Excited-State Intramolecular Hydrogen Transfer of Compact Molecules Controls Amyloid Aggregation Profiles

Abstract

Designing new chromophores by tuning their molecular structures and optimizing their photophysical properties leads to suitable photochromic features. Herein, we report a series of anthraquinone (AQ)-based photosensitizers that undergoes excited-state intramolecular hydrogen transfer and effectively oxidizes amyloidogenic peptides, which significantly affects the subsequent aggregation pathways. DFT calculations showed that the appropriate position of the hydroxyl groups in the AQ backbone and the consequent intramolecular hydrogen transfer can facilitate the energy transfer to triplet oxygen. Biochemical and biophysical investigations confirmed that these photoactive chemical reagents are able to oxidatively modify both metal-free amyloid-β (Aβ) and metal-bound Aβ, thereby redirecting their on-pathway aggregation into off-pathway as well as disassembling their pre-formed aggregates. Moreover, the in vivo histochemical analysis of Aβ species produced upon photoactivation of the most promising candidate demonstrated that they do not aggregate into toxic oligomeric or fibrillar aggregates in the brain. Overall, our combined computational and experimental studies validate a light-based approach for designing small molecules as chemical reagents targeting and controlling amyloidogenic peptides associated with neurodegenerative disorders.