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Sellstedt, Magnus
Publications (10 of 17) Show all publications
Antti, H. & Sellstedt, M. (2018). Cell-Based Kinetic Target-Guided Synthesis of an Enzyme Inhibitor. ACS Medicinal Chemistry Letters, 9(4), 351-353
Open this publication in new window or tab >>Cell-Based Kinetic Target-Guided Synthesis of an Enzyme Inhibitor
2018 (English)In: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 9, no 4, p. 351-353Article in journal (Refereed) Published
Abstract [en]

Finding a new drug candidate for a selected target is an expensive and time-consuming process. Target guided-synthesis, or in situ click chemistry, is a concept where the drug target is used to template the formation of its own inhibitors from reactive building blocks. This could simplify the identification of drug candidates. However, with the exception of one example of an RNA-target, target-guided synthesis has always employed purified targets. This limits the number of targets that can be screened by the method. By applying methods from the field of metabolomics, we demonstrate that target-guided synthesis with protein targets also can be performed directly in cell-based systems. These methods offer new possibilities to conduct screening for drug candidates of difficult protein targets in cellular environments.

Keywords
target-guided synthesis, in situ click chemistry, enzyme catalysis, drug discovery
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-147832 (URN)10.1021/acsmedchemlett.7b00535 (DOI)000430256200010 ()29670699 (PubMedID)
Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-06-09Bibliographically approved
Antti, H. & Sellstedt, M. (2018). Metabolic effects of an aspartate aminotransferase-inhibitor on two T-cell lines. PLoS ONE, 13(12), Article ID e0208025.
Open this publication in new window or tab >>Metabolic effects of an aspartate aminotransferase-inhibitor on two T-cell lines
2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0208025Article in journal (Refereed) Published
Abstract [en]

An emerging method to help elucidate the mode of action of experimental drugs is to use untargeted metabolomics of cell-systems. The interpretations of such screens are however complex and more examples with inhibitors of known targets are needed. Here two T-cell lines were treated with an inhibitor of aspartate aminotransferase and analyzed with untargeted GC-MS. The interpretation of the data was enhanced by the use of two different cell-lines and supports aspartate aminotransferase as a target. In addition, the data suggest an unexpected off-target effect on glutamate decarboxylase. The results exemplify the potency of metabolomics to provide insight into both mode of action and off-target effects of drug candidates.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2018
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-154872 (URN)10.1371/journal.pone.0208025 (DOI)000452640900007 ()30532126 (PubMedID)2-s2.0-85058105205 (Scopus ID)
Available from: 2019-01-04 Created: 2019-01-04 Last updated: 2019-01-04Bibliographically approved
Sellstedt, M., Schwalfenberg, M., Ziegler, S., Antonchick, A. P. & Waldmann, H. (2016). Trienamine catalyzed asymmetric synthesis and biological investigation of a cytochalasin B-inspired compound collection. Organic and biomolecular chemistry, 14(1), 50-54
Open this publication in new window or tab >>Trienamine catalyzed asymmetric synthesis and biological investigation of a cytochalasin B-inspired compound collection
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2016 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 14, no 1, p. 50-54Article in journal (Refereed) Published
Abstract [en]

Due to their enhanced metabolic needs many cancers need a sufficient supply of glucose, and novel inhibitors of glucose import are in high demand. Cytochalasin B (CB) is a potent natural glucose import inhibitor which also impairs the actin cytoskeleton leading to undesired toxicity. With a view to identifying selective glucose import inhibitors we have developed an enantioselective trienamine catalyzed synthesis of a CB-inspired compound collection. Biological analysis revealed that indeed actin impairment can be distinguished from glucose import inhibition and led to the identification of the first selective glucose import inhibitor based on the basic structural architecture of cytochalasin B.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2016
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-128758 (URN)10.1039/C5OB02272J (DOI)000366861800005 ()26606903 (PubMedID)
Available from: 2016-12-14 Created: 2016-12-14 Last updated: 2018-06-09Bibliographically approved
Sellstedt, M., Dang, H. T., Prasad, G. K., Sauer, U. & Almqvist, F. (2013). Four-Component Assembly of Natural-Product-Like Ring-Fused Isoquinuclidines. European Journal of Organic Chemistry, 2013(33), 7476-7479
Open this publication in new window or tab >>Four-Component Assembly of Natural-Product-Like Ring-Fused Isoquinuclidines
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2013 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2013, no 33, p. 7476-7479Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
Keywords
multicomponent reactions, natural products, fused-ring systems, nitrogen­ heterocycles
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-82338 (URN)10.1002/ejoc.201301371 (DOI)000326968100006 ()
Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2018-06-08Bibliographically approved
Andersson, E. K., Bengtsson, C., Evans, M. L., Chorell, E., Sellstedt, M., Lindgren, A. E. .., . . . Chapman, M. R. (2013). Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones. Chemistry and Biology, 20(10), 1245-1254
Open this publication in new window or tab >>Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones
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2013 (English)In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 20, no 10, p. 1245-1254Article in journal (Refereed) Published
Abstract [en]

Enteric bacteria assemble functional amyloid fibers, curli, on their surfaces that share structural and biochemical properties with disease-associated amyloids. Here, we test rationally designed 2-pyridone compounds for their ability to alter amyloid formation of the major curli subunit CsgA. We identified several compounds that discourage CsgA amyloid formation and several compounds that accelerate CsgA amyloid formation. The ability of inhibitor compounds to stop growing CsgA fibers was compared to the same property of the CsgA chaperone, CsgE. CsgE blocked CsgA amyloid assembly and arrested polymerization when added to actively polymerizing fibers. Additionally, CsgE and the 2-pyridone inhibitors prevented biofilm formation by Escherichia coli at the air-liquid interface of a static culture. We demonstrate that curli amyloid assembly and curli-dependent biofilm formation can be modulated not only by protein chaperones, but also by "chemical chaperones."

