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Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
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2018 (English)In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 19, no 22, p. 3001-3009Article in journal (Refereed) Published
Abstract [en]

Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule. Density functional theory calculations show that Py1SA is twisted, while Py2SA is more planar. Still, an analysis of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the two compounds indicates that the degree of electronic coupling between the pyrene and salicylic acid (SA) moieties is larger in Py1SA than in Py2SA. Excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) was observed for the anionic form in polar solvents. We conclude that ICT properties of trans-stilbene derivatives can be utilized for amyloid probe design with large changes in emission spectra and decay times from analogous chemical structures depending on the detailed physical nature of the binding site.less thanbr /greater than (© 2018 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.)

Place, publisher, year, edition, pages
Weinheim, Germany: Wiley-VCH Verlag , 2018. Vol. 19, no 22, p. 3001-3009
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:liu:diva-152767DOI: 10.1002/cphc.201800823ISI: 000450672100006PubMedID: 30183138OAI: oai:DiVA.org:liu-152767DiVA, id: diva2:1264583
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2018-12-10
In thesis
1. Synthesis and characterization of fluorescent stilbene-based probes targeting amyloid fibrils
Open this publication in new window or tab >>Synthesis and characterization of fluorescent stilbene-based probes targeting amyloid fibrils
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) is characterized by two main protein aggregate hallmarks in the brain: extracellular deposition of the amyloid-β (Aβ) in senile plaques and intracellular neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein. The past decade has seen great progress in the development of imaging probes for the non-invasive detection of Aβ and tau aggregates. Here positron emission tomography (PET), single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), are highly promising technologies for clinical diagnostics. However, as a research tool, optical imaging is superior because it is real-time, sensitive, inexpensive, not radioactive and that it in particular affords high-resolution studies both in vitro and in vivo. Fluorescent probes are especially useful for designing novel binding scaffolds for structure investigations of protein aggregates. This thesis describes design, synthesis and evaluation of a series of fluorescent probes for detection of amyloid fibrils, especially Aβ or tau aggregates in vitro.

Firstly, trans-stilbenoid vinylbenzene-1,2-diol with benzene, naphthalene, anthracene, and pyrene are investigated with respect to their photophysical properties free in solution and when bound to amyloid fibrils, including time-resolved fluorescence measurements. It is noted that the extended conjugated systems retained the amyloid targeting properties of the probes and both the anthracene and pyrene moieties extensively enhanced the fluorescence intensity and prolonged lifetimes.

Secondly, the synthesis of two molecules, Py1SA and Py2SA, based on pyrene linked to salicylic acid via a trans-stilbene C = C bond is presented. The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils as well as to fibrils from four other distinct proteins. Additionally, excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) is observed for the anionic form of the probes in polar solvents. This is likely the reason for the spectral differences of the probes when bound to amyloid fibrils.

Moreover, the synthesis of a further development of the Congo red analogue X-34 [2,5-bis(4’-hydroxy-3’-carboxy-styryl) benzene] by rational design and synthesis is described. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of Aβ1-42 and tau as well as selectivity towards the corresponding disease-associated protein aggregates in human post mortem AD tissue.

Lastly, the synthesis of a set of 2,1,3-benzothiadiazole (BTD)-based ligands with different conjugated spacers and variable patterns of OH substitutions of bis-styryl-BTD prototypes were developed. Aβ binding affinities (Aβ1-42 and Aβ1-40 fibrils) and the specificity towards Aβ plaques of all ligands were determined. These findings extend the structure to activity relationships of BTD-based ligands for Aβ fibril binding.

Throughout the studies in this dissertation, new interesting properties of small molecule fluorescence probes have been discovered and analyzed. This knowledge should facilitate the development of noninvasive probes for early detection of Alzheimer's disease and to distinguish different Aβ fibril polymorphs.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 76
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1962
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-152345 (URN)10.3384/diss.diva-152345 (DOI)9789176851876 (ISBN)
Public defence
2018-11-30, Planck, Fysikhuset, Campus Valla, Linköping, 10:15 (English)
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Available from: 2018-10-30 Created: 2018-10-29 Last updated: 2018-11-27Bibliographically approved

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Zhang, JunWang, JunSandberg, AlexanderWu, XiongyuNyström, SofieKonradsson, PeterHammarström, PerDurbeej, BoLindgren, Mikael

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