63208-82-2

Usage

Characteristics

Pifithrin-α is an inhibitor of p53, inhibiting p53-dependent transactivation of p53-responsive genes. Pifithrin-α is also a potent agonist of the aryl hydrocarbon receptor (AhR).

Biological Activity

Inhibitor of p53; reversibly blocks p53-dependent transcriptional activation and apoptosis. Protects against neuronal death in models of stroke and neurodegenerative disorders. Active in vivo ; protects mice from the side-effects of cancer therapy associated with p53 induction. Potentially increases reprogramming efficiency of human somatic cells to induced pluripotent stem cells (iPSCs) by silencing p53. Also aryl hydrocarbon receptor (AHR) agonist, causes upregulation of AHR target gene CYP1A1 (EC 50 = 1.1 μ M).

Biochem/physiol Actions

Pifithrin-α is a reversible inhibitor of p53-mediated apoptosis and p53-dependent gene transcription such as cyclin G, p21/waf1, and mdm2 expression. Pifithrin-α enhances cell survival after genotoxic stress such as UV irradiation and treatment with cytotoxic compounds including doxorubicin, etopoxide, paclitaxel, and cytosine-β-D-arabinofuranoside. Pifithrin-α protects mice from lethal whole body γ-irradiation without an increase in cancer incidence. The protective effect is not seen in p53-null mice or cells expressing a dominant negative mutant of the p53 gene. Protection is conferred by the transient expression of p53 in p53-deficient cell lines.

in vitro

Pifithrin-α inhibits p53-dependent transactivation of p53-responsive genes in ConA cells. Pifithrin-α (10 μM) inhibits apoptotic death of C8 cells induced by Dox, etoposide, Taxol, cytosine arabinoside. Pifithrin-α inhibits p53-dependent growth arrest of human diploid fibroblasts in response to DNA damage but has no effect on p53-deficient fibroblasts. Pifithrin-α may modulate the nuclear import or export (or both) of p53 or may decrease the stability of nuclear p53. Pifithrin-α (100-200 nM) completely suppresses the camptothecin-induced increase in the level of p53 DNA binding as well as the p53-responsive gene Bax in hippocampal cell. Pifithrin-α also decreases the basal level of p53 DNA-binding activity. Pifithrin-α (200 nM) protects cultured hippocampal neurons against death induced by DNA-damaging agents. Pifithrin-α (200 μM) stabilizes mitochondrial function, suppresses caspase activation and protects cultured hippocampal neurons against death induced by glutamate and amyloid β-peptide. Pifithrin α, in addition to p53, can suppress heat shock and glucocorticoid receptor signaling but has no effect on nuclear factor-kappaB signaling. Pifithrin α (10 μM) reduces activation of heat shock transcription factor (HSF1) and increases cell sensitivity to heat. Pifithrin α (10 μM) reduces activation of glucocorticoid receptor and rescues mouse thymocytes from apoptotic death after dexamethasone treatment in HeLa cells. PFTalpha blocks p53-mediated induction of p21/Waf-1 in human embryonic kidney cells. PFTalpha does, however, cause a left shift in the dexamethasone dose response curve by increasing intracellular dexamethasone concentration.

in vivo

Pifithrin-α (2.2 mg/kg i.p.) treatment completely rescues mice (C57BL and Balb/c) of both strains from 60% killing doses of gamma irradiation (8 Gy for C57BL and 6 Gy for Balb/c). Pifithrin-α-injected mice lost less weight than irradiated mice that are not pretreated with the Pifithrin-α. Pifithrin-α (2.2 mg/kg) abrogates p53-dependent regulation of DNA replication after whole-body gamma irradiation in mice. Pifithrin-α (2 mg/kg i.p.) 30 min prior to middle cerebral artery occlusion treatment of mice reduces ischemic brain injury and protects hippocampal neurons against excitotoxic injury. Pifithrin α (3.6 μg/kg i.p.) inhibits Dex-induced degeneration of the thymus in mice. Pifithrin α (2 mg/kg) results in a significantly lower degree of motor disability in rats receiving transient occlusion of the middle cerebral artery as compared with controls. Pifithrin α-treated animals has less motor disability and smaller infarcts when the drug is administered up to an hour after stroke onset. Pifithrin α results in significantly lower motor disability scores in rats than in the vehicle-treated animals at 7 days post-op. Pifithrin α results in significant reduction of apoptosis in rats as indicated by Tunel and caspase 3 staining.

