NecrosulfonamideNecroptosis inhibitor CAS# 1360614-48-7 |
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Quality Control & MSDS
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Chemical structure
3D structure
Cas No. | 1360614-48-7 | SDF | Download SDF |
PubChem ID | 1566236 | Appearance | Powder |
Formula | C18H15N5O6S2 | M.Wt | 461.47 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Solubility | DMSO : ≥ 28 mg/mL (60.68 mM) H2O : < 0.1 mg/mL (insoluble) *"≥" means soluble, but saturation unknown. | ||
Chemical Name | (E)-N-[4-[(3-methoxypyrazin-2-yl)sulfamoyl]phenyl]-3-(5-nitrothiophen-2-yl)prop-2-enamide | ||
SMILES | COC1=NC=CN=C1NS(=O)(=O)C2=CC=C(C=C2)NC(=O)C=CC3=CC=C(S3)[N+](=O)[O-] | ||
Standard InChIKey | FNPPHVLYVGMZMZ-XBXARRHUSA-N | ||
Standard InChI | InChI=1S/C18H15N5O6S2/c1-29-18-17(19-10-11-20-18)22-31(27,28)14-6-2-12(3-7-14)21-15(24)8-4-13-5-9-16(30-13)23(25)26/h2-11H,1H3,(H,19,22)(H,21,24)/b8-4+ | ||
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. |
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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. |
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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. |
Description | Necroptosis inhibitor. Blocks mixed lineage kinase domain-like protein (MLKL), a critical substrate of receptor-interacting serine-threonine kinase 3 (RIP3) during necrosis. Prevents MLKL-RIP1-RIP3 necrosome complex from interacting with downstream necrosis effectors. |
Necrosulfonamide Dilution Calculator
Necrosulfonamide Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 2.167 mL | 10.8349 mL | 21.6699 mL | 43.3398 mL | 54.1747 mL |
5 mM | 0.4334 mL | 2.167 mL | 4.334 mL | 8.668 mL | 10.8349 mL |
10 mM | 0.2167 mL | 1.0835 mL | 2.167 mL | 4.334 mL | 5.4175 mL |
50 mM | 0.0433 mL | 0.2167 mL | 0.4334 mL | 0.8668 mL | 1.0835 mL |
100 mM | 0.0217 mL | 0.1083 mL | 0.2167 mL | 0.4334 mL | 0.5417 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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Necrosulfonamide (NSA) is a pharmacological inhibitor of mixed lineage kinase-like protein (MLKL) [1]. NSA is potent in protecting necrotic/necroptotic death of human HT-29 with an IC50 value of 124 nM [2].
MLKL, a functional RIP3 substrate, can bind to RIP3 through its kinase-like domain but it lacks kinase activity. MLKL can be phosphorylated by RIP3 at the T357 and S358 sites [3].
Treatment with NSA alone did not rescue cell death, while NSA significantly enhanced the protection of zVAD.fmk against BV6/5AC-induced cell death. In the same line, knockdown of MLKL did not significantly protect cells against BV6/5AC cotreatment in the absence of zVAD.fmk [1]. In the Dox-treated HeLa cells, NSA inhibited necrosis. With a higher level of RIP3, the allosteric inhibition of necrostatin-1 on RIP1 was overcome by cells. In contrast, NSA still efficiently prevented necrosis under this condition. Consistently, knockdown of MLKL also blocked necrosis. Under necrosis-inducing conditions, the presence of NSA made tubular mitochondrial morphology remain normal. Consistently the mitochondrial morphological changes were also prevented by the knockdown of MLKL [4]. Even at 5 μM concentration, NSA had no effect on the apoptosis induced by TNF-α plus Smac mimetic in non-RIP3-expressing Panc-1 cells. In the presence of NSA, the discrete RIP3 punctae were detected but failed to enlarge. That meant NSA blocked necrosis at a specific step in the necrosis pathway [3].
Pharmacological treatment with NSA delayed cone degeneration [5].
References:
[1]. Gerges S, Rohde K, Fulda S. Cotreatment with Smac mimetics and demethylating agents induces both apoptotic and necroptotic cell death pathways in acute lymphoblastic leukemia cells[J]. Cancer letters, 2016, 375(1): 127-132.
[2]. Bae JH, Shim JH, Cho YS. Chemical regulation of signaling pathways to programmed necrosis[J]. Archives of pharmacal research, 2014, 37(6): 689-697.
[3]. Wang H, Sun L, Su L, et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3[J]. Molecular cell, 2014, 54(1): 133-146.
[4]. Wang Z, Jiang H, Chen S, et al. The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways[J]. Cell, 2012, 148(1): 228-243.
