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  • 1.
    Chavan, Swapnil
    et al.
    Linnaeus Univ, Linnaeus Univ Ctr Biomat Chem, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, S-39182 Kalmar, Sweden..
    Abdelaziz, Ahmed
    eADMET GmbH, Lichtenbergstr 8, D-85748 Munich, Germany..
    Wiklander, Jesper G.
    Linnaeus Univ, Linnaeus Univ Ctr Biomat Chem, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, S-39182 Kalmar, Sweden..
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Linnaeus Univ, Linnaeus Univ Ctr Biomat Chem, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, S-39182 Kalmar, Sweden..
    A k-nearest neighbor classification of hERG K+ channel blockers2016In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 30, no 3, p. 229-236Article in journal (Refereed)
    Abstract [en]

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 Validating this model against FDA-withdrawn substances indicated that it may even be useful for differentiating between mechanisms underlying QT prolongation.

  • 2. Chavan, Swapnil
    et al.
    Friedman, Ran
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Acute Toxicity-Supported Chronic Toxicity Prediction: A k-Nearest Neighbor Coupled Read-Across Strategy2015In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, no 5, p. 11659-11677Article in journal (Refereed)
    Abstract [en]

    A k-nearest neighbor (k-NN) classification model was constructed for 118 RDT NEDO (Repeated Dose Toxicity New Energy and industrial technology Development Organization; currently known as the Hazard Evaluation Support System (HESS)) database chemicals, employing two acute toxicity (LD50)-based classes as a response and using a series of eight PaDEL software-derived fingerprints as predictor variables. A model developed using Estate type fingerprints correctly predicted the LD50 classes for 70 of 94 training set chemicals and 19 of 24 test set chemicals. An individual category was formed for each of the chemicals by extracting its corresponding k-analogs that were identified by k-NN classification. These categories were used to perform the read-across study for prediction of the chronic toxicity, i.e., Lowest Observed Effect Levels (LOEL). We have successfully predicted the LOELs of 54 of 70 training set chemicals (77%) and 14 of 19 test set chemicals (74%) to within an order of magnitude from their experimental LOEL values. Given the success thus far, we conclude that if the k-NN model predicts LD50 classes correctly for a certain chemical, then the k-analogs of such a chemical can be successfully used for data gap filling for the LOEL. This model should support the in silico prediction of repeated dose toxicity.

  • 3. Elmlund, Louise
    et al.
    Kack, Camilla
    Aastrup, Teodor
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Study of the Interaction of Trastuzumab and SKOV3 Epithelial Cancer Cells Using a Quartz Crystal Microbalance Sensor2015In: Sensors, ISSN 1424-8220, E-ISSN 1424-8220, Vol. 15, no 3, p. 5884-5894Article in journal (Refereed)
    Abstract [en]

    Analytical methods founded upon whole cell-based assays are of importance in early stage drug development and in fundamental studies of biomolecular recognition. Here we have studied the binding of the monoclonal antibody trastuzumab to human epidermal growth factor receptor 2 (HER2) on human ovary adenocarcinoma epithelial cancer cells (SKOV3) using quartz crystal microbalance (QCM) technology. An optimized procedure for immobilizing the cells on the chip surface was established with respect to fixation procedure and seeding density. Trastuzumab binding to the cell decorated sensor surface was studied, revealing a mean dissociation constant, K-D, value of 7 +/- 1 nM (standard error of the mean). This study provides a new perspective on the affinity of the antibody-receptor complex presented a more natural context compared to purified receptors. These results demonstrate the potential for using whole cell-based QCM assay in drug development, the screening of HER2 selective antibody-based drug candidates, and for the study of biomolecular recognition. This real time, label free approach for studying interactions with target receptors present in their natural environment afforded sensitive and detailed kinetic information about the binding of the analyte to the target.

