Unusual Cyclodextrin Derivatives as a New Avenue to Modulate Self‐ and Metal‐Induced Aβ Aggregation

Mounting evidence suggests an important role of cyclodextrins in providing protection in neurodegenerative disorders. Metal dyshomeostasis is reported to be a pathogenic factor in neurodegeneration because it could be responsible for damage involving oxidative stress and protein aggregation. As such, metal ions represent an effective target. To improve the metal‐binding ability of cyclodextrin, we synthesized three new 8‐hydroxyquinoline‐cyclodextrin conjugates with difunctionalized cyclodextrins. In particular, the 3‐difunctionalized regioisomer represents the first example of cyclodextrin with two pendants at the secondary rim, resulting in a promising compound. The derivatives have significant antioxidant capacity and the powerful activity in inhibiting self‐induced amyloid‐β aggregation seems to be led by synergistic effects of both cyclodextrin and hydroxyquinoline. Moreover, the derivatives are also able to complex metal ions and to inhibit metal‐induced protein aggregation. Therefore, these compounds could have potential as therapeutic agents in diseases related to protein aggregation and metal dyshomeostasis.