Place, publisher, year, edition, pages
Elsevier, 2013
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-82340 (URN)10.1016/j.chembiol.2013.07.017 (DOI)000326429400010 ()24035282 (PubMedID)
Funder
Swedish Research Council, 2011-6259, 2010-4730
Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2018-06-08Bibliographically approved
Horvath, I., Sellstedt, M., Weise, C., Nordvall, L.-M., Golla, K. P., Olofsson, A., . . . Wittung-Stafshede, P. (2013). Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: templation and inhibition involve oligomers with different structure. Archives of Biochemistry and Biophysics, 532(2), 84-90
Open this publication in new window or tab >>Modulation of α-synuclein fibrillization by ring-fused 2-pyridones: templation and inhibition involve oligomers with different structure
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2013 (English)In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 532, no 2, p. 84-90Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
α-synuclein, amyloid, oligomer, protein aggregation, spectroscopy, 2-pyridone
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-66116 (URN)10.1016/j.abb.2013.01.012 (DOI)000317257700004 ()23399432 (PubMedID)
Available from: 2013-02-14 Created: 2013-02-14 Last updated: 2018-06-08Bibliographically approved
Sellstedt, M. (2012). Development of 2-Pyridone-based central fragments: Affecting the aggregation of amyloid proteins. (Doctoral dissertation). Umeå, Sweden: Umeå universitet
Open this publication in new window or tab >>Development of 2-Pyridone-based central fragments: Affecting the aggregation of amyloid proteins
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There are many applications of small organic compounds, e.g. as drugs or as tools to study biological systems. Once a compound with interesting biological activity has been found, medicinal chemists typically synthesize small libraries of compounds with systematic differences to the initial “hit” compound. By screening the new ensemble of compounds for their ability to perturb the biological system, insights about the system can be gained. In the work presented here, various ways to synthesize small libraries of ring-fused 2‑pyridones have been developed. Members of this class of peptidomimetic compounds have previously been found to have a variety of biological activities, e.g. as antibacterial agents targeting virulence, and as inhibitors of the aggregation of Alzheimer b‑peptides. The focus in this work has been to alter the core skeleton, the central fragment, of the previously discovered biologically active 2‑pyridones and evaluate the biological effects of these changes. Several new classes of compounds have been constructed and their preparations have included the development of multi-component reactions and a method inspired by diversity-oriented synthesis.

Some of the new compounds have been evaluated for their effect on the fibrillation of different amyloid proteins. Both the Parkinson-associated amyloid protein a-synuclein and the bacterial protein CsgA that is involved in bacterial biofilm formation are affected by subtle changes of the compounds’ central fragments. This is an example of the usefulness of central-fragment alterations as a strategy to probe structure-activity relationships, and the derived compounds may be used as tools in further study of the aggregation of amyloid proteins.

Place, publisher, year, edition, pages
Umeå, Sweden: Umeå universitet, 2012. p. 60
Keywords
2-pyridone, central fragment alteration, multi-component reactions, directed diversity-oriented synthesis, peptidomimetics, amyloid, protein aggregation, pilicide, curlicide
National Category
Organic Chemistry
Research subject
Biorganic Chemistry
Identifiers
urn:nbn:se:umu:diva-53705 (URN)978-91-7459-417-1 (ISBN)
Public defence
2012-04-27, KBC-huset, KB3B1, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 621-2010-4730Knut and Alice Wallenberg Foundation
Available from: 2012-04-05 Created: 2012-04-04 Last updated: 2018-06-08Bibliographically approved
Sellstedt, M., Prasad, G. K., Krishnan, K. S. & Almqvist, F. (2012). Directed diversity-oriented synthesis. Ring-fused 5- to 10-membered rings from a common peptidomimetic 2-pyridone precursor.. Tetrahedron Letters, 53(45), 6022-6024
Open this publication in new window or tab >>Directed diversity-oriented synthesis. Ring-fused 5- to 10-membered rings from a common peptidomimetic 2-pyridone precursor.
2012 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 53, no 45, p. 6022-6024Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Diversity-oriented synthesis, Medium-sized rings, Peptidomimetics, 2-Pyridone
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-58566 (URN)10.1016/j.tetlet.2012.08.100 (DOI)
Available from: 2012-09-03 Created: 2012-09-03 Last updated: 2018-06-08Bibliographically approved
Horvath, I., Weise, C. F., Andersson, E. K., Chorell, E., Sellstedt, M., Bengtsson, C., . . . Wittung-Stafshede, P. (2012). Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation. Journal of the American Chemical Society, 134(7), 3439-3444
Open this publication in new window or tab >>Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation
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2012 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 7, p. 3439-3444Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2012
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-52526 (URN)10.1021/ja209829m (DOI)22260746 (PubMedID)
Available from: 2012-02-24 Created: 2012-02-24 Last updated: 2018-06-08Bibliographically approved
Sellstedt, M. & Almqvist, F. (2011). A three-component reaction forming naphthyridones: synthesis of lophocladine analogs. Organic Letters, 13(19), 5278-5281
Open this publication in new window or tab >>A three-component reaction forming naphthyridones: synthesis of lophocladine analogs
2011 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 13, no 19, p. 5278-5281Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
Washington, D.C.: American Chemical Society, 2011
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-49229 (URN)10.1021/ol202080x (DOI)000295313900077 ()
Available from: 2011-11-11 Created: 2011-11-04 Last updated: 2018-06-08Bibliographically approved
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