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

ABSTRACT: 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

SUBMITTER: Yi Y 

PROVIDER: S-EPMC11925219 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature