Pifithrin-β

Pifithrin-β is a potent p53 inhibitor with an IC50 of 23 μM.

In Vitro:Pifithrin-α, an inhibitor of the p53 protein, is regarded as a lead compound for cancer and neurodegenerative disease therapy. Pifithrin-α is very unstable in culture medium and rapidly converts to its condensation product pifithrin-β, the N-acetyl derivative[2]. After 24 h, the viability assay shows that the pretreatments with 1 and 10 μM pifithrin-β exerts neuroprotective effects[3].

References:
[1]. Christodoulou MS, et al. Synthesis and biological evaluation of imidazolo[2,1-b]benzothiazole derivatives, as potential p53 inhibitors. Bioorg Med Chem. 2011 Mar 1;19(5):1649-57. [2]. Fernández-Cruz ML, et al. Biological and chemical studies on aryl hydrocarbon receptor induction by the p53 inhibitor pifithrin-α and its condensation product pifithrin-β. Life Sci. 2011 Apr 25;88(17-18):774-83. [3]. Da Pozzo E, et al. p53 functional inhibitors behaving like pifithrin-β counteract the Alzheimer peptide non-β-amyloid component effects in human SH-SY5Y cells. ACS Chem Neurosci. 2014 May 21;5(5):390-9.

p53 functional inhibitors behaving like pifithrin-beta counteract the Alzheimer peptide non-beta-amyloid component effects in human SH-SY5Y cells.[Pubmed:24646317]

ACS Chem Neurosci. 2014 May 21;5(5):390-9.

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-beta-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-beta, a small molecule interfering with the p53 functions. Using the structure of a pifithrin-beta 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-beta, as a result of a more effective functional inhibition of p53 target gene transcription.

Biological and chemical studies on aryl hydrocarbon receptor induction by the p53 inhibitor pifithrin-alpha and its condensation product pifithrin-beta.[Pubmed:21362431]

Life Sci. 2011 Apr 25;88(17-18):774-83.

AIMS: Pifithrin alpha (PFTalpha), 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 beta (PFTbeta). The aim of this study was to explore the ability of PFTalpha and of PFTbeta 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). KEY FINDINGS: PFTalpha molecule could not take a planar conformation required for AhR activation whereas PFTbeta showed a conformation similar to those of the prototypical AhR ligand beta-naphthoflavone. In both cell lines, PFTalpha and PFTbeta provoked different responses related with AhR activation. However, when cyclization of PFTalpha to PFTbeta 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 PFTbeta instead of PFTalpha. SIGNIFICANCE: Since PFTalpha 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.