| 1. |
- Ansell, Christopher, et al.
(författare)
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How Learning Aggregates : A Social Network Analysis of Learning between Swedish municipalities
- 2017
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Ingår i: Local Government Studies. - : Informa UK Limited. - 0300-3930 .- 1743-9388. ; 43:7, s. 903-926
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Tidskriftsartikel (refereegranskat)abstract
- Using a unique data set of learning among all 290 Swedish municipalities, we use social network analysis to analyze how learning networks aggregate nationally. To facilitate this analysis, we describe five ideal-typical patterns of aggregation—core-periphery, small world, top-down regionalism, bottom-up regionalism, and urban hierarchy. Each of these ideal types has important implications for how ideas, information, and innovation will circulate among municipalities. Social network analysis allows us to both isolate these patterns and to appreciate composite patterns. The analysis indicates that Swedish municipalities are a small world network with clear regional and hierarchical elements. County seats serve an important role as network hubs.
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| 2. |
- Ansell, Christopher, et al.
(författare)
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Learning Networks Among Swedish Municipalities : Is Sweden a Small World?
- 2017
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Ingår i: Knowledge and Networks. - Cham : Springer International Publishing. - 9783319450223 - 9783319450230 ; , s. 315-336
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Bokkapitel (refereegranskat)abstract
- Distributed, networked learning processes are widely touted as a basis for superior performance. Yet we know relatively little about how learning networks operate in the aggregate. We explore this issue by utilizing a unique data set on learning among Swedish municipalities. The data indicate that geographic proximity and county are the basic structuring properties of the global network. Municipalities learn from their near neighbors, especially from neighbors in the same county, and these two principles produce a high degree of local clustering in the municipal learning networks. At the same time, we also find evidence that Swedish municipalities are a small world linked together on a national basis. Two mechanisms knit the Swedish municipalities together. First, county seats serve as hubs that link local clusters together. Second, local clusters aggregate into regional clusters. Despite a high degree of local clustering, hubs and regions provide a structural basis for the national diffusion of policy ideas and practices among Swedish municipalities.
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| 3. |
- Aronsson, Christopher, et al.
(författare)
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Self-sorting heterodimeric coiled coil peptides with defined and tuneable self-assembly properties
- 2015
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 5:14063
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Tidskriftsartikel (refereegranskat)abstract
- Coiled coils with defined assembly properties and dissociation constants are highly attractive components in synthetic biology and for fabrication of peptide-based hybrid nanomaterials and nanostructures. Complex assemblies based on multiple different peptides typically require orthogonal peptides obtained by negative design. Negative design does not necessarily exclude formation of undesired species and may eventually compromise the stability of the desired coiled coils. This work describe a set of four promiscuous 28-residue de novo designed peptides that heterodimerize and fold into parallel coiled coils. The peptides are non-orthogonal and can form four different heterodimers albeit with large differences in affinities. The peptides display dissociation constants for dimerization spanning from the micromolar to the picomolar range. The significant differences in affinities for dimerization make the peptides prone to thermodynamic social self-sorting as shown by thermal unfolding and fluorescence experiments, and confirmed by simulations. The peptides self-sort with high fidelity to form the two coiled coils with the highest and lowest affinities for heterodimerization. The possibility to exploit self-sorting of mutually complementary peptides could hence be a viable approach to guide the assembly of higher order architectures and a powerful strategy for fabrication of dynamic and tuneable nanostructured materials.
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| 4. |
- Carlsson, Susanne, et al.
(författare)
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Affinity of galectin-8 and its carbohydrate recognition domains for ligands in solution and at the cell surface.