  • 4.
    Golker, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Linnaeus Univ, Ctr Biomat Chem, Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden.
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Linnaeus Univ, Ctr Biomat Chem, Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden.
    The effect of crosslinking density on molecularly imprinted polymer morphology and recognition2016In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 75, p. 423-430Article in journal (Refereed)
    Abstract [en]

    In this report, the crosslinking density of bupivacaine molecularly imprinted methacrylic acid (MAA)-ethylene glycol dimethacrylate (EGDMA) copolymers was investigated through replacement of EGDMA by methyl methacrylate (MMA). The effects were examined using a series of full-scale MD simulations of pre-polymerization mixtures, equilibrium rebinding studies on the corresponding synthesized polymers and morphology characterization through nitrogen sorption measurements. While the extent of hydrogen bonding between the functional monomer MAA and bupivacaine observed in the MD pre-polymerization mixtures was comparable in each of the systems studied, the decrease in degree of crosslinking impacted directly on polymer morphology as observed in BET and BJH studies of surface area and porosity. Further, decreases in the crosslinking density induced reductions in template rebinding capacity as seen from a series of radio-ligand binding studies, demonstrating the importance of crosslinking on the performance of molecularly imprinted MAA-EGDMA copolymers, the polymer system most commonly used in molecular imprinting science and technology.

  • 5.
    Golker, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Olsson, Gustaf D.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Nicholls, Ian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    The influence of a methyl substituent on molecularly imprinted polymer morphology and recognition - Acrylic acid versus methacrylic acid2017In: European Polymer Journal, ISSN 0014-3057, E-ISSN 1873-1945, Vol. 92, p. 137-149Article in journal (Refereed)
    Abstract [en]

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

  • 6. Henschel, Henning
    et al.
    Kloeckner, Jan-Peter
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Prosenc, Marc H.
    Computational and structural studies on the complexation of cobalt(II) acetate by water and pyridine2012In: Journal of Molecular Structure, ISSN 0022-2860, E-ISSN 1872-8014, Vol. 1007, p. 45-51Article in journal (Refereed)
    Abstract [en]

    Four different complexes of the cobalt(II) acetate-pyridine-water system were obtained as dominant species by crystallization from a series of dichloromethane and toluene solutions. The complexes were characterized by terms of X-ray crystal structure determination. Factors in solution properties leading to crystallization of certain complexes are discussed. Furthermore, trends in terms of structure and binding energies in a systematic series of mononuclear cobalt(II) complexes were studied using density functional calculations.

  • 7. Henschel, Henning
    et al.
    Prosenc, Marc H.
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    A density functional study on the factors governing metal catalysis of the direct aldol reaction2011In: Journal of Molecular Catalysis A: Chemical, ISSN 1381-1169, E-ISSN 1873-314X, Vol. 351, p. 76-80Article in journal (Refereed)
    Abstract [en]

    Density functional calculations are employed in the study of the C-C bond formation step of an aldol reaction in presence of a series of metals. Focus was placed on first row d-block metals that have been used in catalysis of direct aldol reactions. The obtained energy profiles are analysed in order to differentiate between factors governing catalysis. Results demonstrate a major influence of d-orbital occupation, and suggest some of the so far less commonly used metals as promising candidates for development of new catalytic systems.

  • 8. Huang, Shan
    et al.
    Engberg, Anna E.
    Linnaeus Univ, Ctr Biomat Chem, Kalmar, Sweden.;Univ & Reg Labs Reg, Dept Clin Chem, Skane, Sweden..
    Jonsson, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sandholm, Kerstin
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Mollnes, Tom Eirik
    Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, Oslo, Norway.;Univ Oslo, KG Jebsen ICR, N-0316 Oslo, Norway.;Nordland Hosp, Res Lab, Bodo, Norway.;Univ Tromso, Fac Hlth Sci, N-9001 Tromso, Norway.;Norwegian Univ Sci & Technol, Ctr Mol Inflammat Res, N-7034 Trondheim, Norway..
    Fromell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ekdahl, Kristina N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Reciprocal relationship between contact and complement system activation on artificial polymers exposed to whole human blood2016In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 77, p. 111-119Article in journal (Refereed)
    Abstract [en]

