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548472-68-0 molecular structure
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4-[4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-2-one

ChemBase ID: 72486
Molecular Formular: C30H30Cl2N4O4
Molecular Mass: 581.4896
Monoisotopic Mass: 580.16441082
SMILES and InChIs

SMILES:
N1(C(C(N=C1c1c(cc(cc1)OC)OC(C)C)c1ccc(cc1)Cl)c1ccc(cc1)Cl)C(=O)N1CCNC(=O)C1
Canonical SMILES:
COc1ccc(c(c1)OC(C)C)C1=NC(C(N1C(=O)N1CCNC(=O)C1)c1ccc(cc1)Cl)c1ccc(cc1)Cl
InChI:
InChI=1S/C30H30Cl2N4O4/c1-18(2)40-25-16-23(39-3)12-13-24(25)29-34-27(19-4-8-21(31)9-5-19)28(20-6-10-22(32)11-7-20)36(29)30(38)35-15-14-33-26(37)17-35/h4-13,16,18,27-28H,14-15,17H2,1-3H3,(H,33,37)
InChIKey:
BDUHCSBCVGXTJM-UHFFFAOYSA-N

Cite this record

CBID:72486 http://www.chembase.cn/molecule-72486.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
4-[4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazole-1-carbonyl]piperazin-2-one
IUPAC Traditional name
4-[4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one
Synonyms
Nutlin-3
(±)-4-[4,5-Bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one
Nutlin-3
Nutlin
Nutlin
4-(4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl)piperazin-2-one
CAS Number
548472-68-0
548472
MDL Number
MFCD07784509
PubChem SID
24724554
162037411
PubChem CID
216345
16755649
Wikipedia Title
Nutlin

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 13.23514  H Acceptors
H Donor LogD (pH = 5.5) 5.166468 
LogD (pH = 7.4) 5.1725135  Log P 5.1725917 
Molar Refractivity 154.1574 cm3 Polarizability 59.535114 Å3
Polar Surface Area 83.47 Å2 Rotatable Bonds
Lipinski's Rule of Five false 

