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Synthesis and characterization of a multi ring-fused 2-pyridone-based fluorescent scaffold
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 Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
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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. no 32, 6171-6178 p.
Keyword [en]
Medicinal chemistry, Heterocycles, Luminescence, Fluorescent probes
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-37882DOI: 10.1002/ejoc.201000796ISI: 000285041500007OAI: oai:DiVA.org:umu-37882DiVA: diva2:370858
Note
Article first published online 24 September 2010Available from: 2010-11-18 Created: 2010-11-18 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Optical characterization of potential drugs and drug delivery systems
Open this publication in new window or tab >>Optical characterization of potential drugs and drug delivery systems
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This Thesis is a characterization study on substances having potency as drugs as well as on a lipid based drug-delivery matrix. The optical properties of newly synthesized molecules with proven pilicide properties have been characterized with several spectroscopic methods. These methods include optical absorption and fluorescence as well as time-resolved fluorescence. Upon covalently linking compounds with high quantum yields of fluorescence to specific parts of the pilicide, the biological impact was found to increase for some of the derivatives. Furthermore, by expanding the aromatic part of the pilicide molecule, a significant increase in the inherent fluorescence was obtained. The S0-S1 absorption band for these molecules was found to originate from an impure electronic transition, vibronically promoted by intensity borrowing from higher electronic states.

Included in this Thesis is the measurement of how deeply some in this class of newly synthesized molecules become situated when placed inside ganglioside GM1 micelles, and how the molecules’ reorientation is affected. By means of radiation-less energy transfer, it was shown that the molecules place themselves close to the hydrophobic-hydrophilic interface inside the GM1 micelles. As a consequence they are exposed to a densely packed environment, which inhibits the free tumbling of the molecule. This restricted tumbling could be measured by means of time-resolved depolarization experiments.

The release of drug-like fluorescent molecules is investigated from a lipid mixture, which upon equilibrium with water forms a mixture of inverted hexagonal and cubic phases. The lipid matrix displayed an extended release over the course of weeks, in vitro, for molecules having a large variation in hydrophobicity.

Place, publisher, year, edition, pages
Umeå: Kemiska institutionen, Umeå universitet, 2011. 35 p.
Keyword
Pilicide, Ganglioside GM1 micelles, Drug Delivery, Elecronic Energy Transfer, UV-Vis Absorption, Fluorescence Spectroscopy
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:umu:diva-40177 (URN)978-91-7459-157-6 (ISBN)
Public defence
2011-03-11, KBC-huset, KB3A9, Umeå Universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2011-02-18 Created: 2011-02-16 Last updated: 2011-02-18Bibliographically approved
2. Development of 2-Pyridone-based central fragments: Affecting the aggregation of amyloid proteins
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. 60 p.
Keyword
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: 2012-04-05Bibliographically approved

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Sellstedt, MagnusRosenbaum, ErikEngström, PatrikBergström, SvenJohansson, Lennart B-ÅAlmqvist, Fredrik

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Sellstedt, MagnusNyberg, AndersRosenbaum, ErikEngström, PatrikBergström, SvenJohansson, Lennart B-ÅAlmqvist, Fredrik
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Department of ChemistryDepartment of Molecular Biology (Faculty of Medicine)Molecular Infection Medicine Sweden (MIMS)Umeå Centre for Microbial Research (UCMR)
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