R-7050
(Synonyms: TNF-α Antagonist III) 目录号 : GC11659
R-7050 是一种新型细胞渗透性三唑并喹喔啉化合物，可选择性抑制 TNF-α；诱导细胞信号传导。
Cas No.:303997-35-5
Sample solution is provided at 25 µL, 10mM.
R-7050 is a novel cell-permeable triazoloquinoxaline compound that selectively inhibited TNF-α induced cellular signaling[2].
In RBL-2H3 cells R-7050 significantly reduced TNF proliferation when autophagy was also inhibited by Baf-A1[7].CA to reduce cell viability in MDA-MB-231 breast cancer cells and tumorigenic HEK 293 cells but not in normal NIH3T3 fibroblast cells. Abundance of TNFA, TNF Receptor 1 (TNFR1) and cleaved caspase-8/-3 proapoptotic proteins to increase with CA treatment. Blocking of TNFA-TNFR1 signalling by small molecule inhibitor, R-7050, reduced the expression of cleaved caspase-8 and caspase-3 at the protein level[3]. TRPA1 channel was positively expressed in the cell bodies and processes of HODs. The expression TRPA1 channel was significantly up-regulated by high concentration of TNF-α, which could be suppressed by R-7050[5].
A single administration of R-7050 reduced neurovascular injury after ICH. In contrast to biologic approaches that directly bind and neutralize TNF-α activity, R-7050 selectively inhibits the association of TNFR with intracellular adaptor molecules, such as TRADD and RIP1, limiting receptor internalization and preventing subsequent cellular responses after TNF-α binding[1]. Capsaicin, a selective TRPV1 agonist, increased ipsilateral afferent renal nerve activity in WT but not TRPV1-/- mice. WD intake increased leptin, IL-6, and TNF-α in adipose tissue, and TNF-α antagonist III, R-7050, decreased leptin in TRPV1-/--WD. The urinary albumin level was higher in TRPV1-/--WD than WT-WD[4]. Treatment with the TNF receptor-1 inhibitor R-7050 during nephrotoxic serum nephritis reduced damage, fibrosis, and necroptosis in wild-type mice and mice with KLF4-deficient macrophages, and abrogated the differences between the two groups in these parameters[6].
References:
[1]. King MD, Alleyne CH Jr,et,al. TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett. 2013 May 10;542:92-6. doi: 10.1016/j.neulet.2013.02.051. Epub 2013 Mar 7. PMID: 23499961; PMCID: PMC3744337.
[2]. Gururaja TL, Yung S, et,al. A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1. Chem Biol. 2007 Oct;14(10):1105-18. doi: 10.1016/j.chembiol.2007.08.012. PMID: 17961823.
[3]. Pal A, Tapadar P, Pal R. Exploring the Molecular Mechanism of Cinnamic Acid-Mediated Cytotoxicity in Triple Negative MDA-MB-231 Breast Cancer Cells. Anticancer Agents Med Chem. 2021;21(9):1141-1150. doi: 10.2174/1871520620666200807222248. PMID: 32767960.
[4]. Zhong B, Ma S, et,al. Ablation of TRPV1 Elevates Nocturnal Blood Pressure in Western Diet-fed Mice. Curr Hypertens Rev. 2019;15(2):144-153. doi: 10.2174/1573402114666181031141840. PMID: 30381083; PMCID: PMC6635649.
[5]. Liu J, Que K, et,al. Tumor Necrosis Factor-α Regulates the TRPA1 Expression in Human Odontoblast-Like Cells. J Pain Res. 2020 Jul 6;13:1655-1664. doi: 10.2147/JPR.S255288. PMID: 32753941; PMCID: PMC7352379.
[6]. Wen Y, Lu X, et,al. KLF4 in Macrophages Attenuates TNFα-Mediated Kidney Injury and Fibrosis. J Am Soc Nephrol. 2019 Oct;30(10):1925-1938. doi: 10.1681/ASN.2019020111. Epub 2019 Jul 23. PMID: 31337692; PMCID: PMC6779357.
[7]. Ayo TE, Adhikari P, et,al. TNF Production in Activated RBL-2H3 Cells Requires Munc13-4. Inflammation. 2020 Apr;43(2):744-751. doi: 10.1007/s10753-019-01161-4. PMID: 31897916; PMCID: PMC7176528.
