Necrostatin-5
(Synonyms: 2-[[3,4,5,6,7,8-六氢-3-(4-甲氧基苯基)-4-氧代[1]苯并噻吩并[2,3-D]嘧啶-2-基]硫代]-乙腈) 目录号 : GC41114A RIP1 kinase inhibitor
Cas No.:337349-54-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling necrosis. Serine/threonine kinase activity of the death domain receptor-associated molecule RIP1 is thought to be essential for Fas ligand-induced and tumor necrosis factor-α (TNF-α) induced necrosis. Necrostatin-5 is a selective allosteric inhibitor of RIP1 kinase that prevents the death of TNF-α-treated FADD-deficient Jurkat cells with an EC50 value of 240 nM.
| Cas No. | 337349-54-9 | SDF | |
| 别名 | 2-[[3,4,5,6,7,8-六氢-3-(4-甲氧基苯基)-4-氧代[1]苯并噻吩并[2,3-D]嘧啶-2-基]硫代]-乙腈 | ||
| Canonical SMILES | O=C(C(C(CCCC1)=C1S2)=C2N=C3SCC#N)N3C4=CC=C(OC)C=C4 | ||
| 分子式 | C19H17N3O2S2 | 分子量 | 383.5 |
| 溶解度 | DMSO: 10 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6076 mL | 13.0378 mL | 26.0756 mL |
| 5 mM | 0.5215 mL | 2.6076 mL | 5.2151 mL |
| 10 mM | 0.2608 mL | 1.3038 mL | 2.6076 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Identification of RIP1 kinase as a specific cellular target of necrostatins
Nat Chem Biol 2008 May;4(5):313-21.PMID:18408713DOI:10.1038/nchembio.83.
Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor-associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and Necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.
Structure-activity relationship analysis of a novel necroptosis inhibitor, Necrostatin-5
Bioorg Med Chem Lett 2007 Mar 1;17(5):1455-65.PMID:17270434DOI:10.1016/j.bmcl.2006.11.056.
Necrostatin-5 (Nec-5) is a novel potent small-molecule inhibitor of necroptosis structurally distinct from previously described Necrostatin-1 (Nec-1), and therefore, represents a new direction for the inhibition of this cellular caspase-independent necrotic cell death mechanism. Here, we describe a series of structural modifications of Nec-5 and the structure-activity relationship (SAR) of Nec-5 series in inhibiting necroptosis.
Study of cardioprotective effects of necroptosis inhibitors on isolated rat heart subjected to global ischemia-reperfusion
Bull Exp Biol Med 2013 Jun;155(2):245-8.PMID:24131001DOI:10.1007/s10517-013-2124-2.
The cardioprotective effects of necroptosis inhibitors necrostatin-1 and Necrostatin-5 were studied on the isolated heart model in rats. Intraperitoneal injection of necrostatin-1 (1.65 mg/kg) or Necrostatin-5 (2.46 mg/kg) 60 min before reperfusion of the isolated heart reduced the infarction zone caused by 30-min global ischemia and 120-min reperfusion. Intracoronary injection of necrostatin-1 (44.5 μmol/liter) caused an increase of left-ventricular systolic pressure, that is produced a positive inotropic effect, but did not reduce the infarction zone.
Pore-Forming Toxins Induce Macrophage Necroptosis during Acute Bacterial Pneumonia
PLoS Pathog 2015 Dec 11;11(12):e1005337.PMID:26659062DOI:10.1371/journal.ppat.1005337.
Necroptosis is a highly pro-inflammatory mode of cell death regulated by RIP (or RIPK)1 and RIP3 kinases and mediated by the effector MLKL. We report that diverse bacterial pathogens that produce a pore-forming toxin (PFT) induce necroptosis of macrophages and this can be blocked for protection against Serratia marcescens hemorrhagic pneumonia. Following challenge with S. marcescens, Staphylococcus aureus, Streptococcus pneumoniae, Listeria monocytogenes, uropathogenic Escherichia coli (UPEC), and purified recombinant pneumolysin, macrophages pretreated with inhibitors of RIP1, RIP3, and MLKL were protected against death. Alveolar macrophages in MLKL KO mice were also protected during S. marcescens pneumonia. Inhibition of caspases had no impact on macrophage death and caspase-1 and -3/7 were determined to be inactive following challenge despite the detection of IL-1β in supernatants. Bone marrow-derived macrophages from RIP3 KO, but not caspase-1/11 KO or caspase-3 KO mice, were resistant to PFT-induced death. We explored the mechanisms for PFT-induced necroptosis and determined that loss of ion homeostasis at the plasma membrane, mitochondrial damage, ATP depletion, and the generation of reactive oxygen species were together responsible. Treatment of mice with Necrostatin-5, an inhibitor of RIP1; GW806742X, an inhibitor of MLKL; and Necrostatin-5 along with co-enzyme Q10 (N5/C10), which enhances ATP production; reduced the severity of S. marcescens pneumonia in a mouse intratracheal challenge model. N5/C10 protected alveolar macrophages, reduced bacterial burden, and lessened hemorrhage in the lungs. We conclude that necroptosis is the major cell death pathway evoked by PFTs in macrophages and the necroptosis pathway can be targeted for disease intervention.
Infiltrated Macrophages Die of Pneumolysin-Mediated Necroptosis following Pneumococcal Myocardial Invasion
Infect Immun 2016 Apr 22;84(5):1457-69.PMID:26930705DOI:10.1128/IAI.00007-16.
Streptococcus pneumoniae (the pneumococcus) is capable of invading the heart. Herein we observed that pneumococcal invasion of the myocardium occurred soon after development of bacteremia and was continuous thereafter. Using immunofluorescence microscopy (IFM), we observed that S. pneumoniae replication within the heart preceded visual signs of tissue damage in cardiac tissue sections stained with hematoxylin and eosin. Different S. pneumoniae strains caused distinct cardiac pathologies: strain TIGR4, a serotype 4 isolate, caused discrete pneumococcus-filled microscopic lesions (microlesions), whereas strain D39, a serotype 2 isolate, was, in most instances, detectable only using IFM and was associated with foci of cardiomyocyte hydropic degeneration and immune cell infiltration. Both strains efficiently invaded the myocardium, but cardiac damage was entirely dependent on the pore-forming toxin pneumolysin only for D39. Early microlesions caused by TIGR4 and microlesions formed by a TIGR4 pneumolysin-deficient mutant were infiltrated with CD11b(+) and Ly6G-positive neutrophils and CD11b(+) and F4/80-positive (F4/80(+)) macrophages. We subsequently demonstrated that macrophages in TIGR4-infected hearts died as a result of pneumolysin-induced necroptosis. The effector of necroptosis, phosphorylated mixed-lineage kinase domain-like protein (MLKL), was detected in CD11b(+) and F4/80(+) cells associated with microlesions. Likewise, treatment of infected mice and THP-1 macrophages in vitro with the receptor-interacting protein 1 kinase (RIP1) inhibitor Necrostatin-5 promoted the formation of purulent microlesions and blocked cell death, respectively. We conclude that pneumococci that have invaded the myocardium are an important cause of cardiac damage, pneumolysin contributes to cardiac damage in a bacterial strain-specific manner, and pneumolysin kills infiltrated macrophages via necroptosis, which alters the immune response.