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  • 1.
    Al-Smadi, Derar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Carboligation using the aldol reaction: A comparison of stereoselectivity and methods2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The research summarized in this thesis focuses on synthesizing aldehyde and aldol compounds as substrates and products for the enzyme D-fructose-6-aldolase (FSA). Aldolases are important enzymes for the formation of carbon-carbon bonds in nature. In biological systems, aldol reactions, both cleavage and formation play central roles in sugar metabolism. Aldolases exhibit high degrees of stereoselectivity and can steer the product configurations to a given enantiomeric and diastereomeric form. To become truly useful synthetic tools, the substrate scope of these enzymes needs to become broadened.

    In the first project, phenylacetaldehyde derivatives were synthesized for the use as test substrates for E. coli FSA. Different methods were discussed to prepare phenylacetaldehyde derivatives, the addition of a one carbon unit to benzaldehyde derivatives using a homologation reaction was successful and was proven efficient and non-sensitive to the moisture. The analogues were prepared through two steps with 75-80 % yields for both meta- and para-substituted compounds.

    The second project focuses on synthesizing aldol compound using FSA enzymes, both wild type and mutated variants selected from library screening, the assay has been successfully used to identify a hit with 10-fold improvement in an R134V/S166G variant. This enzyme produces one out of four possible stereoisomers.

    The third project focuses on the synthesis of a range of aldol compounds using two different approaches reductive cross-coupling of aldehydes by SmI2 or by organocatalysts using cinchonine. Phenylacetaldehydes were reacted with hydroxy-, dihydroxyacetone and hydroxyacetophenone in presence of cinchonine, the reaction was successful with hydroxyacetophenone in moderate yields and 60-99 % de ratio. On the other hand, the aldehydes reacting with methyl- and phenylglyoxal in the presence of SmI2 resulted in moderate yields and without stereoselectivity.

    List of papers
    1. Synthesis of substrates for aldolase-catalyzed reactions: A comparison of methods for the synthesis of substituted phenylacetaldehydes
    Open this publication in new window or tab >>Synthesis of substrates for aldolase-catalyzed reactions: A comparison of methods for the synthesis of substituted phenylacetaldehydes
    Show others...
    2018 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 29, no 9, p. 1187-1190Article in journal (Refereed) Published
    Abstract [en]

    Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic add (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydrolysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-342939 (URN)10.1055/s-0036-1591963 (DOI)000432738600011 ()
    Funder
    Stiftelsen Olle Engkvist Byggmästare
    Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-10-11Bibliographically approved
    2. New Stereoselective Biocatalysts for Carboligation and Retro-Aldol Cleavage Reactions Derived from D-Fructose 6-Phosphate Aldolase
    Open this publication in new window or tab >>New Stereoselective Biocatalysts for Carboligation and Retro-Aldol Cleavage Reactions Derived from D-Fructose 6-Phosphate Aldolase
    Show others...
    2018 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 57, no 40, p. 5877-5885Article in journal (Refereed) Published
    Abstract [en]

    D-Fructose 6-phosphate aldolase (FSA) catalyzes the asymmetric cross-aldol addition of phenylacetaldehyde and hydroxyacetone. We conducted structure guided saturation mutagenesis of noncatalytic active-site residues to produce new FSA variants, with the goal of widening the substrate scope of the wild-type enzyme toward a range of para- and meta-substituted arylated aldehydes. After a single generation of mutagenesis and selection, enzymes with diverse substrate selectivity scopes were identified. The kinetic parameters and stereoselectivities for a subset of enzyme/substrate combinations were determined for the reactions in both the aldol addition and cleavage reaction directions. The achieved collection of new aldolase enzymes provides new tools for controlled asymmetric synthesis of substituted aldols.

    National Category
    Biochemistry and Molecular Biology
    Research subject
    Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-360283 (URN)10.1021/acs.biochem.8b00814 (DOI)000447238100012 ()30204427 (PubMedID)
    Funder
    Stiftelsen Olle Engkvist ByggmästareCarl Tryggers foundation
    Available from: 2018-09-11 Created: 2018-09-11 Last updated: 2018-12-10Bibliographically approved
    3. A Comparison of Synthetic Approaches to Derivatives of 1,4-Substituted 2,3 Dihydroxybutanones
    Open this publication in new window or tab >>A Comparison of Synthetic Approaches to Derivatives of 1,4-Substituted 2,3 Dihydroxybutanones
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-362835 (URN)
    Available from: 2018-10-11 Created: 2018-10-11 Last updated: 2018-10-11
  • 2.
    al-smadi, Derar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Enugala, Thilak Reddy
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Norberg, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kessler, Vadim
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    A Comparison of Synthetic Approaches to Derivatives of 1,4-Substituted 2,3 DihydroxybutanonesManuscript (preprint) (Other academic)
  • 3.
    Al-Smadi, Derar
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Enugala, Thilak Reddy
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Norberg, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Synthesis of substrates for aldolase-catalyzed reactions: A comparison of methods for the synthesis of substituted phenylacetaldehydes2018In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 29, no 9, p. 1187-1190Article in journal (Refereed)
    Abstract [en]

    Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic add (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydrolysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.

  • 4.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Carlsson, Anna-Carin C.
    University of Gothenburg, Gothenburg, Sweden.
    Nekoueishahraki, Bijan
    University of Gothenburg, Gothenburg, Sweden.
    Brath, Ulrika
    University of Gothenburg, Gothenburg, Sweden.
    Erdélyi, Máté
    University of Gothenburg, Gothenburg, Sweden.
    Chapter Two - Solvent Effects on Nitrogen Chemical Shifts2015In: Annual Reports on NMR Spectroscopy, Academic Press , 2015, Vol. 86, p. 73-210Chapter in book (Other academic)
    Abstract [en]