R-7050 是一种新型细胞渗透性三唑并喹喔啉化合物，可选择性抑制 TNF-α；诱导细胞信号传导[2]。
在 RBL-2H3 细胞中，当自噬也被 Baf-A1 抑制时，R-7050 显着降低 TNF 增殖[7].CA 降低 MDA-MB-231 乳腺癌细胞和致瘤性 HEK 293 细胞的细胞活力，但不影响正常的 NIH3T3 成纤维细胞。 TNFA、TNF 受体 1 (TNFR1) 和裂解的 caspase-8/-3 促凋亡蛋白的丰度随着 CA 处理而增加。小分子抑制剂 R-7050 阻断 TNFA-TNFR1 信号通路，在蛋白质水平上降低了裂解的 caspase-8 和 caspase-3 的表达[3]。 TRPA1通道在HODs的细胞体和过程中呈阳性表达。高浓度 TNF-α 可显着上调 TRPA1 通道的表达，并可被 R-7050[5] 抑制。
单次施用 R-7050 可减少 ICH 后的神经血管损伤。与直接结合和中和 TNF-α 的生物学方法相反；活性，R-7050 选择性抑制 TNFR 与细胞内衔接分子（如 TRADD 和 RIP1）的结合，限制受体内化并阻止 TNF-α 后的后续细胞反应；绑定[1]。辣椒素是一种选择性 TRPV1 激动剂，可增加 WT 而非 TRPV1-/- 小鼠的同侧传入肾神经活动。 WD 摄入增加了瘦素、IL-6 和 TNF-α；在脂肪组织中，和 TNF-α；拮抗剂 III，R-7050，减少 TRPV1-/-WD 中的瘦素。 TRPV1-/--WD组的尿白蛋白水平高于WT-WD[4]。在肾毒性血清肾炎期间使用 TNF 受体 1 抑制剂 R-7050 治疗可减少野生型小鼠和 KLF4 缺陷型巨噬细胞小鼠的损伤、纤维化和坏死性凋亡，并消除两组在这些参数上的差异[ 6].
| Kinase experiment [1]: | |
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Preparation Method |
A549 cells plated. The next day, compound library(including R-7050) prepared were added at a final concentration of 10 μM in 0.2% (v/v) DMSO. Cells were preincubated with compounds for 1 hr prior to a 4 hr stimulation with either TNFα or IL-1β. |
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Reaction Conditions |
10 μM R-7050 and cell for 1h |
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Applications |
In TNFα-induced ICAM-1 expression, R-7050 inhibition potency (EC50 = 0.63 μM) was 2- to 3-fold greater than EC50 for IL-1β-induced ICAM-1 expression (1.45 μM). |
| Cell experiment [2]: | |
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Cell lines |
Wild-type RBL-2H3 cells |
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Preparation Method |
Wherever indicated, 6.7 μM of R-7050 (dissolved in DMSO) or 0.1 μM of bafilomycin A1 was added along with anti-TNP IgE during sensitization. |
|
Reaction Conditions |
6.7 μM R-7050 |
|
Applications |
R-7050 significantly reduced TNF proliferation when autophagy was also inhibited by Baf-A1. |
| Animal experiment [3]: | |
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Animal models |
Male CD-1 mice (8–10 weeks old) |
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Preparation Method |
R-7050 (6–18 mg/kg) was administered via intraperitoneal route at the time of injury or up to 2 h post-ICH. |
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Dosage form |
6–18 mg/kg R-7050 for 0.5-2h |
|
Applications |
R-7050 attenuates neurovascular injury after ICH. |
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References: [1]. Gururaja TL, Yung S, Ding R, Huang J, Zhou X, McLaughlin J, Daniel-Issakani S, Singh R, Cooper RD, Payan DG, Masuda ES, Kinoshita T. A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1. Chem Biol. 2007 Oct;14(10):1105-18. doi: 10.1016/j.chembiol.2007.08.012. PMID: 17961823. [2]. Ayo TE, Adhikari P, et,al. TNF Production in Activated RBL-2H3 Cells Requires Munc13-4. Inflammation. 2020 Apr;43(2):744-751. doi: 10.1007/s10753-019-01161-4. PMID: 31897916; PMCID: PMC7176528. [3]. King MD, Alleyne CH Jr, Dhandapani KM. TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett. 2013 May 10;542:92-6. doi: 10.1016/j.neulet.2013.02.051. Epub 2013 Mar 7. PMID: 23499961; PMCID: PMC3744337. |
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| Cas No. | 303997-35-5 | SDF | |
| 别名 | TNF-α Antagonist III | ||
| 化学名 | 8-chloro-4-(phenylthio)-1-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]quinoxaline | ||
| Canonical SMILES | ClC1=CC(N2C3=NN=C2C(F)(F)F)=C(C=C1)N=C3SC4=CC=CC=C4 | ||
| 分子式 | C16H8ClF3N4S | 分子量 | 380.8 |
| 溶解度 | DMSO (warmed with 50ºC water bath) 9 mg/mL (23.64 mM) ;DMF: 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。 | ||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6261 mL | 13.1303 mL | 26.2605 mL |
| 5 mM | 0.5252 mL | 2.6261 mL | 5.2521 mL |
| 10 mM | 0.2626 mL | 1.313 mL | 2.6261 mL |
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| 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，
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1. 首先保证母液是澄清的；
2.
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