Development of a New Distyrylbenzene-Derivative Amyloid-β-aggregation and Fibril Formation Inhibitor
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Several new amyloid-β (Aβ) aggregation inhibitors were synthesized according to our theory that a hydrophilic moiety could be attached to the Aβ-recognition unit for the purpose of preventing amyloid plaque formation. A distyrylbenzene-derivative, DSB(EEX)<sub>3</sub>, which consider the Aβ recognition unit (DSB, 1,4-distyrylbenzene) and expected to bind to amyloid fibrils (β-sheet structure), was combined with the hydrophilic aggregation disrupting element (EEX) (E, Glu; X, 2-(2-(2-aminoethoxy)ethoxy)acetic acid). This DSB(EEX)<sub>3</sub> compound, compared to several others synthesized similarly, was found to be the most active for reducing Aβ toxicity toward IMR-32 human neuroblastoma cells. Moreover, its inhibition of Aβ-aggregation or fibril formation was directly confirmed by transmission electron microscopy and atomic force microscopy. These results suggest that the Aβ aggregation inhibitor DSB(EEX)<sub>3</sub> disrupts clumps of Aβ protein and is a likely candidate for drug development to treat Alzheimer’s disease.
- Chemical and Pharmaceutical Bulletin
Chemical and Pharmaceutical Bulletin 60(9), 1164-1170, 2012
The Pharmaceutical Society of Japan