(214b) Modulation of Amyloid-Beta Aggregation and Cytotoxicity by Halogenated Small Molecules

Numerous small molecules have been identified as amyloid-beta aggregation modulators. However, considering that no amyloid-beta aggregation modulator has been approved by the Food and Drug Administration (FDA), there still remains a need to develop a new type of amyloid-beta aggregation modulators. In order to search for novel small molecule modulators with good biocompatibility, we screened various FDA-approved food coloring dyes and their close analogs. We recently reported that brilliant blue G (BBG), brilliant blue R (BBR), and red food dye erythrosine B (ERB) are novel modulators of amyloid-beta aggregation in vitro and amyloid-beta cytotoxicity in cell-based assays. Furthermore, we hypothesized that ERB can be a new type of amyloid-beta aggregation/cytotoxicity modulators due to its halogen atoms. A significant number of drugs and drug candidates are halogenated. Halogen groups are often inserted during hit-to-lead or lead-to-drug conversions for several reasons, including enhanced antagonistic/agnostic effects due to increased volume and improved oral absorption/BBB permeability. However, halogenated amyloid-beta aggregation modulators were rarely reported. Comparative studies of ERB and its close structural analogs revealed that halogen atoms attached to either xanthene group or benzoate group play an important role in modulation of amyloid-beta aggregation and cytotoxicity. Different amyloid-beta aggregation modulatory mechanisms of ERB analogs were also compared. These findings would enhance our understanding of amyloid-beta aggregation mechanisms and facilitate discovery of lead compounds for future therapeutic development for treatment of Alzheimer's disease.