid form. Further, the determination of eutectic constants is a simple and resource sparing means of obtaining key information on cocrystal stability and solution behavior.

  • 34. Al-Henhena, Nawal
    et al.
    Khalifa, Shaden A. M.
    Ying, Rozaida Poh Yuen
    Hassandarvish, Pouya
    Rouhollahi, Elham
    Al-Wajeeh, Nahla Saeed
    Ali, Habibah Mohd
    Abdulla, Mahmood Ameen
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Chemopreventive effects of Strobilanthes crispus leaf extract on azoxymethane-induced aberrant crypt foci in rat colon2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, 13312Article in journal (Refereed)
    Abstract [en]

    In this work, microscopic and histological studies suggest that Strobilanthes crispus ethanol extract reduce azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. S. crispus is considered a traditional medicine and used as an antioxidant. Its leaf contains a large amount of phenolic compounds to which its radical scavenging role is attributed and enhance its ability to eradicate oxidative stress reactions. The study was designed to determine the chemopreventive effect of S. crispus ethanol extract in vivo and in vitro by elucidating the effect of the extract on intermediate biomarkers which can be used as effective predictors of colon cancer. S. crispus was analyzed for DPPH free radical scavenging, nitric oxide (NO) and ferric acid reduction. The results indicated that S. crispus oral administration significantly inhibited colorectal carcinogenesis induced by AOM as revealed by the reduction in the number of ACF. S. crispus down-regulated the expression of PCNA, Bcl2 and beta-catenin. Additionally, it exerted a pronounced inhibitory effect on MDA and NO levels and stimulatory effect on CAT and GPx activities. These results demonstrate that S. crispus is a chemopreventive agent for colorectal cancer through the suppression of early and intermediate carcinogenic phases that may be related to its flavonoid content.

  • 35.
    Al-Henhena, Nawal
    et al.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia.;Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Khalifa, Shaden A. M.
    Karolinska Univ Hosp, Dept Expt Hematol, SE-14186 Stockholm, Sweden..
    Ying, Rozaida Poh Yuen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Ismail, Salmah
    Univ Malaya, Fac Sci, Inst Biol Sci, Kuala Lumpur 50603, Malaysia..
    Hamadi, Riad
    Sanaa Univ, Fac Med, Dept Biochem, Sanaa, Yemen..
    Shawter, Abdrabu N.
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Idris, Azila Mohd
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Azizan, Ainnul
    Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Al-Wajeeh, Nahla Saeed
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    Abdulla, Mahmood Ameen
    Univ Malaya, Fac Med, Dept Biomed Sci, Kuala Lumpur 50603, Malaysia..
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Malaya, Fac Sci, Dept Chem, Kuala Lumpur 50603, Malaysia..
    Evaluation of chemopreventive potential of Strobilanthes crispus against colon cancer formation in vitro and in vivo2015In: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 15, 419Article in journal (Refereed)
    Abstract [en]

    Background: With cancer being one of the major causes of death around the world, studies are ongoing to find new chemotherapeutic leads. There are common mechanisms for colorectal cancer (CRC) formation. Several are connected with oxidative stress-induced cell apoptosis and others are related to imbalanced homeostasis or intake of drugs/toxins. Plants that have been used for decades in folk and traditional medicine have been accepted as one of the commonest sources of discovered natural agents of cancer chemotherapy and chemoprevention. The aim was to study the antioxidant and chemopreventive effects of Strobilanthes crispus on colorectal cancer formation. Methods: Five groups of rats were injected subcutaneously with AOM, 15 mg/kg body weight, each once weekly for 2 weeks. The cancer group was continued on 10 % Tween-20 feeding for 8 weeks. The standard drug group was continued on 35 mg/kg 5-fluorouracil intraperitoneal injection twice a week for 8 weeks, and the experimental groups were continued on 250 and 500 mg/kg S. crispus extract oral feeding for 8 weeks, respectively. The normal group was injected subcutaneously with normal saline once a week for 2 weeks, followed by oral administration of 10 % Tween-20 for 8 weeks. All the rats were sacrificed after 10 weeks. The colons were evaluated grossly and histopathologically for aberrant crypt foci (ACF). Gene expression was performed for Bax, Bcl2, Defa24, Slc24a3, and APC genes by real-time PCR. S. crispus and its fractions were evaluated for their chemopreventive effects against human colorectal adenocarcinoma cell line HT29 and cytotoxicity for normal human colon epithelial cell line CCD 841, and the active fraction was assessed for its components. Results: We observed significant decrease in total colonic ACF formation, malonaldehyde (MDA) and lactate dehydrogenase (LDH), increase in superoxide dismutase (SOD), up-regulation of APC, Bax and Slc24a3, and down-regulation of Defa24 and Bcl-2 in rats treated with Strobilanthes crispus. Conclusion: Our results support the in vivo protection of S. crispus against CRC formation (azoxymethane-induced aberrant crypt foci) and suggest that the mechanism is highly specific to protect from oxidative insults and the following apoptotic cascade.

  • 36. Al-Henhena, Nawal
    et al.
    Ying, Rozaida Poh Yuen
    Ismail, Salmah
    Najm, Wala
    Khalifa, Shaden A. M.
    El-Seedi, Hesham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Abdulla, Mahmood Ameen
    Chemopreventive Efficacy of Andrographis paniculata on Azoxymethane-Induced Aberrant Colon Crypt Foci In Vivo2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, e111118Article in journal (Refereed)
    Abstract [en]

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and beta-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells.

  • 37. Almeida, M
    et al.
    Boman, A
    Lundstedt, T
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Synthesis of N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidinium acetate [alpha-C-14]2002In: JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol. 45, 371- p.Article in journal (Refereed)
  • 38.
    Alogheli, Hiba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Olanders, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Schaal, Wesley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Anders, Karlén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide2017In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, no 2, 190-202 p.Article in journal (Refereed)
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

  • 39.
    Alsmark, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Foster, Peter G.
    Sicheritz-Ponten, Thomas
    Nakjang, Sirintra
    Embley, T. Martin
    Hirt, Robert P.
    Patterns of prokaryotic lateral gene transfers affecting parasitic microbial eukaryotes2013In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 2, R19- p.Article in journal (Refereed)
    Abstract [en]

    Background: The influence of lateral gene transfer on gene origins and biology in eukaryotes is poorly understood compared with those of prokaryotes. A number of independent investigations focusing on specific genes, individual genomes, or specific functional categories from various eukaryotes have indicated that lateral gene transfer does indeed affect eukaryotic genomes. However, the lack of common methodology and criteria in these studies makes it difficult to assess the general importance and influence of lateral gene transfer on eukaryotic genome evolution. Results: We used a phylogenomic approach to systematically investigate lateral gene transfer affecting the proteomes of thirteen, mainly parasitic, microbial eukaryotes, representing four of the six eukaryotic super-groups. All of the genomes investigated have been significantly affected by prokaryote-to-eukaryote lateral gene transfers, dramatically affecting the enzymes of core pathways, particularly amino acid and sugar metabolism, but also providing new genes of potential adaptive significance in the life of parasites. A broad range of prokaryotic donors is involved in such transfers, but there is clear and significant enrichment for bacterial groups that share the same habitats, including the human microbiota, as the parasites investigated. Conclusions: Our data show that ecology and lifestyle strongly influence gene origins and opportunities for gene transfer and reveal that, although the outlines of the core eukaryotic metabolism are conserved among lineages, the genes making up those pathways can have very different origins in different eukaryotes. Thus, from the perspective of the effects of lateral gene transfer on individual gene ancestries in different lineages, eukaryotic metabolism appears to be chimeric.

  • 40.
    Alsmark, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strese, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Wedén, Christina
    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.
    Microbial diversity of Alcyonium digitatum2013In: Phytochemistry Reviews, ISSN 1568-7767, E-ISSN 1572-980X, Vol. 12, no 3, 531-542 p.Article, review/survey (Refereed)
    Abstract [en]

    Marine multi-cellular organisms are described as sources of many newly discovered bioactive compounds. Meanwhile, it has been demonstrated repeatedly for several natural products of reputed multicellular origin that they are, in fact, produced by endophytic unicellular organisms-such as microbial fungi or bacteria. Consequently, while studying compounds isolated from a living organism, it is essential to ensure that the sample integrity is not compromised. To test the diversity of the endobiome from Alcyonium digitatum, a cold water coral found along the Atlantic coasts of the northern hemisphere, we performed a culture dependent surveyed using a phylogenetic approach. A 1 cm(3) cube from the interior tissue of A. digitatum was excised under aseptic conditions, homogenized, spread onto agar-based growth medium plates and incubated in 22 A degrees C to promote microbial growth. Colonies were transferred to secondary medium plates, incubated, and after harvesting lysed using sterile water to release DNA. 16S and 23S rDNA regions were amplified using PCR, and sequenced for systematic evaluation using phylogenetic analysis. From this survey we identified a broad selection of bacteria, predominantly of the alpha-proteobacterial, bacteriodete, actinobacterial and firmicute lineages, demonstrating a significant biodiversity of the coral bacterial endobiome.

