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Optical characterization of potential drugs and drug delivery systems
Umeå University, Faculty of Science and Technology, Department of Chemistry. (Lennart B-Å Johansson)
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 [en]
Pilicide, Ganglioside GM1 micelles, Drug Delivery, Elecronic Energy Transfer, UV-Vis Absorption, Fluorescence Spectroscopy
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-40177ISBN: 978-91-7459-157-6 (print)OAI: oai:DiVA.org:umu-40177DiVA: diva2:398144
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
List of papers
1. 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
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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
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
2. Unusual light spectroscopic properties of a 2-Pyridone-based multi-ring-fused Fluorescent Scaffold
Open this publication in new window or tab >>Unusual light spectroscopic properties of a 2-Pyridone-based multi-ring-fused Fluorescent Scaffold
2010 (English)In: Journal of Fluorescence, ISSN 1053-0509, E-ISSN 1573-4994, Vol. 20, no 6, 1249-53 p.Article in journal (Refereed) Published
Abstract [en]

UV-VIS absorption and fluorescence spectroscopic properties of six related polyaromatic 2-pyridones have been studied. Excitation of the lowest and rather weak and structure-less transition [epsilon (max) (430 nm) approximately 3,000 mol-1dm3cm-1] gives rise to a broad fluorescence band in the visible region, for these compounds. These S0 <--> S1 transitions are compatible with symmetrically forbidden transitions, promoted by intensity borrowing, as is revealed by fluorescence depolarisation data. With one exception, all compounds exhibit strong fluorescence, with quantum yields in glycerol varying between 40% and 70%. The corresponding fluorescence lifetimes range from 11 ns to 17 ns, while the radiative lifetimes are very similar ( approximately 26 ns), for all compounds. Interestingly and rarely observed, the calculated radiative lifetimes for the weak absorption band are significantly longer, i.e. between 37 and 40 ns.

Place, publisher, year, edition, pages
Springer, 2010
Keyword
2-pyridone derivatives, fluorescence quantum yield, fluorescence lifetime, fluorescence spectrum, radiative lifetime, intensity borrowing
Identifiers
urn:nbn:se:umu:diva-34290 (URN)10.1007/s10895-010-0676-3 (DOI)000285363400012 ()20490634 (PubMedID)
Funder
Swedish Research Council, 550021103
Available from: 2010-05-25 Created: 2010-05-25 Last updated: 2017-12-12Bibliographically approved
3. Locations and reorientations of multi-ring-fused 2-Pyridones in Ganglioside GM1 Micelles
Open this publication in new window or tab >>Locations and reorientations of multi-ring-fused 2-Pyridones in Ganglioside GM1 Micelles
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2011 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, no 5, 1662-1667 p.Article in journal (Refereed) Published
Abstract [en]

Fluorescent multi-ring-fused 2-pyridones, with chemical resemblance to other biologically active 2-pyridone systems, were solubilized in spherical micelles formed by the gangloiside GM1 and studied with respect to their spatial localization and rotational mobility. For this, electronic energy transfer between the multi-ring-fused 2-pyridone (donor) and BODIPY-FL-labeled GM1 was determined, as well as their fluorescence depolarization. From the obtained efficiency of energy transfer to the acceptor group (BODIPY-FL), either localized in the polar or in the nonpolar part of the ganglioside, it has been possible to estimate the most likely localization of the multi-ring-fused 2-pyridones. The center of mass of the studied multi-ring-fused 2-pyridones are located at approximately 33 Å from the micellar center of mass, which corresponds to the internal hydrophobic-hydrophilic interfacial region. At this location, the reorienting rates of the multi-ring-fused 2-pyridones are surprisingly slow with typical correlation times of 35-55 ns. No evidence was found for the formation of ground and excited state dimers, even when two monomers were forced to be near each other via a short covalent linker.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2011
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-40167 (URN)10.1021/la104051z (DOI)
Note
Publication Date on Web January 6, 2011 Available from: 2011-02-16 Created: 2011-02-16 Last updated: 2017-12-11Bibliographically approved
4. Design and synthesis of fluorescently labeled pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms
Open this publication in new window or tab >>Design and synthesis of fluorescently labeled pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Pilicides and curlicides block formation of the E. coli virulence factors pili and curli. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved using a strategy where key pilicide and curlicide substituents were replaced by fluorophores having similar physicochemical properties. The resulting fluorescent compounds had improved anti-virulence activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing both coumarin and 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide scaffold. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated to the bacteria and seem to discriminate between different bacteria in a population.

National Category
Infectious Medicine Organic Chemistry Organic Chemistry Medicinal Chemistry Organic Chemistry
Research subject
Biorganic Chemistry; Infectious Diseases; läkemedelskemi; Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-37170 (URN)
Available from: 2010-10-21 Created: 2010-10-21 Last updated: 2011-02-18Bibliographically approved
5. A characterisation study on the application of inverted lyotropic phases for subcutaneous drug release
Open this publication in new window or tab >>A characterisation study on the application of inverted lyotropic phases for subcutaneous drug release
2010 (English)In: International journal of pharmaceutics, ISSN 1873-3476, Vol. 388, no 1-2, 52-7 p.Article in journal (Refereed) Published
Abstract [en]

An experimental characterisation of lipid mixtures consisting of inverted hexagonal and inverted cubic phases composed of soybean phosphatidylcholine (SPC) and glycerol dioleate (GDO) was performed. The release of five chromophores of varying lipophilicity, used as model drugs, was investigated. Two experimental setups were applied: one based on maintaining sink condition, while a constant volume release medium was employed for the other. For neither setup, no correlation between the model drug lipophilicity and the polarity of the carrier matrix was found. However, the lipid phases showed a prolonged release, spanning weeks, of the model drugs, which exhibit lipophilicity values ranging by four orders of magnitude.

Place, publisher, year, edition, pages
Elsevier B.V., 2010
Keyword
Subcutaneous drug delivery, Drug depot, Lipid formulations, Lipophilicity, Model drugs
Identifiers
urn:nbn:se:umu:diva-30752 (URN)10.1016/j.ijpharm.2009.12.032 (DOI)000275526100006 ()20026201 (PubMedID)
Available from: 2010-01-14 Created: 2010-01-14 Last updated: 2011-04-08Bibliographically approved

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