    Background: Inappropriate and uncontrolled activation of the cascade systems in the blood is a driving force in adverse inflammatory and thrombotic reactions elicited by biomaterials, but limited data are available on the activation of the contact system by polymers and the present study was undertaken to investigate these mechanisms in established models. Methods: Polymer particles were incubated in (1) EDTA-plasma (10 mM) to monitor the adsorption of 20 selected proteins; (2) lepirudin-anticoagulated plasma to evaluate contact system activation, monitored by the formation of complexes between the generated proteases factor[F]XIIa, FXIa and kallikrein and the serpins C1-inhibitor [C1INH] and antithrombin [AT]; (3) lepirudin-anticoagulated whole blood to determine cytokine release. Results: Strong negative correlations were found between 10 cytokines and the ratio of deposited FXII/C1INH, generated FXIIa-C1INH complexes, and kallikrein-C1INH complexes. Formation of FXIIa-C1INH complexes correlated negatively with the amount of C3a and positively with deposited IgG. Conclusions: A reciprocal relationship was found between activation of the contact system and the complement system induced by the polymers studied here. The ratios of FXII/C1INH or C4/C4BP, adsorbed from EDTA-plasma are useful surrogate markers for cytokine release and inflammatory response to materials intended for blood contact.

  • 9. Huang, Shan
    et al.
    Nilsson, Per H.
    Sandholm, Kerstin
    Elmlund, Louise
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Regulation of complement in whole blood by heparin molecularly imprinted polymer particles2012In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 217, no 11, p. 1199-1199Article in journal (Other academic)
  • 10.
    Kathiravan, Subban
    et al.
    Linnaeus Univ, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden.;Linnaeus Univ, Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Linnaeus Univ, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden.;Linnaeus Univ, Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Cobalt Catalyzed, Regioselective C(sp(2))-H Activation of Amides with 1,3-Diynes2017In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 18, p. 4758-4761Article in journal (Refereed)
    Abstract [en]

    The development of a first row transition metal (cobalt)-based catalyst for the as yet unexplored CH activation-driven reaction of 1,3-diynes, themselves a functional class of interest in a range of application areas, to form isoquinolinonesan important structural motif in a number of biologically active substancesis presented. This versatile and inexpensive catalyst employs a covalently attached bidendate-directing group, 8-aminoquinoline. The template directs the CH activation and facilitates the synthesis of a wide range of alkynylated heterocycles under mild conditions and with excellent regioselectivity. This strategy provides a novel and efficient route to diverse heterocyclic frameworks as demonstrated by its late stage application in bisheterocycle syntheses.

  • 11.
    Kathiravan, Subban
    et al.
    Linnaeus Univ, Ctr Biomat Chem, Dept Chem & Biomed Sci, S-39182 Kalmar, Sweden..
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Linnaeus Univ, Ctr Biomat Chem, Dept Chem & Biomed Sci, S-39182 Kalmar, Sweden..
    Monoprotected L-Amino Acid (L-MPAA), Accelerated Bromination, Chlorination, and Iodination of C(sp²)-H Bonds by Iridium(III) Catalysis2017In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 29, p. 7031-7036Article in journal (Refereed)
    Abstract [en]

    Halogenated arenes are important structural motifs commonly found in biologically active molecules and used for a variety of transformations in organic synthesis. Herein, we report the mono-protected L-amino acid (L-MPAA) accelerated iridium(III)-catalyzed halogenation of (hetero)anilides at room temperature. This reaction constitutes the first example of an iridium(III)/L-MPAA-catalyzed general halogenation of (hetero)arenes through C(sp²)-H activation. Furthermore, we demonstrate the potential utility of our method through its use in the synthesis of a quinolone derivative.

  • 12.
    Kathiravan, Subban
    et al.
    Linnaeus Univ, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden.;Linnaeus Univ, Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Linnaeus Univ, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden.;Linnaeus Univ, Ctr Biomat Chem, SE-39182 Kalmar, Sweden..
    Rhodium(III)-catalysed, redox-neutral C(sp(2))-H alkenylation using pivalimide as a directing group with internal alkynes2017In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 58, no 1, p. 1-4Article in journal (Refereed)
    Abstract [en]

    In the presence of [RhCp*Cl(2)l(2), N-pivaloyl anilines react with internal alkynes to give the corresponding 2-alkenylpivalimides under redox neutral conditions through C-H activation. This redox neutral hydroarylation, which does not require an external organic acid, unlocks a regioselective synthetic route to 2-alkenyl anilines and is generally applicable to diversely substituted electron rich and electron poor pivalimides.

