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Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2004 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, no 23, 7830-7835 p.Article in journal (Refereed) Published
Abstract [en]

By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established. Primary amino methylene substituents were introduced via a cyanodehalogenation followed by a borane dimethyl sulfide reduction of the afforded nitrile. In both of these transformations, microwave irradiation proved to be superior to traditional conditions and the primary amines were obtained in good overall yields (55-58% over three steps). To incorporate tertiary aminomethylene substituents in the 2-pyridone framework, a microwave-assisted Mannich reaction using preformed iminium salts proved to be effective. Thus highly substituted 2-pyridones were obtained in 48-93% yields.

 

Place, publisher, year, edition, pages
Easton, Pa.: American Chemical Society , 2004. Vol. 69, no 23, 7830-7835 p.
Identifiers
URN: urn:nbn:se:umu:diva-5469DOI: 10.1021/jo048554yOAI: oai:DiVA.org:umu-5469DiVA: diva2:144994
Available from: 2006-11-02 Created: 2006-11-02 Last updated: 2011-03-11Bibliographically approved
In thesis
1. Peptidomimetics based on ring-fused 2-pyridones: probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors
Open this publication in new window or tab >>Peptidomimetics based on ring-fused 2-pyridones: probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the synthesis and biological evaluation of highly substituted, ring-fused 2-pyridones. The utility of the bicyclic 2-pyridones to gain fundamental insights into the disease processes of bacterial infections and Alzheimer’s disease has been investigated.

The 2-pyridones have mainly been studied as a new class of anti-infective agents termed pilicides. The function of the pilicides has been explored using uropathogenic E. coli (UPEC) as a prototype pathogen and urinary tract infection as a model disease. The pilicides target the infectious ability of UPEC by inhibiting key proteins (chaperones) in the so-called chaperone-usher pathway, thus preventing the assembly of bacterial surface organelles (pili/fimbriae).

Synthetic pathways to aminomethylate the 2-pyridones have been developed in order to increase their aqueous solubility while retaining biological activity. Also, the importance of a carboxylic acid has been demonstrated in studies with various carboxylate derivatives and by bioisosteric replacement. Moreover, synthetic procedures to extend the backbone of the rigid, dipeptide-mimicking 2-pyridones have been established. This rendered peptidomimetic building blocks and structures that alongside their potential use as pilicides are of more general interest in peptidomimetic-related research.

The potential pilicides have been screened for chaperone affinity using relaxation-edited 1H-NMR spectroscopy. In addition, their ability to inhibit pilus biogenesis in E. coli has been demonstrated by assays of hemagglutination, biofilm formation and attachment to bladder cells, as well as with electron and atomic force microscopy. Moreover, it has been confirmed that pilicides regulate the expression of pili without affecting the biofunctional properties of the pilus rod. This was verified by measurements of individual P pili, on living bacteria, using force measuring optical tweezers. The pilicide binding site was investigated using NMR spectroscopy and X-ray crystallography of a pilicide-chaperone complex. Based on the results obtained, a mechanism whereby the pilicides may inhibit pilus assembly was proposed, which was subsequently experimentally supported by surface plasmon resonance assays and genetic analysis.

Finally, based on the generic 2-pyridone scaffold, a new collection of substituted compounds has been synthesized and validated as inhibitors of Amyloid β (Aβ)-peptide aggregation, which has been suggested to be involved in Alzheimer’s disease.

Place, publisher, year, edition, pages
Umeå: Kemi, 2006. 101 p.
Keyword
2-pyridone, peptidomimetic, antibacterial, pili, Escherichia coli, virulence, amyloid, Alzheimer’s.
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-909 (URN)91-7264-157-6 (ISBN)
Public defence
2006-11-24, KB3B1, KBC, Linneaus väg 7, 901 87 Umeå, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2006-11-02 Created: 2006-11-02 Last updated: 2011-04-21Bibliographically approved
2. Synthesis and functionalization of ring-fused 2-pyridones: Targeting pili formation in E. coli
Open this publication in new window or tab >>Synthesis and functionalization of ring-fused 2-pyridones: Targeting pili formation in E. coli
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Bicyclic dihydrothiazolo fused 2-pyridones have been studied as a new class of antibacterial agents, termed pilicides, that target the formation of adhesive bacterial surface organelles (pili) in pathogenic bacteria. Synthetic methods to further functionalize the bicyclic 2-pyridone scaffold have been developed in order to increase water-solubility and thereby facilitate biological evalua-tions. This was accomplished by introducing aminomethylenes at the open position C-6. Tertiary amines were introduced via a microwave–assisted Mannich reaction and a synthetic route based on a formyl intermediate gave access to primary, secondary and tertiary amines, but also to other interesting functionalities. Biological evaluation confirmed that several of the function-alized compounds inhibited pili formation in uropathogenic E. coli., as dem-onstrated by assays of hemagglutination, biofilm formation and adherence to bladder cells. Co-crystallizing one of the pilicides with the target protein gave information about the binding site and based on this a mechanism of action was proposed, which was supported experimentally by surface plas-mon resonance and single point mutations in the protein.

Furthermore, the previously developed acylketene imine reaction used to prepare bicyclic thiazolo fused 2-pyridone pilicides has been developed to allow preparation of other ring-fused 2-pyridone systems. Benzo[a]quinolizine-4-ones and indolo[2,3-a]quinolizine-4-ones could be prepared in a fast and simple manner starting from dihydroisoquinolines and a β-carboline. Finally, this method could also be applied for the preparation of heteroatom analogs of the previously studied sulfur containing pilicides. Biological evaluations established that the sulfur atom can be replaced by oxygen and still maintain the ability to prevent pili assembly.

Place, publisher, year, edition, pages
Umeå: Kemi, 2007. 72 p.
Keyword
2-pyridone, acylketene, antibacterial, biofilm inhibitor, Mannich, Micro-wave-assisted chemistry, peptidomimetic, virulence.
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-1416 (URN)978-91-7264-438-0 (ISBN)
Public defence
2007-11-23, hörsal ALI, fd arbetslivsinstitutet, Umeå, 10:00
Opponent
Supervisors
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2011-03-15Bibliographically approved

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