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 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.
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Elena
E
Simoni
Department of Drug Sciences (Pharmacology Section), University of Pavia, V.le Taramelli 14, 27100, Pavia, Italy.
Melania M
MM
Serafini
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Manuela
M
Bartolini
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Roberta
R
Caporaso
Department of Drug Sciences (Pharmacology Section), University of Pavia, V.le Taramelli 14, 27100, Pavia, Italy.
Antonella
A
Pinto
Department of Drug Sciences (Pharmacology Section), University of Pavia, V.le Taramelli 14, 27100, Pavia, Italy.
Daniela
D
Necchi
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Jessica
J
Fiori
Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso d'Augusto 237, 47921, Rimini, Italy.
Vincenza
V
Andrisano
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
Anna
A
Minarini
Department of Drug Sciences (Pharmacology Section), University of Pavia, V.le Taramelli 14, 27100, Pavia, Italy. cristina.lanni@unipv.it.
Cristina
C
Lanni
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. michela.rosini@unibo.it.
Michela
M
Rosini
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008024:Ligands; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D060589:Zyxin / Q000737:chemistry / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D002934:Cinnamates; D008024:Ligands; D020011:Protective Agents; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D060589:Zyxin; C029010:cinnamic acid; D006861:Hydrogen Peroxide; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases
Alzheimer's disease; amyloid-beta peptide; antioxidants; multifunctional ligands; p53