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  • 51.
    Hall, Michael
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Grundström, Christin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Begum, Afshan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Lindberg, Mikael J.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sauer, Uwe H.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Johansson, Jörgen
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Sauer-Eriksson, A. Elisabeth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Structural basis for glutathione-mediated activation of the virulence regulatory protein PrfA in Listeria2016Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, nr 51, s. 14733-14738Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Infection by the human bacterial pathogen Listeria monocytogenes is mainly controlled by the positive regulatory factor A (PrfA), a member of the Crp/Fnr family of transcriptional activators. Published data suggest that PrfA requires the binding of a cofactor for full activity, and it was recently proposed that glutathione (GSH) could fulfill this function. Here we report the crystal structures of PrfA in complex with GSH and in complex with GSH and its cognate DNA, the hly operator PrfA box motif. These structures reveal the structural basis for a GSH-mediated allosteric mode of activation of PrfA in the cytosol of the host cell. The crystal structure of PrfAWT in complex only with DNA confirms that PrfAWT can adopt a DNA binding-compatible structure without binding the GSH activator molecule. By binding to PrfA in the cytosol of the host cell, GSH induces the correct fold of the HTH motifs, thus priming the PrfA protein for DNA interaction.

  • 52. Hammer, Neal D
    et al.
    McGuffie, Bryan A
    Zhou, Yizhou
    Badtke, Matthew P
    Reineke, Ashley A
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Gestwicki, Jason E
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chapman, Matthew R
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    The C-terminal repeating units of CsgB direct bacterial functional amyloid nucleation2012Ingår i: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 422, nr 3, s. 376-389Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Curli are functional amyloids produced by enteric bacteria. The major curli fiber subunit, CsgA, self-assembles into an amyloid fiber in vitro. The minor curli subunit protein, CsgB, is required for CsgA polymerization on the cell surface. Both CsgA and CsgB are composed of five predicted β–strand-loop-β–strand-loop repeating units that feature conserved glutamine and asparagine residues. Because of this structural homology, we proposed that CsgB might form an amyloid template that initiates CsgA polymerization on the cell surface. To test this model, we purified wild-type CsgB, and found that it self-assembled into amyloid fibers in vitro. Preformed CsgB fibers seeded CsgA polymerization as did soluble CsgB added to the surface of cells secreting soluble CsgA. To define the molecular basis of CsgB nucleation, we generated a series of mutants that removed each of the five repeating units. Each of these CsgB deletion mutants was capable of self-assembly in vitro. In vivo, membrane-localized mutants lacking the 1st, 2nd or 3rd repeating units were able to convert CsgA into fibers. However, mutants missing either the 4th or 5th repeating units were unable to complement a csgB mutant. These mutant proteins were not localized to the outer membrane, but were instead secreted into the extracellular milieu. Synthetic CsgB peptides corresponding to repeating units 1, 2 and 4 self assembled into ordered amyloid polymers, while peptides corresponding to repeating units 3 and 5 did not, suggesting that there are redundant amyloidogenic domains in CsgB. Our results suggest a model where the rapid conversion of CsgB from unstructured protein to a β-sheet-rich amyloid template anchored to the cell surface is mediated by the C-terminal repeating units.

  • 53.
    Hedenström, Mattias
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Emtenäs, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pemberton, Nils
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Åberg, Veronica
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hultgren, Scott J.
    Pinkner, Jerome S.
    Tegman, Viola
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sethson, Ingmar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    NMR studies of interactions between periplasmic chaperones from uropathogenic E-coli and pilicides that interfere with chaperone function and pilus assembly2005Ingår i: ORGANIC & BIOMOLECULAR CHEMISTRY, ISSN 1477-0520, Vol. 3, nr 23, s. 4193-4200Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adherence of uropathogenic Escherichia coli to host tissue is mediated by pili, which are hair-like protein structures extending from the outer cell membrane of the bacterium. The chaperones FimC and PapD are key components in pilus assembly since they catalyse folding of subunits that are incorporated in type 1 and P pili, respectively, and also transport the subunits across the periplasmic space. Recently, compounds that inhibit pilus biogenesis and interfere with chaperone-subunit interactions have been discovered and termed pilicides. In this paper NMR spectroscopy was used to study the interaction of different pilicides with PapD and FimC in order to gain structural knowledge that would explain the effect that some pilicides have on pilus assembly. First relaxation-edited NMR experiments revealed that the pilicides bound to the PapD chaperone with mM affinity. Then the pilicide-chaperone interaction surface was investigated through chemical shift mapping using N-15-labelled FimC. Principal component analysis performed on the chemical shift perturbation data revealed the presence of three binding sites on the surface of FimC, which interacted with three different classes of pilicides. Analysis of structure-activity relationships suggested that pilicides reduce pilus assembly in E. coli either by binding in the cleft of the chaperone, or by influencing the orientation of the flexible F1-G1 loop, both of which are part of the surface by which the chaperone forms complexes with pilus subunits. It is suggested that binding to either of these sites interferes with folding of the pilus subunits, which occurs during formation of the chaperone-subunit complexes. In addition, pilicides that influence the F1-G1 loop also appear to reduce pilus formation by their ability to dissociate chaperone-subunit complexes.

  • 54. Horvath, Dragos
    et al.
    Lisurek, Michael
    Rupp, Bernd
    Kuehne, Ronald
    Specker, Edgar
    von Kries, Jens
    Rognan, Didier
    Andersson, C. David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Enqvist, Per-Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gustavsson, Anna-Lena
    Remez, Nikita
    Mestres, Jordi
    Marcou, Gilles
    Varnek, Alexander
    Hibert, Marcel
    Quintana, Jordi
    Frank, Ronald
    Design of a general-purpose European compound screening library for EU-OPENSCREEN2014Ingår i: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 9, nr 10, s. 2309-2326Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This work describes a collaborative effort to define and apply a protocol for the rational selection of a general-purpose screening library, to be used by the screening platforms affiliated with the EU-OPENSCREEN initiative. It is designed as a standard source of compounds for primary screening against novel biological targets, at the request of research partners. Given the general nature of the potential applications of this compound collection, the focus of the selection strategy lies on ensuring chemical stability, absence of reactive compounds, screening-compliant physicochemical properties, loose compliance to drug-likeness criteria (as drug design is a major, but not exclusive application), and maximal diversity/coverage of chemical space, aimed at providing hits for a wide spectrum of drugable targets. Finally, practical availability/cost issues cannot be avoided. The main goal of this publication is to inform potential future users of this library about its conception, sources, and characteristics. The outline of the selection procedure, notably of the filtering rules designed by a large committee of European medicinal chemists and chemoinformaticians, may be of general methodological interest for the screening/medicinal chemistry community. The selection task of 200K molecules out of a pre-filtered set of 1.4M candidates was shared by five independent European research groups, each picking a subset of 40K compounds according to their own in-house methodology and expertise. An in-depth analysis of chemical space coverage of the library serves not only to characterize the collection, but also to compare the various chemoinformatics-driven selection procedures of maximal diversity sets. Compound selections contributed by various participating groups were mapped onto general-purpose self-organizing maps (SOMs) built on the basis of marketed drugs and bioactive reference molecules. In this way, the occupancy of chemical space by the EU-OPENSCREEN library could be directly compared with distributions of known bioactives of various classes. This mapping highlights the relevance of the selection and shows how the consensus reached by merging the five different 40K selections contributes to achieve this relevance. The approach also allows one to readily identify subsets of target-or target-class-oriented compounds from the EU-OPENSCREEN library to suit the needs of the diverse range of potential users. The final EU-OPENSCREEN library, assembled by merging five independent selections of 40K compounds from various expert groups, represents an excellent example of a Europe-wide collaborative effort toward the common objective of building best-in-class European open screening platforms.

