ES 936
(Synonyms: 5-甲氧基-1,2-二甲基-3-[(4-硝基苯氧基)甲基]吲哚-4,7-二酮) 目录号 : GC14205
ES 936一种有效的特异性NAD(P)H:醌氧化还原酶1（NQO1）抑制剂。
Cas No.:192820-78-3
Sample solution is provided at 25 µL, 10mM.
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ES 936 is a potent and specific NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitor[1-2]. ES 936 exhibits superoxide-scavenging activity and the ability to regulate cancer progression[3-4].
In vitro, treatment of renal cell carcinoma Caki cells with ES 936 (100nM) for 12 hours, ES 936 significantly inhibits the enzymatic activity of NAD(P)H:quinone oxidoreductase 1 (NQO1)[5]. Treatment of low-density cultured human adenocarcinoma HeLa cells with ES 936 (100nM–1μM) for 24 hours, ES 936 significantly stimulates DNA synthesis and cell growth[6]. ES 936 (100nM) pretreatment of TrHBMEC (transformed human bone marrow endothelial cells) for 2 hours, followed by stimulation with TNFα (10ng/ml) for 2-6 hours, ES 936 significantly inhibited the mRNA and protein expression of adhesion molecules such as E-selectin, VCAM-1, and ICAM-1, while also reducing the adhesive function of CD34⁺ hematopoietic cells (KG1a)[7]. ES 936 (500nM) treatment of BxPc-3 human pancreatic cancer cells for 2 hours did not affect the binding of NQO1 to the mitotic spindle, indicating that the association of NQO1 with the spindle is independent of its catalytic activity state[8].
In vivo, daily intraperitoneal injection of ES 936 (5mg/kg) for 10 consecutive days in female athymic nude mice bearing MIA PaCa-2 human pancreatic cancer xenografts, ES 936 significantly inhibits the tumor growth rate[7].
References:
[1] Okubo A, Yasuhira S, Shibazaki M, et al. NAD(P)H dehydrogenase, quinone 1 (NQO1), protects melanin-producing cells from cytotoxicity of rhododendrol. Pigment Cell Melanoma Res. 2016 May;29(3):309-16.
[2] Winski SL, Faig M, Bianchet MA, et al. Characterization of a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1 by biochemical, X-ray crystallographic, and mass spectrometric approaches. Biochemistry. 2001 Dec 18;40(50):15135-42.
[3] Dehn DL, Siegel D, Swann E, et al. Biochemical, cytotoxic, and genotoxic effects of ES936, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, in cellular systems. Mol Pharmacol. 2003 Sep;64(3):714-20.
[4] Reigan P, Colucci MA, Siegel D, et al. Development of indolequinone mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1): NQO1 inhibition and growth inhibitory activity in human pancreatic MIA PaCa-2 cancer cells. Biochemistry. 2007 May 22;46(20):5941-50.
[5] Park EJ, Min KJ, Choi KS, et al. Dicoumarol sensitizes renal cell carcinoma Caki cells to TRAIL-induced apoptosis through down-regulation of Bcl-2, Mcl-1 and c-FLIP in a NQO1-independent manner. Exp Cell Res. 2014 Apr 15;323(1):144-154.
[6] González-Aragón D, Alcaín FJ, Ariza J, et al. ES936 stimulates DNA synthesis in HeLa cells independently on NAD(P)H:quinone oxidoreductase 1 inhibition, through a mechanism involving p38 MAPK. Chem Biol Interact. 2010 Jul 30;186(2):174-83.
[7] Zhou H, Dehn D, Kepa JK, et al. NAD(P)H:quinone oxidoreductase 1-compromised human bone marrow endothelial cells exhibit decreased adhesion molecule expression and CD34+ hematopoietic cell adhesion. J Pharmacol Exp Ther. 2010 Jul;334(1):260-8.
[8] Siegel D, Kepa JK, Ross D. NAD(P)H:quinone oxidoreductase 1 (NQO1) localizes to the mitotic spindle in human cells. PLoS One. 2012;7(9):e44861.
[9] Dehn DL, Siegel D, Zafar KS, et al. 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo. Mol Cancer Ther. 2006 Jul;5(7):1702-9.
