64224-21-1

Basic information

• Product Name: OLTIPRAZ
• Synonyms: NSC 347901;3H-1,2-Dithiole-3-thione,4-methyl-5-(2-pyrazinyl)-;OLTIPRAZ;4-methyl-5-pyrazinyl-3h-1,2-dithiole-3-thione;4-methyl-5-pyrazinyl-3h-2-dithiole-3-thione;5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione;4-Methyl-5-(2-pyrazinyl)-3H-1,2-dithiole-3-thione;4-Methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione
• CAS NO: 64224-21-1
• Molecular Formula: C₈H₆N₂S₃
• Molecular Weight: 226.34
• EINECS: 264-736-6
• Mol File: 64224-21-1.mol
• Article Data: 6

Chemical Properties

• Melting Point: 165-166
• Boiling Point: 408.124 °C at 760 mmHg
• Flash Point: 200.627 °C
• Appearance: red/Solid
• Density: 1.517 g/cm³
• Vapor Pressure: 1.69E-06mmHg at 25°C
• Refractive Index: 1.76
• Storage Temp.: 2-8°C
• Solubility: DMSO: >20mg/mL
• PKA: 0.18±0.10(Predicted)
• Sensitive: Light Sensitive
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
• CAS DataBase Reference: OLTIPRAZ(CAS DataBase Reference)
• NIST Chemistry Reference: OLTIPRAZ(64224-21-1)
• EPA Substance Registry System: OLTIPRAZ(64224-21-1)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36/37/39-36/37
• WGK Germany: 3
• RTECS: JP1293000
• Hazardous Substances Data: 64224-21-1(Hazardous Substances Data)

Usage

Description

OLTIPRAZ is a synthetic, substituted 1,2-dithiole-3-thione compound that has been used as an antischistosomal agent in humans. It upregulates the transcription factor NRF2, prevents insulin resistance and obesity induced by high-fat diets, attenuates the progression of fibrosis, and promotes liver regeneration. Additionally, it activates the constitutive androstane receptor (CAR) and has off-target effects.

Uses

Used in Pharmaceutical Industry:
OLTIPRAZ is used as a schistosomicide agent for treating schistosomiasis, a parasitic disease.
OLTIPRAZ is used as an antineoplastic agent for tumor prevention purposes.
OLTIPRAZ is used as an inducer of Phase II detoxification enzymes, most notably glutathione-S-transferase (GST), to promote liver health and regeneration.

Biochem/physiol Actions

Oltipraz is an activator of Nrf2. Nrf2 (NF-E2-related factor 2) is a transcription factor that binds to antioxidant response elements (AREs) and activates these genes. Oltipraz activates Nrf2 and subsequently elevates expression of the detoxification genes encoding anti-oxidant and multidrug resistance-associated proteins to mediate its chemopreventive efficacy.

References

1) Yu?et al. (2011),?Oltipraz upregulates the nuclear factor (erythroid-derived 2)-like 2 (NRF2) antioxidant system and prevents insulin resistance and obesity induced by a high-fat diet in C57BL/6J mice; Diabetologia,?54?922 2) Shimozono?et al. (2013),?Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model; Mol. Pharmacol,?84?62 3) Eba?et al. (2013),?The nuclear factor erythroid 2-related factor 2 activator oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice; Am. J. Respir. Cell. Mol. Biol.,?49?324 4) Cho?et al. (2009), Oltipraz promotion of liver regeneration after partial hepatectomy: the role of PI3-kinase dependent C/EBPbeta and cyclin E regulation; Arch. Pharm. Res.,?32?625 5) Merrell?et al. (2008),?The Nrf2 activator oltipraz also activates the constitutive androstane receptor; Drug Metab. Dispos.,?36?1716

InChI:InChI=1/C8H6N2S3/c1-5-7(12-13-8(5)11)6-4-9-2-3-10-6/h2-4H,1H3

Upstream product

• 62124-77-0 3-oxo-3-pyrazin-2-yl-propionic acid ethyl ester 
• 6164-79-0 methyl pyrazine-2-carboxylate 
• 98-97-5 2-pyrazylcarboxylic acid 
• 7440-44-0 pyrographite 
• 324737-10-2 methyl 2-methyl-3-(pyrazin-2-yl)-3-oxopropionate 
• 64223-90-1 ethyl 2-methyl-3-oxo-3-(pyrazin-2-yl)propanoate 