    Due to significant developments in cryogenic probe technology and the easy access to inverse detection pulse programmes (HSQC, HMBC), the sensitivity of nitrogen NMR has lately vastly improved. As a consequence, nitrogen NMR has turned into a useful and commonly available tool for solution studies of molecular structure and properties for small organic compounds likewise biopolymers. The high sensitivity of the nitrogen lone pair to changes in the molecular environment, alterations in intra- and intermolecular interactions, and in molecular conformation along with its wide, up to 1200ppm chemical shift dispersion make nitrogen NMR to an exceptionally sensitive reporter tool. The nitrogen chemical shift has been applied in various fields of chemistry, including for instance the studies of transition metal complexes, chemical reactions such as N-alkylation and N-oxidation, tautomerization, protonation–deprotonation equilibria, hydrogen and halogen bonding, and elucidation of molecular conformation and configuration. The 15N NMR data observed in the investigation of these molecular properties and processes is influenced by the medium it is acquired in. This influence may be due to direct coordination of solvent molecules to transition metal complexes, alteration of tautomerization equilibria, and solvent polarity induced electron density changes of conjugated systems, for example. Thus, the solvent may significantly alter the observed nitrogen NMR shifts. This review aims to provide an overview of solvent effects of practical importance, and discusses selected experimental reports from various subfields of chemistry.

  • 5.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. University of Gothenburg, SE-412 96 Gothenburg, Sweden.
    Gräfenstein, Jürgen
    National Sun Yat-Sen University, Kaohsiung, Taiwan.
    Isobe, Minoru
    National Sun Yat-Sen University, Kaohsiung, Taiwan.
    Erdélyi, Máté
    University of Gothenburg, SE-412 96 Gothenburg, Sweden; The Swedish NMR Centre, SE-413 96 Gothenburg, Sweden.
    Sydnes, Magne O
    University of Stavanger, NO-4036 Stavanger, Norway.
    Photochemically Induced Aryl Azide Rearrangement: Solution NMR Spectroscopic Identification of the Rearrangement Product2017In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, no 3, p. 1812-1816Article in journal (Refereed)
    Abstract [en]

    Photolysis of ethyl 3-azido-4,6-difluorobenzoate at room temperature in the presence of oxygen results in the regioselective formation of ethyl 5,7-difluoro-4-azaspiro[2.4]hepta-1,4,6-triene-1-carboxylate, presumably via the corresponding ketenimine intermediate which undergoes a photochemical four-electron electrocyclization followed by a rearrangement. The photorearrangement product was identified by multinuclear solution NMR spectroscopic techniques supported by DFT calculations.

  • 6.
    Andersson, Hanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Discovery of inhibitors of insulin-regulated aminopeptidase as cognitive enhancers2012In: International Journal of Hypertension, ISSN 2090-0384, Vol. 2012, p. 789671-Article, review/survey (Refereed)
    Abstract [en]

    The hexapeptide angiotensin IV (Ang IV) is a metabolite of angiotensin II (Ang II) and plays a central role in the brain. It was reported more than two decades ago that intracerebroventricular injection of Ang IV improved memory and learning in the rat. Several hypotheses have been put forward to explain the positive effects of Ang IV and related analogues on cognition. It has been proposed that the insulin-regulated aminopeptidase (IRAP) is the main target of Ang IV. This paper discusses progress in the discovery of inhibitors of IRAP as potential enhancers of cognitive functions. Very potent inhibitors of the protease have been synthesised, but pharmacokinetic issues (including problems associated with crossing the blood-brain barrier) remain to be solved. The paper also briefly presents an overview of the status in the discovery of inhibitors of ACE and renin, and of AT1R antagonists and AT2R agonists, in order to enable other discovery processes within the RAS system to be compared. The paper focuses on the relationship between binding affinities/inhibition capacity and the structures of the ligands that interact with the target proteins.

  • 7.
    Andersson, Sofia E. M.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Eneljung, Tove
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Tengvall, Sara
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Jirholt, Pernilla
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Stern, Anna
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Henningsson, Louise
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Liang, Bibo
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Solna, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Thorarinsdottir, Katrin
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Holmdahl, Rikard
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Solna, Sweden.;Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Martensson, Inga-Lill
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden..
    Gustafsson, Kenth
    UCL, Inst Child Hlth, Mol Immunol Unit, London, England..
    Gjertsson, Inger
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Rheumatol & Inflammat Res, Box 480, SE-40530 Gothenburg, Sweden.;Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis2016In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, article id 140Article in journal (Refereed)
    Abstract [en]

    Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used. Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naive mice ameliorated the development of CII-induced arthritis. Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.

  • 8.
    Andersson, Vincent
    et al.
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Bergström, Fredrik
    AstraZeneca R&D, CVMD iMed DMPK, SE-43183 Molndal, Sweden..
    Branalt, Jonas
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Grönberg, Gunnar
    AstraZeneca R&D, RIA iMed, SE-43183 Molndal, Sweden..
    Gustafsson, David
    AstraZeneca, AZ Bioventure Hub, Emeriti Pharma AB, S-43183 Molndal, Sweden..
    Karlsson, Staffan
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Polla, Magnus
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Bergman, Joakim
    AstraZeneca R&D, CVMD iMed, SE-43183 Molndal, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Macrocyclic Prodrugs of a Selective Nonpeptidic Direct Thrombin Inhibitor Display High Permeability, Efficient Bioconversion but Low Bioavailability2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 14, p. 6658-6670Article in journal (Refereed)
    Abstract [en]

    The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes. Unexpectedly, the most promising prodrug displayed only moderately higher oral bioavailability in rat than the polar direct thrombin inhibitor, most likely due to rapid metabolism in the intestine or the intestinal wall. To the best of our knowledge, this is the first in vivo ADME study of macrocyclic (acyloxy)alkoxy prodrugs, and it remains to be established if the modest increase in bioavailability is a general feature of this category of prodrugs or not.

