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

In Alzheimer's disease (AD), metal-associated amyloid-beta (metal-A beta) 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-A beta species, modulating the interaction between the metal and A beta, and subsequently altering metal-A beta reactivity. Herein, we report the design, preparation, characterization, and reactivity of two diphenylpropynone derivatives (DPP1 and DPP2) composed of structural moieties for metal chelation and A beta interaction (bifunctionality). The interactions of these compounds with metal ions and A beta 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 A beta aggregation were investigated and monitored by gel electrophoresis and transmission electron microscopy (TEM). Both DPP1 and DPP2 showed reactivity toward metal-A beta species over metal-free A beta species to different extents. In particular, DPP2, which contains a dimethylamino group, exhibited greater reactivity with metal-A beta species than DPP1, suggesting a structure-reactivity relationship. Overall, our studies present a new bifunctional scaffold that could be utilized to develop chemical reagents for investigating metal-A beta species in AD.