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2-氰基-3-[5-(2,5-二氯苯基)-2-呋喃基]-N-5-喹啉基-2-丙烯酰胺

用途

AGK2 是一个选择性 SIRT2 抑制剂,其 IC50 值为 3.5 μM。AGK2 也可以抑制 SIRT1 和 SIRT3,且IC50 值分别为 30 和 91 μM。

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名称

[ CAS 号 ]:
304896-28-4

[ 中文名 ]:
2-氰基-3-[5-(2,5-二氯苯基)-2-呋喃基]-N-5-喹啉基-2-丙烯酰胺

[ 英文名 ]:
AGK2

[英文别名 ]:

ARC 239 dihydrochloride
AGK2

生物活性

[ 描述 ]:

AGK2 是一个选择性 SIRT2 抑制剂,其 IC50 值为 3.5 μM。AGK2 也可以抑制 SIRT1 和 SIRT3,且IC50 值分别为 30 和 91 μM。

[ 相关类别 ]:

研究领域 >> 癌症

[ 靶点 ]

SIRT2:3.5 μM (IC50)

SIRT1:30 μM (IC50)

SIRT3:91 μM (IC50)

[体外研究]

AGK2以剂量依赖性方式显着抑制细胞增殖。 AGK2还以剂量依赖性方式显着抑制细胞生长,而在低剂量下不诱导细胞毒性。在AGK2(5μM)处理后12天,细胞在软琼脂中显示出显着降低的集落形成能力至46％的对照细胞。蛋白质印迹分析显示,AGK2处理后CDK4或CDK6和细胞周期蛋白D1的水平以剂量依赖性方式降低。此外,AGK2抑制p53蛋白的表达[2]。用10μMAGK2处理小胶质细胞BV2细胞导致PAR信号显着增加。用10μMAGK2处理小胶质细胞BV2细胞也导致细胞内ATP的显着降低和细胞晚期凋亡和坏死的显着增加[3]。

[体内研究]

AGK2显着降低血液中的死亡率和降低细胞因子水平(TNF-α：298.3±24.6 vs 26.8±2.8 pg/mL,p = 0.0034; IL-6：633.4±82.8 vs 232.6±133.0 pg/mL,p = 0.0344)与载体对照相比,腹膜液(IL-6：704.8±67.7对比391.4±98.5pg/mL,p = 0.033)。 AGK2还抑制培养脾细胞中TNF-α和IL-6的产生(TNF-α：68.1±6.4 vs 23.9±2.8 pg/mL,p = 0.0009; IL-6：73.1±4.2 vs 49.6±3.0 pg/mL ; p = 0.0051)[4]。

[细胞实验]

将细胞暴露于1mL含有10％FBS的0.3％基础培养基琼脂中的不同浓度的AGK2。将培养物在37℃，5％CO 2培养箱中维持10-15天，并使用倒置显微镜对细胞集落进行评分[2]。

[动物实验]

小鼠腹膜内给予二甲基亚砜（DMSO）中的AGK2（82mg / kg）或单独的DMSO，2小时后给予CLP。监测生存240小时。将AGK2处理小鼠分组为（i）DMSO载体和（ii）AGK2，其中假小鼠（操作但未经任何处理）用作对照。在24和48小时检查腹膜液和外周血的细胞因子产生[4]。

[参考文献]

[1]. Tatum PR, et al. Identification of novel SIRT2-selective inhibitors using a click chemistry approach. Bioorg Med Chem Lett. 2014 Apr 15;24(8):1871-4.

[2]. Kim HW, et al. Sirtuin inhibitors, EX527 and AGK2, suppress cell migration by inhibiting HSF1 protein stability. Oncol Rep. 2016 Jan;35(1):235-42.

[3]. Li Y, et al. Poly(ADP-ribose) polymerase mediates both cell death and ATP decreases in SIRT2 inhibitor AGK2-treated microglial BV2 cells. Neurosci Lett. 2013 Jun 7;544:36-40.

[4]. Zhao T, et al. Selective Inhibition of SIRT2 Improves Outcomes in a Lethal Septic Model. Curr Mol Med. 2015;15(7):634-41.

[相关活性小分子]

物理化学性质

[ 密度 ]:
1.4±0.1 g/cm3

[ 沸点 ]:
675.1±55.0 °C at 760 mmHg

[ 分子式 ]:
C₂₃H₁₃Cl₂N₃O₂

[ 分子量 ]:
434.274

[ 闪点 ]:
362.1±31.5 °C

[ 精确质量 ]:
433.038483

[ PSA ]:
78.92000

[ LogP ]:
5.39

[ 外观性状 ]:
固体;White to Yellow to Orange powder to crystal

[ 蒸汽压 ]:
0.0±2.1 mmHg at 25°C

[ 折射率 ]:
1.718

[ 储存条件 ]:
Room temp

[ 水溶解性 ]:
DMSO: soluble2mg/mL, clear (warmed)

MSDS

详细MSDS(安全技术说明书)

安全信息

[ 个人防护装备 ]:
dust mask type N95 (US);Eyeshields;Gloves

[ 危害码 (欧洲) ]:
Xi: Irritant;

[ 风险声明 (欧洲) ]:
36

[ 安全声明 (欧洲) ]:
26

[ 危险品运输编码 ]:
NONH for all modes of transport

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