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Search: WFRF:(Gising Johan 1981 )

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1.
  • Isaksson, Rebecka, et al. (author)
  • A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
  • 2019
  • In: ChemistryOpen. - : Wiley. - 2191-1363. ; 8:1, s. 114-125
  • Journal article (peer-reviewed)abstract
    • We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.
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2.
  • Wannberg, Johan, et al. (author)
  • N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands
  • 2024
  • In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 265
  • Journal article (peer-reviewed)abstract
    • Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tertbutylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An AT(2)R selective ligand with a Ki of 42 nM was identified in the first series and in the second series, six AT(2)R selective ligands with significantly improved binding affinities and Ki values of <5 nM were discovered. The binding modes to AT(2)R were explored by docking calculations combined with molecular dynamics simulations. Although some of the high affinity ligands exhibited fair stability in human liver microsomes, comparable to that observed with C21 undergoing clinical trials, most ligands displayed a very low metabolic stability with t(1/2) of less than 10 min in human liver microsomes. The most promising ligand, with an AT(2)R K-i value of 4.9 nM and with intermediate stability in human hepatocytes (t(1/2) = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.
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3.
  • Wannberg, Johan, et al. (author)
  • N-(Methyloxycarbonyl)thiophene sulfonamides as high affinity AT2 receptor ligands
  • 2021
  • In: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 29
  • Journal article (peer-reviewed)abstract
    • A series of meta-substituted acetophenone derivatives, encompassing N-(alkyloxycarbonyl)thiophene sulfonamide fragments have been synthesized. Several selective AT2 receptor ligands were identified, among those a tert-butylimidazole derivative (20) with a Ki of 9.3 nM, that demonstrates a high stability in human liver microsomes (t½ = 62 min) and in human hepatocytes (t½ = 194 min). This methyloxycarbonylthiophene sulfonamide is a 20-fold more potent binder to the AT2 receptor and is considerably more stable in human liver microsomes, than a previously reported and broadly studied structurally related AT2R prototype antagonist 3 (C38). Ligand 20 acts as an AT2R agonist and caused an AT2R mediated concentration-dependent vasorelaxation of pre-contracted mouse aorta. Furthermore, in contrast to imidazole derivative C38, the tert-butylimidazole derivative 20 is a poor inhibitor of CYP3A4, CYP2D6 and CYP2C9. It is demonstrated herein that smaller alkyloxycarbonyl groups make the ligands in this series of AT2R selective compounds less prone to degradation and that a high AT2 receptor affinity can be retained after truncation of the alkyloxycarbonyl group. Binding modes of the most potent AT2R ligands were explored by docking calculations combined with molecular dynamics simulations.
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4.
  • Engen, Karin, et al. (author)
  • Inhibition of Insulin-Regulated Aminopeptidase by Imidazo[1,5-α]pyridines; Synthesis and Evaluation
  • 2024
  • In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067.
  • Journal article (peer-reviewed)abstract
    • Inhibition of Insulin-regulated Aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign identifying novel small-molecule based compounds acting as inhibitors of the enzymatic activity IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of imidazo[1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an pIC50 values of 6.0. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound´s metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn2+ ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding.
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7.
  • Frasca, Serena, 1992- (author)
  • Lignocellulosic Biomass Components for Materials Applications
  • 2024
  • Doctoral thesis (other academic/artistic)abstract
    • This thesis presents a comprehensive study of the use of lignocellulosic biomass components in materials, targeting two distinct applications: conductive materials and additive manufacturing. The lignocellulosic biomass components -lignin, cellulose, and hemicellulose- have been identified as promising renewable feedstocks to replace fossil resources and contribute to the green transition. The first work presented focuses on the synthesis of conductive polymers, specifically polypyrroles. The synthesis of the monomers, N-functionalized pyrroles, was achieved by a modified Clauson-Kaas protocol, both performed in continuous flow and in batch. The substrates used, 2,5-dimethoxytetrahydrofuran and anilines, are promising candidates for biomass-based chemical production. The produced N-functionalised pyrroles were then deposited onto electrodes via electropolymerization to obtain thin films and their electrical properties were characterized. Next, the thesis delves into the isolation and valorisation of lignin, specifically into softwood lignin, modified and isolated via a phenol-assisted fractionation. This approach supresses the formation of condensed lignin while simultaneously introducing new functional groups that could be beneficial for a number of applications. Phenolated lignin was obtained with a high degree of functionalization, a well-defined structure and relatively low molecular weight. Detailed analysis of the fractionation conditions and of the corresponding lignin structures gave insights on how to tailor lignin on demand. The potential of the one-step phenolated lignin was investigated for materials applications.Filaments of lignin and polylactic acid (PLA) were produced to be used in additive manufacturing. The study focused on high lignin incorporation to PLA at three different concentrations (30, 50, and 70 wt%). The lignin-PLA filaments were used for 3D printing of dog bone shaped specimens to examine their mechanical properties. Additionally, detailed thermal and chemical analysis were performed to get an in-depth understanding of the materials. The results were compared to the performance of technical lignins that were also included in the study. Importantly, recycling studies of the filaments indicated good printing performance up to three recycling cycles.Another application explored was the production of conductive carbon materials, starting from the modified lignin. The carbonization was performed using a CO2 laser engraver and lignin was the main component in the wet film formulation. The optimized carbonization parameters afforded carbonized films with low sheet resistance (< 7 Ω sq-1). The structural analysis of the carbonized materials revealed the formation of few-layers graphene-like carbon structures. Further applications of these materials are under investigation.These innovative applications showcase the potential for sustainable, biomass-based materials. The lignin fractionation method reported herein can contribute to further advancements in lignin research. A phenol modified lignin with defined structure offers more opportunities in comparison with bulk lignins, with the advantage of tailoring lignin properties to its end use in the same number steps. Biomass-based organic electronics will help paving the way for environmentally friendly advancements in the energy sector.
