2-Deoxy-D-glucose

• Molecular FormulaC₆H₁₂O₅
• Average mass164.156 Da

2-Deoxy-D-glucose(4R,5S,6R)-6-(Hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol(4R,5S,6R)-6-(Hydroxyméthyl)tétrahydro-2H-pyran-2,4,5-triol154-17-6[RN]2-Deoxy-D-arabino-hexopyranose2-deoxy-D-glucopyranose2-deoxyglucose
2-DGD-arabino-2-DesoxyhexoseD-arabino-Hexopyranose, 2-deoxy- [(4R,5S,6R)-6-(Hydroxymethyl)oxane-2,4,5-triol2-deoxyglucopyranose2-deoxymannopyranose2-dGlc61-58-5 [RN]77252-38-1 [RN]D-arabino-2-Deoxyhexoseglucitol, 2,5-anhydro-
2-Deoxy-D-glucoseCAS Registry Number: 154-17-6CAS Name: 2-Deoxy-D-arabino-hexoseAdditional Names: D-arabino-2-desoxyhexose; 2-deoxyglucose; 2-DGManufacturers’ Codes: Ba-2758Molecular Formula: C6H12O5Molecular Weight: 164.16Percent Composition: C 43.90%, H 7.37%, O 48.73%Literature References: Antimetabolite of glucose, q.v., with antiviral activity.
Synthesis: M. Bergmann et al.,Ber.55, 158 (1922); 56, 1052 (1923); J. C. Sowden, H. O. L. Fischer, J. Am. Chem. Soc.69, 1048 (1947); H. R. Bolliger, Helv. Chim. Acta34, 989 (1954); H. R. Bolliger, M. D. Schmid, ibid. 1597, 1671; H. R. Bolliger, “2-Deoxy-D-arabino-hexose (2-Deoxy-D-glucose)” in Methods in Carbohydrate Chemistryvol. I, R. L. Whistler, M. L. Wolfrom, Eds. (Academic Press, New York, 1962) pp 186-189.
Inhibition of influenza virus multiplication: E. D. Kilbourne, Nature183, 271 (1959).
Effects on herpes simplex virus: R. J. Courtney et al.,Virology52, 447 (1973). Mechanism of action studies: M. R. Steiner et al.,Biochem. Biophys. Res. Commun.61, 745 (1974); E. K. Ray et al.,Virology58, 118 (1978). Use in human genital herpes infections: H. A. Blough, R. L. Giuntoli, J. Am. Med. Assoc.241, 2798 (1979); L. Corey, K. K. Holmes, ibid.243, 29 (1980). Effect vs respiratory syncytial viral infections in calves: S. B. Mohanty et al.,Am. J. Vet. Res.42, 336 (1981).Properties: Cryst from acetone or butanone, mp 142-144°. [a]D17.5 +38.3° (35 min) ®+45.9° (c = 0.52 in water); +22.8° (24 hrs) ® +80.8° (c = 0.57 in pyridine).Melting point: mp 142-144°Optical Rotation: [a]D17.5 +38.3° (35 min) ®+45.9° (c = 0.52 in water); +22.8° (24 hrs) ® +80.8° (c = 0.57 in pyridine) Derivative Type: a-FormProperties: Cryst from isopropanol, mp 134-136°. [a]D26 +156° ® +103° (c = 0.9 in pyridine).Melting point: mp 134-136°Optical Rotation: [a]D26 +156° ® +103° (c = 0.9 in pyridine) Use: Exptlly as an antiviral agent.

2-Deoxy-d-glucose is a glucose molecule which has the 2-hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. As such; it acts to competitively inhibit the production of glucose-6-phosphate from glucose at the phosphoglucoisomerase level (step 2 of glycolysis).^[2] In most cells, glucose hexokinase phosphorylates 2-deoxyglucose, trapping the product 2-deoxyglucose-6-phosphate intracellularly (with exception of liver and kidney)^[; thus, labelled forms of 2-deoxyglucose serve as a good marker for tissue glucose uptake and hexokinase activity. Many cancers have elevated glucose uptake and hexokinase levels. 2-Deoxyglucose labeled with tritium or carbon-14 has been a popular ligand for laboratory research in animal models, where distribution is assessed by tissue-slicing followed by autoradiography, sometimes in tandem with either conventional or electron microscopy.