- 2007
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 17:6, s. 663-76
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-8 has two different carbohydrate recognition domains (CRDs), the N-terminal Gal-8N and the C-terminal Gal-8C linked by a peptide, and has various effects on cell adhesion and signaling. To understand the mechanism for these effects further, we compared the binding activities of galectin-8 in solution with its binding and activation of cells. We used glycan array analysis to broaden the specificity profile of the two galectin-8 CRDs, as well as intact galectin-8s (short and long linker), confirming the unique preference for sulfated and sialylated glycans of Gal-8N. Using a fluorescence anisotropy assay, we examined the solution affinities for a subset of these glycans, the highest being 50 nM for NeuAcalpha2,3Lac by Gal-8N. Thus, carbohydrate-protein interactions can be of high affinity without requiring multivalency. More importantly, using fluorescence polarization, we also gained information on how the affinity is built by multiple weak interactions between different fragments of the glycan and its carrier molecule and the galectin CRD subsites (A-E). In intact galectin-8 proteins, the two domains act independently of each other in solution, whereas at a surface they act together. Ligands with moderate or weak affinity for the isolated CRDs on the array are bound strongly by intact galectin-8s. Also galectin-8 binding and signaling at cell surfaces can be explained by combined binding of the two CRDs to low or medium affinity ligands, and their highest affinity ligands, such as sialylated galactosides, are not required.
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| 5. |
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| 6. |
- Collins, Patrick M., et al.
(författare)
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Taloside Inhibitors of Galectin-1 and Galectin-3
- 2012
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Ingår i: Chemical Biology and Drug Design. - : Wiley. - 1747-0285 .- 1747-0277. ; 79:3, s. 339-346
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Tidskriftsartikel (refereegranskat)abstract
- Galectin-1 and galectin-3 have roles in cancer and inflammation. Galectin-1 has recently emerged as a significant protein produced by tumour cells to promote tumour development, angiogenesis and metastasis and consequently represents an important target to inhibit. The design of inhibitors targeting the carbohydrate recognition domain that is known to recognize galactose is an important approach in the fight against cancer. Based on the analysis of crystal structures, we pursued the concept that if the galactose was replaced with talose (the C2 epimer of galactose) as a scaffold, then O2 substituents would be directed closer to the protein surface and provide opportunity to design inhibitors that are more specific towards particular galectins. Our elucidation of X-ray crystal structures of two of our synthesized talosides in complex with galectin-1 and galectin-3 provides the first atomic information on the interactions of galectins, and indeed any protein, with talosides. These results have enabled a structure-based rationale for the specificity differences shown by galectin-1 and galectin-3 towards these talosides and demonstrate new opportunities for further exploitation as specific inhibitors of galectins.
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| 7. |
- Dahlgren, Markus K, et al.
(författare)
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Synthesis of 2-(2-Aminopyrimidine)-2,2-difluoroethanols as Potential Bioisosters of Salicylidene Acylhydrazides
- 2010
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 15:6, s. 4207-12
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Tidskriftsartikel (refereegranskat)abstract
- Salicylidene acylhydrazides are inhibitors of type III secretion in several Gramnegative pathogens. To further develop the salicylidene acylhydrazides, scaffold hopping was applied to replace the core fragment of the compounds. The novel 2-(2-aminopyrimidine)-2,2-difluoroethanol scaffold was identified as a possible analog to thesalicylidene acylhydrazide core structure. The synthesis of a library of 2-(2-aminopyrimidine)-2,2-difluoro-ethanols is described in this paper.
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| 8. |
- Decker, Daniel, 1986-, et al.
(författare)
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Identification and characterization of inhibitors of UDP-glucose and UDP-sugar pyrophosphorylases for in vivo studies
- 2017
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Ingår i: The Plant Journal. - : John Wiley & Sons. - 0960-7412 .- 1365-313X. ; 90:6, s. 1093-1107
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- UDP-sugars serve as ultimate precursors in hundreds of glycosylation reactions (e.g. for protein and lipid glycosylation, synthesis of sucrose, cell wall polysaccharides, etc.), underlying an important role of UDP-sugar-producing enzymes in cellular metabolism. However, genetic studies on mechanisms of UDP-sugar formation were frequently hampered by reproductive impairment of the resulting mutants, making it difficult to assess an in vivo role of a given enzyme. Here, a chemical library containing 17 500 compounds was separately screened against purified UDP-glucose pyrophosphorylase (UGPase) and UDP-sugar pyrophosphorylase (USPase), both enzymes representing the primary mechanisms of UDP-sugar formation. Several compounds have been identified which, at 50 μm, exerted at least 50% inhibition of the pyrophosphorylase activity. In all cases, both UGPase and USPase activities were inhibited, probably reflecting common structural features of active sites of these enzymes. One of these compounds (cmp #6), a salicylamide derivative, was found as effective inhibitor of Arabidopsis pollen germination and Arabidopsis cell culture growth. Hit optimization on cmp #6 yielded two analogs (cmp #6D and cmp #6D2), which acted as uncompetitive inhibitors against both UGPase and USPase, and were strong inhibitors in the pollen test, with apparent inhibition constants of less than 1 μm. Their effects on pollen germination were relieved by addition of UDP-glucose and UDP-galactose, suggesting that the inhibitors targeted UDP-sugar formation. The results suggest that cmp #6 and its analogs may represent useful tools to study in vivo roles of the pyrophosphorylases, helping to overcome the limitations of genetic approaches.
