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Necrosulfonamide

Katalog-Nr.GC10150

Necrosulfonamid (NSA) ist ein spezifischer Inhibitor von MLKL (Mixed Lineage Kinase Domain-ähnliches Protein)[1].

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Necrosulfonamide Chemische Struktur

Cas No.: 1360614-48-7

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10mM (in 1mL DMSO)
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5mg
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10mg
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25mg
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Sample solution is provided at 25 µL, 10mM.

Product has been cited by 2 publications

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

BMDMs

Preparation Method

IL-1β and LDH levels in the cell supernantant of BMDMs from WT (C57BL/6), Gsdmd-/- and Caspase-1-/- mice primed for 2.5 hr with LPS (50 ng/ml), with necrosulfonamide (NSA) (10 µM) added in the last 30 min of priming, then treated with MSU crystals (300 µg/ml, 6 hr) or nigericin (10 µM, 1 hr).

Reaction Conditions

10 µM; 30 min

Applications

The treatment of LPS primed BMDMs with similar concentrations of NSA, (10 µM) efficiently inhibited MSU crystal-induced IL-1β release in a dose dependent manner.

Animal experiment [2]:

Animal models

Seventy male 8-week-old specific pathogen-free (SPF)-grade C57BL/6J mice weighing 20-25 g

Preparation Method

An ALF (Acute liver failure) model was established by lipopolysaccharide/D-galactosamine challenge in C57BL/6J mice. Necrosulfonamide 20 mg/kg was administered by intraperitoneal injection 30 m before the establishment of the animal model.

Dosage form

20 mg/kg; i.p.

Applications

Pyroptosis was activated in ALF model mice. Mice treated with GSDMD inhibitor Necrosulfonamide developed less severe liver failure. Necrosulfonamide reduced the expression of GSDMD, NLRP3, cleaved caspase-1, cleaved caspase-11, and secretion of interleukin-1 beta in ALF mice model.

References:

[1] Rashidi M, et al. The Pyroptotic Cell Death Effector Gasdermin D Is Activated by Gout-Associated Uric Acid Crystals but Is Dispensable for Cell Death and IL-1β Release. J Immunol. 2019 Aug 1;203(3):736-748.
[2] Wu YL, et al. Gasdermin D Inhibitor Necrosulfonamide Alleviates Lipopolysaccharide/D-galactosamine-induced Acute Liver Failure in Mice. J Clin Transl Hepatol. 2022 Dec 28;10(6):1148-1154.

Background

Necrosulfonamid (NSA) ist ein spezifischer Inhibitor von MLKL (Mixed Lineage Kinase Domain-ähnliches Protein)[1]. Necrosulfonamid, ein Inhibitor von GSDMD, könnte die durch PPVI induzierte Aktivierung des NLRP3-Inflammasoms hemmen[2].

Im In-vitro-Wirksamkeitstest wurde gezeigt, dass die IC50-Werte für Necrosulfonamid in zellbasierten Tests zur Nekroptose (NEC), Apoptose (APOP) oder Toxizität (TOX) in Jurkat- und U937-Zellen 1399 nM, 6197 nM, 454 nM bzw. >100.000 nM und 14694 nM betrugen[3]. In vitro hemmte eine Behandlung mit 10 µM oder 20 µM Necrosulfonamid die GSDMD-vermittelte Freisetzung von IL-1β nach Inflammasom-Stimulation vollständig, was selbst noch nach 60 Minuten Stimulation bei Zellen, die mit LPS und Nigericin stimuliert wurden, zu einer Unterdrückung von IL-1β führte[4].