  • 9.
    Balamurugan, Kanagasabai
    et al.
    Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Murugan, Natarajan Arul
    Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden..
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Nordberg, Agneta
    Karolinska Univ Hosp, Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res,Translat Alzheimer Neurobiol,De, S-14186 Stockholm, Sweden..
    Agren, Hans
    Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.;Siberian Fed Univ, Inst Nanotechnol Spect & Quantum Chem, Svobodny Pr 79, Krasnoyarsk 660041, Russia..
    Effect of Alzheimer Familial Chromosomal Mutations on the Amyloid Fibril Interaction with Different PET Tracers: Insight from Molecular Modeling Studies2017In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 8, no 12, p. 2655-2666Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is the most common neurodegenerative disorder. Along with an increasing number of elderly worldwide, it poses a great challenge for the society and health care. Although sporadic AD is the common form of AD, 2-3% of the AD cases are expected to be due to mutations in the fi region of the amyloid precursor protein, which is referred to as autosomal dominant AD (ADAD). These mutations may cause changes in the secondary structure of the amyloid fi fibrils and may alter the fibrillization rate leading to changes in the disease development and could also affect the binding to tracers used in diagnosis. In particular, from some recent clinical studies using PET tracers for detection of fibrillar amyloids, it is evident that in ADAD patients with Arctic mutation no amyloid plaque binding can be detected with the "C Pittsburgh Compound B (C-11-PIB). However, for in vitro conditions, significant binding of H-3-PIB has been reported for the amyloid fibrils carrying the Arctic mutation. The aim of the present study is to investigate if there is any mutation specific binding of commonly used amyloid tracers, namely, florbetaben, florbetapir, FPIB, AZD4694, and AZD2184, by means of molecular modeling techniques. Other than Arctic, ADAD mutations, such as the Dutch, Italian, Iowa, and Flemish mutations, are considered in this study. We report that all tracers except florbetapir show reduced binding affinity toward amyloid beta fibrils with the Arctic mutation when compared to the native type. Moreover, florbetapir is the only tracer that binds to all mutants with increased affinity when compared to the native fibril. The results obtained from these studies could increase the understanding of the structural changes caused by mutation and concomitant changes in the interaction pattern of the PET tracers with the mutated variants, which in turn can be useful in selecting the appropriate tracers for the purpose of diagnosis as well as for designing new tracers with desirable properties.

  • 10.
    Balliu, Aleksandra
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Exploring molecular interactions between polypeptide conjugates and protein targets: Manipulating affinity by chemical modifications2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis molecular interactions between polypeptide conjugates and protein targets were investigated. Polypeptides were derivatized with small organic molecules, peptides and oligonucleotides. New strategies were developed with the aim to increase affinities for proteins of biological interest.

    A 42-residue polypeptide (4-C15L8) conjugated to a small organic molecule 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoic acid (PP1), was shown to bind glycogen phosphorylase a (GPa) in the presence of zinc ions. Under the assumption that hydrophobic interactions dominated the binding energy, the hydrophobic residues of 4-C15L8-PP1 were systematically replaced in order to study their contribution to the affinity enhancement. The replacement of the Nle, Ile and Leu residues by Ala amino acids reduced affinities. The introduction of non-natural L-2-aminooctanoic acid (Aoc) residues into the peptide sequence enhanced the binding affinity for GPa. A decreased KD of 27nM was obtained when Nle5, Ile9 and Leu12 were replaced by Aoc residues, in comparison to the KD value of 280nM obtained for the unmodified 4-C15L8-PP1. It is evident that there are non-obvious hydrophobic binding sites on the surfaces of proteins that could be identified by introducing the more hydrophobic and conformationally flexible Aoc residues. The downsizing of the 42-mer peptide to an 11-mer and the incorporation of three Aoc residues gave rise to a KD of 550 nM, comparable to that of  4-C15L8-PP1 suggesting that bioactive peptides can be downsized by the introduction of Aoc.

    Aiming to improve in vivo stability, the affinity for human serum albumin (HSA) of hydrophobic, positively and negatively charged polypeptide-PP1 conjugates was evaluated. Increased hydrophobicity due to the introduction of Aoc residues did not significantly increase the affinity for HSA. No binding was observed in the case of the most negatively charged polypeptides whereas the slightly negatively and positively charged polypeptides conjugated to PP1 bound HSA with affinities that increased with the positive charge. It was found that polypeptide-PP1 conjugates target the zinc binding site of the HSA. Affinity enhancement was obtained due to the incorporation of PP1 and increased by charge to charge interactions between the positively charged amino acids of the polypeptide and the negatively charged residues of HSA, in close proximity to the HSA zinc binding site. The survival times of the peptide-PP1 conjugates in human serum were extended as a result of binding to HSA. Zn2+ ion chelating agents can be incorporated in potential peptide therapeutics with a short plasma half-life, without increasing their molecular weights.

    List of papers
    1. Exploring Non-obvious Hydrophobic Binding Pockets on Protein Surfaces: Increasing Affinities in Peptide–Protein Interactions
    Open this publication in new window or tab >>Exploring Non-obvious Hydrophobic Binding Pockets on Protein Surfaces: Increasing Affinities in Peptide–Protein Interactions
    2017 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 14, p. 1396-1407Article in journal (Refereed) Published
    Abstract [en]

    A 42-residue polypeptide conjugated to a small-molecule organic ligand capable of targeting the phosphorylated side chain of Ser15 was shown to bind glycogen phosphorylase a (GPa) with a KD value of 280 nm. The replacement of hydrophobic amino acids by Ala reduced affinities, whereas the incorporation of l-2-aminooctanoic acid (Aoc) increased them. Replacing Nle5, Ile9 and Leu12 by Aoc reduced the KD value from 280 to 27 nm. “Downsizing” the 42-mer to an undecamer gave rise to an affinity for GPa an order of magnitude lower, but the undecamer in which Nle5, Ile9 and Leu12 were replaced by Aoc showed a KD value of 550 nm, comparable with that of the parent 42-mer. The use of Aoc residues offers a convenient route to increased affinity in protein recognition as well as a strategy for the “downsizing” of peptides essentially without loss of affinity. The results show that hydrophobic binding sites can be found on protein surfaces by comparing the affinities of polypeptide conjugates in which Aoc residues replace Nle, Ile, Leu or Phe with those of their unmodified counterparts. Polypeptide conjugates thus provide valuable opportunities for the optimization of peptides and small organic compounds in biotechnology and biomedicine.

    Keywords
    affinity enhancement, aminooctanoic acid, hydrophobic amino acids, peptide conjugation, peptides
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-326803 (URN)10.1002/cbic.201700048 (DOI)000405726100009 ()28432776 (PubMedID)
    Available from: 2017-07-31 Created: 2017-07-31 Last updated: 2017-11-02Bibliographically approved
    2. Conjugation of a Dipicolyl Chelate to Polypeptide Conjugates Increases Binding Affinities for Human Serum Albumin and Survival Times in Human Serum
    Open this publication in new window or tab >>Conjugation of a Dipicolyl Chelate to Polypeptide Conjugates Increases Binding Affinities for Human Serum Albumin and Survival Times in Human Serum
    2017 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 14, p. 1408-1414Article in journal (Refereed) Published
    Abstract [en]

    The affinity for human serum albumin (HSA) of a series of 2–5 kDa peptides covalently linked to 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoic acid, a dipicolyl chelator with micromolar affinity for Zn2+, was found by surface plasmon resonance to increase in the presence of 1 μm ZnCl2 at physiological pH. The dependence on polypeptide hydrophobicity was found to be minor, thus suggesting that the conjugates bound to the metal-binding site and not to the fatty-acid-binding site. The affinity of the conjugates increased strongly with the positive charge of the polypeptides, thus implicating the negatively charged protein surface surrounding the metal-binding site. The survival times of the peptides in human serum were extended as a consequence of stronger binding to HSA, thus suggesting that Zn2+-chelating agents might provide a general route to increased survival time of peptides in serum in therapeutic and diagnostic applications without significantly increasing their molecular weights.

    Keywords
    affinity, biosensor, human serum albumin, peptides, zinc-binding site
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-326838 (URN)10.1002/cbic.201700049 (DOI)000405726100010 ()28301711 (PubMedID)
    Available from: 2017-07-31 Created: 2017-07-31 Last updated: 2017-11-02Bibliographically approved
  • 11.
    Balliu, Aleksandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Baltzer, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Conjugation of a Dipicolyl Chelate to Polypeptide Conjugates Increases Binding Affinities for Human Serum Albumin and Survival Times in Human Serum2017In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 14, p. 1408-1414Article in journal (Refereed)
    Abstract [en]

    The affinity for human serum albumin (HSA) of a series of 2–5 kDa peptides covalently linked to 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoic acid, a dipicolyl chelator with micromolar affinity for Zn2+, was found by surface plasmon resonance to increase in the presence of 1 μm ZnCl2 at physiological pH. The dependence on polypeptide hydrophobicity was found to be minor, thus suggesting that the conjugates bound to the metal-binding site and not to the fatty-acid-binding site. The affinity of the conjugates increased strongly with the positive charge of the polypeptides, thus implicating the negatively charged protein surface surrounding the metal-binding site. The survival times of the peptides in human serum were extended as a consequence of stronger binding to HSA, thus suggesting that Zn2+-chelating agents might provide a general route to increased survival time of peptides in serum in therapeutic and diagnostic applications without significantly increasing their molecular weights.

  • 12.
    Balliu, Aleksandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Baltzer, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Exploring Non-obvious Hydrophobic Binding Pockets on Protein Surfaces: Increasing Affinities in Peptide–Protein Interactions2017In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 18, no 14, p. 1396-1407Article in journal (Refereed)
    Abstract [en]

    A 42-residue polypeptide conjugated to a small-molecule organic ligand capable of targeting the phosphorylated side chain of Ser15 was shown to bind glycogen phosphorylase a (GPa) with a KD value of 280 nm. The replacement of hydrophobic amino acids by Ala reduced affinities, whereas the incorporation of l-2-aminooctanoic acid (Aoc) increased them. Replacing Nle5, Ile9 and Leu12 by Aoc reduced the KD value from 280 to 27 nm. “Downsizing” the 42-mer to an undecamer gave rise to an affinity for GPa an order of magnitude lower, but the undecamer in which Nle5, Ile9 and Leu12 were replaced by Aoc showed a KD value of 550 nm, comparable with that of the parent 42-mer. The use of Aoc residues offers a convenient route to increased affinity in protein recognition as well as a strategy for the “downsizing” of peptides essentially without loss of affinity. The results show that hydrophobic binding sites can be found on protein surfaces by comparing the affinities of polypeptide conjugates in which Aoc residues replace Nle, Ile, Leu or Phe with those of their unmodified counterparts. Polypeptide conjugates thus provide valuable opportunities for the optimization of peptides and small organic compounds in biotechnology and biomedicine.

  • 13.
    Chavan, Swapnil
    et al.
    Linnaeus Univ, Linnaeus Univ Ctr Biomat Chem, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, S-39182 Kalmar, Sweden..
    Abdelaziz, Ahmed
    eADMET GmbH, Lichtenbergstr 8, D-85748 Munich, Germany..
    Wiklander, Jesper G.
    Linnaeus Univ, Linnaeus Univ Ctr Biomat Chem, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, S-39182 Kalmar, Sweden..
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Linnaeus Univ, Linnaeus Univ Ctr Biomat Chem, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, S-39182 Kalmar, Sweden..
    A k-nearest neighbor classification of hERG K+ channel blockers2016In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 30, no 3, p. 229-236Article in journal (Refereed)
    Abstract [en]

    A series of 172 molecular structures that block the hERG K+ channel were used to develop a classification model where, initially, eight types of PaDEL fingerprints were used for k-nearest neighbor model development. A consensus model constructed using Extended-CDK, PubChem and Substructure count fingerprint-based models was found to be a robust predictor of hERG activity. This consensus model demonstrated sensitivity and specificity values of 0.78 and 0.61 for the internal dataset compounds and 0.63 and 0.54 for the external (PubChem) dataset compounds, respectively. This model has identified the highest number of true positives (i.e. 140) from the PubChem dataset so far, as compared to other published models, and can potentially serve as a basis for the prediction of hERG active compounds. Validating this model against FDA-withdrawn substances indicated that it may even be useful for differentiating between mechanisms underlying QT prolongation.

