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Development of 2-Pyridone-based central fragments: Affecting the aggregation of amyloid proteins
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Fredrik Almqvist)
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. , 60 p.
Keyword [en]
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: urn:nbn:se:umu:diva-53705ISBN: 978-91-7459-417-1 (print)OAI: oai:DiVA.org:umu-53705DiVA: diva2:513929
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: 2012-04-05Bibliographically approved
List of papers
1. Synthesis of a novel tricyclic peptidomimetic Scaffold
Open this publication in new window or tab >>Synthesis of a novel tricyclic peptidomimetic Scaffold
2008 (English)In: Organic Letters, Vol. 10, no 18, 4005-4007 p.Article in journal (Refereed) Published
Abstract [en]

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

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-10351 (URN)10.1021/ol801506y (DOI)
Available from: 2008-10-13 Created: 2008-10-13 Last updated: 2012-04-05Bibliographically approved
2. Synthesis and characterization of a multi ring-fused 2-pyridone-based fluorescent scaffold
Open this publication in new window or tab >>Synthesis and characterization of a multi ring-fused 2-pyridone-based fluorescent scaffold
Show others...
2010 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 32, 6171-6178 p.Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2010
Keyword
Medicinal chemistry, Heterocycles, Luminescence, Fluorescent probes
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-37882 (URN)10.1002/ejoc.201000796 (DOI)000285041500007 ()
Note
Article first published online 24 September 2010Available from: 2010-11-18 Created: 2010-11-18 Last updated: 2017-12-12Bibliographically approved
3. A three-component reaction forming naphthyridones: synthesis of lophocladine analogs
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, 5278-5281 p.Article 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: 2017-12-08Bibliographically approved
4. A novel heterocyclic Scaffold formed by ring expansion of a cyclic Sulfone to Sulfonamides
Open this publication in new window or tab >>A novel heterocyclic Scaffold formed by ring expansion of a cyclic Sulfone to Sulfonamides
2009 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 11, no 23, 5470-5472 p.Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
American Chemical Society, 2009
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-27674 (URN)10.1021/ol9023024 (DOI)19891461 (PubMedID)
Available from: 2009-11-13 Created: 2009-11-13 Last updated: 2017-12-12Bibliographically approved

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