[5]. Viringipurampeer IA, Mohammadi Z, Shan X, et al. Rip3 knockdown rescues photoreceptor cell death in pde6c zebrafish model of achromatopsia[J]. Investigative Ophthalmology & Visual Science, 2013, 54(15): 5955-5955.
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Necrosulfonamide - Unexpected effect in the course of a sulfur mustard intoxication.[Pubmed:30391637]
Chem Biol Interact. 2019 Jan 25;298:80-85.
Although its first military use in Ypres was 100 years ago, no causal therapy for sulfur mustard (SM) intoxications exists so far. To improve the therapeutic options for the treatment of SM intoxications, we developed a co-culture of keratinocytes (HaCaT cells) and immunocompetent cells (THP-1cells) to identify potential substances for further research. Here, we report on the influence of Necrosulfonamide (NSA) on the course of a SM intoxication in vitro. The cells were challenged with 100, 200 and 300muM SM and after 1h treated with NSA (1, 5, 10muM). NSA was chosen for its known ability to inhibit necroptosis, a specialized pathway of programmed necrosis. However, in our settings NSA showed only mild effects on necrotic cell death after SM intoxication, whereas it had an immense ability to prevent apoptosis. Furthermore, NSA was able to reduce the production of interleukin-6 and interleukin-8 at certain concentrations. Our data highlight NSA as a candidate compound to address cell death and inflammation in SM exposure.
Necrosulfonamide Attenuates Spinal Cord Injury via Necroptosis Inhibition.[Pubmed:29614353]
World Neurosurg. 2018 Jun;114:e1186-e1191.
OBJECTIVE: Spinal cord injury (SCI) is a serious trauma without efficient treatment currently. Necroptosis can be blocked post injury by special inhibitors. This study is to investigate the effects, mechanism, and potential benefit of Necrosulfonamide (NSA) for SCI therapy. METHODS: Pathologic condition was detected using hematoxylin-eosin staining on injured spinal cord and other major organs. Necroptosis-related factors-RIP1, RIP3, and MLKL-were detected using Western blot. Detections on mitochondrial functions such as adenosine triphosphate generation and activities of superoxide dismutase and caspase-3 were also performed. Finally, ethologic performance was detected using a 21-point open-field locomotion test. RESULTS: Reduced lesions and protected neurons were found in the injured spinal cord after treatment with NSA using hematoxylin-eosin staining for pathologic detection. No obvious toxicity on rat liver, kidney, heart, and spleen was detected. Rather than RIP1 and RIP3, MLKL was significantly inhibited by the NSA using Western blot detection. Adenosine triphosphate generation was obviously decreased post injury but slightly increased after the NSA treatment, especially 24 hours post injury. No significant changes were found on activities of superoxide dismutase and caspase-3 after the treatment of NSA. Ethologic performance was significantly improved using a 21-point, open-field locomotion test. CONCLUSIONS: Our research indicates NSA attenuates the spinal cord injury via necroptosis inhibition. It might be a potential and safe chemical benefit for SCI therapy. To our knowledge, this is the first study on the effects of NSA as treatment of traumatic SCI.
Killing a cancer: what are the alternatives?[Pubmed:22576162]
Nat Rev Cancer. 2012 May 11;12(6):411-24.
Evading programmed cell death is one of the hallmarks of cancer. Conversely, inducing cell death by pharmacological means is the basis of almost every non-invasive cancer therapy. Research over the past decade has greatly increased our understanding of non-apoptotic programmed cell death events, such as lysosomal-mediated cell death, necroptosis and cell death with autophagy. It is becoming clear that an intricate effector network connects many of these classical and non-classical death pathways. In this Review, we discuss converging and diverging features of these pathways, as well as attempts to exploit this newly gained knowledge pharmacologically to provide therapeutics for cancer.
Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase.[Pubmed:22265413]
Cell. 2012 Jan 20;148(1-2):213-27.
The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acr ylamide--hereafter referred to as Necrosulfonamide--that specifically blocks necrosis downstream of RIP3 activation. An affinity probe derived from Necrosulfonamide and coimmunoprecipitation using anti-RIP3 antibodies both identified the mixed lineage kinase domain-like protein (MLKL) as the interacting target. MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. Treating cells with Necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.
New components of the necroptotic pathway.[Pubmed:23073834]
Protein Cell. 2012 Nov;3(11):811-7.
Programmed necrosis, also known as necroptosis, has recently drawn great attention. As an important cellular regulation mechanism, knowledge of its signaling components is expanding. Necroptosisis demonstrated to be regulated by the RIP1 and RIP3 kinases, and its pathophysiological importance has been confirmed in a number of disease models. Here we review the new members of this necroptosis pathway, MLKL, PGAM5, Drp1 and DAI, and discuss some of their possible applications according to recent findings.