  • 14.
    Danelius, Emma
    et al.
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Jarvoll, Patrik
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Lood, Kajsa
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Gräfenstein, Jürgen
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Erdélyi, Máté
    University of Gothenburg, SE-41296 Gothenburg, Sweden.
    Halogen Bonding: A Powerful Tool for Modulation of Peptide Conformation2017In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Biochemistry, ISSN 0006-2960, Vol. 56, no 25, p. 3265-3272Article in journal (Refereed)
    Abstract [en]

    Halogen bonding is a weak chemical force that has so far mostly found applications in crystal engineering. Despite its potential for use in drug discovery, as a new molecular tool in the direction of molecular recognition events, it has rarely been assessed in biopolymers. Motivated by this fact, we have developed a peptide model system that permits the quantitative evaluation of weak forces in a biologically relevant proteinlike environment and have applied it for the assessment of a halogen bond formed between two amino acid side chains. The influence of a single weak force is measured by detection of the extent to which it modulates the conformation of a cooperatively folding system. We have optimized the amino acid sequence of the model peptide on analogues with a hydrogen bond-forming site as a model for the intramolecular halogen bond to be studied, demonstrating the ability of the technique to provide information about any type of weak secondary interaction. A combined solution nuclear magnetic resonance spectroscopic and computational investigation demonstrates that an interstrand halogen bond is capable of conformational stabilization of a β-hairpin foldamer comparable to an analogous hydrogen bond. This is the first report of incorporation of a conformation-stabilizing halogen bond into a peptide/protein system, and the first quantification of a chlorine-centered halogen bond in a biologically relevant system in solution.

  • 15.
    Devaraj, Karthik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Ruthenium-catalyzed C-H Functionalization of (Hetero)arenes2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis concerned about the Ru-catalyzed C-H functionalizations on the synthesis of 2-arylindole unit, silylation of heteroarenes and preparation of aryne precursor.

    In the first project, we developed the Ru-catalyzed C2-H arylation of N-(2-pyrimidyl) indoles and pyrroles with nucleophilic arylboronic acids under oxidative conditions. Wide variety of arylboronic acids afforded the desired product in excellent yield regardless of the substituents or functional group electronic nature. Electron-rich heteroarenes are well suited for this method than electron-poor heteroarenes. Halides such as bromide and iodide also survived, further derivatisation of the halide is shown by Heck alkenylation. In order to find catalytic on-cycle intermediate extensive mechanistic experiments have been carried out by preparing presumed ruthenacyclic complexes and C-H/D exchange reactions. It suggested that para-cymene ligand is not present in the catalytic on-cycle intermediate and we suspect that metalation occurs with electrophilic ruthenium center via SEAr mechanism.

    In the second project, we developed the Ru-catalyzed silylation of gramine, tryptamine and their congeners using silanes as coupling partner. The transformation worked well with many different silanes. Regarding directing group, nitrogen atom containing directing groups are more favoured than the oxygen containing directing groups. Wide range of gramines and tryptamines also yielded the desired product in poor to excellent yield. At higher temperature, albeit in low yield, undirected silylation occurred. In order to get some insights about the reaction pathway of the silylation C-H/D exchange experiments were performed, and it revealed the possibility of C4-H activation of gramines by an electron rich metal- Si-H/D experiments showed Si-H activation by Ru is easy.

    In the final project, we presented the closely related aryne precursors from arylboronic acids via Ru-catalyzed C-H silylation of arylboronates and their selective oxidation. Worthy of note, the aryne capture products obtained from arylboronic acids in a single purification.

    List of papers
    1. Ru-Catalysed C-H Arylation of Indoles and Pyrroles with Boronic Acids: Scope and Mechanistic Studies
    Open this publication in new window or tab >>Ru-Catalysed C-H Arylation of Indoles and Pyrroles with Boronic Acids: Scope and Mechanistic Studies
    Show others...
    2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 14, p. 5380-5386Article in journal (Refereed) Published
    Abstract [en]

    The Ru-catalysed C2-H arylation of indoles and pyrroles by using boronic acids under oxidative conditions is reported. This reaction can be applied to tryptophan derivatives and tolerates a wide range of functional groups on both coupling partners, including bromides and iodides, which can be further derivatised selectively. New indole based ruthenacyclic complexes are described and investigated as possible intermediates in the reaction. Mechanistic studies suggest the on-cycle intermediates do not possess a para-cymene ligand and that the on-cycle metalation occurs through an electrophilic attack by the Ru centre.

    Keywords
    catalysis, C-H activation, heterocycles, reaction mechanisms, ruthenium
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-252711 (URN)10.1002/chem.201405931 (DOI)000352504500017 ()25689052 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2015-05-18 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically approved
    2. Ru-Catalysed C-H Silylation of Gramines, Tryptamines and their Congeners
    Open this publication in new window or tab >>Ru-Catalysed C-H Silylation of Gramines, Tryptamines and their Congeners
    2016 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, no 34, p. 5868-5871Article in journal (Refereed) Published
    Abstract [en]

    Selective Ru-catalysed C2–H silylation of heteroarenes is presented. The transformation works with or without directing group assistance and requires no protecting groups. Gramines and tryptamines may be converted efficiently whilst avoiding deleterious elimination side-reactions. Mechanistic studies reveal an unusual activation of the indole C4–H bond by an electron-rich metal.

    Place, publisher, year, edition, pages
    Royal Society of Chemistry, 2016
    National Category
    Organic Chemistry
    Research subject
    Chemistry with specialization in Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-286545 (URN)10.1039/C6CC00803H (DOI)000374396500022 ()27050747 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2016-04-20 Created: 2016-04-20 Last updated: 2017-11-30Bibliographically approved
    3. Synthesis of aryne precursors via transition metal-catalyzed C-H silylation
    Open this publication in new window or tab >>Synthesis of aryne precursors via transition metal-catalyzed C-H silylation
    2014 (English)In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 248Article in journal, Meeting abstract (Other academic) Published
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-247860 (URN)000349167403600 ()
    Conference
    248th National Meeting of the American-Chemical-Society (ACS), AUG 10-14, 2014, San Francisco, CA
    Available from: 2015-03-26 Created: 2015-03-24 Last updated: 2017-12-04Bibliographically approved
  • 16.
    Devaraj, Karthik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Sollert, Carina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Gates, P. J.
    Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England.
    Pilarski, Lukasz
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Ru-Catalysed C-H Silylation of Gramines, Tryptamines and their Congeners2016In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, no 34, p. 5868-5871Article in journal (Refereed)
    Abstract [en]

    Selective Ru-catalysed C2–H silylation of heteroarenes is presented. The transformation works with or without directing group assistance and requires no protecting groups. Gramines and tryptamines may be converted efficiently whilst avoiding deleterious elimination side-reactions. Mechanistic studies reveal an unusual activation of the indole C4–H bond by an electron-rich metal.

