6-diazo-5-oxo-L-nor-Leucine
(Synonyms: 6-重氮-5-氧代-L-正亮氨酸; L-6-Diazo-5-oxonorleucine; DON) 目录号 : GC412246-Diazo-5-oxo-L-nor-Leucine (DON)是一种抑制谷氨酰胺酶的谷氨酰胺类似物,是一种选择性的、基于机制的谷氨酰胺酶失活剂。
Cas No.:157-03-9
Sample solution is provided at 25 µL, 10mM.
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| Cell experiment [1]: | |
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Cell lines |
MC38 cells |
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Preparation Method |
Tumor cells treated with increasing concentrations of 6-Diazo-5-oxo-L-nor-Leucine for 48h. |
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Reaction Conditions |
10-2µM-102µM ;48h |
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Applications |
6-Diazo-5-oxo-L-nor-Leucine inhibited cell proliferation, and the inhibitory effect increased with the increase of concentration. |
| Animal experiment [2]: | |
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Animal models |
Female athymic nude (nu/J) mice (pancreatic cancer cells S2VP10) |
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Preparation Method |
The tumors reached a size of 100 mm and were given to 6-Diazo-5-oxo-L-nor-Leucine at the end of the 4th week, and the mice were killed. |
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Dosage form |
1 mg/kg;5 days a week |
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Applications |
Treatment with 6-Diazo-5-oxo-L-nor-Leucine decreased tumor progression as well as end-of-study tumor weight and volume. |
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References: [1]. Leone RD, Zhao L, et,al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019 Nov 22;366(6468):1013-1021. doi: 10.1126/science.aav2588. Epub 2019 Nov 7. PMID: 31699883; PMCID: PMC7023461. |
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6-Diazo-5-oxo-L-nor-Leucine (DON) is a glutamine analog that inhibits glutaminases, a selective, mechanism-based inactivator of glutamine-using enzymes[1-3].
6-Diazo-5-oxo-L-nor-Leucine(10-2µM-102µM ;48h) inhibited cell proliferation, and the inhibitory effect increased with the increase of concentration[4]. 6-Diazo-5-oxo-L-nor-Leucine (0.3 mM; 1 h) inhibited glutamine catabolism in WI-L2 cells[1].Treatment with 6-Diazo-5-oxo-L-nor-Leucine at 50 µM decreased colony formation in S2VP10 cells[5].
6-Diazo-5-oxo-L-nor-Leucine(1 mg/kg;5 days a week)decreased tumor progression as well as end-of-study tumor weight and volume[6].6-Diazo-5-oxo-l-norleucine as a Glutaminase(GLS) inhibitor that produces long lasting pain relief when applied to the inflamed paw of arthritic rats, DOX(2mM, 0.05ml;2times) can reduce the increase of the skin for vesicular transporters (VGluT2), GLS and glutamate immunoreactivity (IR) caused by surgery in a post-incisional model[7,8].
References:
[1]. Willis RC, Seegmiller JE. The inhibition by 6-diazo-5-oxo-l-norleucine of glutamine catabolism of the cultured human lymphoblast. J Cell Physiol. 1977 Dec;93(3):375-82. doi: 10.1002/jcp.1040930308. PMID: 22551.
[2]. Thangavelu K, Pan CQ, et,al. Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism. Proc Natl Acad Sci U S A. 2012 May 15;109(20):7705-10. doi: 10.1073/pnas.1116573109. Epub 2012 Apr 26. PMID: 22538822; PMCID: PMC3356676.
[3]. Rais R, Lemberg KM, et,al. Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci Adv. 2022 Nov 18;8(46):eabq5925. doi: 10.1126/sciadv.abq5925. Epub 2022 Nov 16. PMID: 36383674; PMCID: PMC9668306.
[4]. Leone RD, Zhao L, et,al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019 Nov 22;366(6468):1013-1021. doi: 10.1126/science.aav2588. Epub 2019 Nov 7. PMID: 31699883; PMCID: PMC7023461.
[5]. Sharma NS, Gupta VK, et,al. Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J Clin Invest. 2020 Jan 2;130(1):451-465. doi: 10.1172/JCI127515. PMID: 31613799; PMCID: PMC6934212.
[6]. Sharma NS, Gupta VK, et,al. Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J Clin Invest. 2020 Jan 2;130(1):451-465. doi: 10.1172/JCI127515. PMID: 31613799; PMCID: PMC6934212.
[7]. Crosby HA, Miller KE. Evaluating the Analgesic Effect of the GLS Inhibitor 6-Diazo-5-Oxo-L-Norleucine in Vivo. Pharm Pharmacol Int J. 2016;3(3):00055. doi: 10.15406/ppij.2015.03.00055. Epub 2016 Jan 8. PMID: 29888760; PMCID: PMC5993434.
