Tuning Reactivity of Diphenylpropynone Derivatives with Metal-Associated Amyloid‑β Species via Structural Modifications

A diphenylpropynone derivative, <b>DPP2</b>, has been recently demonstrated to target metal-associated amyloid-β (metal–Aβ) species implicated in Alzheimer’s disease (AD). <b>DPP2</b> was shown to interact with metal–Aβ species and subsequently control Aβ aggregation (reactivity) in vitro; however, its cytotoxicity has limited further biological applications. In order to improve reactivity toward Aβ species and lower cytotoxicity, along with gaining an understanding of a structure-reactivity-cytotoxicity relationship, we designed, prepared, and characterized a series of small molecules (<b>C1</b>/<b>C2</b>, <b>P1</b>/<b>P2</b>, and <b>PA1</b>/<b>PA2</b>) as structurally modified <b>DPP2</b> analogues. A similar metal binding site to that of <b>DPP2</b> was contained in these compounds while their structures were varied to afford different interactions and reactivities with metal ions, Aβ species, and metal–Aβ species. Distinct reactivities of our chemical family toward in vitro Aβ aggregation in the absence and presence of metal ions were observed. Among our chemical series, the compound (<b>C2</b>) with a relatively rigid backbone and a dimethylamino group was observed to noticeably regulate both metal-free and metal-mediated Aβ aggregation to different extents. Using our compounds, cell viability was significantly improved, compared to that with <b>DPP2</b>. Lastly, modifications on the <b>DPP</b> framework maintained the structural properties for potential blood-brain barrier (BBB) permeability. Overall, our studies demonstrated that structural variations adjacent to the metal binding site of <b>DPP2</b> could govern different metal binding properties, interactions with Aβ and metal–Aβ species, reactivity toward metal-free and metal-induced Aβ aggregation, and cytotoxicity of the compounds, establishing a structure-reactivity-cytotoxicity relationship. This information could help gain insight into structural optimization for developing nontoxic chemical reagents toward targeting metal–Aβ species and modulating their reactivity in biological systems