  • 55.
    Horvath, Istvan
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sellstedt, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Weise, Christoph
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nordvall, Lina-Maria
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Golla, Krishna Prasad
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Larsson, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: templation and inhibition involve oligomers with different structure2013Ingår i: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 532, nr 2, s. 84-90Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In a recent study we discovered that a ring-fused 2-pyridone compound triggered fibrillization of a key protein in Parkinson's disease, α-synuclein. To reveal how variations in compound structure affect protein aggregation, we now prepared a number of strategic analogs and tested their effects on α-synuclein amyloid fiber formation in vitro. We find that, in contrast to the earlier templating effect, some analogs inhibit α-synuclein fibrillization. For both templating and inhibiting compounds, the key species formed in the reactions are α-synuclein oligomers that contain compound. Despite similar macroscopic appearance, the templating and inhibiting oligomers are distinctly different in secondary structure content. When the inhibitory oligomers are added in seed amounts, they inhibit fresh α-synuclein aggregation reactions. Our study demonstrates that small chemical changes to the same central fragment can result in opposite effects on protein aggregation.

  • 56.
    Horvath, Istvan
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Weise, Christoph F
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, Emma K
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sellstedt, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hultgren, Scott J
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
    Chapman, Matthew
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wolf-Watz, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation2012Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, nr 7, s. 3439-3444Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Small organic molecules that inhibit functional bacterial amyloid fibers, curli, are promising new antibiotics. Here we investigated the mechanism by which the ring-fused 2-pyridone FN075 inhibits fibrillation of the curli protein CsgA. Using a variety of biophysical techniques, we found that FN075 promotes CsgA to form off-pathway, non-amyloidogenic oligomeric species. In light of the generic properties of amyloids, we tested whether FN075 would also affect the fibrillation reaction of human α-synuclein, an amyloid-forming protein involved in Parkinson's disease. Surprisingly, FN075 stimulates α-synuclein amyloid fiber formation as measured by thioflavin T emission, electron microscopy (EM), and atomic force microscopy (AFM). NMR data on (15)N-labeled α-synuclein show that upon FN075 addition, α-synuclein oligomers with 7 nm radius form in which the C-terminal 40 residues remain disordered and solvent exposed. The polypeptides in these oligomers contain β-like secondary structure, and the oligomers are detectable by AFM, EM, and size-exclusion chromatography (SEC). Taken together, FN075 triggers oligomer formation of both proteins: in the case of CsgA, the oligomers do not proceed to fibers, whereas for α-synuclein, the oligomers are poised to rapidly form fibers. We conclude that there is a fine balance between small-molecule inhibition and templation that depends on protein chemistry.

  • 57.
    Hussain, Munawar
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Banchelin, Thomas Sainte-Luce
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Olsson, Roger
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Enantioselective synthesis of substituted piperidines by addition of aryl Grignard reagents to pyridine N-oxides2013Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 15, nr 1, s. 54-57Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The synthesis of optically active piperidines by enantioselective addition of aryl Grignard reagents to pyridine N-oxides and lithium binolate followed by reduction is reported for the first time. The reaction results in high yields (51-94%) in combination with good ee (54-80%). Some of these products were subsequently recrystallized, affording enhanced optical purities (>99% ee).

  • 58. Jain, Neha
    et al.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nagamatsu, Kanna
    Evans, Margery L.
    Li, Xinyi
    McMichael, Brennan
    Ivanova, Magdalena I.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Buxbaum, Joel N.
    Chapman, Matthew R.
    Inhibition of curli assembly and Escherichia coli biofilm formation by the human systemic amyloid precursor transthyretin2017Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 46, s. 12184-12189Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During biofilm formation, Escherichia coli and other Enterobacteriaceae produce an extracellular matrix consisting of curli amyloid fibers and cellulose. The precursor of curli fibers is the amyloidogenic protein CsgA. The human systemic amyloid precursor protein transthyretin (TTR) is known to inhibit amyloid-β (Aβ) aggregation in vitro and suppress the Alzheimer’s-like phenotypes in a transgenic mouse model of Aβ deposition. We hypothesized that TTR might have broad antiamyloid activity because the biophysical properties of amyloids are largely conserved across species and kingdoms. Here, we report that both human WT tetrameric TTR (WT-TTR) and its engineered nontetramer-forming monomer (M-TTR, F87M/L110M) inhibit CsgA amyloid formation in vitro, with M-TTR being the more efficient inhibitor. Preincubation of WT-TTR with small molecules that occupy the T4 binding site eliminated the inhibitory capacity of the tetramer; however, they did not significantly compromise the ability of M-TTR to inhibit CsgA amyloidogenesis. TTR also inhibited amyloid-dependent biofilm formation in two different bacterial species with no apparent bactericidal or bacteriostatic effects. These discoveries suggest that TTR is an effective antibiofilm agent that could potentiate antibiotic efficacy in infections associated with significant biofilm formation.

  • 59.
    Klinth, Jeanna E
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Pinkner, Jerome S
    Hultgren, Scott J
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Uhlin, Bernt Eric
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Axner, Ove
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Impairment of the biomechanical compliance of P pili: a novel means of inhibiting uropathogenic bacterial infections?2012Ingår i: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 41, nr 3, s. 285-295Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gram-negative bacteria often initiate their colonization by use of extended attachment organelles, so called pili. When exposed to force, the rod of helix-like pili has been found to be highly extendable, mainly attributed to uncoiling and recoiling of its quaternary structure. This provides the bacteria with the ability to redistribute an external force among a multitude of pili, which enables them to withstand strong rinsing flows, which, in turn, facilitates adherence and colonization processes critical to virulence. Thus, pili fibers are possible targets for novel antibacterial agents. By use of a substance that compromises compliance of the pili, the ability of bacteria to redistribute external forces can be impaired, so they will no longer be able to resist strong urine flow and thus be removed from the host. It is possible such a substance can serve as an alternative to existing antibiotics in the future or be a part of a multi-drug. In this work we investigated whether it is possible to achieve this by targeting the recoiling process. The test substance was purified PapD. The effect of PapD on the compliance of P pili was assessed at the single organelle level by use of force-measuring optical tweezers. We showed that the recoiling process, and thus the biomechanical compliance, in particular the recoiling process, can be impaired by the presence of PapD. This leads to a new concept in the search for novel drug candidates combating uropathogenic bacterial infections-"coilicides", targeting the subunits of which the pilus rod is composed.

  • 60.
    Krishnan, K. Syam
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Good, James A. D.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Mirkhanov, Shamil
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Lennart B. -Å.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Synthesis of fluorescent ring-fused 2-pyridone peptidomimetics2013Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 23, s. 12207-12213Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thiazolino fused 2-pyridones peptidomimetics are of significant biological importance due to their ability to interfere with adhesive fiber formation in uropathogenic Escherichia coli and oligomerization of amyloid fibres. We have developed an efficient synthetic route to fluorescent BODIPY analogues, with structural diversification from a key intermediate enabling introduction of C-2 substituents and late incorporation of the BODIPY moiety. A mild lithium halide mediated hydrolysis enabled preparation of peptidomimetic fluorophores with useful photophysical properties for further chemical biology applications.

  • 61.
    Kulén, Martina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Lindgren, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Hansen, Sabine
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Cairns, Andrew G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Grundström, Christin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Begum, Afshan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    van der Lingen, Ingeborg
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hall, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Sauer, Uwe H.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Johansson, Jörgen
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Sauer-Eriksson, A. Elisabeth
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Structure-based design of inhibitors targeting PrfA, the master virulence regulator of Listeria monocytogenes2018Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, nr 9, s. 4165-4175Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Listeria monocytogenes is a bacterial pathogen that controls much of its virulence through the transcriptional regulator PrfA. In this study, we describe structure guided design and synthesis of a set of PrfA inhibitors based on ring-fused 2-pyridone heterocycles. Our most effective compound decreased virulence factor expression, reduced bacterial uptake into eukaryotic cells, and improved survival of chicken embryos infected with L. monocytogenes compared to previously identified compounds. Crystal structures identified an intraprotein "tunnel" as the main inhibitor binding site (A1), where the compounds participate in an extensive hydrophobic network that restricts the protein's ability to form functional DNA-binding helix−turn−helix (HTH) motifs. Our studies also revealed a hitherto unsuspected structural plasticity of the HTH motif. In conclusion, we have designed 2-pyridone analogues that function as site-A1 selective PrfA inhibitors with potent antivirulence properties.

  • 62.
    Larsson, Andreas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Susanne M. C.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome S.
    Hultgren, Scott J.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli2005Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, nr 4, s. 935-945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A peptide library targeting protein-protein interactions crucial for pilus assembly in Gram negative bacteria has been designed using statistical molecular design. A nonamer peptide scaffold was used, with seven positions being varied. The selection was performed in the building block space, and previously known structure-activity data were included in the design procedure. This resulted in a heavily reduced library consisting of 32 peptides which was prepared by solid-phase synthesis. The ability of the peptides to inhibit the protein-protein interaction between the periplasmic chaperone FimC and the pilus adhesin FimH was then determined in an ELISA. Novel peptides with the capability to inhibit the FimC/FimH protein(-)protein interaction to the same extent as the native FimC peptides were discovered. Multivariate QSAR studies of the response in the ELISA gave valuable information on the properties of amino acids which were preferred at the seven positions in the nonamer scaffold. This information can be used in attempts to develop optimized peptides and peptidomimetics that inhibit pilus assembly in pathogenic bacteria.

  • 63.
    Larsson, Andreas
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Spjut, Sara
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    An improved procedure for the synthesis of enaminones - Dimer building blocks in beta-strand mimetics2005Ingår i: SYNTHESIS-STUTTGART, ISSN 0039-7881, Vol. 15, s. 2590-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    @-Tides have been shown to have the same characteristics as a peptide in the P-strand conformation and to have the ability to self-associate into dimeric beta-sheets. Aza-cyclohexaenaminones, obtained by condensation of a protected azacyclohexa-3,5-dione and amino acid esters, are the key building-blocks in the synthesis of @-tides. An improved three-step synthetic sequence to these enaminones has been developed that takes advantage of microwave-assisted chemistry in two of the steps to enhance the reaction rates. It was also found that the enaminone building blocks can be obtained by direct condensation of the aza-cyclohexa-3,5-dione with amino acid esters, without prior activation of the diketone. Multivariate design was used to optimize this microwave-assisted condensation, resulting in a short reaction time (300 s) and high yields (67-94%).

  • 64. Lee, Yvonne M
    et al.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Hultgren, Scott J
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Targeting virulence for antimicrobial chemotherapy2003Ingår i: Current Opinion in Pharmacology, Vol. 3, nr 5, s. 513-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Untreatable bacterial infections constitute a dark but valid threat, with numbers of antibiotic resistant pathogens, as well as newly emerging ones, rising quickly. To combat this dangerous prospect, growing research into antimicrobials could be aimed at targeting the virulence of pathogens. Virulence refers to an organism’s ability to establish an infection and cause disease. Many steps involved in the infection process can be targeted, including adherence, invasion and host defense evasion. Identification and characterization of virulence factors that aid in bacterial pathogenicity will lead to new drugs that can be applied to a variety of pathogens.

  • 65. Lindström, Anton
    et al.
    Pettersson, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Berglund, Anders
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Hierarchical PLS modeling for predicting the binding of a comprehensive set of structurally diverse protein-ligand complexes.2006Ingår i: Journal of Chem Inf Model, ISSN 1549-9596, Vol. 46, nr 3, s. 1154-1167Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new approach is presented for predicting ligand binding to proteins using hierarchical partial-least-squares regression to latent structures (Hi-PLS). Models were based on information from the 2002 release of the PDBbind database containing (after in-house refinement) high-resolution X-ray crystallography and binding affinity (Kd or Ki) data for 612 protein-ligand complexes. The complexes were characterized by four different descriptor blocks: three-dimensional (3D) structural descriptors of the proteins, protein-ligand interactions according to the Validate scoring function, binding site surface areas, and ligand 2D and 3D descriptors. These descriptor blocks were used in Hi-PLS models, generated using both linear and nonlinear terms, to relate the characterizations to pKd/i. The results show that each of the four descriptor blocks contributed to the model, and the predictions of pKd/i of the internal test set gave a root-mean-square error of prediction (RMSEP) of 1.65. The data were further divided according to the structural classification of the proteins, and Hi-PLS models were constructed for the resulting subclasses. The models for the four subclasses differed considerably in terms of both their ability to predict pKd/i (with RMSEPs ranging from 0.8 to 1.56) and the descriptor block that had the strongest influence. The models were validated with an external test set of 174 complexes from the 2003 release of the PDBbind database. The overall results show that the presented Hi-PLS methodology could facilitate the difficult task of predicting binding affinity.