  • 41.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Wållberg, Helena
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Dunås, Finn
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Löfblom, John
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Ståhl, Stefan
    Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no Suppl. 2, S219-S220 p.Article in journal (Other academic)
    Abstract [en]

    Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1±0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172±32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

  • 42.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Wållberg, Helena
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Dunås, Finn
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Medical Radiation Sciences.
    Löfblom, John
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Ståhl, Stefan
    Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with 188Re2014In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 87, 519-528 p.Article in journal (Refereed)
    Abstract [en]

    Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1 ± 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172 ± 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

  • 43.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, H.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, T.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Improving of molecular design of a novel Affibody-fused HER2-recognising anticancer toxin using radionuclide-based techniques2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, S178-S178 p.Article in journal (Refereed)
  • 44.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 3, 1185-1194 p.Article in journal (Refereed)
    Abstract [en]

    Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide 111In. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)3 purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, 111In-(HE)3-ZHER2-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

  • 45.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Radiolabeled Probes Targeting Tyrosine-Kinase Receptors For Personalized Medicine2014In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 14, 2275-2292 p.Article in journal (Refereed)
    Abstract [en]

    Receptor tyrosine kinases (RTK) are transmembrane receptors regulating cellular proliferation, differentiation, apoptosis, motility and recruitment of the vasculature. Aberrant expression and/or function of RTK have been detected in many malignant tumors and are considered to be a part of the transformed phenotype. The action of several classes of anti-cancer drugs is based on specific recognition of RTK. Monoclonal antibodies target extracellular binding domains, while tyrosine kinase inhibitors (TKI) bind to intracellular kinase domains to suppress RTK signaling. The issues regarding the efficient use of RTK targeting are the inter- and intra-patient heterogeneity of RTK expression and the changes of expression levels during the course of disease and in response to therapy. Radionuclide molecular imaging of RTK expression may aid in selecting patients who would benefit from RTK-targeting therapy and in identifying non-responders. Therefore, the therapy would be more personalized. Currently, radiolabeled proteins (monoclonal antibodies and their fragments, natural peptides ligands to RTK and de novo selected affinity proteins) and TKI and their analogues are under development for the visualization of RTK. In this review, we discuss the advantages and disadvantages of these approaches.

  • 46.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Perols, Anna
    Eriksson Karlström, Amelie
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Boschetti, Frederic
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with 111In using a maleimido derivative of NODAGA2012In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 4, 518-529 p.Article in journal (Refereed)
    Abstract [en]

    Introduction

    Affibody molecules have demonstrated potential for radionuclide molecular imaging. The aim of this study was to synthesize and evaluate a maleimido derivative of the 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) for site-specific labeling of anti-HER2 Affibody molecule.

    Methods

    The maleimidoethylmonoamide NODAGA (MMA-NODAGA) was synthesized and conjugated to ZHER2:2395 Affibody molecule having a C-terminal cysteine. Labeling efficiency, binding specificity to and cell internalization by HER2-expressing cells of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 were studied. Biodistribution of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 and [111In-MMA-DOTA-Cys61]-ZHER2:2395 was compared in mice.

    Results

    The affinity of [MMA-NODAGA-Cys61]-ZHER2:2395 binding to HER2 was 67 pM. The 111In-labeling yield was 99.6%±0.5% after 30 min at 60°C. [111In-MMA-NODAGA-Cys61]-ZHER2:2395 bound specifically to HER2-expressing cells in vitro and in vivo. Tumor uptake of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 in mice bearing DU-145 xenografts (4.7%±0.8% ID/g) was lower than uptake of [111In-MMA-DOTA-Cys61]-ZHER2:2395 (7.5%±1.6% ID/g). However, tumor-to-organ ratios were higher for [111In-MMA-NODAGA-Cys61]-ZHER2:2395 due to higher clearance rate from normal tissues.