  • 17.
    Diwakarla, Shanti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Reddy Vanga, Sudarsana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Shamsudin Khan, Yasmin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Ng, Leelee
    Pham, Vi
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Lundback, Thomas
    Jenmalm-Jensen, Annika
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Engen, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Yeen Chai, Siew
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density2016In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 89, no 4, p. 413-424Article in journal (Refereed)
    Abstract [en]

    Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

  • 18.
    Doak, Bradley C.
    et al.
    Monash Univ, MIPS, Dept Med Chem, Parkville, Vic, Australia..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Drug discovery beyond the rule of 5-Opportunities and challenges2017In: Expert Opinion on Drug Discovery, ISSN 1746-0441, E-ISSN 1746-045X, Vol. 12, no 2, p. 115-119Article in journal (Refereed)
  • 19.
    Dollevoet, Kim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    C-H activation of indoles catalyzed by a ruthenium-complex: Synthesis of 2-3-hexene-1-(pyrimidin-2-yl)1H-indole2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 20.
    Emanuelsson, Rikard
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Huang, Hao
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Sjödin, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Enthalpic versus Entropic Contribution to the Quinone Formal Potential in a Polypyrrole-Based Conducting Redox Polymer2016In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 120, no 38, p. 21178-21183Article in journal (Refereed)
    Abstract [en]

    A conducting redox polymer (CPR) based on pyrrole with a hydroquinone pendant group was synthesized through electropolymerization of the corresponding monomer. The formal potential (E-0') in aqueous solution at different pH as well as in MeCN containing equal amounts of pyridiniumtriflates and the corresponding free pyridine with different pK(a) was investigated. E-0' could be completely recovered in MeCN, and by utilizing pyridine bases with different donor acceptor strengths, a decrease of 61 meV/pK(a) was found that corresponded exactly to the pH dependence of E-0' in aqueous electrolyte. To separate the entropic and enthalpic contributions to E-0', temperature-dependent electrochemistry was performed. Two different modes of operation with changing pH/pK(a) between the two media were revealed. In MeCN, E-0' varies only because of the enthalpic contribution as the entropic contribution is unaffected by change in pKa. In water, there is primarily an entropic contribution to E-0' with changing pH due to solvation of the proton. The presented results are expected to open up for new design possibilities of CRPs based on ion coordinating redox groups for electrical energy storage.

  • 21.
    Eriksson, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Olsson, Ulf
    Swedish Univ Agr Sci, Unit Appl Stat & Math, Uppsala, Sweden..
    Marteinsdottir, Ina
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Holstad, Maria
    Univ Uppsala Hosp, Dept Neurosci, Psychiat Unit, Uppsala, Sweden..
    Ågren, Hans
    Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Hartvig, Per
    Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark..
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right-Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0159538Article in journal (Refereed)
    Abstract [en]

    Study Objective To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD) and asymptomatic controls. Background Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women. Methods Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP), radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs): the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain". Results There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001). Menstrual phase changes in this asymmetry (premenstrual-follicular) correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006). The PMD group showed a strong inverse correlation between phase changes (pre-menstrual-follicular) in plasma levels of estradiol and phase changes in the laterality (dx/sin) of radiotracer activity in the dorsolateral prefrontal ROI (r(s) = -0.635; 0.027). The control group showed no such correlation. Conclusion Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral prefrontal cortices was found to strongly correlate to premenstrual irritability. A causal relationship here seems plausible, and the findings give further support to an underlying frontal brain disturbance in hormonally influenced serotonergic activity in women with PMD. Because of the small number of subjects in the study, these results should be considered preliminary, requiring verification in larger studies.

  • 22.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wahlstedt, Kurt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bani, Massimo
    GlaxoSmithKline, Verona, Italy.
    Pich, Emilio Merlo
    GlaxoSmithKline, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Verona, Italy.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, no 11, p. 1775-1783Article in journal (Refereed)
    Abstract [en]

    Abstract Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40 mg), the NK1R antagonist GR205171 (n=6; 5 mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

  • 23.
    Furmark, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Marteinsdottir, Ina
    Linkoping Univ, Dept Clin & Expt Med, Ctr Social & Affect Neurosci, Linkoping, Sweden.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Heurling, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tillfors, Maria
    Univ Orebro, Ctr Hlth & Med Psychol, Orebro, Sweden.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Hartvig, Per
    Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark.
    Fischer, Håkan
    Stockholm Univ, Dept Psychol, Stockholm, Sweden.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Southern Denmark Univ, Odense Univ Hosp, Odense, Denmark.
    Eriksson, Elias
    Gothenburg Univ, Dept Pharmacol, Gothenburg, Sweden.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder.2016In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 30, no 10, p. 1028-1035Article in journal (Refereed)
    Abstract [en]

    It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[β -(11)C]tryptophan, [(11)C]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [(11)C]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions.

