6-diazo-5-oxo-L-nor-Leucine|157-03-9|安捷凯

Background

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].

参考文献:
[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]。

Protocol

Cell experiment [1]:

Cell lines

MC38 cells

Preparation Method

Tumor cells treated with increasing concentrations of 6-Diazo-5-oxo-L-nor-Leucine for 48h.

Reaction Conditions

10^-2μM-10²μM ;48h

Applications

6-Diazo-5-oxo-L-nor-Leucine inhibited cell proliferation, and the inhibitory effect increased with the increase of concentration.

Animal experiment [2]:

Animal models

Female athymic nude (nu/J) mice (pancreatic cancer cells S2VP10)

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.

Dosage form

1 mg/kg;5 days a week

Applications

Treatment with 6-Diazo-5-oxo-L-nor-Leucine decreased tumor progression as well as end-of-study tumor weight and volume.

参考文献:

[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.
[2].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.

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生命科学

有机化学

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材料科学

6-diazo-5-oxo-L-nor-Leucine

6-diazo-5-oxo-L-nor-Leucine详情

Background

Protocol

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