| Reference | 1. ACS Chem Neurosci. 2014 May 21;5(5):390-9. doi: 10.1021/cn4002208. Epub 2014 Mar
28.
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p53 functional inhibitors behaving like pifithrin-β counteract the Alzheimer
peptide non-β-amyloid component effects in human SH-SY5Y cells.
<br>
Da Pozzo E(1), La Pietra V, Cosimelli B, Da Settimo F, Giacomelli C, Marinelli L,
Martini C, Novellino E, Taliani S, Greco G.
<br>
Author information: <br>
(1)Dipartimento di Farmacia, Università di Pisa , Via Bonanno Pisano 6, 56126
Pisa, Italy.
<br>
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.
<br><br>
2. Life Sci. 2011 Apr 25;88(17-18):774-83. doi: 10.1016/j.lfs.2011.02.019. Epub 2011
Feb 26.
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Biological and chemical studies on aryl hydrocarbon receptor induction by the p53
inhibitor pifithrin-α and its condensation product pifithrin-β.
<br>
Fernández-Cruz ML(1), Valdehita A, Alonso M, Mann E, Herradón B, Navas JM.
<br>
Author information: <br>
(1)Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA),
Departamento de Medio Ambiente, Carretera de la Coruña Km. 7.5, Madrid, Spain.
[email protected]
<br>
AIMS: Pifithrin α (PFTα), an inhibitor of the p53 protein, is regarded as a lead
compound for cancer and neurodegenerative disease therapy. There is some evidence
that this compound activates the aryl hydrocarbon receptor (AhR) in a complete
independent way of the p53 inhibition and that it is easily converted to its
condensation product pifithrin β (PFTβ). The aim of this study was to explore the
ability of PFTα and of PFTβ to induce a variety of AhR mediated processes.
MAIN METHODS: Computational analysis using quantum chemical calculations and
chemical analysis have been used to study the conformation of the compounds as
well as the cyclization reaction. The AhR mediated processes of these compounds
have been studied in a rainbow trout cell line (RTG-2) and in a rat hepatoma cell
line (H4IIE).<br>
KEY FINDINGS: PFTα molecule could not take a planar conformation required for AhR
activation whereas PFTβ showed a conformation similar to those of the
prototypical AhR ligand β-naphthoflavone. In both cell lines, PFTα and PFTβ
provoked different responses related with AhR activation. However, when
cyclization of PFTα to PFTβ was hampered by acetylation of the exocyclic
nitrogen, all these responses were not observed. These results lead to the
conclusion that the activation of the AhR is probably caused by PFTβ instead of
PFTα.<br>
SIGNIFICANCE: Since PFTα is a promising compound for the development of new
pharmaceuticals inhibiting p53, the chemical instability of this compound as well
as the capacity of its transformation product should be taken into account.
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