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Purity: >98.00%

实验参考方法

Cell experiment [1]:
Cell lines	Pancreatic cancer PaCa-2 and Panc-1 cells
Preparation Method	Cells were were maintained at 37 ⊿in 5% CO2 and grown in Dulbecco's Modified Eagle's Medium with 10% cosmic calf serum. PaCa-2 and Panc-1 cells were treated with E3330 for 72 and 48 hours, respectively.
Reaction Conditions	0-135 µM for 48, 72 h
Applications	E3330 was found to effectively slow the growth rate of cells in a dose-dependent manner, with an ED50 of 135 and 87 µmol/L for PaCa-2 and Panc-1, respectively.
Animal experiment [1]:
Animal models	Nonobese diabetic/severe combined immunodeficient mice (NOD/SCID) mice
Preparation Method	PaCa-2 cells (2.5 × 106) in 0.2 mL of DMEM media were implanted s.c. into the right flanks of NOD/SCID mice. E3330 was dissolved in 4% CremophorEL:EtOH (1:1)/saline solution or methylcellulose (0.5%). When tumor volumes were greater than 100 mm3, E3330 was administered orally twice daily, 8 hours apart, at 25 mg/kg for 10 to 12 days (5 days on 2 days off schedule). Tumors were measured biweekly and followed for approximately 6 weeks.
Dosage form	25 mg/kg, orally twice daily, for 10 to 12 days (5 days on 2 days off schedule)
Applications	In contrast to vehicle-control tumors, PaCa-2 xenografts showed a significant tumor growth delay.
References: [1] : Fishel M L, Jiang Y, Rajeshkumar N V, et al. Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor GrowthAPE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth[J]. Molecular cancer therapeutics, 2011, 10(9): 1698-1708.

产品描述

E3330 is a small-molecule inhibitor of apurinic-apyrimidinic endonuclease/redox effector factor (APE1/Ref-1) redox domain function (IC50, 50 μmol/L) ^[1,2].

E3330(10-30 μM, 72h) inhibits not only the growth but also the migratory abilities of pancreatic cancer cells in vitro ^[1].The co-incubation of E3330(30 μM, 3 h ) and cisplatin (5-20 μM, 72 h) significantly decreased cell viability compared to cisplatin alone in the human NSCLC cell line H1975 ^[3]. E3330 treatment prevented the functional activation of NF-κB via the alteration of APE1 subcellular trafficking and reduced IL-6 and IL-8 expression induced by TNF-α ^[4]. E3330 clearly suppressed secretion of inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL-6) and IL-12 and inflammatory mediators nitric oxide (NO) as well as prostaglandin E2 (PGE2) from the LPS-stimulated RAW264.7 cells ^[5].

E3330 (10-100 mg/kg, oral) treatment 1 hr after galactosamine challenge attenuated the liver injury. E3330 was effective when administered p.o. 6 or 12 hr after galactosamine challenge in the galactosamine-induced hepatitis model in F344 rats ^[6]. The injection of TNF in combination with galactosamine resulted in severe liver injury. Oral pretreatment with 100 and 300 mg/kg of E3330 30 min prior to the injection of galactosamine/TNF significantly attenuated the increase in plasma L-alanine aminotransferase and L-aspartate aminotransferase activities ^[7]. The estimated half-life (t1/2) of E3330 was 3.7 hours in mice ^[2].

References:
[1]. Zou G M, Maitra A. Small-molecule inhibitor of the AP endonuclease 1/REF-1 E3330 inhibits pancreatic cancer cell growth and migration[J]. Molecular cancer therapeutics, 2008, 7(7): 2012-2021.
[2]. Fishel M L, Colvin E S, Luo M, et al. Inhibition of the redox function of APE1/Ref-1 in myeloid leukemia cell lines results in a hypersensitive response to retinoic acid-induced differentiation and apoptosis[J]. Experimental hematology, 2010, 38(12): 1178-1188.
[3]. Manguinhas R, Fernandes A S, Costa J G, et al. Impact of the APE1 redox function inhibitor E3330 in non-small cell lung cancer cells exposed to cisplatin: increased cytotoxicity and impairment of cell migration and invasion[J]. Antioxidants, 2020, 9(6): 550.
[4]. Cesaratto L, Codarin E, Vascotto C, et al. Specific inhibition of the redox activity of ape1/ref-1 by e3330 blocks tnf-α-induced activation of IL-8 production in liver cancer cell lines[J]. PLoS One, 2013, 8(8): e70909.
[5]. Jedinak A, Dudhgaonkar S, Kelley M R, et al. Apurinic/Apyrimidinic endonuclease 1 regulates inflammatory response in macrophages[J]. Anticancer research, 2011, 31(2): 379-385.
[6]. Nagakawa J, Hirota K, Hishinuma I, et al. Protective effect of E3330, a novel quinone derivative, in galactosamine-induced hepatitis in rats[J]. Journal of Pharmacology and Experimental Therapeutics, 1993, 264(1): 496-500.
[7]. Nagakawa J, Hishinuma I, Hirota K, et al. Protective effects of E3330, a novel quinone derivative, on galactosamine/tumor necrosis factor-α-induced hepatitis in mice[J]. European journal of pharmacology, 1992, 229(1): 63-67.