  • 13. Liu, Tao
    et al.
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Öberg, Tomas
    Comparison of theoretical and experimental models for characterizing solvent properties using reversed phase liquid chromatography2011In: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 702, no 1, p. 37-44Article in journal (Refereed)
    Abstract [en]

    Theoretical and experimental quantitative structure-retention relationships (QSRR) models are useful for characterizing solvent properties and column selectivity in reversed phase liquid chromatography (RPLC). The chromatographic behavior of a model analyte. the herbicide atrazine, in a system derived from nine organic solvents and three chromatographic columns was used for developing QSRR models. Multiple linear regression (MLR) and partial least squares regression (PLSR) were used as statistical approaches. The similarities and differences between linear solvation energy relationships (LSER), and semi-empirical and theoretical molecular models were demonstrated. QSRR models show high predictive power, and can successfully predict retention factor (log k) for new solvents. The models are useful for solvent optimization and reducing time for method development in RPLC. The herbicide atrazine can be readily analyzed at a low level, and all three columns provided good resolution, high-performance and symmetrical peaks. The method is suitable for analysis of atrazine in water samples.

  • 14.
    Mandal, Sudip
    et al.
    Indian Inst Technol Madras, Chem, Madras, Tamil Nadu, India.
    Suriyanarayanan, Subramanian
    Linnaeus Univ, Chem & Biomed Sci, Kalmar, Sweden.
    Nicholls, Ian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Ramanujam, Kothandaraman
    Indian Inst Technol Madras, Chem, Madras, Tamil Nadu, India.
    Electrochemically synthesized molecularly imprinted polyaniline nanostructure: A recognition matrix for biotinylated targets2018In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 255Article in journal (Other academic)
  • 15.
    Nicholls, Ian A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed, S-39182 Kalmar, Sweden..
    Chavan, Swapnil
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed, S-39182 Kalmar, Sweden..
    Golker, Kerstin
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed, S-39182 Kalmar, Sweden..
    Karlsson, Björn C. G.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed, S-39182 Kalmar, Sweden..
    Olsson, Gustaf D.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed, S-39182 Kalmar, Sweden..
    Rosengren, Annika M.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed, S-39182 Kalmar, Sweden..
    Suriyanarayanan, Subramanian
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed, S-39182 Kalmar, Sweden..
    Wiklander, Jesper G.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed, S-39182 Kalmar, Sweden..
    Theoretical and Computational Strategies for the Study of the Molecular Imprinting Process and Polymer Performance2015In: Molecularly Imprinted Polymers In Biotechnology, Cham, Switzerland: Springer, 2015, p. 25-50Chapter in book (Refereed)
    Abstract [en]

    The development of in silico strategies for the study of the molecular imprinting process and the properties of molecularly imprinted materials has been driven by a growing awareness of the inherent complexity of these systems and even by an increased awareness of the potential of these materials for use in a range of application areas. Here we highlight the development of theoretical and computational strategies that are contributing to an improved understanding of the mechanisms underlying molecularly imprinted material synthesis and performance, and even their rational design.

  • 16.
    Nilsson Ekdahl, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lambris, John
    University of Pennsylvania.
    Elwing, Hans
    Götebors universitet.
    Ricklin, Daniel
    University of Pennsylvania.
    Nilsson, Per H.
    Linneuniversitetet.
    Teramura, Yuji
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nicholls, Ian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategie2011In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 63, no 12, p. 1042-1050Article, review/survey (Refereed)
    Abstract [en]

    When an artificial biomaterial (e.g., a stent or implantable pump) is exposed to blood, plasma proteins immediately adhere to the surface, creating a new interface between the biomaterial and the blood. The recognition proteins within the complement and contact activation/coagulation cascade systems of the blood will be bound to, or inserted into, this protein film and generate different mediators that will activate polymorphonuclear leukocytes and monocytes, as well as platelets. Under clinical conditions, the ultimate outcome of these processes may be thrombotic and inflammatory reactions, and consequently the composition and conformation of the proteins in the initial layer formed on the surface will to a large extent determine the outcome of a treatment involving the biomaterial, affecting both the functionality of the material and the patient's life quality. This review presents models of biomaterial-induced activation processes and describes various strategies to attenuate potential adverse reactions by conjugating bioactive molecules to surfaces or by introducing nanostructures.

  • 17. Olsson, Gustaf D.
    et al.
    Karlsson, Bjorn C. G.
    Shoravi, Siamak
    Wiklander, Jesper G.
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Mechanisms underlying molecularly imprinted polymer molecular memory and the role of crosslinker: resolving debate on the nature of template recognition in phenylalanine anilide imprinted polymers2012In: Journal of Molecular Recognition, ISSN 0952-3499, E-ISSN 1099-1352, Vol. 25, no 2, p. 69-73Article in journal (Refereed)
    Abstract [en]

    A series of molecular dynamics simulations of prepolymerization mixtures for phenylalanine anilide imprinted co-(ethylene glycol dimethacrylate-methacrylic acid) molecularly imprinted polymers have been employed to investigate the mechanistic basis for template selective recognition in these systems. This has provided new insights on the mechanisms underlying template recognition, in particular the significant role played by the crosslinking agent. Importantly, the study supports the occurrence of template self-association events that allows us to resolve debate between the two previously proposed models used to explain this system's underlying recognition mechanisms. Moreover, the complexity of the molecular level events underlying template complexation is highlighted by this study, a factor that should be considered in rational molecularly imprinted polymer design, especially with respect to recognition site heterogeneity.

  • 18.
    Olsson, Gustaf D.
    et al.
    Linnaeus Univ, Linnaeus Ctr Biomat Chem, S-39182 Kalmar, Sweden..
    Niedergall, Klaus
    Fraunhofer Inst Interfacial Engn & Biotechnol IGB, Stuttgart, Germany..
    Bach, Monika
    Fraunhofer Inst Interfacial Engn & Biotechnol IGB, Stuttgart, Germany.;Univ Stuttgart, Inst Interfacial Engn & Plasmatechnol IGVT, D-70174 Stuttgart, Germany..
    Karlsson, Björn C. G.
    Linnaeus Univ, Linnaeus Ctr Biomat Chem, S-39182 Kalmar, Sweden..
    Tovar, Guenter
    Fraunhofer Inst Interfacial Engn & Biotechnol IGB, Stuttgart, Germany.;Univ Stuttgart, Inst Interfacial Engn & Plasmatechnol IGVT, D-70174 Stuttgart, Germany..
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry. Linnaeus Univ, Linnaeus Ctr Biomat Chem, S-39182 Kalmar, Sweden..
    Simulation of imprinted emulsion prepolymerization mixtures2015In: Polymer journal, ISSN 0032-3896, E-ISSN 1349-0540, Vol. 47, no 12, p. 827-830Article in journal (Refereed)
  • 19. Rosengren, Annika M.
    et al.
    Karlsson, Bjorn C. G.
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Monitoring the Distribution of Warfarin in Blood Plasma2012In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 3, no 8, p. 650-652Article in journal (Refereed)
    Abstract [en]

    Warfarin is an anticoagulant drug extensively used in the treatment and prevention of thrombotic disorders. Previous studies have shown that warfarin binds extensively to blood plasma proteins and that only a small fraction of the drug is unbound and thus available for therapeutic function. Both warfarin's narrow therapeutic window and the susceptibility of anticoagulant function to patient-dependent factors necessitate regular monitoring. In this study, we have shown that the lifetimes for each of the various bound and free forms of the drug in blood plasma can be quantified in situ by time-correlated single-photon counting fluorescence spectroscopy over the clinically significant concentration range. A relationship between the blood coagulation and the distribution of fluorescence lifetimes was observed. The in situ detection of clinically relevant concentrations of warfarin in its respective bound and unbound forms could provide a prognostic tool for use in patient treatment.