  • 24.
    Ge, Changrong P
    et al.
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Tong, Dongmei R
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden.;Southern Med Univ, Dept Pathophysiol, Key Lab Shock & Microcirculat Res Guangdong, Guangzhou, Guangdong, Peoples R China..
    Liang, Bibo T
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden.;Southern Med Univ, Dept Pathophysiol, Key Lab Shock & Microcirculat Res Guangdong, Guangzhou, Guangdong, Peoples R China..
    Lönnblom, Erik S
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Schneider, Nadine K
    Goethe Univ, Fraunhofer Inst Mol Biol & Appl Ecol IME, Project Grp Translat Med & Pharmacol, Frankfurt, Germany.;Goethe Univ, Div Rheumatol, Univ Hosp Frankfurt, Frankfurt, Germany..
    Hagert, Cecilia U
    Univ Turku, Medicity Res Lab, Turku, Finland.;Natl Doctoral Programme Informat & Struct Biol, Turku, Finland..
    Viljanen, Johan V.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Ayoglu, Burcu R
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, Affin Prote, Stockholm, Sweden..
    Stawikowska, Roma T
    Florida Atlantic Univ, Dept Chem & Biochem, Jupiter, FL USA..
    Nilsson, Peter C
    KTH Royal Inst Technol, Sch Biotechnol, Sci Life Lab, Affin Prote, Stockholm, Sweden..
    Fields, Gregg B
    Florida Atlantic Univ, Dept Chem & Biochem, Jupiter, FL USA..
    Skogh, Thomas A
    Linkoping Univ, Dept Rheumatol, Dept Clin & Expt Med, Linkoping, Sweden..
    Kastbom, Alf R
    Linkoping Univ, Dept Rheumatol, Dept Clin & Expt Med, Linkoping, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Burkhardt, Harald T
    Goethe Univ, Fraunhofer Inst Mol Biol & Appl Ecol IME, Project Grp Translat Med & Pharmacol, Frankfurt, Germany.;Goethe Univ, Div Rheumatol, Univ Hosp Frankfurt, Frankfurt, Germany..
    Dobritzsch, Doreen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Holmdahl, Rikard K
    Karolinska Inst, Sect Med Inflammat Res, Dept Med Biochem & Biophys, Stockholm, Sweden.;Univ Turku, Medicity Res Lab, Turku, Finland.;Natl Doctoral Programme Informat & Struct Biol, Turku, Finland.;Southern Med Univ, Ctr Med Immunopharmacol Res, Guangzhou, Guangdong, Peoples R China..
    Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage2017In: JCI INSIGHT, ISSN 2379-3708, Vol. 2, no 13, article id e93688Article in journal (Refereed)
    Abstract [en]

    Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.

  • 25. Giordanetto, Fabrizio
    et al.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties?2014In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 2, p. 278-95Article in journal (Refereed)
    Abstract [en]

    Macrocycles are ideal in efforts to tackle "difficult" targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (N = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 Å(2). Moreover, insight from a group of "de novo designed" oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space.

  • 26.
    Golker, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Olsson, Gustaf D.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Nicholls, Ian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    The influence of a methyl substituent on molecularly imprinted polymer morphology and recognition - Acrylic acid versus methacrylic acid2017In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 92, p. 137-149Article in journal (Refereed)
    Abstract [en]

    In this report, we have investigated factors contributing to the morphology and template recognition of bupivacaine-imprinted copolymers of methacrylic acid (MAA) and ethyleneglycol dimethacrylate (EGDMA). To this end, MAA, the most commonly used functional monomer in non-covalent molecular imprinting protocols, was compared and contrasted with the closely related acrylic acid (AA) in terms of polymer morphologies, recognition characteristics, and molecular level events in the corresponding pre-polymerization mixtures. Two series of analogous bupivacaine-imprinted EGDMA-copolymers containing increasing fractions of either AA or MAA were studied through all-component MD simulations in the pre-polymerization phase, equilibrium binding experiments on corresponding synthesized polymers and morphology characterization by N-2-sorption measurements. A higher degree of hydrogen bonding frequency between respective functional monomer and bupivacaine was recorded for the mixtures containing AA compared to those containing MAA. In contrast, results from binding experiments demonstrated higher binding capacities for the polymers prepared with MAA than for those prepared with AA, which is explained by differences in polymer morphology. The surface areas and pore volumes of the AA-polymers were higher than for the MAA-polymers and the overall pore structure in the AA-polymers was ink-bottle shaped while the pores in the MAA-polymers were slit-shaped. We suggest that the methyl substituent of MAA contributes to differences in the reaction kinetics for AA and MAA during polymerization and resulted in different morphologies, in particular pore shape, which affected mass-transfer and consequently the binding qualities of the materials.

  • 27.
    Gustav, Hulu
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Improved Reaction Conditions for Rhodium-catalyzed Hydroarylation of C60 Fullerenes with Tolylboronic acid: Towards bis[60] fullerene dumbbells2018Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    The full text will be freely available from 2020-06-08 16:25
  • 28.
    Huang, Hao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Karlsson, Christoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Mamedov, Fikret
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Molecular Biomimetics.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Gogoll, A
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Sjödin, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials. Waseda Univ, Dept Appl Chem, Tokyo 1698555, Japan..
    Polaron Disproportionation Charge Transport in a Conducting Redox Polymer2017In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 121, no 24, p. 13078-13083Article in journal (Refereed)
    Abstract [en]

    Herein we report a mechanistic study of the charge transport in poly-3-((2,5-hydroquinone)vinyl)-1H-pyrrole by conductance measurements at various temperatures performed in situ during doping of the polypyrrole backbone in contact with an aqueous electrolyte. Charge transport was found to occur by electron hopping with associated electron transfer activation energies in the range of 0.08-0.2 eV. In situ electron paramagnetic resonance experiments indicated polarons as the dominant charge carriers and the charge transport was found to follow a second-order dependence with respect to the number of accumulated charges. Based on the findings, we present a polaron comproportionation/disproportionation model for electron conduction in poly-3-((2,5-hydroquinone)vinyl)-1H-pyrrole, thus, providing a complement to existing models for charge propagation in conducting polymers.

  • 29.
    Huang, Hao
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Karlsson, Christoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Gogoll, Adolf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Sjödin, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Synthesis and Characterization of Poly-3-((2,5-hydroquinone)vinyl)-1H-pyrrole: investigation on Backbone/Pendant Interactions in a Conducting Redox Polymer2017In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 19, no 16, p. 10427-10435Article in journal (Refereed)
    Abstract [en]

    We herein report the synthesis and electrochemical characterization of poly-3-((2,5-hydroquinone)vinyl)-1H-pyrrole, consisting of a polypyrrole backbone derivatized at the beta position by a vinyl-hydroquinone pendant group. The structure of the polymer was characterized by solid state NMR spectroscopy. The interactions between the polypyrrole backbone and the oxidized quinone or reduced hydroquinone pendant groups are probed by several in situ methods. In situ attenuated total reflectance-Fourier transform infrared spectroscopy shows spectroscopic response from both the doping of the polymer backbone and the redox activity of the pendant groups. Using an in situ Electrochemical Quartz Crystal Microbalance we reveal that the polymer doping is unaffected by the pendant group redox chemistry, as opposed to previous reports. Despite the continuous doping the electrochemical conversion from the hydroquinone state to the quinone state results in a significant conductance drop, as observed by in situ conductivity measurements using an InterDigitated Array electrode set-up. Twisting of the conducting polymer backbone as a result of a decreased separation between pendant groups due to π-π stacking in the oxidized state is suggested as the cause of this conductance drop.

