Synthesis and evaluation of benzothiazole-triazole and benzothiadiazole-triazole scaffolds as potential molecular probes for amyloid-β aggregation

Dyrager, Christine; Vieira, Rafael P.; Nyström, Sofie; Nilsson, K. Peter R.; Storr, Tim

doi:10.1039/c6nj01703g

Cited by 44 publications

(35 citation statements)

References 38 publications

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“…This evidence suggests an increase in the specificity of NIAD-4 concerning ThT in acidic conditions. Beyond NIAD-4 dye, three other probes (L1, L2, and L3 reported in Figure A3) with a molecular structure similar to ThT were proposed by Dyrager and co-workers [48] for the detection and visualization of Aβ1-42 plaques in transgenic mice brain slices. Nevertheless, despite the capability of these dyes to emit significant photoluminescence quantum yields, they did not exhibit the expected "turn-on" features.…”

Section: Fl Extrinsic Dyes and Imaging Technology Of Amyloid Fibersmentioning

confidence: 99%

Fluorescence Phenomena in Amyloid and Amyloidogenic Bionanostructures

et al. 2020

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Nanoscale optical labeling is an advanced bioimaging tool. It is mostly based on fluorescence (FL) phenomena and enables the visualization of single biocells, bacteria, viruses, and biological tissues, providing monitoring of functional biosystems in vitro and in vivo, and the imaging-guided transportation of drug molecules. There is a variety of FL biolabels such as organic molecular dyes, genetically encoded fluorescent proteins (green fluorescent protein and homologs), semiconductor quantum dots, carbon dots, plasmonic metal gold-based nanostructures and more. In this review, a new generation of FL biolabels based on the recently found biophotonic effects of visible FL are described. This intrinsic FL phenomenon is observed in any peptide/protein materials folded into β-sheet secondary structures, irrespective of their composition, complexity, and origin. The FL effect has been observed both in natural amyloid fibrils, associated with neurodegenerative diseases (Alzheimer’s, Parkinson’s, and more), and diverse synthetic peptide/protein structures subjected to thermally induced biological refolding helix-like→β-sheet. This approach allowed us to develop a new generation of FL peptide/protein bionanodots radiating multicolor, tunable, visible FL, covering the entire visible spectrum in the range of 400–700 nm. Newly developed biocompatible nanoscale biomarkers are considered as a promising tool for emerging precise biomedicine and advanced medical nanotechnologies (high-resolution bioimaging, light diagnostics, therapy, optogenetics, and health monitoring).

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Section: Fl Extrinsic Dyes and Imaging Technology Of Amyloid Fibersmentioning

confidence: 99%

Fluorescence Phenomena in Amyloid and Amyloidogenic Bionanostructures

et al. 2020

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“…The brominated benzothiadiazole 3.26 was formed from refluxing commercially available benzothiadiazole 3.25 with bromine, in a 48% aqueous solution of HBr. While only one equivalent of bromine was added, steam distillation of the reaction mixture yielded ~30% of mono-brominated benzothiadiazole, ~30% of di-brominated benzothiadiazole, and ~30% of unreacted starting material, which is consistent to that reported within literature 460. The glycolated cyclopentadithiophene unit 3.10 was lithiated with 1.05 equivalents of n-BuLi before addition of 2-iso-propoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to produce theborylated intermediate Suzuki coupling of 3.13 and 3.26 with aqueous potassium carbonate and catalytic tetrakis(triphenylphosphine)palladium(0) in refluxing toluene yielded 3.27 in a 55% yield.…”

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confidence: 90%

Development of a Library of Novel Compounds for Use in Organic Solar Cells

McGregor¹

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Currently, the most common method of optimising organic solar cells is to synthesise new materials before fabricating and testing devices under a wide range of processing conditions to empirically determine the optimum conditions, with other measurements supporting the explanation. This is both a laborious and material intensive process. Simplification of device optimisation processes would likely enable devices to be more easily manufactured at a lower cost. In turn, it would be expected for organic solar cells to become more accessible to the consumer, decreasing the need for fossil fuels. Two approaches to simplifying organic solar cell manufacture were investigated.First, a series of triphenylamine (TPA) centred materials were synthesised to act as nonfullerene acceptors. However, as all four synthesised TPA materials showed comparable optoelectronic properties which were complimentary to that of common donor P3HT, no distinction towards the relative device performance could be made based on these parameters alone. As bulk heterojunction (BHJ) morphology is critical to device performance, differential scanning calorimetry (DSC) in conjunction with X-ray diffraction (XRD) provided improved screening capabilities. When blended with P3HT at varying concentrations and deposited from solution, the morphological differences of the resulting blended films were probed by thermal methods to successfully predict the optimum donor:acceptor pair. Application of Flory-Huggins theory and Kyu plots to determine the interaction parameter ( 0 ) reveal that the materials must be miscible to enable low-energy interfaces, while phase separation into pure domains enables charges to be extracted from the device through continuous percolation pathways. The donor:acceptor pair with the highest positive value of 0 demonstrated a PCE of 2.0% and JSC above 4 mA/cm 2 , while the pair with the lowest 0 value lead to poor device performance (<0.4% PCE) due to excessive mixing. DSC methods were also able to provide a calculated critical solvation concentration (wcrit); below which the donor and acceptor were expected to become immiscible and perform poorly due to limited phase separation and non-ordered regimes. Additional insights provided by DSC analysis include the observation of a coldcrystallisation process; where liquidation upon heating nucleates crystallisation. Typically due to the entrapment of disordered phases, the DSC experiment was able to provide insight towards highly variable device performance, which otherwise may have been attributed to manufacturing errors.Secondly, further simplification of organic solar cells to homojunction (i.e., single component) devices was completed. Materials with low exciton binding energies are able to efficiently separate into free charge carriers and limit recombination pathways. The binding energy of an exciton is dependent on a number of factors, such as that described by the Wannier-Mott construct, which states that the exciton binding energy is proportional to the inverse square of the d...

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“…17 Although a large number of fluorescent small molecule BTD derivatives were applied to bioimaging analyses of several cell types, little is known about this class of bio-probes used to stain Aβ plaques and NFTs in Alzheimer's disease (AD). Nilsson and coworkers reported on L3 (Figure 1.1B), which can intensely stain Aβ plaques, 18 and HS-169 ( Figure 1.1B) intensely stain Aβ plaques and NFTs. 19 In view of all the positive effects of the photoluminescent properties of π-extended BTDs, we wish this new class of bio-probes could fill the gap not occupied by the use of current classical scaffolds and be key player in the future of molecular bio-probes, especially in the field of AD.…”

Section: 13-benzothiadiazole (Btd) Derivatives As Fluorescent Probmentioning

confidence: 92%

“…Note that R2 and R3 are usually H atoms and that R1 and R4 are the groups in the positions commonly used for π-extensions. B) Chemical structures of BTD derivatives reported previously [18][19].…”

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confidence: 99%

Synthesis and characterization of fluorescent stilbene-based probes targeting amyloid fibrils

Zhang

2018

Linköping Studies in Science and Technology. Dissertations

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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...

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Synthesis and evaluation of benzothiazole-triazole and benzothiadiazole-triazole scaffolds as potential molecular probes for amyloid-β aggregation

Abstract: Fluorescent scaffolds that can be easily modifiedviaclick chemistry were investigated as probes for Aβ-plaque deposits in mouse tissue.

Cited by 44 publications

References 38 publications

Fluorescence Phenomena in Amyloid and Amyloidogenic Bionanostructures

Fluorescence Phenomena in Amyloid and Amyloidogenic Bionanostructures

Development of a Library of Novel Compounds for Use in Organic Solar Cells

Synthesis and characterization of fluorescent stilbene-based probes targeting amyloid fibrils

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