In vivo wurden männliche erwachsene C57BL/6-Mäuse zweimal täglich intraperitoneal mit 5 mg/kg Necrosulfonamid verabreicht, was signifikant die Hämatomgröße reduzierte, entzündliche Zellen und Zytokine unterdrückte und die Blut-Hirn-Schranke im Vergleich zu Kontrollen schützte[1]. In vivo wurden Ratten mit Necrosulfonamid (10 mg/kg) injiziert, wodurch die NOD-ähnlichen Rezeptor 3 (NLRP3)-, GSDMD-N-, phosphorylierten MLKL- und phosphorylierten RIP3-Level im Herzmuskelgewebe sowie entsprechende Reduktionen der Entzündungszytokin-Level reduziert wurden[5]. In vivo verbesserte eine intraperitoneale Injektion von 1, 5 oder 10 mg/kg Necrosulfonamid bei Mäusen die motorische Funktion und das Rückenmarksödem bei SCI-Mäusen mit einem therapeutischen Fenster[6]. In vivo wurde Ratten durch intraperitoneale Verabreichung von 0,5 mg/Körpergewicht Necrosulfonamid geschützt vor Lungen-IRI durch Hemmung der Nekroptose[7]. Mäuse wurden mit NSA behandelt (0,5 mg/kg/Tag für drei Tage und dann jeden zweiten Tag i.p. injiziert), was Defekte in der motorischen Leistungsfähigkeit wiederherstellte sowie TH+-Faserdefizite und TH+-Zellverlust in einem Mausmodell von PD[8]. In vivo wurden Ratten intraperitoneal mit 1,65 mg/kg/Tag Necrosulfonamid für sechs Wochen behandelt und zeigten eine deutliche Verbesserung der durch AlCl3 verursachten räumlichen Lern- und Gedächtnisdefizite, wie durch verbesserte Leistung in Morris-Wasser- und Y-Mazes gezeigt wurde[9].

References:
[1] Zhang X, et al. Necrosulfonamide Alleviates Acute Brain Injury of Intracerebral Hemorrhage via Inhibiting Inflammation and Necroptosis. Front Mol Neurosci. 2022 Jun 2;15:916249.
[2] Teng JF, et al. Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer. Cancers (Basel). 2020 Jan 13;12(1):193.
[3] RÜbbelke M, et al. Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis. Proc Natl Acad Sci U S A. 2020 Dec 29;117(52):33272-33281.
[4] Rathkey JK, et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci Immunol. 2018 Aug 24;3(26):eaat2738.
[5] He F, et al. Necrosulfonamide improves post-resuscitation myocardial dysfunction via inhibiting pyroptosis and necroptosis in a rat model of cardiac arrest. Eur J Pharmacol. 2022 Jul 5;926:175037.
[6] Jiao J, et al. Necrosulfonamide Ameliorates Neurological Impairment in Spinal Cord Injury by Improving Antioxidative Capacity. Front Pharmacol. 2020 Jan 9;10:1538.
[7] Ueda S, et al. Protective effect of necrosulfonamide on rat pulmonary ischemia-reperfusion injury via inhibition of necroptosis. J Thorac Cardiovasc Surg. 2022 Feb;163(2):e113-e122.
[8] Leem YH, et al. Necrosulfonamide exerts neuroprotective effect by inhibiting necroptosis, neuroinflammation, and α-synuclein oligomerization in a subacute MPTP mouse model of Parkinson's disease. Sci Rep. 2023 May 31;13(1):8783.
[9] Motawi TMK, et al. Ameliorative Effect of Necrosulfonamide in a Rat Model of Alzheimer's Disease: Targeting Mixed Lineage Kinase Domain-like Protein-Mediated Necroptosis. ACS Chem Neurosci. 2020 Oct 21;11(20):3386-3397.

Chemical Properties

Cas No. 1360614-48-7 SDF
Chemical Name (E)-N-[4-[[(3-Methoxy-2-pyrazinyl)amino]sulfonyl]phenyl]-3-(5-nitro-2-thienyl)-2-propenamide
Canonical SMILES COC1=NC=CN=C1NS(=O)(=O)C2=CC=C(C=C2)NC(=O)C=CC3=CC=C(S3)[N+](=O)[O-]
Formula C18H15N5O6S2 M.Wt 461.47
Löslichkeit ≥ 46.1mg/mL in DMSO Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

Prepare stock solution
1 mg 5 mg 10 mg
1 mM 2.167 mL 10.8349 mL 21.6699 mL
5 mM 0.4334 mL 2.167 mL 4.334 mL
10 mM 0.2167 mL 1.0835 mL 2.167 mL
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