Nature-Inspired Multifunctional Ligands: Focusing on Amyloid-Based Molecular Mechanisms of Alzheimer’s Disease

The amyloidogenic pathway is a prominent feature of Alzheimer’s disease (AD). However, growing evidence suggests that a linear disease model based on b-amyloid peptide (Ab) alone is not likely to be realistic, which therefore calls for further investigations on the other actors involved in the play. The prooxidant environment induced by Ab in AD pathology is well established, and a correlation among Ab, oxidative stress, and conformational changes in p53 has been suggested. In this study, we applied a multifunctional approach to identify allyl thioesters of variously substituted trans-cinnamic acids for which the pharmacological profile was strategically tuned by hydroxy substituents on the aromatic moiety. Indeed, only catechol derivative 3 [(S)-allyl (E)-3-(3,4-dihydroxyphenyl)prop-2- enethioate] inhibited Ab fibrilization. Conversely, albeit to different extents, all compounds were able to decrease the formation of reactive oxygen species in SH-SY5Y neuroblastoma cells and to prevent alterations in the conformation of p53 and its activity mediated by soluble sub-lethal concentrations of Ab. This may support an involvement of oxidative stress in Ab function, with p53 emerging as a potential mediator of their functional interplay.