Details
Stereochemistry | ACHIRAL |
Molecular Formula | C19H12Cl3N3OS |
Molecular Weight | 436.742 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 1 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
ClC1=CC=C(C=C1)C2=C(\C=N\OCC3=CC(Cl)=C(Cl)C=C3)N4C=CSC4=N2
InChI
InChIKey=ZQWBOKJVVYNKTL-AUEPDCJTSA-N
InChI=1S/C19H12Cl3N3OS/c20-14-4-2-13(3-5-14)18-17(25-7-8-27-19(25)24-18)10-23-26-11-12-1-6-15(21)16(22)9-12/h1-10H,11H2/b23-10+
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) is a novel potent and selective agonist for the human orphan nuclear receptor CAR (constitutive androstane receptor). CITCO displayed an EC50 of 49 nM in a CAR FRET assay and showed 50-fold selectivity for CAR over PXR. CITCO displayed no activity against a panel of 15 other nuclear receptors at a concentration of 10 µM. In hepatocytes CITCO induced CAR nuclear translocation and induced the CAR target gene CYP2B6. The cell proliferation of several ovarian cell lines expressing CAR significantly increased when CITCO was combined with anticancer agents compared with any anticancer agent alone. The up-regulation of MDR1 and UGT1A1 by anticancer agents was further enhanced in the presence of CITCO. Combination of CITCO with any anticancer agents significantly enhanced CAR-mediated transcription compared with any anticancer agents alone and CAR down-regulation completely inhibited the transcription in the presence of CITCO and/or anticancer agents. Inhibition of CAR pathway could be a novel therapeutic approach for the augmentation of sensitivity to anticancer agents, or to overcome resistance, in the treatment of ovarian cancer. CITCO has being shown to inhibit growth and expansion of brain tumour stem cells. CITCO induced a dose-dependent decrease in growth and expansion of CD133(+) BTSCs as gliospheres in culture. Cell cycle arrest and apoptosis in BTSCs were induced by CITCO, but not in normal astrocytes. Growth of s.c BTSC xenograft in nude mice was also inhibited by CITCO. CITCO inhibits the growth and expansion of BTSCs, suggesting the use of CAR agonists for the treatment of brain tumour.
Originator
Approval Year
PubMed
Title | Date | PubMed |
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Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. | 2005 Sep |
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Antagonist- and inverse agonist-driven interactions of the vitamin D receptor and the constitutive androstane receptor with corepressor protein. | 2005 Sep |
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Constitutive androstane receptor (CAR) as a potential sensing biomarker of persistent organic pollutants (POPs) in aquatic mammal: molecular characterization, expression level, and ligand profiling in Baikal seal (Pusa sibirica). | 2006 Nov |
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Induction of human CYP2A6 is mediated by the pregnane X receptor with peroxisome proliferator-activated receptor-gamma coactivator 1alpha. | 2006 Nov |
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The environmental estrogen, nonylphenol, activates the constitutive androstane receptor. | 2007 Aug |
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Comparison of immortalized Fa2N-4 cells and human hepatocytes as in vitro models for cytochrome P450 induction. | 2008 Jun |
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Preservation of hepatic phenotype in lentiviral-transduced primary human hepatocytes. | 2008 Jun 17 |
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Modulation of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) by 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives, ligands of peripheral benzodiazepine receptor (PBR). | 2011 Apr 25 |
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The human constitutive androstane receptor promotes the differentiation and maturation of hepatic-like cells. | 2013 Dec 15 |
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Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture. | 2014 Aug 1 |
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Chrysin, baicalein and galangin are indirect activators of the human constitutive androstane receptor (CAR). | 2015 Mar 4 |
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Pyrene is a Novel Constitutive Androstane Receptor (CAR) Activator and Causes Hepatotoxicity by CAR. | 2015 Oct |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21224854
BTSC xenograft in nude mice: The mice were treated intraperitoneally with 25 and 100 mg CITCO in 25 ml DMSO on days 22, 24, 26, 30 and 36 following
xenograft. In vivo treatment with CITCO on days 22, 24, 26, 30 and 36 resulted in a dose-dependent decrease in tumour volume.
Route of Administration:
Intraperitoneal
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27530964
Curator's Comment: Treatment with 2.5 uM CITCO resulted in a significant increase in the transcription of CAR in both T98G–BTSC and U87MG–BTSCs in 48 h. Western blot analyses showed that the T98G and U87MG glioma, and BTSCs
express very low levels of CAR protein that increased significantly
following treatment with 2.5mM CITCO in 48 h. However, higher
concentrations of CITCO (>10 uM) inhibited or abolished CAR
expression in both T98G- and U87MG-derived BTSCs https://www.ncbi.nlm.nih.gov/pubmed/21224854
6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO) (50 and 100 nM) induced a concentration-responsive increase in CYP2B6 gene expression in primary human hepatocytes.
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