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| 9. |
- Decker, Daniel, 1986-, et al.
(författare)
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The structure-activity relationship of the salicylimide derived inhibitors of UDP-sugar producing pyrophosphorylases
- 2018
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Ingår i: Plant Signalling & Behavior. - : Taylor & Francis. - 1559-2316 .- 1559-2324. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- UDP-sugars are key precursors for biomass production in nature (synthesis of cellulose, hemicellulose, etc.). They are produced de novo by distinct UDP-sugar producing pyrophosphorylases. Studies on the roles of these enzymes using genetic knockouts were hampered by sterility of the mutants and by functional-complementation from related enzyme(s), hindering clear interpretation of the results. In an attempt to override these difficulties, we turned to the reverse chemical genetics approaches to identify compounds which interfere with the activity of those enzymes in vivo. Hit expansion on one of such compounds, a salicylimide derivative, allowed us to identify several inhibitors with a range of activities. The present study provides a structure-activity relationship for these compounds.
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| 10. |
- Gustafsson, Sofia B, et al.
(författare)
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High tumour cannabinoid CB(1) receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer
- 2011
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Ingår i: PLOS ONE. - San Francisco, CA : Public Library of Science. - 1932-6203. ; 6:8, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome. Methodology/Principal Findings: CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and >= 2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB1IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 8565 and 66+/-8%; tumour interior, 86+/-4% and 63+/-8% for the CB(1)IR<2 and CB(1)IR >= 2 groups, respectively. Conclusions/Significance: The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.
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| 11. |
- Hillgren, J. Mikael, et al.
(författare)
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Syntheses of pseudoceramines A-D and a new synthesis of spermatinamine, bromotyrosine natural products from marine sponges
- 2012
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry. - 1477-0520 .- 1477-0539. ; 10:6, s. 1246-1254
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Tidskriftsartikel (refereegranskat)abstract
- Herein we report the total syntheses of pseudoceramine A-D (2-5) and spermatinamine (1) isolated from the marine sponge Pseudoceratina sp. Direct acyl substitution of α-hydroxyiminoesters with amine nucleophiles was developed as a key transformation. The synthetic compounds confirm the reported structures and importantly gives access to non-symmetrical spermine based natural products carrying two different bromotyrosine building blocks. Our new synthesis of spermatinamine is two steps shorter and more efficient than the previously reported sequence.
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| 12. |
- Islam, Md. Koushikul, et al.
(författare)
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High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection
- 2016
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Ingår i: Journal of Biomolecular Screening. - : Sage Publications. - 1087-0571 .- 1552-454X. ; 21:4, s. 354-362
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Tidskriftsartikel (refereegranskat)abstract
- Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by 80%, with 50% cell viability at 50 mu M concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with 60% inhibition of RVFV infection at 3.12 mu M compound concentration and 50% cell viability at 25 mu M were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection.
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| 13. |
- Latham, Christopher D., et al.
(författare)
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The contribution made by lattice vacancies to the Wigner effect in radiation-damaged graphite
- 2013
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Ingår i: Journal of Physics. - : IOP Publishing. - 0953-8984 .- 1361-648X. ; 25:13
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Tidskriftsartikel (refereegranskat)abstract
- Models for radiation damage in graphite are reviewed and compared, leading to a re-examination of the contribution made by vacancies to annealing processes. A method based on density functional theory, using large supercells with orthorhombic and hexagonal symmetry, is employed to calculate properties and behaviour of lattice vacancies and displacement defects. It is concluded that annihilation of intimate Frenkel defects marks the onset of recovery in electrical resistivity, which occurs when the temperature exceeds about 160 K. Migration of isolated monovacancies is estimated to have an activation energy Ea ≈ 1.1 eV. Coalescence into divacancy defects occurs in several stages, with different barriers at each stage, depending on the path. The formation of pairs ultimately yields up to 8.9 eV energy, which is nearly 1.0 eV more than the formation energy for an isolated monovacancy. Processes resulting in vacancy coalescence and annihilation appear to be responsible for the main Wigner energy release peak in radiation-damaged graphite, occurring at about 475 K.
