1637739-82-2

Basic information

• Product Name: 6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
• Synonyms: BQU57;6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
• CAS NO: 1637739-82-2
• Molecular Formula: C16H13F3N4O
• Molecular Weight: 334.2958296
• Product Categories: Inhibitors
• Mol File: 1637739-82-2.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 493.4±45.0 °C(Predicted)
• Appearance: /
• Density: 1.43±0.1 g/cm3(Predicted)
• Solubility: insoluble in H2O; ≥16.55 mg/mL in DMSO; ≥9.2 mg/mL in EtOH
• PKA: 2.92±0.40(Predicted)
• CAS DataBase Reference: 6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(1637739-82-2)
• EPA Substance Registry System: 6-amino-1,3-dimethyl-4-(4-(trifluoromethyl)phenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile(1637739-82-2)

Safety Data

• Hazardous Substances Data: 1637739-82-2(Hazardous Substances Data)

Usage

Uses

BQU57 ia a novel blocker of Ral function.

Biological Activity

bqu57 is a derivative of rbc8. it show selectivity for ral relative to the gtpases ras and rhoa and inhibit tumour xenograft growth. the binding of bqu57 to ralb–gdp was with a dissociation constant (kd) of 7.760.6 mm by using isothermal titration calorimetry (itc). it was similar to the results from surface plasmon resonance (spr), which had a kd value of 4.761.5 mm 1.rbc8 or bqu57 can effectively inhibited the colony formation in soft agar of the ral-dependent lines h2122 and h358, but not h460 or calu-6. the ic50 value of rbc8 was 3.5 mm in h2122 cells and 3.4 mm in h358 cells; and the ic50 value of bqu57 was 2.0 mm in h2122 cells and 1.3 mm in h358 cells. rbc8 or bqu57 treatment showed no further inhibition of colony formation after ral knockdown 1.rbc8 and bqu57 acted specifically through the gdp-bound form of ral proteins. rbc8 and bqu57 inhibited both ral a and ral b activation in both the h2122 and h358 cell lines by a ral pull-down assay using ralbp1-bound agarose beads 1.the inhibition of ral activity and tumour growth by these compounds were evaluated in human lung cancer xenografts in mice. rbc8 and bqu57 showed good properties in vivo. rbc8 and bqu57 entry into tumour tissue 3 h after dosing, and were detectable in tumour tissue 1. bqu57 (10, 20 and 50mg per kg bodyweight) was intraperitoneal injected into h2122 tumour xenografts, and the activation of ral in tumour extracts was analysed in ralbp1 pull-down assays. both rala and ralb were inhibited by rbc8 and bqu57. but no inhibition of ras or rhoa activity was happened 1.

references

1. yan c, liu d, li l et al. discovery and characterization of small molecules that target the gtpase ral. nature. 2014 nov 20;515(7527):443-7.

Upstream product

• 455-19-6 4-Trifluoromethylbenzaldehyde 
• 2749-59-9 1,3-dimethyl-5-pyrazolone 
• 109-77-3 malononitrile 
• 75833-84-0 2-(4-trifluoromethylbenzylidene)malononitrile 

Relevant articles and documents

Discovery and characterization of small molecules that target the GTPase Ral

The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and 1 H- 15 N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.

Synthesis of novel Ral inhibitors: An in vitro and in vivo study

Chemical synthesis was performed to produce a series of 6-amino-1,3-disubstituted-4-phenyl-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile compounds (14–57) which were characterized by1H NMR,13C NMR and LC/MS–MS. These compounds were assessed for their effect on the in vitro anchorage independent growth of human lung cancer cell line H2122 and IC50values calculated. Two of the more potent compounds, BQU057 40 and BQU082 57 also displayed a dose dependent effect on RalA and RalB activity in H2122 spheroids using the common RalBP1 pull-down assay. Mouse PK and tissue distribution studies on 40 and 57 were performed and demonstrated that parent drug was present in tumor 3.0 h post ip (50 mg/Kg) dose.