Downstream Products

• 84201-40-1 7-methyl-6,8-bis(methylthio)pyrrolo<1,2-a>pyrazine 
• 64224-71-1 4-methyl-5(2-pyrazinyl)-1,2-dithiole-3-one 
• 84201-42-3 (8-Carboxymethylsulfanyl-7-methyl-pyrrolo[1,2-a]pyrazin-6-ylsulfanyl)-acetic acid 
• 87578-53-8 7-methyl-6 (or 8-)-methylthio-pyrrolo<1,2-a>pyrazine disulphide 
• 103428-51-9 6,8-dimethylthio-7-formylpyrrolo <1,2-a> pyrazine 
• 114969-39-0 6-Ethyldisulfanyl-7-methyl-8-methylsulfanyl-pyrrolo[1,2-a]pyrazine 

Relevant articles and documents

Synthesis and biological evaluation of 1,2-dithiol-3-thiones and pyrrolo[1,2-a]pyrazines as novel hypoxia inducible factor-1 (HIF-1) inhibitor

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor which is strongly associated with tumor survival, progression, and therapeutic resistance. Accordingly, it has been suggested that the inhibition of the HIF-1 pathway can suppress tumor, and it has become an important therapeutic target. In present study, oltipraz, its metabolite M2, and their derivatives were synthesized and evaluated as HIF-1α inhibitors. Among the synthesized, benzyl-substituted pyrrolo[1,2-a]pyrazine 2g most potently inhibited HIF-1α protein accumulation (81% at 10 μM) and VEGF, GLUT-1 transcription (77% and 92% at 10 μM, respectively).

Abrogation of hyperosmotic impairment of insulin signaling by a novel class of 1,2-dithiole-3-thiones through the inhibition of S6K1 activation

A previous study from this laboratory showed that oltipraz and synthetic dithiolethiones prevent tumor necrosis factor-α-induced hepatic insulin resistance via AMP-activated protein kinase-dependent p70S6 kinase (S6K) 1 inhibitory pathway. This study investigated whether oltipraz and a novel class of 1,2-dithiole-3-thiones were capable of preventing insulin resistance induced by hyperosmotic stress, thereby enhancing insulin-dependent signals, and, if so, whether the restoration of insulin signal was mediated with the inhibition of S6K1 activity stimulated by hyperosmotic stress. In HepG2 cells, oltipraz treatment inhibited insulin receptor substrate (IRS) 1 serine phosphorylation, a marker of insulin resistance, induced by sorbitol-, mannitol-, or sodium chloride-induced hyperosmotic stress. Consequently, this allowed cells to restore insulin signals, which was evidenced by decrease in the ratio of serine to tyrosine phosphorylations of IRS1 and increase in the phosphorylations of Akt and glycogen synthase kinase (GSK) 3β. Hyperosmotic stress markedly activated S6K1; S6K1 activation was completely abolished by oltipraz pretreatment. An experiment using dominant-negative S6K1 supports the essential role of S6K1 in the hyperosmolarity-stimulated phosphorylation of IRS1. Transfection of constitutive active mutant S6K1 eliminated the protective effect of oltipraz on GSK3β phosphorylation, indicating that oltipraz restores insulin signaling by inhibiting S6K1 activation. A variety of synthetic 1,2-dithiole-3-thione derivatives also inhibited S6K1 activity and insulin resistance induced by hyperosmotic stress in HepG2 cells. The results of this study demonstrate that a novel class of 1,2-dithiole-3-thiones improve insulin sensitivity under the condition of hyperosmotic stress, which results from the inhibition of S6K1 activation. Copyright

Dithiolthione compounds for the treatment of neurological disorders and for memory enhancement

The invention provides methods to treat neurological disorders such as Alzheimer's disease, or to slow the progression of such diseases, or to treat and/or prevent other disorders as disclosed in the specification, by administering to patients, or delivering to the tissues of such patients, oltipraz or related compounds as disclosed in the specification.