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Nutlin-3a chiral

MDM2 inhibitor, antiproliferative and antiproapoptotic CAS# 675576-98-4

Nutlin-3a chiral

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Chemical structure

Nutlin-3a chiral

3D structure

Chemical Properties of Nutlin-3a chiral

Cas No. 675576-98-4 SDF Download SDF
PubChem ID 11433190 Appearance Powder
Formula C30H30Cl2N4O4 M.Wt 581.49
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Nutlin-3a chiral
Solubility DMSO : ≥ 100 mg/mL (171.97 mM)
H2O : < 0.1 mg/mL (insoluble)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-[(4S,5R)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazole-1-carbonyl]piperazin-2-one
SMILES CC(C)OC1=C(C=CC(=C1)OC)C2=NC(C(N2C(=O)N3CCNC(=O)C3)C4=CC=C(C=C4)Cl)C5=CC=C(C=C5)Cl
Standard InChIKey BDUHCSBCVGXTJM-WUFINQPMSA-N
Standard 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)/t27-,28+/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Nutlin-3a chiral

DescriptionNutlin-3 is a small-molecule inhibitor of mouse double minute 2 (MDM2) with IC50 value of 0.09 μM.
TargetsMDM2    
IC500.09 μM     

Protocol

Kinase experiment [1]:

Binding assays

Competition assays were performed on a Biacore S51 (Biacore Inc., Piscataway, NJ). A Series S Sensor chip CM5 was derivatized for immobilization of a PentaHis antibody for capture of the His-tagged p53. The level of capture was ~ 200 response units (1 response unit corresponds to 1 pg of protein per mm2). The concentration of MDM2 protein was kept constant at 300 nM. Nutlin-3a was dissolved in DMSO at 10 mM and further diluted to make a concentration series of nutlin-3a in each MDM2 test sample. The assays were run at 25℃ in running buffer (10 mM Hepes, 0.15 M NaCl, 2% DMSO). MDM2-p53 binding in the presence of nutlin-3a was calculated as a percentage of binding in the absence of nutlin-3a and IC50 was calculated using Microsoft Excel.

Cell experiment [1]:

Cell lines

HCT116 and SW480 cells.

Preparation method

Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

1, 2, 4, 8, 16 μM; 8 h.

Applications

Nutlin-3a chiral induces the expression of MDM2 and p21 in HCT116 cells with wild-type p53. In HCT116, RKO, and SJSA-1 cells, nutlin-3a chiral (10, 20 or 30 μM) exhibits antiproliferative activity. In SJSA-1 osteosarcoma cells, nutlin-3a chiral (10 μM) induces apoptosis.

Animal experiment [1]:

Animal models

Nude mice bearing subcutaneous human cancer xenografts (SJSA-1).

Dosage form

200 mg/kg; twice daily for 20 days; administrated orally.

Application

Nutlin-3 inhibits tumor growth by 90%. The mice don’t lose significant weight and don’t show any grossabnormalities upon necropsy at the end of the treatment.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science, 2004, 303(5659): 844-848.

Nutlin-3a chiral Dilution Calculator

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Nutlin-3a chiral Molarity Calculator

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Preparing Stock Solutions of Nutlin-3a chiral

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.7197 mL 8.5986 mL 17.1972 mL 34.3944 mL 42.993 mL
5 mM 0.3439 mL 1.7197 mL 3.4394 mL 6.8789 mL 8.5986 mL
10 mM 0.172 mL 0.8599 mL 1.7197 mL 3.4394 mL 4.2993 mL
50 mM 0.0344 mL 0.172 mL 0.3439 mL 0.6879 mL 0.8599 mL
100 mM 0.0172 mL 0.086 mL 0.172 mL 0.3439 mL 0.4299 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Nutlin-3a chiral

Nutlin-3 is a small-molecule inhibitor of MDM2 (mouse double minute 2) with IC50 value of 0.09μM [1].

Nutlin-3 binds MDM2 in the TP53-bindingpocket, thereby interfering with MDM2-directed TP53 degradation. This has been shown to cause cell cycle arrest, growth inhibitionand apoptosis in both solid tumors and lymphoid neoplasms.In mantle cell lymphoma(MCL), it is reported that Nutlin-3 can inhibit cell growth and activate apoptosis in bothwt-TP53(IC50 of 1 to 10μM) and mt-TP53(IC50 of 22.5μM) cells [2].

Nutlin-3 can also effectcell cycle in gastric cancer cell lines. It induces G1 arrest inMKN-45 and SNU-1 cell lines. In vitro assay shows Nutlin-3can enhance the antitumoreffects of conventional chemotherapeutic agents in several gastric cancer cell lines. And in in vivo assay, Nutlin-3 significantly inhibits the growth of xenograft tumors [3].

References:
[1] Lyubomir T.Vassilev et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Science.2004, 303: 844-848.
[2] Yoko Tabe, Denise Sebasigari, Linhua Jin, et al.MDM2 Antagonist Nutlin-3 Displays Antiproliferative andProapoptotic Activity in Mantle Cell Lymphoma. Clin Cancer Res. 2009, 15:933-942.
[3] Shinji Endo,Kenji Yamato,Sachiko Hirai,Toshikazu Moriwaki,Kuniaki Fukuda,Hideo Suzuki,Masato Abei,Ichiro Nakagawa and IchinosukeHyodo.Potent in vitro and in vivo antitumor effects ofMDM2 inhibitor nutlin-3 in gastric cancer cells.Cancer Science. 2011, 102 (3): 605-613.

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References on Nutlin-3a chiral

Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: a platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition.[Pubmed:25017623]

J Org Chem. 2014 Aug 1;79(15):6913-38.

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.

An alpha-quaternary chiral latam derivative, YH-304 as a novel broad-spectrum anticancer agent.[Pubmed:27748805]

Int J Oncol. 2016 Dec;49(6):2480-2486.

Previously, we reported that alpha-quaternary chiral lactam derivatives have broad spectrum anticancer activity. However, the underlying molecular mechanisms and its relevance are largely unknown. In the present study, we report progress on alpha-quaternary chiral lactam analogues that address this, focusing on the novel analogue YH-304 as a candidate to broadly target human cancer cells. The effect of YH-304 on cell transformation was assessed by clonogenic assay in non-small cell lung cancer cells (NSCLCs) A549 and 226B. Proapoptotic activity of YH-304 was determined by TUNEL assay and cleaved PARP, cleaved caspase-9, and Bax as markers for apoptosis. The p53-dependency and therapeutic spectrum of YH-304 was assessed by western blot analysis, real-time PCR, and cell viability assays in cells expressing endogenous wild or mutant p53. The effect of YH-304 on angiogenesis in vivo was examined by bFGF-mediated angiogenesis assay in zebrafish. Finally, the effect of YH-304 on AKT and ERK activation (phosphorylation) as a putative mechanism underlying the effect of YH-304 on bFGF-mediated angiogenesis was assessed using western blotting. We found that YH-304 significantly decreases the colony-forming activities of both A549 and 226B cells, inducing cellular apoptosis. Unlike nutlin-3 (p53 pathway activator), YH-304 did not affect the expression levels of p53 and its target gene such as p21 and thus showed p53-independent anticancer activity with broad spectrum. In addition, YH-304 inhibited bFGF-induced angiogenesis in vivo through mediating AKT and ERK signaling pathway, which plays an important role in bFGF activation and angiogenesis. Taken together, our data indicate that YH-304 may represent a novel therapeutic option for the treatment of cancer in a p53-independent manner.

Catalytic, Enantioselective Synthesis of Stilbene cis-Diamines: A Concise Preparation of (-)-Nutlin-3, a Potent p53/MDM2 Inhibitor.[Pubmed:22708054]

Chem Sci. 2011 Jan 1;2(6):1076-1079.

The first highly diastereo- and enantioselective additions of aryl nitromethane pronucleophiles to aryl aldimines are described. Identification of an electron rich chiral Bis(Amidine) catalyst for this aza-Henry variant was key to this development, leading ultimately to differentially protected cis-stilbene diamines in two steps. This method then became the lynchpin for an enantioselective synthesis of (-)-Nutlin-3 (Hoffmann-LaRoche), a potent cis-imidazoline small molecule inhibitor of p53-MDM2 used extensively as a probe of cell biology and currently in drug development.

Preparation of (-)-Nutlin-3 using enantioselective organocatalysis at decagram scale.[Pubmed:24127627]

J Org Chem. 2013 Nov 1;78(21):10605-16.

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 degrees 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.

Understanding the interplay of weak forces in [3,3]-sigmatropic rearrangement for stereospecific synthesis of diamines.[Pubmed:22676401]

Acc Chem Res. 2012 Aug 21;45(8):1345-55.

Chiral diamines are important building blocks for constructing stereoselective catalysts, including transition metal based catalysts and organocatalysts that facilitate oxidation, reduction, hydrolysis, and C-C bond forming reactions. These molecules are also critical components in the synthesis of drugs, including antiviral agents such as Tamiflu and Relenza and anticancer agents such as oxaliplatin and nutlin-3. The diaza-Cope rearrangement reaction provides one of the most versatile methods for rapidly generating a wide variety of chiral diamines stereospecifically and under mild conditions. Weak forces such as hydrogen bonding, electronic, steric, oxyanionic, and conjugation effects can drive this equilibrium process to completion. In this Account, we examine the effect of these individual weak forces on the value of the equilibrium constant for the diaza-Cope rearrangement reaction using both computational and experimental methods. The availability of a wide variety of aldehydes and diamines allows for the facile synthesis of the diimines needed to study the weak forces. Furthermore, because the reaction generally takes place cleanly at ambient temperature, we can easily measure equilibrium constants for rearrangement of the diimines. We use the Hammett equation to further examine the electronic and oxyanionic effects. In addition, computations and experiments provide us with new insights into the origin and extent of stereospecificity for this rearrangement reaction. The diaza-Cope rearrangement, with its unusual interplay between weak forces and the equilibrium constant of the reaction, provides a rare opportunity to study the effects of the fundamental weak forces on a chemical reaction. Among these many weak forces that affect the diaza-Cope rearrangement, the anion effect is the strongest (10.9 kcal/mol) followed by the resonance-assisted hydrogen-bond effect (7.1 kcal/mol), the steric effect (5.7 kcal/mol), the conjugation effect (5.5 kcal/mol), and the electronic effect (3.2 kcal/mol). Based on both computation and experimental data, the effects of these weak forces are additive. Understanding the interplay of the weak forces in the [3,3]-sigmatropic reaction is interesting in its own right and also provides valuable insights for the synthesis of chiral diamine based drugs and catalysts in excellent yield and enantiopurity.

Description

Nutlin-3a, an active enantiomer of Nutlin-3, is a potent murine double minute (MDM2) inhibitor (IC50=90 nM). Nutlin-3a inhibits MDM2-p53 interactions and stabilizes the p53 protein, and induces cell autophagy and apoptosis. Nutlin-3a has the potential for the study of TP53 wild-type ovarian carcinomas.

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