  • 20.
    Rosengren-Holmberg, Jenny P.
    et al.
    Linnaeus Univ, Dept Chem & Biomed Sci, Ctr Biomat Chem, SE-39182 Kalmar, Sweden.;Swedish Natl Forens Ctr, Drugs Unit, SE-58194 Linkoping, Sweden..
    Andersson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Smith, James R.
    Univ Portsmouth, Sch Pharm & Biomed Sci, Portsmouth PO1 2DT, Hants, England..
    Alexander, Cameron
    Univ Nottingham, Sch Pharm, Nottingham NG7 2RD, England..
    Alexander, Morgan R.
    Univ Nottingham, Sch Pharm, Nottingham NG7 2RD, England..
    Tovar, Guenter
    Univ Stuttgart, Inst Interfacial Engn, D-70569 Stuttgart, Germany.;Fraunhofer Inst Interfacial Engn & Biotechnol, D-70569 Stuttgart, Germany..
    Ekdahl, Kristina N.
    Linnaeus Univ, Dept Chem & Biomed Sci, Ctr Biomat Chem, SE-39182 Kalmar, Sweden.;Univ Uppsala Hosp, Clin Immunol Sect, Rudbeck Lab C5, Dept Oncol Radiol & Clin Immunol, SE-75185 Uppsala, Sweden..
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC. Linnaeus Univ, Dept Chem & Biomed Sci, Ctr Biomat Chem, SE-39182 Kalmar, Sweden.
    Heparin molecularly imprinted surfaces for the attenuation of complement activation in blood2015In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 3, no 8, p. 1208-1217Article in journal (Refereed)
    Abstract [en]

    Heparin-imprinted synthetic polymer surfaces with the ability to attenuate activation of both the complement and the coagulation system in whole blood were successfully produced. Imprinting was achieved using a template coated with heparin, a highly sulfated glycosaminoglycan known for its anticoagulant properties. The N,N'-diacryloylpiperazine-methacrylic acid copolymers were characterized using goniometry, AFM and XPS. The influence of the molecular imprinting process on morphology and template rebinding was demonstrated by radioligand binding assays. Surface hemocompatibility was evaluated using human whole blood without anticoagulants followed by measurement of complement activation markers C3a and sC5b-9 and platelet consumption as a surrogate coagulation activation marker. The observed low thrombogenicity of this copolymer combined with the attenuation of complement activation induced by the molecular imprint offer potential for the development of self-regulating surfaces with important potential clinical applications. We propose a mechanism for the observed phenomena based upon the recruitment of endogenous sulfated glycosaminoglycans with heparin-like activities.

  • 21. Schillinger, E.
    et al.
    Möder, M.
    Olsson, G. D.
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Sellergren, B.
    An artificial estrogen receptor through combinatorial imprinting2012In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 46, p. 14773-14783Article in journal (Refereed)
    Abstract [en]

    Polymeric sorbents targeting endocrine-disrupting estrogen active compounds (EAC) were prepared by terpolymer imprinting using 17β-estradiol (E2) as template. From a group of eight functional monomers representing Brønsted acids, bases, hydrogen-bond donors and acceptors, as well as π-interacting monomers, a terpolymer library that comprises all possible binary combinations of the functional monomers was prepared. Binding tests revealed that imprinted polymers exhibit a markedly higher affinity for E2 compared to nonimprinted polymers (NIPs) or polymers prepared by using single functional monomers. A combination of methacrylic acid (MAA) and p-vinylbenzoic acid offered a particularly promising lead polymer, displaying an imprinting factor of 17 versus 2.4 for a benchmark polymer prepared by using only MAA as functional monomer. The saturation capacities ascribed to imprinted sites were four to five times higher for this polymer compared to previously reported imprinted polymers. NMR titrations and molecular dynamics simulations corroborated these results, indicating an orthogonal preference of the two functional monomers with respect to the E2 3-OH and 17-OH groups. The optimized polymer exhibited a retentivity for EACs that correlates with their inhibitory effect on the natural receptor. By using the optimized molecularly imprinted polymers (MIPs) in a model water-purification system, they were capable of completely removing ppb levels of a small group of EACs from water. This is in contrast to the performance of nonimprinted polymers and well-established sorbents for water purification (e.g., active carbon), which still contained detectable amounts of the compounds after treatment. Receptor mimics: Combinatorially optimized imprinted polymers (MIPs, see figure) targeting endocrine disruptors exhibited a retentivity for estrogen active compounds (EACs), correlating with their inhibitory effect on the natural receptor. By using the optimized MIPs in a model system for water purification, they were capable of near-complete removal of ppb levels of a small group of EACs from water.

