Leveraging heterocycle-fused 1,4-benzoquinone to design chemical modulators for both metal-free and metal-bound...

The complex pathology of Alzheimer's disease includes various pathogenic components, such as metal-free amyloid-β (Aβ) and metal-bound Aβ (metal-Aβ). Here we report an effective strategy for developing novel heterocycle-fused 1,4-benzoquinone (BQ) compounds to control the aggregation and toxicity of both metal-free Aβ and metal-Aβ. We designed and synthesized these compounds by fusing BQ with 3-pyrazolone responsible for metal chelation. The compounds' ability to form covalent bonds with Aβ is tuned by the annulation of the BQ moiety and the type, position, and number of substituents on the 3-pyrazolone group. Furthermore, the BQ functionality on the 3-pyrazolone framework can undergo o-hydroxylation, enhancing its metal chelation in a bidentate manner. Our results demonstrate that these heterocycle-fused BQ compounds can redirect the assembly of Aβ into less toxic aggregates by binding to metal ions, modifying Aβ structures in both the absence and presence of metal ions, and promoting oxidative changes to Aβ. This study highlights the importance of structural modifications and optimizations of BQ to leverage its strength of covalently cross-linking to Aβ and overcome its limitations in metal chelation and cytotoxicity, which are critical for designing chemical modulators for metal-free Aβ and metal-Aβ. Our approach offers a novel strategy for developing chemical modulators towards metal-related peptides and proteins as well as therapeutic agents for metal-associated amyloid disorders.