Glucose metabolism; glycolysis; hexokinase; HSV-1; Antimetabolites; Antiviral Agents； 2 - DG targets hexokinase. It can be phosphorylated by hexokinase to form 2 - DG - 6 - phosphate, which accumulates in cells and inhibits hexokinase activity, thus blocking glycolysis. It also competitively inhibits phosphoglucose isomerase as 2 - DG - 6 - phosphate can compete with fructose - 6 - phosphate for phosphoglucose isomerase.

In MCF-7 cells, 2-Deoxy-D-glucose (2-DG), 4, 8, or 16 mM, dramatically decreased ATP levels in a dose- and time-dependent manner that was comparable to the effect of 2-DG on cell growth. exposure to 4, 8 or 16 mM 2-Deoxy-D-glucose 1, 3 or for 5 days in a way that depends on the dose and the amount of time [1]. When 2-DG is administered, pentose phosphate pathway (PPP) responders are upregulated, and 6-phosphate endpoint dehydrogenase produces more NADPH. The 2-DG reduced form of glutathione is elevated in NB4 cells due to an increase in NADPH and an upregulation of glutathione synthetase expression [3].

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In mammary tumor cells, 2 - DG inhibits cell growth in a dose - and time - dependent manner. It reduces cell viability, blocks cell cycle progression at the G1/S phase, and induces apoptosis. The mechanism may be related to the inhibition of glycolysis, which leads to a decrease in ATP production and an increase in reactive oxygen species (ROS) levels [1]
In leukemia cells, 2 - DG disrupts the metabolic balance, leading to a decrease in glucose consumption and lactate production. It also causes a decrease in intracellular ATP levels and an increase in ROS, which may lead to cell death [3]

2-Deoxy-D-glucose (0.03%, w/w) postponed the possible beginning of breast cancer and led to a statistically significant 7% reduction in final body weight [1]. 2. During extraction, 2-Deoxy-D-glucose (3 mmol/kg, iv) is lowered in a dose-dependent manner [2].
Note: Despite the numerous preclinical and clinical studies, the use of 2-DG in cancer and viral treatment has been limited. Its rapid metabolism and short half-life (according to Hansen et al., after treatment with infusion of 50 mg/kg2-DG, its plasma half-life was only 48 min), make 2-DG a relatively poor drug candidate. Moreover, 2-DG must be given at relatively high concentrations (≥5 mmol/L) to compete with blood glucose. According to Stein et al., the dose of 45 mg/kg received orally on days 1–14 was defined as safe because patients did not experience any dose-limiting toxicities. Notably, at the dose of 60 mg/kg, two patients experienced dose-limiting toxicity of grade 3–asymptomatic QTc prolongation. According to former studies published by Burckhardt et al. and Stalder et al., among patients exposed to 2-DG, non-specific T wave flattening and QT prolongation, without any event of severe arrhythmia, developed.[4]

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In lipopolysaccharide/d - galactosamine (LPS/D - Gal) - induced lethal liver injury mouse models, 2 - DG treatment suppresses the elevation of plasma aminotransferases, alleviates histopathological abnormalities, and improves the survival rate of mice. It also suppresses the production of pro - apoptotic cytokine TNF - α, the phosphorylation of JNK, the activation of the caspase cascade, and the number of TUNEL - positive apoptotic hepatocytes [4]

ATP assay. The effect of 2-DG on ATP level in the cells was determined using an ENLITEN ATP assay kit (Promega Corporation, Kadison, WI), the bioluminescence was detected using a TD 20/20 luminometer (Turner Biosystem, Sunnyvale, CA), and the amount of ATP per well was standardized by the cell number estimated by crystal violet method described above.[1]

Using MCF-7 human breast cancer cells to investigate the signaling pathways perturbed by disruption of glucose metabolism, 2-DG reduced cell growth and intracellular ATP in a dose- and time-dependent manner (P < 0.01). Treatment with 2-DG increased levels of phosphorylated AMP-activated protein kinase and Sirt-1 and reduced phosphorylated Akt (P < 0.05). These studies support the hypothesis that DER inhibits carcinogenesis, in part, by limiting glucose availability and that energy metabolism is a target for the development of ERMA for chemoprevention.[1]

