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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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Related in: MedlinePlus

Synthesis of HS-84. Reagents and conditions: a) 1,4-dioxane/MeOH, PEPPSI™-IPr, K2CO3, 70 °C, 20 min; b) MeOH, H2SO4, 70 °C, 16 h; c) NBS, DMF, 0 °C to RT, 16 h; d) NaOH (1 m), 1,4-doxane, 60 °C, 16 h.
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fig06: Synthesis of HS-84. Reagents and conditions: a) 1,4-dioxane/MeOH, PEPPSI™-IPr, K2CO3, 70 °C, 20 min; b) MeOH, H2SO4, 70 °C, 16 h; c) NBS, DMF, 0 °C to RT, 16 h; d) NaOH (1 m), 1,4-doxane, 60 °C, 16 h.

Mentions: The new LCOs were synthesized in a similar fashion as previously reported.11, 12, 17 Thiophene trimer 133 was used as precursor for the synthesis of target compounds p-KTAA and HS-42 (Scheme 1). Electrophilic aromatic substitution on trimer 1 using N-bromosuccinimide in DMF gave dibrominated thiophene trimer 2 in 94 % yield. Compound 2 was subjected to a Suzuki coupling with 5-acetyl-2-thienylboronic acid (3) using K2CO3 and the palladium-catalyst PEPPSI™-IPr. Due to solubility problems, after workup, the crude methylester pentamer was subsequently hydrolyzed with 1 m aqueous NaOH in dioxane and water to give p-KTAA in an overall yield of 83 % over two steps. Compound 417 was coupled to compound 2 according to the above-mentioned Suzuki conditions affording pentamer 5 in 48 % yield. Hydrolysis with 1 m aqueous NaOH in dioxane and water gave HS-42 quantitatively (Scheme 1). The synthetic approach towards pentameric oligothiophene HS-84 required the dimeric thiophene 8 (Scheme 2). This intermediate was prepared according to the same palladium cross-coupling conditions as described above using monomers 633 and 7, followed by esterification under acidic conditions using methanol as solvent and nucleophile in an overall yield of 71 % over two steps. Bromination of the intermediate 8 with N-bromosuccinimide in DMF afforded the key precursor 9 in 73 % yield. Following the previous procedure dibrominated dimer 9 was coupled to 2,5-thiophenediylbisboronic acid (10) yielding methyl ester pentamer 11 in 80 %. Final hydrolysis as for HS-42 and p-KTAA gave HS-84 quantitatively (Scheme 2). After synthesis and purification, the solvatochromism and viscosity-dependent spectral changes of the dyes were assessed as described above.12


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)

Synthesis of HS-84. Reagents and conditions: a) 1,4-dioxane/MeOH, PEPPSI™-IPr, K2CO3, 70 °C, 20 min; b) MeOH, H2SO4, 70 °C, 16 h; c) NBS, DMF, 0 °C to RT, 16 h; d) NaOH (1 m), 1,4-doxane, 60 °C, 16 h.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig06: Synthesis of HS-84. Reagents and conditions: a) 1,4-dioxane/MeOH, PEPPSI™-IPr, K2CO3, 70 °C, 20 min; b) MeOH, H2SO4, 70 °C, 16 h; c) NBS, DMF, 0 °C to RT, 16 h; d) NaOH (1 m), 1,4-doxane, 60 °C, 16 h.
Mentions: The new LCOs were synthesized in a similar fashion as previously reported.11, 12, 17 Thiophene trimer 133 was used as precursor for the synthesis of target compounds p-KTAA and HS-42 (Scheme 1). Electrophilic aromatic substitution on trimer 1 using N-bromosuccinimide in DMF gave dibrominated thiophene trimer 2 in 94 % yield. Compound 2 was subjected to a Suzuki coupling with 5-acetyl-2-thienylboronic acid (3) using K2CO3 and the palladium-catalyst PEPPSI™-IPr. Due to solubility problems, after workup, the crude methylester pentamer was subsequently hydrolyzed with 1 m aqueous NaOH in dioxane and water to give p-KTAA in an overall yield of 83 % over two steps. Compound 417 was coupled to compound 2 according to the above-mentioned Suzuki conditions affording pentamer 5 in 48 % yield. Hydrolysis with 1 m aqueous NaOH in dioxane and water gave HS-42 quantitatively (Scheme 1). The synthetic approach towards pentameric oligothiophene HS-84 required the dimeric thiophene 8 (Scheme 2). This intermediate was prepared according to the same palladium cross-coupling conditions as described above using monomers 633 and 7, followed by esterification under acidic conditions using methanol as solvent and nucleophile in an overall yield of 71 % over two steps. Bromination of the intermediate 8 with N-bromosuccinimide in DMF afforded the key precursor 9 in 73 % yield. Following the previous procedure dibrominated dimer 9 was coupled to 2,5-thiophenediylbisboronic acid (10) yielding methyl ester pentamer 11 in 80 %. Final hydrolysis as for HS-42 and p-KTAA gave HS-84 quantitatively (Scheme 2). After synthesis and purification, the solvatochromism and viscosity-dependent spectral changes of the dyes were assessed as described above.12

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