  • 66. Olsen, Laura K.
    et al.
    Cairns, Andrew G.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Moriarty, Niamh
    Cabre, Silvia
    Alamilla, Veronica R.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Dowd, Eilís
    McKernan, Declan P.
    Viral mimetic priming enhances α-synuclein-induced degeneration: implications for Parkinson's disease2019Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 80, s. 525-535Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Evidence is accumulating to suggest that viral infections and consequent viral-mediated neuroinflammation may contribute to the etiology of idiopathic Parkinson’s disease. Moreover, viruses have been shown to influence α-synuclein oligomerization as well as the autophagic clearance of abnormal intra-cellular proteins aggregations, both of which are key neuropathological events in Parkinson’s disease pathogenesis. To further investigate the interaction between viral-mediated neuroinflammation and α-synuclein aggregation in the context of Parkinson’s disease, this study sought to determine the impact of viral neuroinflammatory priming on α-synuclein aggregate-induced neuroinflammation and neurotoxicity in the rat nigrostriatal pathway. To do so, male Sprague-Dawley rats were intra-nigrally injected with a synthetic mimetic of viral dsRNA (poly I:C) followed two weeks later by a peptidomimetic small molecule which accelerates α-synuclein fibril formation (FN075). The impact of the viral priming on α-synuclein aggregation-induced neuroinflammation, neurodegeneration and motor dysfunction was assessed. We found that prior administration of the viral mimetic poly I:C significantly exacerbated or precipitated the α-synuclein aggregate induced neuropathological and behavioral effects. Specifically, sequential exposure to the two challenges caused a significant increase in nigral microgliosis (p < 0.001) and astrocytosis (p < 0.01); precipitated a significant degeneration of the nigrostriatal cell bodies (p < 0.05); and precipitated a significant impairment in forelimb kinesis (p < 0.01) and sensorimotor integration (p < 0.01). The enhanced sensitivity of the nigrostriatal neurons to pathological α-synuclein aggregation after viral neuroinflammatory priming further suggests that viral infections may contribute to the etiology and pathogenesis of Parkinson’s disease.

  • 67. Omattage, Natalie S.
    et al.
    Deng, Zengqin
    Pinkner, Jerome S.
    Dodson, Karen W.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Yuan, Peng
    Hultgren, Scott J.
    Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli2018Ingår i: Nature Microbiology, E-ISSN 2058-5276, Vol. 3, nr 12, s. 1362-1368Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chaperone-usher pathway pili are extracellular proteinaceous fibres ubiquitously found on Gram-negative bacteria, and mediate host-pathogen interactions and biofilm formation critical in pathogenesis in numerous human diseases(1). During pilus assembly, an outer membrane macromolecular machine called the usher catalyses pilus biogenesis from the individual subunits that are delivered as chaperone-subunit complexes in the periplasm. The usher orchestrates pilus assembly using all five functional domains: a 24-stranded transmembrane beta-barrel translocation domain, a beta-sandwich plug domain, an amino-terminal periplasmic domain and two carboxy-terminal periplasmic domains (CTD1 and CTD2)(2-6). Despite extensive structural and functional characterization, the mechanism by which the usher is activated to initiate pilus biogenesis is unknown. Here, we present the crystal structure of the full-length PapC usher from Escherichia coli in complex with its cognate PapDG chaperone-subunit complex in a pre-activation state, elucidating molecular details of how the usher is specifically engaged by allosteric interactions with its substrate preceding activation and how the usher facilitates the transfer of subunits from the amino-terminal periplasmic domain to the CTDs during pilus assembly. This work elucidates the intricate workings of a molecular machine that catalyses chaperone-usher pathway pilus assembly and opens the door for the development of potent inhibitors to block pilus biogenesis.

  • 68.
    Pemberton, Nils
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Microwave-assisted synthesis and functionalization of 2-pyridones, 2-quinolones and other ring-fused 2-pyridones2006Ingår i: Microwave-assisted synthesis of hetreocycles / [ed] Erik Van der Eycken and C. Oliver Kappe, Springer-Verlag , 2006, s. 1-30Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    2-pyridones are important heterocycles with great applicability in medicinal chemistry and this core structure can be found in compounds with various biological/medicinal applications. Here we show how microwave-assisted chemistry can be used to effectively synthesize and functionalize substituted monocyclic 2-pyridones, 2-quinolones and other ring-fused 2-pyridones. The chapter covers recent advancements in this field mainly describing methods developed with instruments specially designed for microwave-assisted organic synthesis (MAOS).

  • 69.
    Pemberton, Nils
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Emtenäs, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Boström, Dan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Domaille, Peter J
    Greenberg, William A
    Levin, Michael D
    Zhu, Zuolin
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Cycloaddition of 2-thiazolines and acyl ketenes under acidic conditions results in bicyclic 1,3-oxazinones and not 6-acylpenams as earlier reported2005Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 7, nr 6, s. 1019-1021Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Optically active 2-thiazolines 4 were previously reported to react with acyl Meldrum's acid derivatives 5 under acidic conditions (HCl (g) in benzene) to stereoselectively give 6-acylpenams 1. Recently we have discovered that the structure elucidation of these compounds was incorrect. Thus, we report new data showing that instead of acyl -lactams, the optically active isomers 3R,9R-1,3-oxazinones 3a-g are obtained stereoselectively in 38-93% yields.

  • 70.
    Pemberton, Nils
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jakobsson, Lotta
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Synthesis of multi ring-fused 2-pyridones via an acyl-ketene imine cyclocondensation2006Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 8, nr 5, s. 935-938Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polycyclic ring-fused 2-pyridones (5a−e and 9a−e) have been prepared via a microwave-assisted acyl-ketene imine cyclocondensation. Starting from 3,4-dihydroisoquinolines (4a−b) or 3,4-dihydroharman (8), fused 2-pyridones could be prepared in a one-step procedure. By using either Meldrum's acid derivatives (1a−d) or 1,3-dioxine-4-ones (7a−b) as acyl-ketene sources, mono- or disubstitution of the fused 2-pyridone ring could be accomplished. As an application of the method, a formal synthesis of the indole alkaloid sempervilam was performed.

  • 71.
    Pemberton, Nils
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome
    Jones, Jennifer
    Jakobsson, Lotta
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hultgren, Scott J.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Functionalization of bicyclic 2-pyridones targeting pilus biogenesis in uropathogenic Escherichia coli2007Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 48, nr 26, s. 4543-4546Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Substituted bicyclic 2-pyridones, termed pilicides, prevent pilus assembly in uropathogenic Escherichia coli. Based on the bioactive methyl ester protected 2-pyridone 4, further functionalization at C-6 has yielded a set of new compounds, which have been evaluated for their ability to inhibit pilus formation in uropathogenic E. coli. The key intermediate in the synthesis was formylated 2-pyridone 5, which could be obtained via a Vilsmeier reaction. This versatile intermediate was converted into secondary and tertiary amines via reductive amination and could also be converted to other interesting functionalities using simple chemical transformations.

  • 72.
    Pemberton, Nils
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Pinkner, Jerome S
    Edvinsson, Sofie
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Hultgren, Scott J
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Synthesis and evaluation of dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones - Targeting pilus biogenesis in uropathogenic bacteria2008Ingår i: Tetrahedron, Vol. 64, nr 40, s. 9368-76Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dihydrothiazolo ring-fused 2-pyridones have previously been shown to inhibit pilus assembly in uropathogenic Escherichia coli. Methods have now been developed to synthesize both dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones. To obtain the nitrogen analogs, Cbz-protected imidazolines were reacted with an acyl-Meldrum's acid derivative under acidic conditions. To prepare the oxygen analogs, a one-pot procedure was developed that allowed synthesis of dihydrooxazolo ring-fused 2-pyridones starting from acylated serine derivatives. After hydrolysis to their corresponding carboxylic acids and lithium carboxylates, biological evaluation revealed that the sulfur could be replaced by an oxygen atom and still maintains the ability to inhibit pilus assembly in uropathogenic E. coli. However, introducing a secondary amine instead of oxygen resulted in a substantial decrease in biological activity.