[8]. Miller KE, Hoffman EM, et,al. Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms. Pharmacol Ther. 2011 Jun;130(3):283-309. doi: 10.1016/j.pharmthera.2011.01.005. Epub 2011 Jan 26. PMID: 21276816; PMCID: PMC5937940.
6-Diazo-5-oxo-L-nor-Leucine (DON)是一种抑制谷氨酰胺酶的谷氨酰胺类似物,是一种选择性的、基于机制的谷氨酰胺酶失活剂[1-3]。
6-Diazo-5-oxo-L-nor-Leucine(10-2µM-102µM;48h)对细胞增殖有抑制作用,且抑制作用随浓度的增加而增强[4]。6-Diazo-5-oxo-L-nor-Leucine(0.3 mM;1 h)抑制WI-L2细胞谷氨酰胺分解代谢[1]。6-Diazo-5-oxo-L-nor-Leucine在50 µM下处理可减少S2VP10细胞的集落形成[5]。
6-Diazo-5-oxo-L-nor-Leucine (1 mg/kg,5 days a week)可降低肿瘤进展以及肿瘤的重量和体积[6]。6-Diazo-5-oxo-L-nor-Leucine作为谷氨酰胺酶抑制剂,应用于关节炎大鼠炎症足部,6-Diazo-5-oxo-L-nor-Leucine(2mM, 0.05ml;2times)可降低小鼠切口手术引起的皮肤中囊泡膜谷氨酸转运体、谷氨酰胺酶和谷氨酸免疫反应性(IR)的增加[7,8]。
| Cas No. | 157-03-9 | SDF | |
| 别名 | 6-重氮-5-氧代-L-正亮氨酸; L-6-Diazo-5-oxonorleucine; DON | ||
| 化学名 | 6-diazo-5-oxo-L-norleucine | ||
| Canonical SMILES | OC([C@@H](N)CCC(C=[N+]=[N-])=O)=O | ||
| 分子式 | C6H9N3O3 | 分子量 | 171.2 |
| 溶解度 | >1mg/mL in DMSO, >10mg/mL in Water(Need warm the tube at 50 ℃ and shake it in the ultrasonic bath for a while) | 储存条件 | Store at -20°C,protect from light, stored under nitrogen |
| 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。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 5.8411 mL | 29.2056 mL | 58.4112 mL |
| 5 mM | 1.1682 mL | 5.8411 mL | 11.6822 mL |
| 10 mM | 0.5841 mL | 2.9206 mL | 5.8411 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 | ||||||||||
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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，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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The control of adrenocortical cytodifferentiation by extracellular matrix
Differentiation 1980;17(2):93-103.PMID:6256247DOI:10.1111/j.1432-0436.1980.tb01085.x
Adult rat adrenal cortical cells maintained in medium supplemented with horse serum (HS) from cohesive epithelial islands secrete large amounts of corticosterone. Such cells do not produce detectable extracellular material (ECM) and are not motile. Cultures exposed to fetal calf serum supplements (FCS) produce metachromatic ECM, modulate to a fibroblastic morphology, and become motile. Within 24 h, steroid production by these cells drop 100-fold. Cells now resemble myofibroblastic "stem" cells of the adrenal cortical capsule, and express structural and functional bimorphism by exhibiting a myofibroblastic phenotype while retaining responsiveness to adrenocorticotropic hormone (ACTH) and limited corticosteroid secreting capacity. Exposure of the myofibroblastic cells to ACTH in FCS overrides the effect of FSC: ECM disappears, steroid production increases several fold, and cells develop an epithelial morphology. The possibility that ECM produced in response to FCS may be responsible for the alteration from a highly differentiated, non-motile adrenocortical cell to a less differentiated, motile adrenocortical stem cell was investigated by inhibition studies using 6-diazo-5-oxo-L-nor-Leucine (DON) and by exogenously added components of ECM. DON, a glutamine analogue, inhibited the synthesis of metachromatic ECM in FCS, and prevented the modulation to a fibroblastic morphology, onset of motility, and decrease in steroid production. Addition of hyaluronic acid, but not of chondroitin sulfate, to the epithelioid secretory cells promoted a drop in steroid production and slight alteration in morphology and movement. Both results are consistent with the possibility that metachromatic ECM production is responsible for the reversion of the steroid secretory to the myofibroblastic phenotype. This effect was mimicked by maintaining cells on polystyrene surfaces that were sulfonated to a negative charge density similar to that of ECM. This result implies that the negative charge of ECM may contribute to the expression of the adrenocortical stem cell phenotype, and that its effect is extracellular. A possible physiologic role for ECM-mediated control of adrenal cortical differentiation is proposed.