Development of a new distyrylbenzene-derivative amyloid-β-aggregation and fibril formation inhibitor

Abstract

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)3, 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)3 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)3 disrupts clumps of Aβ protein and is a likely candidate for drug development to treat Alzheimer's disease. © 2012 The Pharmaceutical Society of Japan.