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Synthesis and characterization of fluorescent stilbene-based probes targeting amyloid fibrils
Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2018. , s. 76
Serie
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1962
Nationell ämneskategori
Organisk kemi
Identifikatorer
URN: urn:nbn:se:liu:diva-152345DOI: 10.3384/diss.diva-152345ISBN: 9789176851876 (tryckt)OAI: oai:DiVA.org:liu-152345DiVA, id: diva2:1259358
Disputation
2018-11-30, Planck, Fysikhuset, Campus Valla, Linköping, 10:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2018-10-30 Skapad: 2018-10-29 Senast uppdaterad: 2018-11-27Bibliografiskt granskad
Delarbeten
1. trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils
Öppna denna publikation i ny flik eller fönster >>trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils
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2017 (Engelska)Ingår i: ACS Omega, ISSN 2470-1343, Vol. 2, nr 8, s. 4693-4704Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

It was previously reported that two naphthyl-based trans-stilbene probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (1) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (3), can bind to both native transthyretin (TTR) and misfolded protofibrillar TTR at physiological concentrations, displaying distinct emission maxima bound to the different conformational states (>100 nm difference). To further explore this amyloid probe scaffold to obtain extended fluorescence lifetimes, two new analogues with expanded aromatic ring systems (anthracene and pyrene), (E)-4-(2-(anthracen-2-yl)vinyl)benzene-1,2-diol (4) and (E)-4-(2-(pyren-2-yl)vinyl)benzene-1,2-diol (5), were synthesized employing the palladium-catalyzed Mizoroki–Heck reaction. (E)-4-Styrylbenzene-1,2-diol (2), 3, 4, and 5 were investigated with respect to their photophysical properties in methanol and when bound to insulin, lysozyme, and Aβ1-42 fibrils, including time-resolved fluorescence measurements. In conclusion, 4 and 5 can bind to both native and fibrillar TTR, becoming highly fluorescent. Compounds 2–5 bind specifically to insulin, lysozyme, and Aβ1-42 fibrils with an apparent fluorescence intensity increase and moderate binding affinities. The average fluorescence lifetimes of the probes bound to Aβ1-42 fibrils are 1.3 ns (2), 1.5 ns (3), 5.7 ns (4), and 29.8 ns (5). In summary, the variable aromatic moieties of the para-positioned trans-stilbenoid vinyl-benzene-1,2-diol with benzene, naphthalene, anthracene, and pyrene showed that the extended conjugated systems retained the amyloid targeting properties of the probes. Furthermore, both the anthracene and pyrene moieties extensively enhanced the fluorescence intensity and prolonged lifetimes. These attractive probe properties should improve amyloid detection and characterization by fluorescence-based techniques.

Ort, förlag, år, upplaga, sidor
American Chemical Society (ACS), 2017
Nyckelord
Fluorescence; Glycoproteins; Molecular association; Molecular recognition; Optical materials; Quantum transition; Spectra
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:liu:diva-151658 (URN)10.1021/acsomega.7b00535 (DOI)000409924000069 ()
Tillgänglig från: 2018-09-28 Skapad: 2018-09-28 Senast uppdaterad: 2019-11-08Bibliografiskt granskad
2. Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.
Öppna denna publikation i ny flik eller fönster >>Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.
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2018 (Engelska)Ingår i: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 19, nr 22, s. 3001-3009Artikel i tidskrift (Refereegranskat) 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.)

Ort, förlag, år, upplaga, sidor
Weinheim, Germany: Wiley-VCH Verlag, 2018
Nationell ämneskategori
Teoretisk kemi
Identifikatorer
urn:nbn:se:liu:diva-152767 (URN)10.1002/cphc.201800823 (DOI)000450672100006 ()30183138 (PubMedID)
Tillgänglig från: 2018-11-20 Skapad: 2018-11-20 Senast uppdaterad: 2019-11-08
3. Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues
Öppna denna publikation i ny flik eller fönster >>Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues
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2018 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, nr 28, s. 7210-7216Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We revisited the Congo red analogue 2,5-bis(4-hydroxy-3-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimers disease (AD) pathology comprising A beta and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. 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 A beta 1-42 (13-300nmK(d)) and Tau (16-200nmK(d)) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant A beta 1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for A pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of A fibrils.

Ort, förlag, år, upplaga, sidor
WILEY-V C H VERLAG GMBH, 2018
Nyckelord
Alzheimers disease; amyloid ligands; dyes/pigments; fluorescence; microscopy
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:liu:diva-148653 (URN)10.1002/chem.201800501 (DOI)000434074800013 ()29543355 (PubMedID)
Anmärkning

Funding Agencies|China Scholarship Council; Swedish Research Council [2015-04521]; Goran Gustafsson Foundation; Swedish Alzheimer Foundation; Swedish Brain foundation; Linkoping University (LiU-Neuro); NIH/NINDS [R21 NS080576]

Tillgänglig från: 2018-06-18 Skapad: 2018-06-18 Senast uppdaterad: 2019-11-08

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