E3330 是脱嘌呤-脱嘧啶核酸内切酶/氧化还原效应因子 (APE1/Ref-1) 氧化还原结构域功能的小分子抑制剂（IC50，50 μmol/L）^[1,2]。

E3330(10-30 μM, 72h) 在体外抑制胰腺癌细胞的生长和迁移能力^[1]。E3330(30 μM, 3 h ) 和顺铂（5-20 μM，72 小时）在人 NSCLC 细胞系 H1975 ^[3] 中与单独使用顺铂相比显着降低了细胞活力。 E3330 治疗通过改变 APE1 亚细胞运输和减少 TNF-α 诱导的 IL-6 和 IL-8 表达来阻止 NF-κB 的功能激活^[4]。 E3330 明显抑制炎症细胞因子的分泌，包括肿瘤坏死因子-α (TNF-α)、白细胞介素 (IL-6) 和 IL-12，以及来自 LPS 刺激的炎症介质一氧化氮 (NO) 和前列腺素 E2 (PGE2) RAW264.7 细胞 ^[5].

半乳糖胺攻击后 1 小时，E3330（10-100 mg/kg，口服）治疗减轻了肝损伤。 E3330 口服给药时有效。在 F344 大鼠的半乳糖胺诱导的肝炎模型中，半乳糖胺攻击后 6 或 12 小时 ^[6]。结合半乳糖胺注射 TNF 会导致严重的肝损伤。在注射半乳糖胺/TNF 前 30 分钟口服 100 和 300 mg/kg E3330 预处理可显着减弱血浆 L-丙氨酸氨基转移酶和 L-天冬氨酸氨基转移酶活性的增加^[7]。 E3330 在小鼠中的估计半衰期 (t1/2) 为 3.7 小时^[2]。

Chemical Properties

Cas No.	136164-66-4	SDF
别名	APX-3330
化学名	(E)-2-((4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methylene)undecanoic acid
Canonical SMILES	CCCCCCCCC/C(C(O)=O)=C([H])\C(C1=O)=C(C(C(OC)=C1OC)=O)C
分子式	C₂₁H₃₀O₆	分子量	378.46
溶解度	≥ 75.4mg/mL in DMSO, ≥ 75.4mg/mL in EtOH	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。
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。

溶解性数据

制备储备液
		1 mg	5 mg	10 mg
	1 mM	2.6423 mL	13.2114 mL	26.4229 mL
	5 mM	0.5285 mL	2.6423 mL	5.2846 mL
	10 mM	0.2642 mL	1.3211 mL	2.6423 mL

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Research Update

Cohen Syndrome: Review of the Literature

Cureus2018 Sep 18;10(9):e3330.PMID: 30473963DOI: 10.7759/cureus.3330

Cohen syndrome was initially described as a syndrome including obesity, hypotonia, mental deficiency, and facial, oral, ocular and limb anomalies. Leukopenia, especially neutropenia, was later described as a feature of Cohen syndrome. Cohen syndrome is caused by an autosomal recessive (AR) mutation of the vacuolar protein sorting 13 homolog B (VPS13B, also referred to as COH1) gene on chromosome 8q22.2.

Impact of the APE1 Redox Function Inhibitor E3330 in Non-small Cell Lung Cancer Cells Exposed to Cisplatin: Increased Cytotoxicity and Impairment of Cell Migration and Invasion

Antioxidants (Basel)2020 Jun 24;9(6):550.PMID: 32599967DOI: 10.3390/antiox9060550

Elevated expression levels of the apurinic/apyrimidinic endonuclease 1 (APE1) have been correlated with the more aggressive phenotypes and poor prognosis of non-small cell lung cancer (NSCLC). This study aimed to assess the impact of the inhibition of the redox function of APE1 with E3330 either alone or in combination with cisplatin in NSCLC cells. For this purpose, complementary endpoints focusing on cell viability, apoptosis, cell cycle distribution, and migration/invasion were studied. Cisplatin decreased the viability of H1975 cells in a time- and concentration-dependent manner, with IC₅₀ values of 9.6 ?M for crystal violet assay and 15.9 ?M for 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. E3330 was clearly cytotoxic for concentrations above 30 ?M. The co-incubation of E3330 and cisplatin significantly decreased cell viability compared to cisplatin alone. Regarding cell cycle distribution, cisplatin led to an increase in sub-G1, whereas the co-treatment with E3330 did not change this profile, which was then confirmed in terms of % apoptotic cells. In addition, the combination of E3330 and cisplatin at low concentrations decreased collective and chemotactic migration, and also chemoinvasion, by reducing these capabilities up to 20%. Overall, these results point to E3330 as a promising compound to boost cisplatin therapy that warrants further investigation in NSCLC.