2-DG is uptaken by the glucose transporters of the cell. Therefore, cells with higher glucose uptake, for example tumor cells, have also a higher uptake of 2-DG. Since 2-DG hampers cell growth, its use as a tumor therapeutic has been suggested, and in fact, 2-DG is in clinical trials. ^[3] A recent clinical trial showed 2-DG can be tolerated at a dose of 63 mg/kg/day, however the observed cardiac side-effects (prolongation of the Q-T interval) at this dose and the fact that a majority of patients’ (66%) cancer progressed casts doubt on the feasibility of this reagent for further clinical use.^[4] However, it is not completely clear how 2-DG inhibits cell growth. The fact that glycolysis is inhibited by 2-DG, seems not to be sufficient to explain why 2-DG treated cells stop growing.^[5] Because of its structural similarity to mannose, 2DG has the potential to inhibit N-glycosylation in mammalian cells and other systems, and as such induces ER stress and the Unfolded Protein Response (UPR) pathway.^[6][7][8]

Clinicians have noted that 2-DG is metabolised in the pentose phosphate pathway in red blood cells at least, although the significance of this for other cell types and for cancer treatment in general is unclear.

Work on the ketogenic diet as a treatment for epilepsy have investigated the role of glycolysis in the disease. 2-Deoxyglucose has been proposed by Garriga-Canut et al. as a mimic for the ketogenic diet, and shows great promise as a new anti-epileptic drug.^[9][10] The authors suggest that 2-DG works, in part, by increasing the expression of Brain-derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Arc (protein) (ARC), and Basic fibroblast growth factor (FGF2).^[11] Such uses are complicated by the fact that 2-deoxyglucose does have some toxicity.

A study found that by combining the sugar 2-deoxy-D-glucose (2-DG) with fenofibrate, a compound that has been safely used in humans for more than 40 years to lower cholesterol and triglycerides, an entire tumor could effectively be targeted without the use of toxic chemotherapy.^[12][13]

2-DG has been used as a targeted optical imaging agent for fluorescent in vivo imaging.^[14][15] In clinical medical imaging (PET scanning), fluorodeoxyglucose is used, where one of the 2-hydrogens of 2-deoxy-D-glucose is replaced with the positron-emitting isotope fluorine-18, which emits paired gamma rays, allowing distribution of the tracer to be imaged by external gamma camera(s). This is increasingly done in tandem with a CT function which is part of the same PET/CT machine, to allow better localization of small-volume tissue glucose-uptake differences.

Resistance to 2-DG has been reported in HeLa cells ^[16] and in yeast;^[17][8] in the latter, it involves the detoxification of a metabolite derived from 2-DG (2DG-6-phosphate) by a phosphatase. Despite the existence of such a phosphatase in human (named HDHD1A) However it is unclear whether it contributes to the resistance of human cells to 2DG or affects FDG-based imaging.

PATENT

https://patents.google.com/patent/US6933382B2/en2-deoxy-D-glucose is useful in control of respiratory infections and for application as an antiviral agent for treatment of human genital herpes.Prior art for preparation of 2-deoxy-D-glucose while operable, tend to be expensive and time consuming. Reference may be made to Bergmann M., Schotte, H., Lechinsky, W., Ber, 55, 158 (1922) and Bergmann, M., Schotte, H., Lechinsky, W., Ber 56, 1052 (1923) which disclose the preparation of 2-deoxy-D-glucose in low yield by mineral acid catalyzed addition of water to D-glucal. Another method of producing 2-deoxy-D-glucose is from diethyldithioacetal derivative of D-glucose (Bolliger, H. R. Schmid, M. D., Helv. Chim. Acta 34, 989 (1951); Bolliger, H. R., Schmid, M. D., Helv, Chim. Acta 34, 1597 (1951); Bolliger, H. R Schmid, M. D., Helv. Chim. Acta 34, 1671 (1951) and from D-arabinose by reaction with nitromethane followed by acetylation, reduction and hydrolysis (Sowden, J. C., Fisher, H. O. L., J. Am. Chem., 69, 1048 (1947). However these methods result in the formation of 2-deoxy-D-glucose in low yield and of inferior purity due to the formation of several by-products and involve use of toxic reagents such as ethanethiol and nitromethane. As a result purification of 2-deoxy-D-glucose has to be done by recrystallisation which is tedious, time consuming and difficult.

