| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
CYP3A4 15 μM (Ki)
Raf kinases (C-Raf, B-Raf), vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptor (PDGFR-beta), c-Kit, FLT3, and RET. Sorafenib N-oxide is a linear-mixed inhibitor of microsomal CYP3A4, with a Ki of 15 uM, but this is not its primary anti-cancer target. As a metabolite of sorafenib, it retains the multi-kinase inhibitory activity of the parent drug, targeting the same set of kinases involved in tumor cell proliferation and angiogenesis. |
|---|---|
| ln Vitro |
Sorafenib N-oxide is an active metabolite that contributes to the pharmacological activity of sorafenib. It is a potent inhibitor of several kinases. Specifically, it inhibits FLT3 that contains the internal tandem duplication mutation (FLT3-ITD) with a Kd of 70 nM, and it inhibits the proliferation of MV4-11 acute myeloid leukemia (AML) cells expressing FLT3-ITD with an IC50 of 25.8 nM. It also inhibits CYP3A4 activity with a Ki of 15 uM, indicating potential for drug-drug interactions when administered with other CYP3A4 substrates. As a metabolite, it is not typically tested as a standalone drug in cell-free assays for Raf or VEGFR activity; the parent sorafenib is the primary test compound.
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| ln Vivo |
Sorafenib N-oxide is not administered to animals as a standalone test article, as it is a metabolite of sorafenib. Its in vivo effects are studied as part of the overall pharmacological and toxicological profile of the parent drug sorafenib. In animal models of cancer (e.g., xenograft models of RCC or HCC), oral administration of sorafenib results in the in vivo generation of sorafenib N-oxide, which circulates at concentrations comparable to or even higher than the parent drug in some species (e.g., in humans, the AUC of sorafenib N-oxide is 5-10% of that of the parent compound). The metabolite contributes to the anti-tumor efficacy and to the side effects (e.g., hypertension, diarrhea, hand-foot skin reaction) seen with sorafenib treatment.
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| Enzyme Assay |
The inhibitory activity of sorafenib N-oxide against CYP3A4 is measured in a standard in vitro CYP inhibition assay. Human liver microsomes (0.25 mg/mL protein) are incubated with a CYP3A4-specific probe substrate (e.g., 50 uM midazolam) in the presence of varying concentrations of sorafenib N-oxide (0-100 uM) in 100 mM potassium phosphate buffer (pH 7.4) at 37degC for 10 min. The reaction is initiated by adding an NADPH-regenerating system. After termination by adding cold acetonitrile containing an internal standard, the metabolite (1'-hydroxymidazolam) is quantified by LC-MS/MS. The Ki value is determined by Dixon plot analysis.
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| Cell Assay |
Sorafenib N-oxide is not typically tested in cell-based assays as a standalone compound for anti-cancer activity. However, in a proliferation assay, MV4-11 AML cells (which express the FLT3-ITD mutation) are seeded in 96-well plates and treated with sorafenib N-oxide (0.1-1000 nM) for 72 hours. Cell viability is measured by the CellTiter-Glo luminescent assay. The IC50 for inhibition of cell proliferation is calculated using a non-linear regression model.
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| Animal Protocol |
Sorafenib N-oxide is not administered to animals as a standalone test article. To study the contribution of sorafenib N-oxide to the in vivo activity of sorafenib, researchers have developed rat models where sorafenib N-oxide is administered directly (e.g., by intravenous or intraperitoneal injection) and its concentration in plasma and tissues is compared to that of the parent sorafenib. In typical efficacy studies, mice bearing tumor xenografts (e.g., HepG2 liver cancer xenografts) are treated with sorafenib (30-100 mg/kg, oral gavage, once daily) for 2-4 weeks. At study termination, plasma and tumor homogenates are analyzed by LC-MS/MS to quantify the concentrations of sorafenib and sorafenib N-oxide.
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| ADME/Pharmacokinetics |
Not applicable for the metabolite alone. For the parent drug sorafenib, the pharmacokinetics are well-characterized: sorafenib has an oral bioavailability of 40-50% in humans, a long terminal half-life (approximately 25-48 hours), high plasma protein binding (99.5%), and a large volume of distribution. Sorafenib N-oxide is the major circulating metabolite in humans, with an area under the curve (AUC) that is 5-10% of the parent drug. It has a longer elimination half-life than the parent drug (approx. 30-50 hours) and is primarily excreted in the feces.
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| Toxicity/Toxicokinetics |
The toxicity of sorafenib N-oxide is best characterized as part of the safety profile of sorafenib. Sorafenib is toxic to the gastrointestinal tract (causing diarrhea, nausea, vomiting), skin (hand-foot skin reaction, rash, alopecia), and cardiovascular system (hypertension, bleeding, cardiac ischemia). It is also hepatotoxic. Sorafenib N-oxide is believed to contribute to the CYP3A4-mediated drug-drug interaction potential of sorafenib, as it is a linear-mixed inhibitor of CYP3A4 (Ki = 15 uM). This can increase the plasma concentrations of other drugs metabolized by CYP3A4, increasing their toxicity.
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| References | |
| Additional Infomation |
Sorafenib N-oxide is not approved as a drug itself, but the parent drug, sorafenib (Nexavar®), is an FDA-approved medication. Sorafenib is a first-line treatment for advanced renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-resistant advanced thyroid carcinoma. Sorafenib N-oxide is an active metabolite that circulates in patients taking sorafenib and contributes to the overall anti-cancer efficacy and side effect profile. As a research chemical, sorafenib N-oxide can be used as an analytical reference standard for pharmacokinetic studies and as a tool to investigate the metabolism and drug-drug interaction potential of sorafenib.
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| Molecular Formula |
C21H16CLF3N4O4
|
|---|---|
| Molecular Weight |
480.82
|
| Exact Mass |
480.081
|
| CAS # |
583840-03-3
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| PubChem CID |
9826472
|
| Appearance |
Typically exists as solids at room temperature
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| Density |
1.455g/cm3
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| Boiling Point |
591.655ºC at 760 mmHg
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| Melting Point |
220-222ºC
|
| Flash Point |
311.622ºC
|
| Index of Refraction |
1.601
|
| LogP |
6.12
|
| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
33
|
| Complexity |
678
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CNC(=O)C1=[N+](C=CC(=C1)OC2=CC=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)[O-]
|
| InChi Key |
BQAZCCVUZDIZDC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16ClF3N4O4/c1-26-19(30)18-11-15(8-9-29(18)32)33-14-5-2-12(3-6-14)27-20(31)28-13-4-7-17(22)16(10-13)21(23,24)25/h2-11H,1H3,(H,26,30)(H2,27,28,31)
|
| Chemical Name |
4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-1-oxidopyridin-1-ium-2-carboxamide
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| Synonyms |
Sorafenib N-oxide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0798 mL | 10.3989 mL | 20.7978 mL | |
| 5 mM | 0.4160 mL | 2.0798 mL | 4.1596 mL | |
| 10 mM | 0.2080 mL | 1.0399 mL | 2.0798 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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