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9.
  • Frasca, Serena, et al. (author)
  • Toward Biomass-Based Organic Electronics : Continuous Flow Synthesis and Electropolymerization of N-Substituted Pyrroles
  • 2024
  • In: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 9:12, s. 13852-13859
  • Journal article (peer-reviewed)abstract
    • Pyrroles are foundational building blocks in a wide array of disciplines, including chemistry, pharmaceuticals, and materials science. Currently sourced from nonrenewable fossil sources, there is a strive to explore alternative and sustainable synthetic pathways to pyrroles utilizing renewable feedstocks. The utilization of biomass resources presents a compelling solution, particularly given that several key bulk and fine chemicals already originate from biomass. For instance, 2,5-dimethoxytetrahydrofuran and aniline are promising candidates for biomass-based chemical production. In this study, we present an innovative approach for synthesizing N-substituted pyrroles by modifying the Clauson-Kaas protocol, starting from 2,5-dimethoxytetrahydrofuran as the precursor. The developed methodology offers the advantage of producing pyrroles under mild reaction conditions with the potential for catalyst-free reactions depending upon the structural features of the substrate. We devised protocols suitable for both continuous flow and batch reactions, enabling the conversion of a wide range of anilines and sulfonamides into their respective N-substituted pyrroles with good to excellent yields. Moreover, we demonstrate the feasibility of depositing thin films of the corresponding polymers onto electrodes through in situ electropolymerization. This innovative application showcases the potential for sustainable, biomass-based organic electronics, thus, paving the way for environmentally friendly advancements in this field.
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10.
  • Frasca, Serena, et al. (author)
  • Toward biomass-based organic electronics: Continuous flow synthesis and electropolymerization of N-substituted polypyrroles
  • 2023
  • In: ACS Spring meeting 2023. - Indianapolis.
  • Conference paper (peer-reviewed)abstract
    • Pyrroles are important building blocks in many areas of chemistry, pharmaceuticals and materials. Pyrroles are currently fossil-based and transition to renewable alternatives demands new synthetic pathways. The use of biomass is a very attractive option for more sustainable solutions and several bulk and fine chemical are already produced from biomass. 2,5-Dimethoxytetrahydrofuran is an example of fine chemical derived from carbohydrate fraction of biomass. Here we report the synthesis of N-substituted pyrroles through a modified Clauson-Kass protocol starting from 2,5-dimethoxytetrahydrofuran. The proposed method allows to obtain pyrroles under mild reaction conditions and it can be performed catalyst-free. The protocol works both in continuous flow and under batch conditions.. A wide range of anilines and sulphonamides are transformed to corresponding N-substituted pyrroles in good to excellent yields. Conductive films are achieved through electropolymerization and they show distinct redox activity. Current efforts entail the application of the material in sensors or energy storage devices. The proposed method opens the pathway to sustainable biomass-based organic electronics.
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  • Result 1-10 of 23
Type of publication
journal article (14)
other publication (4)
conference paper (3)
doctoral thesis (2)
Type of content
peer-reviewed (16)
other academic/artistic (7)
Author/Editor
Larhed, Mats (14)
Hallberg, Mathias, 1 ... (8)
Strømme, Maria, 1970 ... (7)
Lindh, Jonas, 1977- (7)
Karlén, Anders (4)
Gutierrez-de-Teran, ... (3)
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Wannberg, Johan (3)
Backlund, Maria (3)
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Henriksson, Martin (1)
Odell, Luke R (1)
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McElroy, Stuart P (1)
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University
Uppsala University (23)
Karolinska Institutet (1)
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English (22)
Swedish (1)
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Engineering and Technology (7)
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