  • 73.
    Pemberton, Nils
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Åberg, Veronica
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almstedt, Hanna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Westermark, Andreas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones2004Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, nr 23, s. 7830-7835Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established. Primary amino methylene substituents were introduced via a cyanodehalogenation followed by a borane dimethyl sulfide reduction of the afforded nitrile. In both of these transformations, microwave irradiation proved to be superior to traditional conditions and the primary amines were obtained in good overall yields (55-58% over three steps). To incorporate tertiary aminomethylene substituents in the 2-pyridone framework, a microwave-assisted Mannich reaction using preformed iminium salts proved to be effective. Thus highly substituted 2-pyridones were obtained in 48-93% yields.

     

  • 74. Perdersen, Martin Nors
    et al.
    Fodera, Vito
    Horvath, Istvan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    van Maarschalkerweerd, Andreas
    Toft, Katrine Norgaard
    Weise, Christoph
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Wolf-Watz, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Vestergaard, Bente
    Direct Correlation Between Ligand-Induced alpha-Synuclein Oligomers and Amyloid-like Fibril Growth2015Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, artikel-id 10422Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075: protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha-synuclein fibril elongation.

  • 75. Petzold, Daniel
    et al.
    Singh, Pardeep
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    König, Burkhard
    Visible light mediated synthesis of β chloro ketones from aryl cyclopropanes2019Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 58, s. 8577-8580Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report the visible light mediated synthesis of β chloro ketones from aryl cyclopropanes, oxygen, hydrochloric acid and nitric acid. The operationally simple and catalyst free method uses cheap standard lab reagents and displays a broad functional group tolerance. Moreover, scale up of the reaction and late stage functionalization of bioactive compounds is possible, providing the opportunity to utilize the cyclopropane ring as a masked β chloro ketone in a reaction sequence. We propose a light‐driven radical chain reaction initiated by the reaction of diluted hydrochloric and nitric acid producing small quantities of molecular chlorine. The mechanistic hypothesis is supported by 18O labelling and UV‐VIS experiments, cyclovoltammetry and several control reactions.

  • 76. Pinkner, Jerome S.
    et al.
    Remaut, Han
    Buelens, Floris
    Miller, Eric
    Åberg, Veronica
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pemberton, Nils
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Larsson, Andreas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Seed, Patrick
    Waksman, Gabriel
    Hultgren, Scott J.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria2006Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 47, s. 17897-17902Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone–usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by 90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone–subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.

  • 77. Pokrzywa, Malgorzata
    et al.
    Pawelek, Katarzyna
    Kucia, Weronika Elzbieta
    Sarbak, Szymon
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    Effects of small-molecule amyloid modulators on a Drosophila model of Parkinson's disease2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 9, artikel-id e0184117Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alpha-synuclein (aS) amyloid formation is involved in Parkinson's disease (PD); therefore, small molecules that target aS and affect its aggregation are of interest as future drug candidates. We recently reported modified ring-fused 2-pyridones that modulate aS amyloid formation in vitro. Here, we describe the effects of such molecules on behavioral parameters of a Drosophila model of PD (i.e., flies expressing human aS), using a new approach (implemented in a commercially available FlyTracker system) to quantify fly mobility. FlyTracker allows for automated analysis of walking and climbing locomotor behavior, as it collects large sequences of data over time in an unbiased manner. We found that the molecules per se have no toxic or kinetic effects on normal flies. Feeding aS-expressing flies with the amyloid-promoting molecule FN075, remarkably, resulted in increased fly mobility at early time points; however, this effect switched to reduced mobility at later time points, and flies had shorter life spans than controls. In contrast, an amyloid inhibitor increased both fly kinetics and life span. In agreement with increased aS amyloid formation, the FN075-fed flies had less soluble aS, and in vitro aS-FN075 interactions stimulated aS amyloid formation. In addition to a new quantitative approach to probe mobility (available in FlyTracker), our results imply that aS regulates brain activity such that initial removal (here, by FN075-triggered assembly of aS) allows for increased fly mobility.

  • 78.
    Rosenbaum, Erik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sellstedt, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Lennart B-Å
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Unusual light spectroscopic properties of a 2-Pyridone-based multi-ring-fused Fluorescent Scaffold2010Ingår i: Journal of Fluorescence, ISSN 1053-0509, E-ISSN 1573-4994, Vol. 20, nr 6, s. 1249-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    UV-VIS absorption and fluorescence spectroscopic properties of six related polyaromatic 2-pyridones have been studied. Excitation of the lowest and rather weak and structure-less transition [epsilon (max) (430 nm) approximately 3,000 mol-1dm3cm-1] gives rise to a broad fluorescence band in the visible region, for these compounds. These S0 <--> S1 transitions are compatible with symmetrically forbidden transitions, promoted by intensity borrowing, as is revealed by fluorescence depolarisation data. With one exception, all compounds exhibit strong fluorescence, with quantum yields in glycerol varying between 40% and 70%. The corresponding fluorescence lifetimes range from 11 ns to 17 ns, while the radiative lifetimes are very similar ( approximately 26 ns), for all compounds. Interestingly and rarely observed, the calculated radiative lifetimes for the weak absorption band are significantly longer, i.e. between 37 and 40 ns.

  • 79.
    Sachl, Radek
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Rosenbaum, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sellstedt, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Lennart B-Å
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Locations and reorientations of multi-ring-fused 2-Pyridones in Ganglioside GM1 Micelles2011Ingår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, nr 5, s. 1662-1667Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fluorescent multi-ring-fused 2-pyridones, with chemical resemblance to other biologically active 2-pyridone systems, were solubilized in spherical micelles formed by the gangloiside GM1 and studied with respect to their spatial localization and rotational mobility. For this, electronic energy transfer between the multi-ring-fused 2-pyridone (donor) and BODIPY-FL-labeled GM1 was determined, as well as their fluorescence depolarization. From the obtained efficiency of energy transfer to the acceptor group (BODIPY-FL), either localized in the polar or in the nonpolar part of the ganglioside, it has been possible to estimate the most likely localization of the multi-ring-fused 2-pyridones. The center of mass of the studied multi-ring-fused 2-pyridones are located at approximately 33 Å from the micellar center of mass, which corresponds to the internal hydrophobic-hydrophilic interfacial region. At this location, the reorienting rates of the multi-ring-fused 2-pyridones are surprisingly slow with typical correlation times of 35-55 ns. No evidence was found for the formation of ground and excited state dimers, even when two monomers were forced to be near each other via a short covalent linker.

  • 80. Sarvary, Ian
    et al.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Frejd, Torbjörn
    Asymmetric Reduction of Ketones with Catecholborane Using 2,6-BODOL Complexes of Titanium(iv) as Catalysts2001Ingår i: Chemistry - A European Journal, Vol. 7, nr 10, s. 2158-66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Reductions performed with TiIV complexes of ligands based on bicyclo[2.2.2]octane diols 5 and 6 are effective catalysts in the reduction of prochiral ketones to optically active alcohols, with catecholborane as the reducing agent. Methyl ketones are favored and enantiomeric excesses (ee) of 98 % have been achieved with acetophenone as the substrate. Several other substrates were tested, among them 2-octanone, which gave 2-octanol in 87 % ee. Further details of the method were examined, for example, temperature, solvent composition, amount of molecular sieves (4 Å), and catecholborane quality, as well as the sensitivity of the ligands towards acids. NMR spectroscopic methods were used to gain some insight into the complexes formed between the ligands and [Ti(OiPr)4]. A dimeric structure is proposed for the pre-catalyst.

    Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2111/2001/f2647_s.pdf from the author.

  • 81.
    Sellstedt, Magnus
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    A novel heterocyclic Scaffold formed by ring expansion of a cyclic Sulfone to Sulfonamides2009Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 11, nr 23, s. 5470-5472Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A novel heterocyclic scaffold with a peptidomimetic backbone structure has been synthesized. The scaffold is formed by insertion of primary amines into a cyclic sulfone to give the corresponding ring-expanded sulfonamides. By varying the amine component, a series of potentially biologically interesting compounds has been synthesized.

  • 82.
    Sellstedt, Magnus
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    A three-component reaction forming naphthyridones: synthesis of lophocladine analogs2011Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 13, nr 19, s. 5278-5281Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A three-component reaction forming dihydro 2,7-naphthyridine-1-ones has been developed. These unstable dihydro intermediates can be either oxidized or reduced to form naphthyridones or tetrahydro naphthyridones, respectively. The reaction tolerates a large variety of aldehydes and amines, and the produced compounds are analogs of the natural product lophocladine A.

  • 83.
    Sellstedt, Magnus
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Development of a three-component reaction forming naphtyridones: Synthesis of lophocladine analogs2011Ingår i: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 242, s. 255-ORGN-Artikel i tidskrift (Refereegranskat)
  • 84.
    Sellstedt, Magnus
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis of a novel tricyclic peptidomimetic Scaffold2008Ingår i: Organic Letters, Vol. 10, nr 18, s. 4005-4007Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An efficient method to synthesize a novel rigid tricyclic peptidomimetic scaffold through ring-closure of amino-functionalized bicyclic 2-pyridones has been discovered. The scaffold can function as a peptide backbone mimetic (highlighted) with two substituents independently variable to fine-tune biological response. Halogenation of the pyrazolo ring followed by Suzuki couplings made it possible to introduce substituents with variable electronic properties late in the synthetic route, which is preferable in library synthesis.

  • 85.
    Sellstedt, Magnus
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Dang, Hung The
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Prasad, G. Krishna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sauer, Uwe
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Four-Component Assembly of Natural-Product-Like Ring-Fused Isoquinuclidines2013Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2013, nr 33, s. 7476-7479Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A four-component reaction between formyl-substituted 2-pyridones, aldehydes, amines, and activated alkenes has been developed. The resulting products are ring-fused natural-product-like isoquinuclidines. Three carbon–carbon bonds, two carbon–nitrogen bonds, and four or five stereocentres are formed in the reaction with overall product yields in the range 23–67 %. In most cases a single diastereomer was obtained. An intramolecular version of the reaction yielded analogues of the multi-ring-fused natural product catharanthine in a single step.

  • 86.
    Sellstedt, Magnus
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nyberg, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Rosenbaum, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Engström, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Wickström, Malin
    Department of Medicinal Sciences, Division of Clinical Pharmacology, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Gullbo, Joachim
    Department of Medicinal Sciences, Division of Clinical Pharmacology, Uppsala University Hospital, 75185 Uppsala, Sweden.
    Bergström, Sven
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Johansson, Lennart B-Å
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis and characterization of a multi ring-fused 2-pyridone-based fluorescent scaffold2010Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 32, s. 6171-6178Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A series of compounds based on a novel fluorescent scaffold have been synthesized. Most of the compounds displayed high quantum yields of fluorescence and unusually long fluorescence lifetimes. HeLa cells were treated with one of the compounds and its use as a fluorescent dye was demonstrated with fluorescence confocal microscopy.

  • 87.
    Sellstedt, Magnus
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Prasad, G Krishna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Krishnan, K Syam
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Directed diversity-oriented synthesis. Ring-fused 5- to 10-membered rings from a common peptidomimetic 2-pyridone precursor.2012Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 53, nr 45, s. 6022-6024Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A variety of ring-fused 2-pyridone-based central fragments were prepared using a strategy inspired by diversity-oriented synthesis. The produced compounds are diverse, yet focused, analogs of biologically active peptidomimetic 2-pyridones.

  • 88. Shaffer, Carrie L.
    et al.
    Good, James A. D.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Kumar, Santosh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Krishnan, K. Syam
    Gaddy, Jennifer A.
    Loh, John T.
    Chappell, Joseph
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Cover, Timothy L.
    Hadjifrangiskou, Maria
    Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens2016Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 7, nr 2, artikel-id e00221-16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS-mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In H. pylori, KSK85 impedes biogenesis of the pilus appendage associated with the cag T4SS, while C10 disrupts cag T4SS activity without perturbing pilus assembly. In addition to the effects in H. pylori, we demonstrate that these compounds disrupt interbacterial DNA transfer by conjugative T4SSs in Escherichia coli and impede vir T4SS-mediated DNA delivery by Agrobacterium tumefaciens in a plant model of infection. Of note, C10 effectively disarmed dissemination of a derepressed IncF plasmid into a recipient bacterial population, thus demonstrating the potential of these compounds in mitigating the spread of antibiotic resistance determinants driven by conjugation. To our knowledge, this study is the first report of synthetic small molecules that impair delivery of both effector protein and DNA cargos by diverse T4SSs. IMPORTANCE Many human and plant pathogens utilize complex nanomachines called type IV secretion systems (T4SSs) to transport proteins and DNA to target cells. In addition to delivery of harmful effector proteins into target cells, T4SSs can disseminate genetic determinants that confer antibiotic resistance among bacterial populations. In this study, we sought to identify compounds that disrupt T4SS-mediated processes. Using the human gastric pathogen H. pylori as a model system, we identified and characterized two small molecules that prevent transfer of an oncogenic effector protein to host cells. We discovered that these small molecules also prevented the spread of antibiotic resistance plasmids in E. coli populations and diminished the transfer of tumor-inducing DNA from the plant pathogen A. tumefaciens to target cells. Thus, these compounds are versatile molecular tools that can be used to study and disarm these important bacterial machines.

  • 89.
    Singh, Pardeep
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Adolfsson, Dan E.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Cairns, Andrew G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bartens, Christian
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Olofsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pyridine-Fused 2-Pyridones via Povarov and A3 Reactions: Rapid Generation of Highly Functionalized Tricyclic Heterocycles Capable of Amyloid Fibril Binding2019Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, nr 7, s. 3887-3903Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We here describe the use of three-component reactions to synthesize tricyclic pyridine ring-fused 2-pyridones. The developed protocols have a wide substrate scope and allow for the installation of diverse chemical functionalities on the tricyclic central fragment. Several of these pyridine-fused rigid polyheterocycles are shown to bind to Aβ and α-synuclein fibrils, which are associated with neurodegenerative diseases.