  • 22.
    Shoravi, Siamak
    et al.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Olsson, Gustaf D.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Karlsson, Bjorn C. G.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Bexborn, Fredrik
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Abghoui, Younes
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Hussain, Javed
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Wiklander, Jesper G.
    Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden..
    Nicholls, Ian A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Linnaeus Univ, Bioorgan & Biophys Chem Lab, Ctr Biomat Chem, Dept Chem & Biomed Sci, SE-39182 Kalmar, Sweden.;Uppsala Univ, BMC, Dept Chem, SE-75123 Uppsala, Sweden..
    In silico screening of molecular imprinting prepolymerization systems: oseltamivir selective polymers through full-system molecular dynamics-based studies2016In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 18, p. 4210-4219Article in journal (Refereed)
    Abstract [en]

    All-component molecular dynamics studies were used to probe a library of oseltamivir molecularly imprinted polymer prepolymerization mixtures. Polymers included one of five functional monomers (acrylamide, hydroxyethylmethacrylate, methacrylic acid, 2-(triflouromethyl)acrylic acid, 4-vinylpyridine) and one of three porogens (acetonitrile, chloroform, methanol) combined with the crosslinking agent ethylene glycol dimethacrylate and initiator 2,2'-azobis(2-methylpropionitrile). Polymers were characterized by nitrogen gas sorption measurements and SEM, and affinity studies performed using radioligand binding in various media. In agreement with the predictions made from the simulations, polymers prepared in acetonitrile using either methacrylic or trifluoromethacrylic acid demonstrated the highest affinities for oseltamivir. Further, the ensemble of interactions observed in the methanol system provided an explanation for the morphology of polymers prepared in this solvent. The materials developed here offer potential for use in solid-phase extraction or for catalysis. The results illustrate the strength of this in silico strategy as a potential prognostic tool in molecularly imprinted polymer design.

  • 23.
    Suriyanarayanan, Subramanian
    et al.
    Linnaeus Univ, Ctr Biomat Chem, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden..
    Mandal, Sudip
    Indian Inst Technol Madras, Dept Chem, Chennai 600036, Tamil Nadu, India..
    Ramanujam, Kothandaraman
    Indian Inst Technol Madras, Dept Chem, Chennai 600036, Tamil Nadu, India..
    Nicholls, Ian
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Linnaeus Univ, Ctr Biomat Chem, Dept Chem & Biomed Sci, Bioorgan & Biophys Chem Lab, SE-39182 Kalmar, Sweden.
    Electrochemically synthesized molecularly imprinted polythiophene nanostructures as recognition elements for an aspirin-chemosensor2017In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 253, p. 428-436Article in journal (Refereed)
    Abstract [en]

    A chemosensor utilizing electro-polymerized film, as recognition element, has been devised and tested for selective determination of aspirin. The sensor consists of molecularly imprinted polymer (MIP) recognition elements electrodeposited as polymeric nanowires on gold-coated quartz resonator. A nano structures were prepared by electrochemical co-polymerization of the preformed complex between the template, aspirin, the functional monomers, 3-thienylboronic acid (3-TBA) and 3-thiopheneacetic acid (3-TAA), and thiophene, which was employed as a cross-linker. This nanostructure upon leaching aspirin serve as MIP. Polymerizations were performed in acetonitrile (MIP-org) as well as a micelle forming medium (MIP-mic). For MIP nanowire (MIP-ano) synthesis, sacrificial alumina templates were used during electro-polymerization in acetonitrile. Scanning electron microscope studies revealed compactly arranged polythiophene nanowires of uniform thickness in MIP-ano film, and MIP-mic film produced aggregated micron sized polymer structures. Density functional theoretical studies indicated a stable hydrogen bond-based complexation of aspirin by 3-TBA and 3-TAA in the pre-polymerization mixture implying that the MIP film thus prepared could selectively rebind the aspirin template. The MIP-ano-based chemosensor was sensitive towards aspirin (0.5-10 mM), over clinically relevant range (0.15-0.5 mM) under optimized FIA conditions. The sensitivity (20.62 Hz/mM) of the MIP-ano was eight and fifteen times higher than the MIP-mic (2.80 Hz/mM) and MIP-org (1.10 Hz/mM). Notably, the sensor selectively discriminates aspirin from structurally or functionally related interferants and metabolites, such as, salicylic acid, acetylsalicyloyl chloride and ibuprofen.

1 - 23 of 23
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