  • 30.
    Huang, Xiao
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Conducting Redox Polymers for Electrode Materials: Synthetic Strategies and Electrochemical Properties2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Organic electrode materials represent an intriguing alternative to their inorganic counterparts due to their sustainable and environmental-friendly properties. Their plastic character allows for the realization of light-weight, versatile and disposable devices for energy storage. Conducting redox polymers (CRPs) are one type of the organic electrode materials involved, which consist of a π-conjugated polymer backbone and covalently attached redox units, the so-called pendant. The polymer backbone can provide conductivity while it is oxidized or reduced (i. e., p- or n-doped) and the concurrent redox chemistry of the pendant provides charge capacity. The combination of these two components enables CRPs to provide both high charge capacity and high power capability. This dyad polymeric framework provides a solution to the two main problems associated with organic electrode materials based on small molecules: the dissolution of the active material in the electrolyte, and the sluggish charge transport within the material. This thesis introduces a general synthetic strategy to obtain the monomeric CRPs building blocks, followed by electrochemical polymerization to afford the active CRPs material. The choice of pendant and of polymer backbone depends on the potential match between these two components, i.e. the redox reaction of the pendant and the doping of backbone occurring within the same potential region. In the thesis, terephthalate and polythiophene were selected as the pendant and polymer backbone respectively, to get access to low potential CRPs. It was found that the presence of a non-conjugated linker between polymer backbone and pendant is essential for the polymerizability of the monomers as well as for the preservation of individual redox activities. The resulting CRPs exhibited fast charge transport within the polymer film and low activation barriers for charge propagation. These low potential CRPs were designed as the anode materials for energy storage applications. The combination of redox active pendant as charge carrier and a conductive polymer backbone reveals new insights into the requirements of organic matter based electrical energy storage materials.

    List of papers
    1. Matching Diethyl Terephthalate with n-Doped Conducting Polymers
    Open this publication in new window or tab >>Matching Diethyl Terephthalate with n-Doped Conducting Polymers
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    2015 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 119, no 33, p. 18956-18963Article in journal (Refereed) Published
    Abstract [en]

    The combination of small, high charge capacity molecules as pendant groups with a conducting polymer backbone having good electronic conductivity upon doping, gives the possibility to design a high capacity conducting redox polymer material for electric energy storage applications. The desired synergetic effect of the two components requires energy matching as well as chemical compatibility of the pendant group and the polymer backbone. Here we investigate the matching of diethyl terephthalate (DeT) with the thiophene-based conducting polymers polythiophene (PT), poly(3,4-ethylenedioxythiophene) (PEDOT), and polyphenylthiophene. We show that a stable and well-defined electrochemical response of DeT is achieved, together with all conducting polymers except for PT in tetrabutylammonium hexafluorophosphate electrolyte, indicating good energy match as well as chemical compatibility between DeT and polymers. By varying the size of ammonium cations in the electrolytes, we further show how this size affects the conductivity and the cycling stability of the polymers and also that the n-doping performance of all conducting polymers can be improved by the use of smaller alkyl ammonium cations. On the basis of these results, we suggest that PEDOT and PT are suitable candidates for a polymer backbone in conducting redox polymers with DeT pendant groups.

    National Category
    Nano Technology
    Identifiers
    urn:nbn:se:uu:diva-262423 (URN)10.1021/acs.jpcc.5b05067 (DOI)000360026200015 ()
    Funder
    Swedish Foundation for Strategic Research Swedish Research CouncilCarl Tryggers foundation Swedish Energy Agency
    Available from: 2015-09-17 Created: 2015-09-15 Last updated: 2017-12-04Bibliographically approved
    2. Synthesis and Redox Properties of Thiophene Terephthalate Building Blocks for Low-Potential Conducting Redox Polymers
    Open this publication in new window or tab >>Synthesis and Redox Properties of Thiophene Terephthalate Building Blocks for Low-Potential Conducting Redox Polymers
    Show others...
    2015 (English)In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 119, no 49, p. 27247-27254Article in journal (Refereed) Published
    Abstract [en]

    Terephthalate-substituted thiophene derivatives are promising redox-active components for anode materials in lithium-ion batteries. In this study, we present the synthesis of substituted 2-(thiophen-3-yl)terephthalate derivatives (TTDs) as suitable monomers for thiophene-based conducting redox polymers, along with their characterization by electrochemical and spectroscopic techniques. Density functional theory (DFT) calculations, utilizing the universal solvation model based on solute electron density (SMD), were used to predict both the first and the second reduction potentials of these TTDs. The computational results showed good agreement with the experimental data in nonaqueous acetonitrile solvent, with mean absolute errors of 30 and 40 mV for the first and second reduction steps, respectively. Time-dependent (TD) DFT calculations on TTDs indicated terephthalate local transitions at both 200 and 240 nm and charge-transfer transitions above 300 nm by examination of the involved molecular orbitals.

    National Category
    Nano Technology
    Research subject
    Engineering Science with specialization in Nanotechnology and Functional Materials
    Identifiers
    urn:nbn:se:uu:diva-268481 (URN)10.1021/acs.jpcc.5b08518 (DOI)000366339000008 ()
    Funder
    Swedish Research Council, VR 621-2011-4423Swedish Foundation for Strategic Research Swedish Energy Agency
    Available from: 2015-12-05 Created: 2015-12-05 Last updated: 2017-12-01Bibliographically approved
    3. Conducting Redox Polymer Based Anode Materials for High Power Electrical Energy Storage
    Open this publication in new window or tab >>Conducting Redox Polymer Based Anode Materials for High Power Electrical Energy Storage