    Conclusions

    MMA-NODAGA is a promising chelator for site-specific labeling of targeting proteins containing unpaired cysteine. Appreciable influence of chelators on targeting properties of Affibody molecules was demonstrated.

  • 47.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Perols, Anna
    Tsourma, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Robillard, Marc
    Rossin, Raffaella
    Ten Hoeve, Wolter
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Feasibility of affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting2016In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 3, 431-436 p.Article in journal (Refereed)
    Abstract [en]

    Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal re-absorption of affibody molecules prevents the use of residualizing radiometals, including a number of promising low energy beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys.

    Methods:

    TCO was conjugated to the anti-HER2 affibody molecule Z2395. DOTA-tetrazine was labeled with indium-111 and lutetium-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts.

    Results:

    125I-Z2395-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45±16 pM. 111In-tetrazine bound specifically and selectively to Z2395-TCO pre-treated cells. In vivo studies demonstrated HER2-specific 125I-Z2395-TCO accumulation in xenografts. TCO-mediated 111In-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z2395-TCO. At 1 h post injection, the tumor uptake of 111In-tetrazine and 177Lu-tetrazine was ca. 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of 111In in comparison with direct targeting.

    Conclusion:

    The feasibility of affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pretargeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.

  • 48.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Rosik, D.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Karlstrom, A. Eriksson
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Comparative evaluation of anti-HER2 affibody molecules labeled with 68Ga and 111In using maleimido derivatives of DOTA and NODAGA2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no S2, S299-S299 p.Article in journal (Other academic)
  • 49.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Rosik, Daniel
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Eriksson Karlström, Amelie
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Influence of Nuclides and Chelators on Imaging Using Affibody Molecules: Comparative Evaluation of Recombinant Affibody Molecules Site-Specifically Labeled with 68Ga and 111In via Maleimido Derivatives of DOTA and NODAGA2013In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 24, no 6, 1102-1109 p.Article in journal (Refereed)
    Abstract [en]

    Accurate detection of cancer-associated molecular abnormalities in tumors could make cancer treatment more personalized. Affibody molecules enable high contrast imaging of tumor-associated protein expression shortly after injection. The use of the generator-produced positron-emitting radionuclide 68Ga should increase sensitivity of HER2 imaging. The chemical nature of radionuclides and chelators influences the biodistribution of Affibody molecules, providing an opportunity to further increase the imaging contrast. The aim of the study was to compare maleimido derivatives of DOTA and NODAGA for site-specific labeling of a recombinant ZHER2:2395 HER2-binding Affibody molecule with 68Ga. DOTA and NODAGA were site-specifically conjugated to the ZHER2:2395 Affibody molecule having a C-terminal cysteine and labeled with 68Ga and 111In. All labeled conjugates retained specificity to HER2 in vitro. Most of the cell-associated activity was membrane-bound with a minor difference in internalization rate. All variants demonstrated specific targeting of xenografts and a high tumor uptake. The xenografts were clearly visualized using all conjugates. The influence of chelator on the biodistribution and targeting properties was much less pronounced for 68Ga than for 111In. The tumor uptake of 68Ga-NODAGA-ZHER2:2395 and 68Ga-DOTA-ZHER2:2395 and tumor-to-blood ratios at 2 h p.i. did not differ significantly. However, the tumor-to-liver ratio was significantly higher for 68Ga-NODAGA- ZHER2:2395 (8 ± 2 vs 5.0 ± 0.3) offering the advantage of better liver metastases visualization. In conclusion, influence of chelators on biodistribution of Affibody molecules depends on the radionuclides and reoptimization of labeling chemistry is required when a radionuclide label is changed.

  • 50.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Tsourma, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Preclin PET Platform, Uppsala, Sweden..
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Perols, A.
    KTH, Div Prot Technol, Stockholm, Sweden..
    Robillard, M.
    Tagworks Pharmaceut, Eindhoven, Netherlands..
    Rossin, R.
    Tagworks Pharmaceut, Eindhoven, Netherlands..
    ten Hoeve, W.
    Syncom BV, Groningen, Netherlands..
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Karlstrom, A. Eriksson
    KTH, Div Prot Technol, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting: proof-of-principle2015In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 42, no S1, S246-S246 p.Article in journal (Other academic)
1234567 1 - 50 of 1740
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf