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Pentameric thiophene-based ligands that spectrally discriminate amyloid-β and tau aggregates display distinct solvatochromism and viscosity-induced spectral shifts.

Simon RA, Shirani H, Aslund KO, Bäck M, Haroutunian V, Gandy S, Nilsson KP - Chemistry (2014)

Bottom Line: Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections.The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate.We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Linköping University, 581 83 Linköping (Sweden).

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Chemical structures, Lippert–Mataga solvatochromism plots and viscosity plots of the pentameric LCOs: A) p-KTAA, B) HS-84, and C) HS-42. For the solvatochromism, solvents of increasing polarity in the following order: ethyl acetate, octanol, dimethyl sulfoxide (DMSO), ethylene glycol, methanol, and water were used. For the viscosity experiments, LCOs were mixed in solutions of ethylene glycol and glycerol with increasing concentrations of glycerol. The LCO concentration was 300 nm for all experiments.
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fig03: Chemical structures, Lippert–Mataga solvatochromism plots and viscosity plots of the pentameric LCOs: A) p-KTAA, B) HS-84, and C) HS-42. For the solvatochromism, solvents of increasing polarity in the following order: ethyl acetate, octanol, dimethyl sulfoxide (DMSO), ethylene glycol, methanol, and water were used. For the viscosity experiments, LCOs were mixed in solutions of ethylene glycol and glycerol with increasing concentrations of glycerol. The LCO concentration was 300 nm for all experiments.

Mentions: In order to test our hypothesis that pentameric LCOs for optimal spectral discrimination of Aβ deposits and NFTs should display distinct solvatochromism as well as spectral shifts due to solvent viscosity, three novel anionic pentameric LCO analogues to p-FTAA were synthesized (Figure 3). Firstly, the terminal carboxyl groups were replaced by ketones, resulting in p-KTAA, an anionic pentamer with the same central trimer building block as p-FTAA and neutral polarizable π-acceptor groups (ketones) extending the thiophene backbone instead of negatively charged carboxyl groups. Secondly, the positions of the acetic acid side chains were altered on the trimer building block to render HS-84, an isomer to p-FTAA having the acetic side chains of the trimeric building block tail-to-tail instead of head-to-head. Thirdly, a pentamer (HS-42) lacking the terminal carboxyl groups extending the conjugated backbone, but displaying the same amount of net charge (−4) as p-FTAA was synthesized.3


Pentameric thiophene-based ligands that spectrally discriminate amyloid-β and tau aggregates display distinct solvatochromism and viscosity-induced spectral shifts.

Simon RA, Shirani H, Aslund KO, Bäck M, Haroutunian V, Gandy S, Nilsson KP - Chemistry (2014)

Chemical structures, Lippert–Mataga solvatochromism plots and viscosity plots of the pentameric LCOs: A) p-KTAA, B) HS-84, and C) HS-42. For the solvatochromism, solvents of increasing polarity in the following order: ethyl acetate, octanol, dimethyl sulfoxide (DMSO), ethylene glycol, methanol, and water were used. For the viscosity experiments, LCOs were mixed in solutions of ethylene glycol and glycerol with increasing concentrations of glycerol. The LCO concentration was 300 nm for all experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221846&req=5

fig03: Chemical structures, Lippert–Mataga solvatochromism plots and viscosity plots of the pentameric LCOs: A) p-KTAA, B) HS-84, and C) HS-42. For the solvatochromism, solvents of increasing polarity in the following order: ethyl acetate, octanol, dimethyl sulfoxide (DMSO), ethylene glycol, methanol, and water were used. For the viscosity experiments, LCOs were mixed in solutions of ethylene glycol and glycerol with increasing concentrations of glycerol. The LCO concentration was 300 nm for all experiments.
Mentions: In order to test our hypothesis that pentameric LCOs for optimal spectral discrimination of Aβ deposits and NFTs should display distinct solvatochromism as well as spectral shifts due to solvent viscosity, three novel anionic pentameric LCO analogues to p-FTAA were synthesized (Figure 3). Firstly, the terminal carboxyl groups were replaced by ketones, resulting in p-KTAA, an anionic pentamer with the same central trimer building block as p-FTAA and neutral polarizable π-acceptor groups (ketones) extending the thiophene backbone instead of negatively charged carboxyl groups. Secondly, the positions of the acetic acid side chains were altered on the trimer building block to render HS-84, an isomer to p-FTAA having the acetic side chains of the trimeric building block tail-to-tail instead of head-to-head. Thirdly, a pentamer (HS-42) lacking the terminal carboxyl groups extending the conjugated backbone, but displaying the same amount of net charge (−4) as p-FTAA was synthesized.3

Bottom Line: Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections.The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate.We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Linköping University, 581 83 Linköping (Sweden).

Show MeSH
Related in: MedlinePlus