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

Reactivity of Diphenylpropynone Derivatives Toward Metal-Associated Amyloid‑β Species

In Alzheimer’s disease (AD), metal-associated amyloid-β (metal–Aβ) species have been suggested to be involved in neurotoxicity; however, their role in disease development is still unclear. To elucidate this aspect, chemical reagents have been developed as valuable tools for targeting metal–Aβ species, modulating the interaction between the metal and Aβ, and subsequently altering metal–Aβ reactivity. Herein, we report the design, preparation, characterization, and reactivity of two diphenylpropynone derivatives (<b>DPP1</b> and <b>DPP2</b>) composed of structural moieties for metal chelation and Aβ interaction (bifunctionality). The interactions of these compounds with metal ions and Aβ species were confirmed by UV–vis, NMR, mass spectrometry, and docking studies. The effects of these bifunctional molecules on the control of in vitro metal-free and metal-induced Aβ aggregation were investigated and monitored by gel electrophoresis and transmission electron microscopy (TEM). Both <b>DPP1</b> and <b>DPP2</b> showed reactivity toward metal–Aβ species over metal-free Aβ species to different extents. In particular, <b>DPP2</b>, which contains a dimethylamino group, exhibited greater reactivity with metal–Aβ species than <b>DPP1</b>, suggesting a structure-reactivity relationship. Overall, our studies present a new bifunctional scaffold that could be utilized to develop chemical reagents for investigating metal–Aβ species in AD

Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (<b><b>ML</b></b>) prototype of a rationally designed molecule obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound <b><b>ML</b></b> targets metal-free and metal-bound Aβ (metal–Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of <b><b>ML</b></b> to its structural moieties (i.e., 4-(dimethylamino)­phenol (<b>DAP</b>) and (8-aminoquinolin-2-yl)­methanol (<b>1</b>)) for reactivity with Aβ and metal–Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, <b><b>ML</b></b> is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity