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| Targets |
NecroX-7 targets high-mobility group box 1 (HMGB1), a nuclear protein that functions as a pro-inflammatory cytokine when released into the extracellular space. HMGB1 is a damage-associated molecular pattern (DAMP) molecule that activates the immune system through binding to receptors such as TLR-4 and RAGE (receptor for advanced glycation end-products). NecroX-7 inhibits the release of HMGB1, thereby reducing HMGB1-mediated inflammatory responses. Additionally, NecroX-7 is a potent free radical scavenger that prevents the production of mitochondria-specific reactive nitrogen species (ROS) induced by tert-butyl hydroperoxide or doxorubicin in H9C2 cells and hepatocytes. This dual mechanism—inhibiting HMGB1 release and scavenging free radicals—underlies its protective effects in various models of injury and inflammation.
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| ln Vitro |
NecroX-7 (0–40 μM, 3–4 days) suppresses T cells that are active or dividing without resulting in cell death [1]. In a dose-dependent manner, NecroX-7 (0-40 μM) dramatically lowers HMGB1 levels [1]. NecroX-7 prevents tert-butyl hydroperoxide or doxorubicin-induced production of mitochondria-specific reactive nitrogen species (ROS) in H9C2 cells and hepatocytes [1]. The increase in regulatory T cells caused by necroX-7 may be connected to the control of differentiation signals that occurs independently of HMGB1 [1].
In vitro, NecroX-7 (0–40 μM, 3–4 days) suppresses active or dividing T cells without resulting in cell death. In a dose-dependent manner, NecroX-7 (0-40 μM) dramatically lowers HMGB1 levels. NecroX-7 prevents tert-butyl hydroperoxide or doxorubicin-induced production of mitochondria-specific reactive nitrogen species (ROS) in H9C2 cells and hepatocytes. The increase in regulatory T cells caused by NecroX-7 may be connected to the control of differentiation signals that occurs independently of HMGB1. These in vitro activities demonstrate the compound's ability to modulate immune responses, reduce oxidative stress, and inhibit HMGB1-mediated inflammation. |
| ln Vivo |
NecroX-7 (0-0.3 mg/kg, intravenously, every 2 days for 2 weeks) inhibits severe tissue damage and dramatically lowers mortality related to GVHD [1]. NecroX-7 protects mice from fatal GVHD through mutual regulation of regulatory T/Th1 cells, attenuating systemic HMGB1 accumulation and inhibiting HMGB1-mediated inflammatory responses [1].
In vivo, NecroX-7 (0-0.3 mg/kg, intravenously, every 2 days for 2 weeks) inhibits severe tissue damage and dramatically lowers mortality related to GVHD in mouse models. NecroX-7 protects mice from fatal GVHD through mutual regulation of regulatory T/Th1 cells, attenuating systemic HMGB1 accumulation and inhibiting HMGB1-mediated inflammatory responses. In female BALB/c and C57BL/6 mice with GVHD, intravenous administration of NecroX-7 at doses ≥0.1 mg/kg resulted in statistically significant prolongation of survival, with 30-60% of mice surviving beyond 50 days. Clinical symptoms were dramatically improved, survival time was prolonged, and mice had diminished clinical manifestations of acute GVHD, including weight loss, hunched posture, diarrhea, and fur ruffles. These in vivo studies demonstrate NecroX-7's therapeutic potential in inflammatory and immune-mediated diseases. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for NecroX-7 are not extensively documented. The compound's mechanism involves inhibition of HMGB1 release and free radical scavenging rather than direct enzyme inhibition. HMGB1 levels can be measured by ELISA or Western blot in cell culture supernatants or lysates. The compound's free radical scavenging activity can be assessed using assays such as DPPH radical scavenging, ABTS radical cation decolorization, or measurement of reactive oxygen/nitrogen species using fluorescent probes (e.g., DCFH-DA) in cells treated with oxidants such as tert-butyl hydroperoxide or doxorubicin. These assays are used to characterize the compound's antioxidant and anti-inflammatory activities.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: CD4 T Cell Tested Concentrations: 0, 0.625, 1.25, 2.5, 5, 10, 20 and 40 μM Incubation Duration: 3-4 days Experimental Results: demonstrated significant reduction in splenocyte proliferation in a dose-dependent manner sexual manner. Modulates alloreactive T cell responses. Cell-based assays for NecroX-7 are conducted in various cell types including T cells, H9C2 cells (cardiomyoblasts), and hepatocytes. T cell proliferation assays: CD4 T cells are treated with NecroX-7 at concentrations of 0, 0.625, 1.25, 2.5, 5, 10, 20, and 40 μM for 3-4 days, and proliferation is measured by [³H]-thymidine incorporation or CFSE dilution. HMGB1 release is measured by ELISA in cell culture supernatants. ROS production is measured using fluorescent probes in H9C2 cells and hepatocytes treated with tert-butyl hydroperoxide or doxorubicin. These cell-based assays characterize the compound's immunomodulatory, antioxidant, and cytoprotective effects. |
| Animal Protocol |
Animal/Disease Models: Female BALB/c and C57BL/6 mice (8 weeks old, with GVHD) [1]
Doses: 0.03, 0.1 and 0.3 mg/kg Route of Administration: intravenous (iv) (iv)injection, once every 2 days, continuously Secondary Experimental Results: At doses ≥0.1 mg/kg, statistically significant prolongation of survival was observed: 30-60% of mice in these treatment groups survived beyond 50 days. Clinical symptoms were Dramatically improved, survival time was prolonged, and mice had diminished clinical manifestations of acute GVHD, including weight loss, hunched posture, diarrhea, and fur ruffles. In vivo animal experiments with NecroX-7 have been conducted in mouse models of graft-versus-host disease (GVHD). Female BALB/c and C57BL/6 mice (8 weeks old) with GVHD were treated with NecroX-7 at doses of 0.03, 0.1, and 0.3 mg/kg administered intravenously every 2 days for 2 weeks. Endpoints included survival, clinical symptoms (weight loss, hunched posture, diarrhea, fur ruffles), and histological analysis of tissue damage. At doses ≥0.1 mg/kg, statistically significant prolongation of survival was observed, with 30-60% of mice surviving beyond 50 days. These studies demonstrate the compound's efficacy in attenuating GVHD and reducing mortality. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of NecroX-7 have not been extensively characterized in published literature. The compound has molecular weight 439.57 and molecular formula C24H29N3O3S. It is soluble in DMSO and other organic solvents. For in vivo studies, NecroX-7 has been administered intravenously at doses of 0.03-0.3 mg/kg. Specific pharmacokinetic parameters such as half-life, Cmax, AUC, bioavailability, and tissue distribution have not been reported. Storage: powder at -20°C for 3 years, in solvent at -80°C for 1 year. Researchers planning in vivo studies should conduct appropriate pharmacokinetic characterization.
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| Toxicity/Toxicokinetics |
Toxicology data for NecroX-7 are limited in publicly available sources. The compound has demonstrated protective effects in models of acetaminophen toxicity and ischemia/reperfusion injury, suggesting a favorable safety profile at therapeutic doses. In GVHD mouse models, NecroX-7 at doses up to 0.3 mg/kg (i.v., every 2 days for 2 weeks) was well-tolerated and reduced mortality. Comprehensive toxicology studies (acute and chronic toxicity, genotoxicity, reproductive toxicity) have not been extensively reported. The compound is for research use only and is not approved for human therapeutic use. Standard laboratory safety precautions should be followed when handling NecroX-7.
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| References | |
| Additional Infomation |
NecroX-7 has CAS number 1120332-55-9, molecular formula C24H29N3O3S, and molecular weight 439.57. It is a potent free radical scavenger and HMGB1 inhibitor. NecroX-7 works as an antidote to acetaminophen toxicity and exerts protective effects by inhibiting the release of HMGB1 in ischemia/reperfusion injury. NecroX-7 inhibits HMGB1-induced TNF and IL-6 release and may be utilized in GVHD research. Purity: ≥98%. Synonyms: 5-[(1,1-dioxido-4-thiomorpholinyl)methyl]-2-phenyl-N-(tetrahydro-2H-pyran-4-yl)-1H-indol-7-amine. Not approved for clinical use; for research purposes only. The compound is a valuable tool for studying HMGB1-mediated inflammation, oxidative stress, and immune regulation.
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| Molecular Formula |
C24H29N3O3S
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| Molecular Weight |
439.570364713669
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| Exact Mass |
439.192
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| CAS # |
1120332-55-9
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| PubChem CID |
44187164
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| Appearance |
Off-white to yellow solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
31
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| Complexity |
671
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1C2=C(C=C(CN3CCS(=O)(=O)CC3)C=C2NC2CCOCC2)C=C1C1=CC=CC=C1
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| InChi Key |
UZRCNCPUOFYHRB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H29N3O3S/c28-31(29)12-8-27(9-13-31)17-18-14-20-16-22(19-4-2-1-3-5-19)26-24(20)23(15-18)25-21-6-10-30-11-7-21/h1-5,14-16,21,25-26H,6-13,17H2
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| Chemical Name |
5-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-N-(oxan-4-yl)-2-phenyl-1H-indol-7-amine
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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)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~227.50 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2750 mL | 11.3748 mL | 22.7495 mL | |
| 5 mM | 0.4550 mL | 2.2750 mL | 4.5499 mL | |
| 10 mM | 0.2275 mL | 1.1375 mL | 2.2750 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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