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| 14. |
- Masuyer, Geoffrey, et al.
(författare)
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Inhibition mechanism of human galectin-7 by a novel galactose- benzylphosphate inhibitor
- 2012
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 279:2, s. 193-202
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Tidskriftsartikel (refereegranskat)abstract
- Galectins are involved in many cellular processes due to their ability to bind carbohydrates. Understanding their functions has shown the necessity for potent and specific galectin inhibitors. Human galectin-7 (hGal-7), in particular, has been highlighted as an important marker in many types of cancer by either inhibiting or promoting tumour growth. Producing ligands able to selectively target hGal-7 will offer promising tools for deciphering cancer processes in which hGal-7 is involved as well as present potential solutions for future therapeutics. Here we report the high resolution crystal structure of hGal-7 in complex with a synthetic 2-O-benzylphosphate-galactoside inhibitor (which is > 60-fold more potent than its parent galactoside). The high resolution crystallographic analysis highlights the validity of using saccharide derivatives, conserving properties of the galactose binding, while enhanced affinity and specificity is provided by the added phosphate group. This structural information will allow the design of further inhibitors with improved potency and specificity.
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| 15. |
- Odqvist, Lina, et al.
(författare)
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Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus
- 2019
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 78:10, s. 1363-1370
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-κB signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.
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| 16. |
- Salomonsson, Emma, et al.
(författare)
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Mutational tuning of galectin-3 specificity and biological function.
- 2010
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Ingår i: The Journal of biological chemistry. - 1083-351X. ; 285, s. 35079-35091
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Tidskriftsartikel (refereegranskat)abstract
- Galectins are defined by a conserved beta-galactoside binding site, which has been linked to many of their important functions in e.g. cell adhesion, signaling and intracellular trafficking. Weak adjacent sites may enhance or decrease affinity for natural beta-galactoside containing glycoconjugates, but little is known about the biological role of this modulation of affinity (fine specificity). We have now produced 10 mutants of human galectin-3, with changes in these adjacent sites, which have altered carbohydrate-binding fine specificity but which retain the basic beta-galactoside binding activity as show by glycan-array binding and a solution-based fluorescence anisotropy assay. Each mutant was also tested in two biological assays to provide a correlation between fine specificity and function. Galectin-3 R186S, which has selectively lost affinity for LacNAc, a disaccharide moiety commonly found on glycoprotein glycans, has lost the ability to activate neutrophil leukocytes and intracellular targeting into vesicles. K176L has increased affinity for beta-galactosides substituted with GlcNAcbeta1-3 as found in poly-N-acetyllactosaminoglycans, and increased potency to activate neutrophil leukocytes, even though it has lost other aspects of galectin-3 fine specificity. G182A has altered carbohydrate-binding fine specificity and altered intracellular targeting into vesicles, a possible link to the intracellular galectin-3-mediated anti-apoptotic effect known to be lost by this mutant. Finally, the mutants have helped to define the differences in fine specificity shown by Xenopus, mouse and human galectin-3 and as such, evidence for adaptive change during evolution.
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| 17. |
- Strand, Mårten, et al.
(författare)
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2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 2
- 2012
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society Microbiology. - 0066-4804 .- 1098-6596. ; 56:11, s. 5735-5743
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex viruses (HSV-1 and HSV-2) are responsible for life-long latent infections in humans, with periods of viral reactivation associated with recurring ulcerations in the orofacial and genital tract. In immunosuppressed patients and neonates, HSV infections are associated with severe morbidity, and in some cases even mortality. Today, acyclovir is the standard therapy for management of HSV infections. However, the need for novel antiviral agents is apparent since HSV isolates resistant to acyclovir therapy are frequently isolated in immunosuppressed patients. In this study, we assessed the anti-HSV activity of the anti-adenoviral compounds 2-[2-(2-benzoylamino)-benzoylamino]benzoic acid, (Benzavir-1) and 2-[4,5-difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, (Benzavir-2) on HSV-1 and HSV-2. Both compounds were active against both viruses. Importantly, Benzavir-2 had similar potency to acyclovir against both HSV types and it was active against clinical acyclovir-resistant HSV isolates.