ES 936一种有效的特异性NAD(P)H:醌氧化还原酶1（NQO1）抑制剂[1-2]。ES 936具有超氧化物清除活性及调控癌症发展活性[3-4]。
在体外，ES 936（100nM）处理肾细胞癌Caki细胞12小时，显著抑制NAD(P)H:醌氧化还原酶1（NQO1）的酶活性[5]。ES 936（100nM–1μM）处理低密度培养的人腺癌HeLa细胞24小时，显著刺激DNA合成和细胞生长[6]。ES 936（100nM）预处理TrHBMEC（转化人骨髓内皮细胞）2小时，随后以TNFα（10ng/ml）刺激2-6小时，显著抑制E-selectin、VCAM-1和ICAM-1等黏附分子的mRNA及蛋白表达，同时降低CD34+造血细胞（KG1a）的黏附功能[7]。ES 936（500nM）处理BxPc-3人胰腺癌细胞2小时，ES 936处理不影响NQO1与有丝分裂纺锤体的结合，表明NQO1与纺锤体的结合不依赖于其催化活性状态[8]。
在体内，ES 936（5mg/kg）每日腹腔注射一次，连续10天处理携带MIA PaCa-2人胰腺癌异种移植瘤的雌性无胸腺裸鼠，显著抑制肿瘤生长速率[8]。
| Cell experiment [1]: | |
Cell lines | Caki cells (human renal cell carcinoma cell line) |
Preparation Method | Caki cells were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 20mM HEPES buffer, and 100μg/mL gentamicin at 37°C, 5% CO₂. Caki cells were treated with ES 936 (100nM) for 12 hours to assess NQO1 inhibition or in combination with TRAIL (50ng/mL) for 24 hours to evaluate apoptosis. |
Reaction Conditions | 100nM for 12h (NQO1 activity assay); 100nM for 24h (apoptosis analysis). |
Applications | ES 936 significantly inhibited NQO1 enzyme activity in Caki cells but did not enhance TRAIL-induced apoptosis. In contrast to dicoumarol, ES 936 had no effect on reactive oxygen species (ROS) generation or mitochondrial oxygen consumption. ES 936 treatment alone did not alter the expression of anti-apoptotic proteins (Bcl-2, Mcl-1, c-FLIP) or induce ER stress markers (CHOP, GRP78). |
| Animal experiment [2]: | |
Animal models | Female athymic nude mice (Ncr nu/nu) bearing MIA PaCa-2 human pancreatic xenograft tumors |
Preparation Method | Mice were subcutaneously inoculated with MIA PaCa-2 cells (2×10⁷cells/mouse) in a 75:25 medium/Matrigel suspension. When tumors reached ~200mm³ (~14 days post-implantation), mice were randomized into control and treatment groups. ES 936 (5mg/kg) was administered intraperitoneally daily for 10 days. Tumor volumes were measured regularly during and after treatment. |
Dosage form | 5mg/kg; i.p.; Daily for 10 days. |
Applications | ES 936 treatment significantly inhibited tumor growth rates compared to DMSO-treated controls, with a maximal T/C (tumor volume ratio). Growth inhibition was sustained during the treatment period (days 1–10) but reversed after cessation of therapy (days 11–20), indicating dependency on continuous ES 936 exposure. |
References: | |
| Cas No. | 192820-78-3 | SDF | |
| 别名 | 5-甲氧基-1,2-二甲基-3-[(4-硝基苯氧基)甲基]吲哚-4,7-二酮 | ||
| 化学名 | 5-methoxy-1,2-dimethyl-3-((4-nitrophenoxy)methyl)-1H-indole-4,7-dione | ||
| Canonical SMILES | O=C(C(OC)=C1)C2=C(C1=O)N(C)C(C)=C2COC(C=C3)=CC=C3[N+]([O-])=O | ||
| 分子式 | C18H16N2O6 | 分子量 | 356.33 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.8064 mL | 14.0319 mL | 28.0639 mL |
| 5 mM | 561.3 μL | 2.8064 mL | 5.6128 mL |
| 10 mM | 280.6 μL | 1.4032 mL | 2.8064 mL |
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