title: p53 functional inhibitors behaving like pifithrin-β counteract the Alzheimer peptide non-β-amyloid component effects in human SH-SY5Y cells.
abstract: Alzheimer's disease (AD) develops from a complex setting of genetic and biochemical alterations, including an increased level of p53 in the brain. Here, the robust and specific activation of p53 by the fibrillar non-β-amyloid component (NAC) of AD was demonstrated in human neuroblastoma SH-SY5Y cells. For the first time, the increase in the level of p53 target gene transcription, the cell cycle arrest, and the induction of apoptosis elicited by NAC were evidenced. These effects were counterbalanced by pifithrin-β, a small molecule interfering with the p53 functions. Using the structure of a pifithrin-β analogue as a reference, a pharmacophore-based virtual screening of the ZINC database was performed. Among the resulting hits, 20 druglike heterocyclic compounds were selected and evaluated for their neuroprotective activity against fibrillar NAC in the human SH-SY5Y cellular model. Three compounds exhibited neuroprotective effects. In particular, 2-(4-methoxyphenyl)-7-methyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine resulted in a promising lead compound for further development of anti-AD agents in terms of neuroprotection, reducing the rate of NAC-induced cell death with an activity higher than that of pifithrin-β, as a result of a more effective functional inhibition of p53 target gene transcription.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa , Via Bonanno Pisano 6, 56126 Pisa, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Chiara
authors.initials: C
authors.lastname: Giacomelli
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D006576:Heterocyclic Compounds, 4 or More Rings; D018696:Neuroprotective Agents; D016159:Tumor Suppressor Protein p53; C558699:pifithrin-beta; D014050:Toluene; D015032:Zinc