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| 18. |
- Öberg, Christopher, et al.
(författare)
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Arginine Binding Motifs: Design and Synthesis of Galactose-Derived Arginine Tweezers as Galectin-3 Inhibitors.
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 51:7, s. 2297-2301
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Tidskriftsartikel (refereegranskat)abstract
- Anionic O2 derivatives of methyl 3-deoxy-3-(4-methylbenzamido)-1-thio-beta- d-galactopyranoside have been synthesized as inhibitors against galectin-3. The sulfate, H-phosphonate, and benzyl phosphate derivatives showed an increased affinity as compared to the parent unsubstituted galactopyranoside. Modeling revealed arginine-144 being pinched by the C3 benzamide and O2 anionic substituents in that the benzamide stacked face-to-face and the anionic O2 substituent ion-paired with the guanidinium moiety.
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| 19. |
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| 20. |
- Öberg, Christopher, et al.
(författare)
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Inhibition of Galectins with Small Molecules
- 2011
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Ingår i: Chimia. - : Swiss Chemical Society. - 0009-4293 .- 2673-2424. ; 65:1-2, s. 18-23
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Tidskriftsartikel (refereegranskat)abstract
- Evidence that the galectin family of proteins plays crucial roles in cancer, inflammation, and immunity has accumulated over the last decade. The galectins have consequently emerged as interesting drug targets. A majority of galectin functions occurs by means of cross-linking glycoproteins and by doing so controlling gly-coproteirl cellular localization and residence times. The glycoprotein cross-linking occurs when galectin dimers or multimers, or galectins with two binding sites, bind galactose-containing glycans of the glycoproteins. Such galectin-glycan interactions have been successfully blocked with compounds having multivalent presentation of galactose, lactose, or N-acetyllactosamine, with peptides, and with small carbohydrate (galactose) derivatives. This review summarizes and analyzes attempts to develop efficient and selective small-molecule galectin inhibitors through derivatization of monosaccharides, mainly galactosides, with non-carbohydrate structures that protrude into subsites adjacent to the core-conserved galactose-recognizing site of the galectins.
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| 21. |
- Öberg, Christopher, et al.
(författare)
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Protein subtype-targeting through ligand epimerization: talose-selectivity of galectin-4 and galectin-8.
- 2008
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X. ; 18:13, s. 3691-3694
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Tidskriftsartikel (refereegranskat)abstract
- A series of O2 and O3-derivatized methyl beta-d-talopyranosides were synthesized and evaluated in vitro as inhibitors of the galactose-binding galectin-1, -2, -3, -4 (N- and C-terminal domains), 8 (N-terminal domain), and 9 (N-terminal domain). Galectin-4C and 8N were found to prefer the d-talopyranose configuration to the natural ligand d-galactopyranose configuration. Derivatization at talose O2 and/or O3 provided selective submillimolar inhibitors for these two galectins.
