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Microwave-assisted decarboxylation of bicyclic 2-pyridone scaffolds and identification of A beta-peptide aggregation inhibitors
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
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2005 (Engelska)Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 3, nr 15, s. 2817-2823Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

A reagent-free microwave-assisted decarboxylation procedure for carboxylic acid functionalized bicyclic 2-pyridones has been developed. This new method, based on microwave heating at 220 degrees C for 600 seconds in N-methyl pyrrolidone (NMP), proved to be practical and very efficient, resulting in decarboxylated 2-pyridones in near-quantitative yields. The decarboxylated products and the intermediate 2-pyridones in the form of carboxylic acid methyl esters and carboxylic acids were screened for their effect on A beta-peptide aggregation. Two out of the 21 2-pyridones described in this study inhibited amyloid formation of the Alzheimer A beta(1-40) peptide. The effect was seen even at a 4 : 1 ratio of 2-pyridone and monomeric A beta-peptide.

Ort, förlag, år, upplaga, sidor
London, U.K.: Royal Society of Chemistry , 2005. Vol. 3, nr 15, s. 2817-2823
Nyckelord [en]
RING-FUSED 2-PYRIDINONES, ALZHEIMERS-DISEASE, ELECTRON-TRANSFER, OLIGOMERS, ACIDS, NEUROTOXICITY, DERIVATIVES, MECHANISM, RADICALS, ESTERS
Nationell ämneskategori
Annan medicinsk grundvetenskap
Identifikatorer
URN: urn:nbn:se:umu:diva-13466DOI: 10.1039/b503294fPubMedID: 16032359OAI: oai:DiVA.org:umu-13466DiVA, id: diva2:153137
Tillgänglig från: 2007-10-12 Skapad: 2007-10-12 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Peptidomimetics based on ring-fused 2-pyridones: probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors
Öppna denna publikation i ny flik eller fönster >>Peptidomimetics based on ring-fused 2-pyridones: probing pilicide function in uropathogenic E. coli and identification of Aβ-peptide aggregation inhibitors
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Kemi, 2006. s. 101
Nyckelord
2-pyridone, peptidomimetic, antibacterial, pili, Escherichia coli, virulence, amyloid, Alzheimer’s.
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-909 (URN)91-7264-157-6 (ISBN)
Disputation
2006-11-24, KB3B1, KBC, Linneaus väg 7, 901 87 Umeå, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2006-11-02 Skapad: 2006-11-02 Senast uppdaterad: 2011-04-21Bibliografiskt granskad

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Chorell, ErikOlofsson, AndersSauer-Eriksson, ElisabethAlmqvist, Fredrik

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Chorell, ErikOlofsson, AndersSauer-Eriksson, ElisabethAlmqvist, Fredrik
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Kemiska institutionenUmeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten)Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet)
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Organic and biomolecular chemistry
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