Suppression of choroidal neovascularization through inhibition of APE1/Ref-1 redox activity

Invest Ophthalmol Vis Sci2014 Jun 26;55(7):4461-9.PMID: 24970265DOI: 10.1167/iovs.14-14451

Purpose: The redox function of APE1/Ref-1 is a key regulator in pathological angiogenesis, such as retinal neovascularization and tumor growth. In this study, we examined whether inhibition of APE1/Ref-1 redox function by a small molecule inhibitor E3330 suppresses experimental choroidal neovascularization (CNV) in vitro and in vivo.
Methods: Primate choroid endothelial cells (CECs) received treatment of 0 to 100 米M E3330 alone or cotreatment of E3330 and 500 米g/mL anti-VEGF antibody bevacizumab. Choroid endothelial cell angiogenic function was examined by cell proliferation, migration, and tube formation assays. The effects of E3330 on NF-百B and STAT3 signaling pathways were determined by reporter gene assay, Western blot, and ELISA. Laser-induced CNV mouse model was used to test the effects of E3330 in vivo. Potential toxicity of E3330 was evaluated by TUNEL assay.
Results: The E3330 of 25 to 100 米M dose-dependently suppressed CEC proliferation, migration, and tube formation, in the absence of noticeable cell toxicity. Lower doses of E3330 (10-20 米M) reduced the transcriptional activity of NF-百B and STAT3 without affecting protein phosphorylation of both molecules. At the same time, E3330 downregulated MCP-1 production in CECs. The antiangiogenic effect of E3330 was comparable and additive to bevacizumab. The E3330 effectively attenuated the progression of laser-induced CNV in mice after a single intravitreal injection.
Conclusions: The APE1/Ref-1 redox function regulates multiple transcription factors and inflammatory molecules, and is essential for CEC angiogenesis. Specific inhibition of APE1/Ref-1 redox function with E3330 may represent a promising novel treatment for wet AMD.

Protective effect of E3330, a novel quinone derivative, in galactosamine-induced hepatitis in rats

J Pharmacol Exp Ther1993 Jan;264(1):496-500.PMID: 8423547DOI: 10.1089/ars.2010.3410

The effect of E3330 ((2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2-++ +propenoic acid), a novel quinone derivative, was studied in the galactosamine-induced hepatitis model in F344 rats, in which endogenous endotoxin is believed to play a critical pathogenetic role. Subcutaneous injection of 300 mg/kg of galactosamine into rats resulted in liver injury. Oral treatment with E3330 (10-100 mg/kg) 1 hr after galactosamine challenge attenuated the liver injury. E3330 was also effective when administered p.o. 6 or 12 hr after galactosamine challenge. Subcutaneous injection of 1000 mg/kg of galactosamine into rats resulted in more severe liver injury with endotoxemia. The plasma endotoxin was detected 24 to 48 hr after the galactosamine challenge. The time course of increase in plasma endotoxin level was in good agreement with that in plasma aminotransferase activity. E3330 (100 mg/kg) significantly attenuated the liver injury, but did not affect the endotoxin level. Exogenous administration of endotoxin enhanced the hepatotoxicity of galactosamine. Pretreatment with E3330 also protected rats from severe liver injury induced with endotoxin plus galactosamine. These results suggest that E3330 may exert its hepatoprotective effects through inhibition of an effect of endotoxin in galactosamine-induced hepatitis in rats.

Functional analysis of novel analogues of E3330 that block the redox signaling activity of the multifunctional AP endonuclease/redox signaling enzyme APE1/Ref-1

Antioxid Redox Signal2011 Apr 15;14(8):1387-401.PMID: 20874257DOI: 10.1089/ars.2010.3410

APE1 is a multifunctional protein possessing DNA repair and redox activation of transcription factors. Blocking these functions leads to apoptosis, antiangiogenesis, cell-growth inhibition, and other effects, depending on which function is blocked. Because a selective inhibitor of the APE redox function has potential as a novel anticancer therapeutic, new analogues of E3330 were synthesized. Mass spectrometry was used to characterize the interactions of the analogues (RN8-51, 10-52, and 7-60) with APE1. RN10-52 and RN7-60 were found to react rapidly with APE1, forming covalent adducts, whereas RN8-51 reacted reversibly. Median inhibitory concentration (IC(50) values of all three compounds were significantly lower than that of E3330. EMSA, transactivation assays, and endothelial tube growth-inhibition analysis demonstrated the specificity of E3330 and its analogues in blocking the APE1 redox function and demonstrated that the analogues had up to a sixfold greater effect than did E3330. Studies using cancer cell lines demonstrated that E3330 and one analogue, RN8-51, decreased the cell line growth with little apoptosis, whereas the third, RN7-60, caused a dramatic effect. RN8-51 shows particular promise for further anticancer therapeutic development. This progress in synthesizing and isolating biologically active novel E3330 analogues that effectively inhibit the APE1 redox function validates the utility of further translational anticancer therapeutic development.

E3330

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