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| 22. |
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| 23. |
- Öberg, Christopher
(författare)
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Small-Molecule Galectin Inhibitors - On Tweezers and Talosides
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abstract Work on the design, synthesis, and biological evaluation of galectin inhibitors is presented. The most significant results relate to the development of galactose-based arginine “tweezers” and taloside-based galectin inhibitors. The galectins are a β-galactoside binding protein family. They are involved in cancer and inflammation, thus comprising interesting pharmaceutical targets. Galactose-based tweezers were designed to enhance the affinity to galectin-3 by a simultaneous π-cation and polar interaction with an arginine in the extended carbohydrate recognition domain (CRD). First, a range of substituents involved in the polar interaction were synthesized, which afforded inhibitors with an affinity down to ca 87 μM against galectin-3. Data suggests that the affinity is reversely related to the partial charge of the anionic O2 substituents. We propose that the affinity-enhancing effect of the introduced anion in forming a salt-bridge is attenuated by penalties in obtaining the biologically active conformation, which is supported by NMR. Second, to further clarify the basis of the simultaneous π-cation and polar interaction with arginine, tweezers with a range of aromatic moieties were synthesized, presumably allowing the direct interactions to be subtracted to leave only the contribution from the added anion. The tweezers design was subsequently incorporated into a thio-di-galactoside scaffold to afford an affinity of below 100 nM. Taloside-based galectin inhibitors offer the potential to introduce substituents that can explore previously inaccessible regions of the galectin CRD. The region accessible with talosides is typically rich in basic amino acid residues (notably arginines), consequently a library of β-talosides with electron-rich substituents were synthesized. Galectin-4C and -8N both prefer methyl taloside to methyl galactoside and taloside-based inhibitors with affinities two orders of magnitude higher, relative to reference methyl β-galactoside, were found against galectin-4. No mammalian taloside-processing enzymes are known, potentially allowing talosides to overcome the enzymatic degradation plaguing carbohydrate-based drugs. These projects were undertaken with a clear focus towards providing enhanced galectin inhibitors as biological probes and potential pharmaceutical agents. To this end, synthetic methods have also been developed to provide starting material for the inhibitors. The galactose-based tweezers require 3-azido-3-deoxy-galactosides, a starting material that was limited by cumbersome synthesis. Methodology development has provided new routes to both O and S glycosides, providing improved yield and convenience for the studied intermediates. Talosides, notably β-configured, are challenging synthetic targets. A new route to β-talosides via β-idosides has been developed aiming for flexible introduction of C2 and C3 substituents, thus far the O2/O3 β-taloside has been successfully obtained.
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| 24. |
- Öberg, Christopher, et al.
(författare)
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Synthesis of 3-amido-3-deoxy-beta-D-talopyranosides: all-cis-substituted pyranosides as lectin inhibitors
- 2011
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 67:47, s. 9164-9172
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Tidskriftsartikel (refereegranskat)abstract
- 3-Deoxy-3-amino-beta-D-talopyranosides have been synthesized for the first time. The amines were obtained from galactopyranosides through 2,3-anhydrogulosides that were opened to idosides followed by an oxidation/reductive amination sequence. From the amines, 11 corresponding 3-deoxy-3-arylamido-beta-talopyranosides have been synthesized and evaluated as inhibitors against galectin-1, -2, -3, -4C, -4N, -7, -8N and -9N. The synthesized talosamides showed selectivity for Galectin-4C with three of the mono-saccharides having dissociation constants at around 100 mu M against the lectin, which is more than two orders of magnitude better than methyl beta-galactoside and significantly better than the previous best galectin-4C monosaccharide inhibitor. (C) 2011 Elsevier Ltd. All rights reserved.
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| 25. |
- Öberg, Christopher, et al.
(författare)
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Synthesis of 3-azido-3-deoxy-beta-d-galactopyranosides.
- 2009
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Ingår i: Carbohydrate Research. - : Elsevier BV. - 1873-426X .- 0008-6215. ; 344:11, s. 1282-1284
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Tidskriftsartikel (refereegranskat)abstract
- Three efficient routes to 3-azido-3-deoxy-beta-d-galactopyranosides were developed relying on a double inversion protocol at C3. Two of the routes were demonstrated to work with both O- and S-glycosides. In all three routes, the 2-O-acetyl-3-azido-4,6-O-benzylidene-3-deoxy-beta-d-galactopyranosides were obtained by an azide inversion of the key intermediates 2-O-acetyl-4,6-O-benzylidene-3-O-trifluoromethanesulfonyl-beta-d-gulopyranosides. The intermediate gulopyranosides were in turn obtained from 2-O-acetyl-4,6-O-benzylidene-3-O-trifluoromethanesulfonyl-beta-d-galactopyranosides, installed in one pot from the 4,6-O-benzylidene-beta-d-galactopyranosides, by inversion with nitrite or acetate. For O-glycosides, the gulopyranoside configuration could alternatively be obtained from the 4,6-O-benzylidene-beta-d-galactopyranoside by elimination to give the 2,3-dianhydro derivative followed by a highly stereoselective cis-dihydroxylation.
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| 26. |
- Öberg, Christopher T., et al.
