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Nature‐Inspired Multifunctional Ligands: Focusing on Amyloid‐Based Molecular Mechanisms of Alzheimer's Disease
Author(s) -
Simoni Elena,
Serafini Melania M.,
Bartolini Manuela,
Caporaso Roberta,
Pinto Antonella,
Necchi Daniela,
Fiori Jessica,
Andrisano Vincenza,
Minarini Anna,
Lanni Cristina,
Rosini Michela
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500422
Subject(s) - oxidative stress , reactive oxygen species , chemistry , moiety , amyloid (mycology) , catechol , mediator , amyloid precursor protein , disease , biochemistry , oxidative phosphorylation , stereochemistry , amyloid β , microbiology and biotechnology , alzheimer's disease , biology , medicine , inorganic chemistry
The amyloidogenic pathway is a prominent feature of Alzheimer's disease (AD). However, growing evidence suggests that a linear disease model based on β‐amyloid peptide (Aβ) alone is not likely to be realistic, which therefore calls for further investigations on the other actors involved in the play. The pro‐oxidant environment induced by Aβ in AD pathology is well established, and a correlation among Aβ, 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 Aβ 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 Aβ. This may support an involvement of oxidative stress in Aβ function, with p53 emerging as a potential mediator of their functional interplay.