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For mammary tumor cells, different concentrations of 2 - DG are added to the cell culture medium, and the cells are cultured for different time periods (such as 24h, 48h, 72h). Then, the cell viability is detected by the MTT method, and the cell cycle is analyzed by flow cytometry using propidium iodide staining. Apoptosis is detected by Annexin V - FITC/PI double - staining and flow cytometry. Intracellular ATP levels are measured by a luciferase - based assay, and ROS levels are detected by fluorescent probes [1]
For leukemia cells, they are cultured in the presence of 2 - DG, and the glucose consumption and lactate production in the culture medium are measured at regular intervals. Intracellular ATP levels are detected by a luciferase - based assay, and ROS levels are detected by fluorescent probes [3]

For the carcinogenesis study, ninety 21-day-old female Sprague-Dawley rats were injected i.p. with 50 mg of 1-methyl-1-nitrosourea per kilogram of body weight. Following injection, animals were ad libitum fed AIN-93G diet containing 0.00%, 0.02%, or 0.03% (w/w) 2-DG for 5 weeks. 2-DG decreased the incidence and multiplicity of mammary carcinomas and prolonged cancer latency (P < 0.05). The 0.02% dose of 2-DG had no effect on circulating levels of glucose, insulin, insulin-like growth factor-I, IGF binding protein-3, leptin, or body weight gain. [1]

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In the LPS/D - Gal - induced liver injury mouse model, 2 - DG is dissolved in normal saline. Mice are intraperitoneally injected with 2 - DG at a dose of 200 mg/kg once a day for 7 consecutive days. The control group is injected with the same volume of normal saline. Then, the plasma aminotransferase levels are measured, and the liver tissue is used for histopathological examination and TUNEL staining to detect apoptosis [4]

Absorption, Distribution and Excretion
When using conventional clearance and shut-down techniques to study the excretion of 2-deoxyglucose in the kidneys of dogs and mice, it was found that the average reabsorption rate in the renal tubules was 68-89% of the filtration load, with the reabsorption site located in the proximal tubules. Metabolism/Metabolites Following daily intraperitoneal injection of 50 mg/kg body weight of 2-deoxy-D-glucose for 7 consecutive days, 2-deoxy-D-glucose was converted to 6-phosphate in the testes and liver of mice.

Interactions
Intraperitoneal injection of large doses of 2-deoxyglucose into rats caused changes in electroretinograms, with a decrease in both α and β waves. D-glucose antagonized this effect. Grant, WM, Ophthalmic Toxicology, 2nd ed., Springfield, Illinois: Charles C. Thomas, 1974, p. 353.
Simultaneous administration of glucose doses exceeding the maximum tubular transport capacity inhibited tubular reabsorption of 2-deoxyglucose. Therefore, the tubular reabsorption process may be the same as that of glucose reabsorption. WOOSLEY RL et al.; Tubular transport of 2-deoxy-D-glucose in dogs and rats; J PHARMACOL EXP THER 173(1) 13 (1970)
In anestrogenic sheep, 2-deoxyglucose infusion inhibited estradiol-induced LH release but had no inhibitory effect on LH-RH-induced LH release. CRUMP AD et al.; In sheep, estradiol-induced luteinizing hormone (LH) release was inhibited by 2-deoxyglucose infusion; J PHYSIOL (LONDON) 330: 93P (1982)
2-Deoxy-D-glucose inhibits the repair of X-ray-induced potentially lethal damage in mouse Ehrlich ascites tumor cells.

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Non-human toxicity excerpt
Intraperitoneal injection of high doses of 2-deoxyglucose in rats resulted in changes in electroretinograms, manifested as a decrease in both alpha and beta waves. Grant, WM, Ophthalmic Toxicology, 2nd ed., Springfield, Illinois: Charles C. Thomas Press, 1974, p. 93. 353
...120 mg/rat/day daily from day 9 to day 20 of gestation... Embryo resorption rate was 69%, and all surviving fetuses were malformed. No eye malformations, cleft lip and palate, or limb lesions were observed. No malformations were observed in surviving rat fetuses after administration of 1 g/kg body weight on days 8, 9, 10, or 11. Interactions Intraperitoneal injection of high doses of 2-deoxyglucose in rats resulted in changes in electroretinograms, manifested as a decrease in both alpha and beta waves. D-glucose antagonized this effect. Concomitant administration of glucose doses exceeding the rat's maximum tubular transport capacity inhibited tubular reabsorption of 2-deoxyglucose. Therefore, the tubular reabsorption process may be analogous to glucose reabsorption. In anestrus sheep, 2-deoxyglucose infusion inhibited estradiol-induced LH release but had no inhibitory effect on LH-RH-induced LH release. 2-Deoxy-D-glucose inhibited the repair of X-ray-induced potentially lethal damage in mouse Ehrlich ascites tumor cells. For more complete data on 2-deoxy-D-glucose interactions (6 in total), please visit the HSDB record page.

[1]. Zhu Z, et al. 2-Deoxyglucose as an energy restriction mimetic agent: effects on mammary carcinogenesis and on mammary tumor cell growth in vitro. Cancer Res. 2005 Aug 1;65(15):7023-30.
[2]. Ueyama A, et al. Nonradioisotope assay of glucose uptake activity in rat skeletal muscle using enzymatic measurement of 2-deoxyglucose 6-phosphate in vitro and in vivo. Biol Signals Recept. 2000 Sep-Oct;9(5):267-74.
[3]. Miwa H, et al. Leukemia cells demonstrate a different metabolic perturbation provoked by 2-deoxyglucose. Oncol Rep. 2013 May;29(5):2053-7
[4]. Int J Mol Sci. 2020 Jan; 21(1): 234.

2-Deoxy-D-glucose has been reported and data is available in Streptomyces nigra. 2-Deoxy-D-glucose is a non-metabolizable glucose analogue in which the hydroxyl group at the 2-position of glucose is replaced by a hydrogen atom, possessing potential glycolysis inhibitory and antitumor activities. Although its exact mechanism of action is not fully elucidated, after administration of 2-deoxy-D-glucose (2-DG), it competes with glucose for uptake by proliferating cells (e.g., tumor cells). 2-DG inhibits the first step of glycolysis, thereby preventing cellular energy production, which may lead to reduced tumor cell proliferation. 2-Deoxy-D-glucose is a metabolite found or produced in Saccharomyces cerevisiae. 2-Deoxy-D-arabinohexose is a glucose antimetabolite with antiviral activity.

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Therapeutic Use
Antimetabolites; Antiviral Drugs
Drugs (Veterinary): Topical treatment of female guinea pig genital herpes with agarose gel or miconazole nitrate ointment failed to prevent the occurrence of genital lesions or reduce the average titer of retrievable virus in vaginal swabs from infected animals.

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2-DG is a glucose analogue and the first proposed caloric restriction mimic. By inhibiting glycolysis, it can mimic the metabolic, hormonal, and physiological effects of caloric restriction and has beneficial effects on chronic pathological processes such as cancer, Alzheimer's disease, and Parkinson's disease. It can also protect rats from acute ischemic injury. Its inhibitory effect on glycolysis is of great significance for studying tumor cell metabolism and developing anticancer strategies [4].

C6H12O5

164.1565

164.068

C, 43.90; H, 7.37; O, 48.73

154-17-6

2-Deoxy-D-glucose-d;188004-07-1;2-Deoxy-D-glucose-13C;201612-55-7;2-Deoxy-D-glucose-13C-1;119897-50-6

108223

White to off-white solid powder

1.4±0.1 g/cm3

456.7±45.0 °C at 760 mmHg

146-147ºC

244.1±25.2 °C

0.0±2.5 mmHg at 25°C

1.534

Endogenous metabolite

-3.07

4

5

5

11

116

3

O([H])[C@]([H])([C@@]([H])(C([H])([H])O[H])O[H])[C@@]([H])(C([H])([H])C([H])=O)O[H]

VRYALKFFQXWPIH-PBXRRBTRSA-N

InChI=1S/C6H12O5/c7-2-1-4(9)6(11)5(10)3-8/h2,4-6,8-11H,1,3H2/t4-,5-,6+/m1/s1

2-Deoxy-D-arabinohexose

2-deoxy-D-glucose; Deoxyglucose; 154-17-6; 2-Deoxy-D-arabino-hexose; 2-Desoxy-D-glucose; 2-DG; (3R,4S,5R)-3,4,5,6-tetrahydroxyhexanal; 2-Deoxy-D-mannose;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ≥ 24 mg/mL (~146.20 mM)

Solubility in Formulation 1: 130 mg/mL (791.91 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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Solubility in Formulation 2: ~130 mg/mL (~792 mM) in PBS

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 (Please use freshly prepared in vivo formulations for optimal results.)