Pifithrin-α, p-nitro, cyclic

Uses

p-nitro-Cyclic Pifithrin-α is an inactivator of p53 that blocks p53-dependent transcriptional activation and apoptisis. Anti-cancer agent.

General Description

A cell-permeable p53 inhibitor that exhibits 10-fold higher potency (ED₅₀ = 30 nM in protecting etoposide-induced cortical neuron death) and 50% longer half-life (t_1/2 = 6h in neuron culture medium at 37°C) than Pifithrin-α (Cat. No. 506132). However, despite its in vitro efficacy, this inhibitor is not effective when adminstered in rats in vivo. For in vivo applications, please consider Pifithrin-α, p-Nitro (Cat. No. 506152).

Biological Activity

p-nitro-cyclic pifithrin-α is an inactivator of p53.the activation of the tumor suppressor gene p53 plays a key role in regulating the in-vitro death of neurons, following apoptotic stimuli molecules including glutamate and dna-damaging agents. thus, p53 inhibitors may prove effective in suppressing the degenerative processes in neurodegenerative disorders.

Biochem/physiol Actions

Cell permeable: yes

in vitro

pifithrin-α (pft-α) was identified as an inactivator of p53 blocking p53-dependent transcriptional activation and apoptosis. cyclic pft-α was a stable analog of pft-α. p-nitro-cyclic pft-α, a cell-permeable form of cyclic pft-α, was found to be one order of magnitude more active than pft-α in protecting cortical neurons exposed to etoposide. p-nitro-cyclic pft-α acted in a p53-dependently but did not block phosphorylation of p53 on ser15 in response to etoposide treatment, although it prevented p53 posttranscriptional activity [1].

in vivo

in a previou study, c57bl/6 mice were fed a high-fat (hfd) or control diet for 8 weeks; pft was administered three times per week. results showed that pft administration could suppress hfd-induced weight gain, steatosis, oxidative stress, alt elevation, and apoptosis. pft treatment also able to blunt the hfd-induced upregulation of mirna34a and increase sirt1 expression. in the livers of hfd-fed, pft-treated mice, activation of the sirt1/pgc1α/pparα axis increased the expression of malonyl-coa decarboxylase [2].

References

[1] . pietrancosta, n.,moumen, a.,dono, r., et al. imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: discovery of a highly potent in vivo inhibitor and its action mechanism. journal of medicinal chemistry 49(12), 3645-3652 (2006).
[2] derdak z, villegas ka, harb r, wu am, sousa a, wands jr. inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease. j hepatol. 2013 apr;58(4):785-91.