  • 90.
    Singh, Pardeep
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Cairns, Andrew G.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Adolfsson, Dan E.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sauer, Uwe H.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis of Densely Functionalized N-Alkenyl 2-Pyridones via Benzyne-Induced Ring Opening of Thiazolino-Fused 2-Pyridones2019Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 21, s. 6946-6950Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report the synthesis of 6-arylthio-substituted-N-alkenyl 2-pyridones by ring opening of bicyclic thiazolino-2-pyridones with arynes. Varied functionalization was used to investigate scope and substituent influences on reactivity. Selected conditions favor thioether ring opening over [4 + 2] cycloaddition and an unusual aryne incorporating ring expansion. Deuterium labeling was used to clarify observed reactivity. Using the knowledge, we produced drug-like molecules with complex substitution patterns and show how thioether ring opening can be used on scaffolds with competing reactivities.

  • 91.
    Singh, Pardeep
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Krishnan, K Syam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kindahl, Tomas
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis of multiring fused 2‑pyridones via a nitrene insertion reaction: fluorescent modulators of α‑synuclein amyloid formation2015Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, nr 24, s. 6194-6197Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An efficient, straightforward method for the synthesis of thiazolo-2-pyridone embedded peptidomimetic polyheterocycles via a catalyst-free, microwave-assisted, intramolecular C−H amination reaction is reported. All the synthesized polyheterocycles were evaluated for their fluorescent properties and effect on α-synuclein amyloid formation.

  • 92.
    Strand, Mårten
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Carlsson, Marcus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Uvell, Hanna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Islam, Koushikul
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Edlund, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Cullman, Inger
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Altermark, Björn
    Mei, Ya-Fang
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Willassen, Nils-Peder
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria2014Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 12, nr 2, s. 799-821Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adenovirus infections in immunocompromised patients are associated with high mortality rates. Currently, there are no effective anti-adenoviral therapies available. It is well known that actinobacteria can produce secondary metabolites that are attractive in drug discovery due to their structural diversity and their evolved interaction with biomolecules. Here, we have established an extract library derived from actinobacteria isolated from Vestfjorden, Norway, and performed a screening campaign to discover anti-adenoviral compounds. One extract with anti-adenoviral activity was found to contain a diastereomeric 1:1 mixture of the butenolide secondary alcohols 1a and 1b. By further cultivation and analysis, we could isolate 1a and 1b in different diastereomeric ratio. In addition, three more anti-adenoviral butenolides 2, 3 and 4 with differences in their side-chains were isolated. In this study, the anti-adenoviral activity of these compounds was characterized and substantial differences in the cytotoxic potential between the butenolide analogs were observed. The most potent butenolide analog 3 displayed an EC50 value of 91 μM and no prominent cytotoxicity at 2 mM. Furthermore, we propose a biosynthetic pathway for these compounds based on their relative time of appearance and structure.

  • 93.
    Svensson, Anette
    et al.
    Organic Chemistry 2 Center for Chemistry and Chemical Engineering Lund Institute of Technology, Lund University P.O. Box 124, SE-221 00 Lund, Sweden.
    Larsson, Andreas
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Emtenäs, Hans
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Fex, Tomas
    3Active Biotech, Lund Research Center P.O. Box 724, SE-220 07 Lund, Sweden.
    Hultgren, Scott J.
    Department of Molecular Microbiology Washington University School of Medicine 660 South Euclid Avenue, St. Louis, MO 63110, USA.
    Pinker, Jerome S.
    Department of Molecular Microbiology Washington University School of Medicine 660 South Euclid Avenue, St. Louis, MO 63110, USA.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Design and evaluation of Pilicides: Potential novel antibacterial agents directed against Uropathogenic Escherichia coli2001Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, ChemBioChem (Online), ISSN '1439-7633', Vol. 2, nr 12, s. 915-918Artikel i tidskrift (Refereegranskat)
  • 94.
    Tengel, Tobias
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Fex, Tomas
    Emtenäs, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sethson, Ingmar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Use of 19F NMR spectroscopy to screen chemical libraries for ligands that bind to proteins2004Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 2, nr 5, s. 725-731Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Identification of compounds from chemical libraries that bind to macromolecules by use of NMR spectroscopy has gained increasing importance during recent years. A simple methodology based on F-19 NMR spectroscopy for the screening of ligands that bind to proteins, which also provides qualitative information about relative binding strengths and the presence of multiple binding sites, is presented here. A library of fluorinated compounds was assembled and investigated for binding to the two bacterial chaperones PapD and FimC, and also to human serum albumin (HSA). It was found that library members which are bound to a target protein could be identified directly from line broadening and/or induced chemical shifts in a single, one-dimensional F-19 NMR spectrum. The results obtained for binding to PapD using F-19 NMR spectroscopy agreed well with independent studies based on surface plasmon resonance, providing support for the versatility and accuracy of the technique. When the library was titrated to a solution of PapD chemical shift and linewidth changes were observed with increasing ligand concentration, which indicated the presence of several binding sites on PapD and enabled the assessment of relative binding strengths for the different ligands. Screening by F-19 NMR spectroscopy should thus be a valuable addition to existing NMR techniques for evaluation of chemical libraries in bioorganic and medicinal chemistry.

  • 95. Vain, Thomas
    et al.
    Raggi, Sara
    Ferro, Noel
    Barange, Deepak Kumar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Chemical Biology Umeå, Chemical Biology Consortium Sweden.
    Kieffer, Martin
    Ma, Qian
    Doyle, Siamsa M.
    Thelander, Mattias
    Pařízková, Barbora
    Novák, Ondřej
    Ismail, Alexandre
    Enquist, Per-Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Chemical Biology Umeå, Chemical Biology Consortium Sweden.
    Rigal, Adeline
    Łangowska, Małgorzata
    Ramans Harborough, Sigurd
    Zhang, Yi
    Ljung, Karin
    Callis, Judy
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Chemical Biology Umeå, Chemical Biology Consortium Sweden.
    Kepinski, Stefan
    Estelle, Mark
    Pauwels, Laurens
    Robert, Stéphanie
    Selective auxin agonists induce specific AUX/IAA protein degradation to modulate plant development2019Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 13, s. 6463-6472Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The plant hormone auxin coordinates almost all aspects of plant development. Throughout plant life, the expression of hundreds of genes involved in auxin regulation is orchestrated via several combinatorial and cell-specific auxin perception systems. An effective approach to dissect these complex pathways is the use of synthetic molecules that target specific processes of auxin activity. Here, we describe synthetic auxins, RubNeddins (RNs), which act as selective auxin agonists. The RN with the greatest potential for dissecting auxin perception was RN4, which we used to reveal a role for the chromatin remodeling ATPase BRAHMA in apical hook development. Therefore, the understanding of RN mode of action paves the way to dissecting specific molecular components involved in auxin-regulated developmental processes.Auxin phytohormones control most aspects of plant development through a complex and interconnected signaling network. In the presence of auxin, AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) transcriptional repressors are targeted for degradation by the SKP1-CULLIN1-F-BOX (SCF) ubiquitin-protein ligases containing TRANSPORT INHIBITOR RESISTANT 1/AUXIN SIGNALING F-BOX (TIR1/AFB). CULLIN1-neddylation is required for SCFTIR1/AFB functionality, as exemplified by mutants deficient in the NEDD8-activating enzyme subunit AUXIN-RESISTANT 1 (AXR1). Here, we report a chemical biology screen that identifies small molecules requiring AXR1 to modulate plant development. We selected four molecules of interest, RubNeddin 1 to 4 (RN1 to -4), among which RN3 and RN4 trigger selective auxin responses at transcriptional, biochemical, and morphological levels. This selective activity is explained by their ability to consistently promote the interaction between TIR1 and a specific subset of AUX/IAA proteins, stimulating the degradation of particular AUX/IAA combinations. Finally, we performed a genetic screen using RN4, the RN with the greatest potential for dissecting auxin perception, which revealed that the chromatin remodeling ATPase BRAHMA is implicated in auxin-mediated apical hook development. These results demonstrate the power of selective auxin agonists to dissect auxin perception for plant developmental functions, as well as offering opportunities to discover new molecular players involved in auxin responses.

