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GW4869

カタログ番号GC19186

GW4869 は、IC50 が 1 μM の非競合的中性スフィンゴミエリナーゼ (N-SMase) 阻害剤です。

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GW4869 化学構造

Cas No.: 6823-69-4

サイズ 価格 在庫数 個数
2mg
$61.00
在庫あり
5mg
$88.00
在庫あり
10mg
$147.00
在庫あり
25mg
$308.00
在庫あり
50mg
$529.00
在庫あり

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Sample solution is provided at 25 µL, 10mM.

Product has been cited by 3 publications

Product Documents

Quality Control & SDS

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Protocol

Cell experiment [1]:

Cell lines

MCF7 human breast cancer cells

Preparation method

GW-4869 was routinely stored at −80 °C as a 1.5 mm stock suspension in DMSO. Right before use, the suspension was solubilized by the addition of 5% methane sulfonic acid (MSA) (2.5 μl of 5% MSA in sterile double-distilled H2O were added to 50 μl of GW4869 stock suspension; therefore, the concentration of the GW-4869 stock solution at the time of the experiments was 1.43 mm). The suspension was mixed and warmed up at 37 °C until clear.

Reaction Conditions

30 min

Applications

GW4869 is a noncompetitive neutral sphingomyelinase (N-SMase) inhibitor with an IC50 of 1 μM.GW4869 (10 μm) partially inhibited TNF-induced sphingomyelin (SM) hydrolysis, and 20 μm of the compound was protected completely from the loss of SM. The action of GW4869 occurred downstream of the drop in glutathione, which was shown previously to occur upstream of the activation of N-SMase. GW4869 does not interfere with other key TNF-mediated signaling effects. GW4869 was able, in a dose-dependent manner, to significantly protect from cell death as measured by nuclear condensation, caspase activation, PARP degradation, and trypan blue uptake.

Animal experiment [2]:

Animal models

Male wild-type C57BL/6 mice

Dosage form

GW 4869, dissolved in DMSO (0.005%), was intraperitoneally (i.p.) injected at one dose of 2.5μg/g before sham or CLP surgery.

Applications

Pre-treatment with GW 4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. WT mice pretreated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival.

References:

[1]. Luberto, Chiara, et al. "Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase." Journal of Biological Chemistry 277.43 (2002): 41128-41139.

[2]. Essandoh, Kobina, et al. "Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1852.11 (2015): 2362-2371.

Background

GW4869は、IC50が1μMの非競合性中立スフィンゴミエリナーゼ阻害剤です。

GW4869(10μM)は、TNFによるスフィンゴミエリン(SM)の加水分解を部分的に抑制し、20μMの化合物は完全にSMの喪失から保護されます。 10〜20μM GW4869を添加すると、セラミドの初期蓄積が完全に阻害されますが、この効果は後の時間点(24時間)では部分的に失われます。 GW4869の作用はグルタチオン低下以降で発生します。 GW4869は投与量依存性で細胞死から有意な保護効果を示すことができます。これらの保護効果は、ミトコンドリアからシトクロムc放出およびカスパーゼ9活性化の有意な阻害と共に伴います。したがって、N-SMase活性化をミトコンドリア機能不全上流側に局在させることができます[1]。

GW4869の前処置は、RAW264.7 マクロファージにおけるエキソソームとプロ炎症サイトカイン(TNF-α、IL-1β、IL-6)の放出を有意に低下させます。LPS処理またはCLP手術後12時間後、GW4869で予処置されたWTマウスは、コントロールのPBS注入マウスよりも血清中のエキソソームとプロ炎症サイトカインが少なくなります。したがって、GW4869治療は敗血症誘発性心臓炎を軽減し、心筋抑制を軟化し生存期間を延長します[2]。

References:
[1]. Luberto C, et al. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutralsphingomyelinase. J Biol Chem. 2002 Oct 25;277(43):41128-39.
[2]. Essandoh K, et al. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim Biophys Acta. 2015 Nov;1852(11):2362-71.
[3]. Nakamura H, et al. Sphingomyelin Regulates the Activity of Secretory Phospholipase A2 in the Plasma Membrane. J Cell Biochem. 2015 Sep;116(9):1898-907.

Chemical Properties

Cas No. 6823-69-4 SDF
Chemical Name 3,3'-(1,4-phenylene)bis[N-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-dihydrochloride-2-propenamide
Canonical SMILES O=C(NC1=CC=C(C2=NCCN2)C=C1)/C=C/C3=CC=C(/C=C/C(NC4=CC=C(C5=NCCN5)C=C4)=O)C=C3.[H]Cl.[H]Cl
Formula C30H30Cl2N6O2 M.Wt 577.5
溶解度 Water : < 0.1 mg/mL (insoluble);DMSO : 0.044 mg/mL (0.08 mM) 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 1.7316 mL 8.658 mL 17.316 mL
5 mM 0.3463 mL 1.7316 mL 3.4632 mL
10 mM 0.1732 mL 0.8658 mL 1.7316 mL
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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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Related Video

    GW4869-GlpBio

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Average Rating: 5 ★★★★★ (Based on Reviews and 4 reference(s) in Google Scholar.)

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