(författare)
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Arene-anion based arginine-binding motif on a galactose scaffold : Structure-activity relationships of interactions with arginine-rich galectins
- 2011
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Ingår i: Chemistry: A European Journal. - : Wiley. - 1521-3765 .- 0947-6539. ; 17:29, s. 8139-8144
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Tidskriftsartikel (refereegranskat)abstract
- Two series of C3-benzamido and O2-anion-substituted galactopyranosides were synthesized and studied as binders to arginine-rich proteins galectin-1, -3, -7, -8N (N-terminal domain), and -9N (N-terminal domain). The first series had a 4-methylbenzamide at C3 and the anionic O2-substituent was varied. The second series varied the 4-substituent of the C3-benzamide, whereas the anionic O2 substituent was kept as a sulfate. The influence of the O2-anion substituent correlated negatively with the oxygen charge density in case of galectin-1, -3, and -9N. In the second series, the electron-donating capacity of the 4-substituent of the C3-benzamides correlated positively with the magnitude of the affinity enhancement by the 2O-sulfate.
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| 27. |
- Öberg, Christopher T., et al.
(författare)
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Copper-free huisgen 1,3-dipolar cycloaddition to 3-benzotriazolo-3-deoxy-β-D-galactopyranoside : Cyclization of a galactopyranoside azide and benzyne
- 2010
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Ingår i: Trends in Carbohydrate Research. - 0975-0304. ; 2:2, s. 1-4
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Tidskriftsartikel (refereegranskat)abstract
- Methyl 2-O-acetyl-3-benzotriazolo-4,6-O-benzylidene-3-deoxy- β -D-galactopyranoside was assembled by reacting benzyne, from 2-trimethylsilyl-trifluoromethansulfonylbenzene, and a secondary galactopyranoside azide in a copper-free Huisgen 1,3-dipolar cycloaddition. Following deprotection, the resulting benzotriazoles were evaluated as galectin inhibitors resulting in a 2-4 fold increase in affinity against galectin-1, -2 and -4 N-terminus compared to the parent methyl galactoside.
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| 28. |
- Öberg, Christopher T, et al.
(författare)
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Synthesis, biological evaluation, and structure-activity relationships of 2-[2-(benzoylamino)benzoylamino]benzoic acid analogues as inhibitors of adenovirus replication
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:7, s. 3170-3181
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Tidskriftsartikel (refereegranskat)abstract
- 2-[2-Benzoylamino)benzoylamino]benzoic acid (1) was previously identified as a potent and nontoxic antiadenoviral compound ( Antimicrob. Agents Chemother. 2010 , 54 , 3871 ). Here, the potency of 1 was improved over three generations of compounds. We found that the ortho, ortho substituent pattern and the presence of the carboxylic acid of 1 are favorable for this class of compounds and that the direction of the amide bonds (as in 1) is obligatory. Some variability in the N-terminal moiety was tolerated, but benzamides appear to be preferred. The substituents on the middle and C-terminal rings were varied, resulting in two potent inhibitors, 35g and 35j, with EC(50) = 0.6 μM and low cell toxicity.
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| 29. |
- Öberg, Sven, et al.
(författare)
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Effect of functionalization and charging on resonance energy and radial breathing modes of metallic carbon nanotubes
- 2016
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Ingår i: Physical Review B. - 2469-9950 .- 2469-9969. ; 93:4
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Tidskriftsartikel (refereegranskat)abstract
- While changes in resonant Raman scattering measurements are commonly used to measure the effect of chemical functionalization on single-walled carbon nanotubes, the precise effects of functionalization on these spectra have yet to be clearly identified. In this density functional theory study, we explore the effects of functionalization on both the nanotube resonance energy and frequency shifts in radial breathing mode. Charge transfer effects cause a shift in the first Van Hove singularity spacings, and hence resonance excitation energy, and lead to a decrease in the radial breathing mode frequency, notably when the Fermi level decreases. By varying stochastically the effective mass of carbon atoms in the tube, we simulate the mass effect of functionalization on breathing mode frequency. Finally, full density functional calculations are performed for different nanotubes with varying functional group distribution and concentration using fluorination and hydrogenation, allowing us to determine overall effect on radial breathing mode and charge transfer. The results concur well with experiment, and we discuss the importance when using Raman spectroscopy to interpret experimental functionalization treatments
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