  • 96. Varga, M G
    et al.
    Shaffer, C L
    Sierra, J C
    Suarez, G
    Piazuelo, M B
    Whitaker, M E
    Romero-Gallo, J
    Krishna, U S
    Delgado, A
    Gomez, M A
    Good, James A D
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Skaar, E P
    Correa, P
    Wilson, K T
    Hadjifrangiskou, M
    Peek, R M
    Pathogenic Helicobacter pylori strains translocate DNA and activate TLR9 via the cancer-associated cag type IV secretion system2016Ingår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, nr 48, s. 6262-6269Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Helicobacter pylori (H. pylori) is the strongest identified risk factor for gastric cancer, the third most common cause of cancer-related death worldwide. An H. pylori constituent that augments cancer risk is the strain-specific cag pathogenicity island, which encodes a type IV secretion system (T4SS) that translocates a pro-inflammatory and oncogenic protein, CagA, into epithelial cells. However, the majority of persons colonized with CagA+ H. pylori strains do not develop cancer, suggesting that other microbial effectors also have a role in carcinogenesis. Toll-like receptor 9 (TLR9) is an endosome bound, innate immune receptor that detects and responds to hypo-methylated CpG DNA motifs that are most commonly found in microbial genomes. High-expression tlr9 polymorphisms have been linked to the development of premalignant lesions in the stomach. We now demonstrate that levels of H. pylori-mediated TLR9 activation and expression are directly related to gastric cancer risk in human populations. Mechanistically, we show for the first time that the H. pylori cancer-associated cag T4SS is required for TLR9 activation and that H. pylori DNA is actively translocated by the cag T4SS to engage this host receptor. Activation of TLR9 occurs through a contact-dependent mechanism between pathogen and host, and involves transfer of microbial DNA that is both protected as well as exposed during transport. These results indicate that TLR9 activation via the cag island may modify the risk for malignancy within the context of H. pylori infection and provide an important framework for future studies investigating the microbial-epithelial interface in gastric carcinogenesis.

  • 97.
    Wang, Xiaoyang
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kauppi, Anna M
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Olsson, Roger
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Efficient Solution-Phase Parallel Synthesis of 4-Substituted N-Protected Piperidines2003Ingår i: European Journal of Organic Chemistry, Vol. 23, s. 4586-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Practical conditions for the synthesis of 4-substituted N-protected piperidines through CuCN·2LiBr-catalyzed organozinc additions to 1-acylpyridinium salts and subsequent hydrogen-transfer hydrogenation have been established. The reaction sequence is performed at room temperature and provides 4-substituted N-protected piperidines in excellent overall yields without the isolation of intermediate dihydropyridines. In those cases in which the organozinc addition results in mixtures of 2- and 4-substituted dihydropyridines, the 2-substituted isomers are efficiently scavenged with maleic anhydride and subsequently removed by a mild extractive workup with NaHCO3 (sat.). The N-acyl group can conveniently be exchanged from N-phenoxycarbonyl to N-tBoc, thus allowing orthogonal deprotection strategies.

  • 98.
    Wixe, Torbjörn
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    An improved synthesis of 3-[1-(trifluoromethy1)-3H-1,2-diazirin-3-yl] aniline: a key intermediate in the synthesis of photoaffinity probes2017Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 58, nr 34, s. 3350-3352Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An improved synthesis of 3-[3-(trifluoromethyl)-3H-1,2-diazirin-3-yflaniline, achieving an overall yield of 38% over seven steps is reported. Only three chromatographic separations were needed and the preparation of similar to 0.7 g of the target compound was demonstrated. The stability of the diazirine in solution at room temperature while exposed to ambient light was studied. No significant degradation of the compound was observed over the course of five weeks in a 130 mM sample and only minor degradation was observed in weaker samples (10, 5, and 2.5 mM), as demonstrated by H-1 and F-19 NMR.

  • 99. Zhou, Yizhou
    et al.
    Smith, Daniel
    Leong, Bryan J
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Chapman, Matthew R
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    Promiscuous cross-seeding between bacterial amyloids promotes interspecies biofilms2012Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, nr 42, s. 35092-35103Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyloids are highly aggregated proteinaceous fibers historically associated with neurodegenerative conditions including Alzheimer's, Parkinson's and prion-based encephalopathies. Polymerization of amyloidogenic proteins into ordered fibers can be accelerated by preformed amyloid aggregates derived from the same protein in a process called seeding. Seeding of disease-associated amyloids and prions is highly specific and cross-seeding is usually limited or prevented. Here we describe the first study on the cross-seeding potential of bacterial functional amyloids. Curli are produced on the surface of many Gram-negative bacteria where they facilitate surface attachment and biofilm development. Curli fibers are composed of the major subunit CsgA and the nucleator CsgB, which templates CsgA into fibers. Our results showed that curli subunit homologs from Escherichia coli, Salmonella typhimurium LT2 and Citrobacter koseri were able to cross-seed in vitro. The polymerization of E. coli CsgA was also accelerated by fibers derived from a distant homolog in Shewanella oneidensis that shares less than 30% identity in primary sequence. Cross-seeding of curli proteins was also observed in mixed colony biofilms with E. coli and S. typhimurium. CsgA secreted from E. coli csgB- mutants assembled into fibers on adjacent S. typhimurium that presented CsgB on its surfaces. Similarly, CsgA secreted by S. typhimurium csgB- mutants formed curli on CsgB-presenting E. coli. This interspecies curli assembly enhanced bacterial attachment to agar surfaces and supported pellicle biofilm formation. Collectively, this work suggests that the seeding specificity among curli homologs is relaxed and that heterogeneous curli fibers can facilitate multispecies biofilm development.

  • 100.
    Åberg, Veronica
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Pilicides—small molecules targeting bacterial virulence2007Ingår i: Organic & Biomolecular Chemistry, Vol. 5, s. 1827-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In a time of emerging bacterial resistance there is a vital need for new targets and strategies in antibacterial therapy. Using uropathogenic Escherichia coli as a model pathogen we have developed a class of compounds, pilicides, which inhibit the formation of virulence-associated organelles termed pili. The pilicides interfere with a highly conserved bacterial assembly and secretion system called the chaperone–usher pathway, which is abundant in a vast number of Gram-negative pathogens and serves to assemble multi-protein surface fibers (pili/fimbriae). This class of compounds provides a platform to gain insight into important biological processes such as the molecular mechanisms of the chaperone–usher pathway and the sophisticated function of pili. Pili are primarily involved in bacterial adhesion, invasion and persistence to host defenses. On this basis, pilicides can aid the development of new antibacterial agents.

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