References

1) Komarov et al. (1999), A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy; Science, 285 1733 2) Komarova and Gudkov et al. (2000), Suppression of p53: a new approach to overcome the side effects of antitumor therapy; Biochemistry, 65 41 3) Culmsee et al. (2001), A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid-peptide; J. Neurochem., 77 220 4) Hoagland et al. (2005), The p53 inhibitor pifithrin-α is a potent agonist of the aryl hydrocarbon receptor; J. Pharmacol. Exp. Ther., 314 630 5) Abdelalim and Tooyama (2012), The p53 inhibitor, pifithrin-α, suppresses self-renewal of embryonic stem cells; Biochem. Biophys. Res. Comm., 420 605

InChI:InChI=1/C16H18N2OS/c1-11-6-8-12(9-7-11)14(19)10-18-13-4-2-3-5-15(13)20-16(18)17/h6-9,17H,2-5,10H2,1H3

Upstream product

• 108-94-1 cyclohexanone 
• 2933-29-1 2-Amino-4,5,6,7-tetrahydrobenzothiazole 
• 619-41-0 4-(bromoacetyl)toluene 

Downstream Products

• 511296-88-1 cyclic pifithrin-α 
• 60477-34-1 2-(4-methylphenyl)-5,6,7,8-tetrahydrobenzo[d]-imidazo[2,1-b]thiazole 

Relevant academic research and scientific papers

PIFITHRIN ANALOGUES AND METHODS OF TREATING RETT SYNDROME

Disclosed herein are Pifithrin compounds, methods of treating Rett Syndrome, brain fusion organoids comprising a fusion between a cerebral cortex (Cx) organoid and the ganglionic eminence (GE) organoid, one of which comprises, consists essentially of, or

Imino-tetrahydro-benzothiazole derivatives as p53 inhibitors: Discovery of a highly potent in vivo inhibitor and its action mechanism

Several neurological disorders manifest symptoms that result from the degeneration and death of specific neurons. p53 is an important modulator of cell death, and its inhibition could be a therapeutic approach to several neuropathologies. Here, we report

Novel cyclized Pifithrin-α p53 inactivators: Synthesis and biological studies

Starting from various cyclic or bicyclic ketones, we have synthesized novel Pifithrin-α analogues bearing different methyl substituted phenyl ketone groups at the N3-position of the 2-iminothiazole heterocycle. From stability studies in a biolo

Inhibitors of apoptosis in lymphocytes: Synthesis and biological evaluation of compounds related to pifithrin-α

The chemoprotection of cells from apoptosis induced by toxins or ionizing radiation could be important for biodefense and in the treatment of acute injuries. We describe a series of small heterocycles, including fused benzothiazoles, benzimidazoles, and related compounds, that abrogate thymocyte apoptosis induced by dexamethasone and γ-irradiation. To optimize the protective activity of the previously reported pifithrin-α (PFT-α, 1), various derivatives and analogues of this and the corresponding ring-closed imidazobenzothiazole (IBT, 39) were synthesized. The aromatic analogues of 39 were more protective than 39, while the aromatic analogues of 1 were not active. Compound 19 containing a pyrrolidinyl substituent on the phenyl ring provided potent antiapoptotic activity (EC50 of 1.31 μM compared to 4.16 μM for 1). Modification of aromatic 39 with a pyrrolidinyl para substituent (compound 60) enhanced the activity, lowering the EC50 to 0.35 μM. Also, 60 provided significant protection against γ-irradiation-induced apoptosis, as expected. Compounds 19 and 60 may be promising for potential clinical development.

Tetrahydrobenzothiazole analogues as neuroprotective agents

This invention relates generally to tetrahydrobenzothiazole analogues and tetrahydrobenzooxyzole analogues, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to methods of treatment using these com

Novel p53 inactivators with neuroprotective action: Syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives

Tumor suppressor protein, p53, is an intracellular protein that is critical within the biochemical cascade that leads to cell death via apoptosis. Recent studies identified the tetrahydrobenzothiazole analogue, pifithrin-α (2), as a p53 inhibitor that was effective in protecting neuronal cells against a variety of lethal insults and reducing the side effects of anticancer drugs. As up-regulation of p53 has been described as a common feature of several neurodegenerative disorders, including Alzheimer's disease, 2 and novel analogues (3-16) were synthesized to (i) assess the value of tetrahydrobenzothiazole analogues as neuroprotective agents and (ii) define the structural requirements for p53 inactivation. Not only did 2 exhibit neuroprotective activity in both tissue culture and in vivo stroke models but also compounds 6, 7, 10, 13, 15, and 16 proved to be highly potent in protecting PC12 cells and compounds 3, 4, and 6 were highly potent in protecting primary hippocampal cells against death induced by the DNA-damaging agent, camptothecin.