PROPERTIES

PROPERTIES

Physical Property Safety Information Pharmacology Properties Product Information Bioassay(PubChem)
Solubility
DMSO expand Show data source
DMSO: soluble20 mg/mL expand Show data source
H2O: insoluble expand Show data source
Apperance
powder expand Show data source
Storage Condition
-20°C expand Show data source
European Hazard Symbols
Irritant Irritant (Xi) expand Show data source
MSDS Link
Download expand Show data source
German water hazard class
3 expand Show data source
Risk Statements
36/37/38 expand Show data source
Safety Statements
26-36 expand Show data source
GHS Pictograms
GHS07 expand Show data source
GHS Signal Word
Warning expand Show data source
GHS Hazard statements
H315-H319-H335 expand Show data source
GHS Precautionary statements
P261-P305 + P351 + P338 expand Show data source
Personal Protective Equipment
dust mask type N95 (US), Eyeshields, Gloves expand Show data source
Storage Temperature
-20°C expand Show data source
Target
MDM2 expand Show data source
Purity
≥98% (HPLC) expand Show data source
98% expand Show data source
Salt Data
Free Base expand Show data source
Shipped in
wet ice expand Show data source
Empirical Formula (Hill Notation)
C30H30Cl2N4O4 expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals Wikipedia Wikipedia Sigma Aldrich Sigma Aldrich
Selleck Chemicals - S1061 external link
Research Area
Description Cancer
Biological Activity
Description Nutlin-3 is a potent and selective Mdm2 antagonist with IC50 of 90 nM.
Targets Mdm2
IC50 90 nM [1]
In Vitro Nutlin-3 potently inhibits the MDM2-p53 interaction, leading to the activation of the p53 pathway. Nutlin-3 treatment induces the expression of MDM2 and p21, and displays potent antiproliferative activity with IC50 of ~1.5 μM, only in cells with wild-type p53 such as HCT116, RKO and SJSA-1, but not in the mutant p53 cell lines SW480 and MDA-MB-435. In SJSA-1 cells, Nutlin-3 treatment at 10 μM for 48 hours significantly induces caspase-dependent cell apoptosis by ~45%. Although Nutlin-3 also inhibits the growth and viability of human skin (1043SK) and mouse embryo (NIH/3T3) with IC50 of 2.2 μM and 1.3 μM, respectively, cells remain viable 1 week post-treatment even at 10 μM of Nutlin-3, in contrast with the SJSA-1 cells with viability lost at 3 μM of Nutlin-3 treatment. [1] Nutlin-3 does not induce the phosphorylation of p53 on key serine residues and reveals no difference in their sequence-specific DNA binding and ability to transactivate p53 target genes compared with phosphorylated p53 induced by the genotoxic drugs doxorubicin and etoposide, demonstrating that phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis. [2] Although binding less efficiently to MDMX than to MDM2, Nutlin-3 can block the MDMX–p53 interaction and induce the p53 pathway in retinoblastoma cells (Weri1) with IC50 of 0.7 μM. [3] Nutlin-3 at 30 μM also disrupts endogenous p73-HDM2 interaction and enhances the stability and proapoptotic activities of p73, leading to the dose-dependent cell growth inhibition and apoptosis induction in cells without wild-type p53. [4]
In Vivo Oral administration of Nutlin-3 at 200 mg/kg twice daily for 3 weeks significantly inhibits the tumor growth of SJAS-1 xenografts by 90%, comparable with the effect of doxorubicin treatment with 81% inhibition of tumor growth. [1]
Clinical Trials
Features
Protocol
Kinase Assay [1]
Biacore study Competition assay is performed on a Biacore S51. A Series S Sensor chip CM5 is utilized for the immobilization of a PentaHis antibody for capture of the His-tagged p53. The level of capture is ~200 response units (1 response unit corresponds to 1 pg of protein per mm2). The concentration of MDM2 protein is kept constant at 300 nM. Nutlin-3 is dissolved in DMSO at 10 mM and further diluted to make a concentration series of Nutlin-3 in each MDM2 test sample. The assay is run at 25 °C in running buffer (10 mM Hepes, 0.15 M NaCl, 2% DMSO). MDM2-p53 binding in the presence of Nutlin-3 is calculated as a percentage of binding in the absence of Nutlin-3 and IC50 is calculated.
Cell Assay [1]
Cell Lines HCT116, RKO, SJSA-1, SW480, and MDA-MB-435
Concentrations Dissolved in DMSO, final concentrations ~ 30 μM
Incubation Time 8, 24, and 48 hours
Methods Cells are exposed to various concentrations of Nutlin-3 for 8, 24 and 48 hours. The transcriptional levels of p21 and MDM2 genes are analyzed by real-time PCR, and protein levels by western blotting. Cell viability is measured by the MTT assay. Cell apoptosis is determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining with flow cytometry and fluorescence microscopy.
Animal Study [1]
Animal Models Athymic female nude mice (Nu/Nu-nuBR) injected subcutaneously with SJSA-1 cells
Formulation Formulated in 2% Klucel, 0.5% Tween 80
Doses 200 mg/kg
Administration Orally, twice a day
References
[1] Vassilev LT, et al. Science, 2004, 303(5659), 844-848.
[2] Thompson T, et al. J Biol Chem, 2004, 279(51), 53015-53022.
[3] Laurie NA, et al. Nature, 2006, 444(7115), 61-66.
[4] Lau LM, et al. Oncogene, 2008, 27(7), 997-1003.
Sigma Aldrich - N6287 external link
Biochem/physiol Actions
Nutlin-3 is a Mdm2 (mouse double minute 2) antagonist, p53 pathway activator, and apoptosis inducer.
Legal Information
Sold under license from Hoffman-La Roche, Inc. US patent 6,734,302.

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PATENTS

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