548472-68-0

Basic information

• Product Name: NUTLIN-3
• Synonyms: (+/-)-4-[4,5-BIS(4-CHLOROPHENYL)-2-(2-ISOPROPOXY-4-METHOXY-PHENYL)-4,5-DIHYDRO-IMIDAZOLE-1-CARBONYL]-PIPERAZIN-2-ONE;NUTLIN-3;2-Piperazinone, 4-[[(4R,5S)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-, rel-;4-[4,5-Bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one;Piperazinone, 4-[[(4R,5S)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-, rel-;4-[4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-Methoxy-phenyl)-4,5-dihydro-iMidazole-1-carbonyl]-piperazin-2-one;Nutlin-3, >=98%;NUTLIN-3 (Free base)
• CAS NO: 548472-68-0
• Molecular Formula: C30H30Cl2N4O4
• Molecular Weight: 581.49
• EINECS: 200-258-5
• Product Categories: Inhibitors
• Mol File: 548472-68-0.mol
• Article Data: 8

Chemical Properties

• Appearance: /solid
• Density: 1.36 g/cm³
• Refractive Index: 1.647
• Storage Temp.: −20°C
• Solubility: DMSO: 20 mg/mL, soluble
• PKA: 14.35±0.20(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20° for up to 1 month.
• CAS DataBase Reference: NUTLIN-3(CAS DataBase Reference)
• NIST Chemistry Reference: NUTLIN-3(548472-68-0)
• EPA Substance Registry System: NUTLIN-3(548472-68-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• WGK Germany: 3
• Hazardous Substances Data: 548472-68-0(Hazardous Substances Data)

Usage

Description

(±)-Nutlin-3 is a racemic mixture of the p53-Mdm2 protein-protein interaction inhibitor (?)-nutlin-3 and its less active enantiomer (+)-nutlin-3 . In vivo, (±)-nutlin-3 (200 mg/kg twice daily) reduces tumor volume in an SJSA-1 osteosarcoma mouse xenograft model.

Uses

(+/-)-Nutlin-3 is a small molecule MDM2 antagonist.

Biochem/physiol Actions

Nutlin-3, an antagonist of a human homolog of murine double minute 2 (HDM2). It has the ability to inhibit the HDM2-directed degradation of p53. Nutlin-3 can also enhance the transcriptional activities of p73.

References

1) Vassilev et al. (2004), In vivo activation of the p53 pathway by small-molecule antagonists of MDM2; Science, 303 844 2) Ghassemifar et al. (2012), MDM2 antagonism by nutlin-3 induces death in human medulloblastoma cells; Neurosci. Lett., 513 106 3) Manfe et al. (2012), MDM2 inhibitor nutlin-3 induces apoptosis and senescence in cutaneous T-cell lymphoma: role of p53; J. Invest. Dermatol., 132 1487 4) Kunkele et al. (2012), Pharmacological activation of the p53 pathway by nutlin-3 exerts anti-tumoral effects in medulloblastomas; Neuro. Oncol., 14 859

InChI:InChI=1/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)

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Relevant articles and documents

Chiral synthesis method for producing cis-imidazoline compounds for pharmaceutical use

This invention provides a method for enantioselective synthesis of cis-imidazolines and related structures through chiral resolution. A chiral acid is used to separate enantiomeric precursors of the cis-imidazolines from a racemic mixture by selective cry

Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis -stilbene diamines: A platform for the preparation of single-enantiomer cis -imidazolines for protein-protein inhibition

The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein-protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate-catalyst matching. This method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein-protein interactions.

Preparation of (-)-nutlin-3 using enantioselective organocatalysis at decagram scale

Chiral nonracemic cis-4,5-bis(aryl)imidazolines have emerged as a powerful platform for the development of cancer chemotherapeutics, stimulated by the Hoffmann-La Roche discovery that Nutlin-3 can restore apoptosis in cells with wild-type p53. The lack of efficient methods for the enantioselective synthesis of cis-imidazolines, however, has limited their more general use. Our disclosure of the first enantioselective synthesis of (-)-Nutlin-3 provided a basis to prepare larger amounts of this tool used widely in cancer biology. Key to the decagram-scale synthesis described here was the discovery of a novel bis(amidine) organocatalyst that provides high enantioselectivity at warmer reaction temperature (-20 C) and low catalyst loadings. Further refinements to the procedure led to the synthesis of (-)-Nutlin-3 in a 17 g batch and elimination of all but three chromatographic purifications.