EXAMPLE 1To a solution of 3,4,6-tri-O-benzyl-D-glucal (39 g, 0.09 mmol) in dichloromethane (20 ml) and methanol (100 ml) was added N-bromosuccinimide (18.7 g, 0.09 mil) during 10 min. at room temperature and stirred for 4 h. After completion of the reaction solvent was distilled off. The resultant residue extracted into carbon tetrachloride (2×100 ml) and organic phase concentrated to obtain methyl 2-bromo 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-gluco-/mannopyranoside as a syrup. Quantity obtained 50 g. ¹H NMR (200 MHz, CDCl₃) 3.40-4.00 (m, 7H, H-2,5,6,6′ and OCH₃) 4.30-5.10 (m, 9H, H-1,3,4 and 3×PhCH₂O), 7.10-7.60 (m 15H, Ar—H). A solution of methyl 2-bromo-2-deoxy-3,4,6-tri-O-benzyl/α/β-D-gluco-/mannopyranoside (50 g) in methanol (300) was charged into one liter autoclave along with Raney nickel (10 ml) Et₃N (135 ml) and subjected to hydrogenation at 120 psi pressure at 50° C. for 8 h. After completion of the reaction the catalyst was filtered off and the residue washed with methanol (25 ml). The filtrate was concentrate to obtain methyl 2-deoxy-3,4,6-tri-O-benzyl-α/β-D-glucopyranoside as a syrup (37.9 g, 89%). ¹H NMR (200 MHz CDCl₃): δ 1.50-2.40 (m,2H,H-2,2′), 3.32, 3.51 (2s, 3H, OCH₃) 3.55-4.00 (m, 5, H-3,4,5,6,6′) 4.30-5.00 (M 7H, 3×PhCH₂, H-1), 7.10-7.45 (m, 15H, Ar—H). The syrup of methyl 2-deoxy-3,4, 6-tri-O-benzyl-α/β-D-glucopyranoside (37.9 g) was dissolved in methanol (200 ml). 1 g of 5% Pd/C was added and hydrogenated at 150 psi pressure at room temperature. After 5 hours catalyst was filtered off and solvent evaporated. Quantity of the methyl 2-deoxy-α/β-D-glucopyranoside obtained 10.5 g (70%). [α]_D+25.7° (c 1.0, MeOH), ¹H NMR (200 MHz, D₂O); δ 1.45-2.40 (m, 2H, H-2,2′) 3.20-4.80, (m 9H, H-1,3,4,5,6,6′—OCH₃).EXAMPLE 2To a solution of D-glucal (64.6 g, 0.44 mmol) in methanol (325 ml) at 10° C. was added N-bromosuccinimide (78.7 g, 0.44 mol) during 40 min. maintaining the temperature between 10-15° C. during the addition. The reaction mixture was stirred at room temperature. After 5 hours solvent was evaporated to obtain a residue which was refluxed in ethyl acetate (100 ml). Ethyl acetate layer was discarded to leave a residue of methyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside (105 g) as a syrup. [α]_D+36° (c 1.0, MeOH). ¹H NMR (200 MHz, D₂O): δ 3.47, 3.67 (2s, 3H, OCH₃), 3.70-4.05 (m, 6h, H-2,3,4,5,6,6′), 4.48-5.13 (2₈, 1H, 1H, H-1). The syrupy methyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside was dissolved in methanol (400 ml), a slurry of 80 g Raney nickel (a 50% slurry in methanol), Et₃N (30 ml) and hydrogenated in a Parr apparatus at 120 psi. After 8-9 hours, the reaction mixture was filtered through a Celite filter pad and washed with MeOH. The washings and filtrate were combined and triturated with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and traces of succinimide. The filtrate was concentrated to a residue. The isolated yield of methyl 2-deoxy-α/β-D-glucopyranoside was 89%.Ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside:When solvent was ethanol instead of methanol the compound obtained was ethyl 2-bromo-2deoxy-α/β-D-gluco-/mannopyranoside. ¹H NMR (200 MHz, D₂O): δ 1.10-1.32 (m, 3H, CH₃), 2.80 (s, 4H, —CO(CH₂)₂CO—NH—), 3.40-4.10 (m, 8H, H-2,3,4,5,6,6′, CH₂), 4.40, 5.20 (2s 1H, H-1, α/β).Isopropyl 2-bromo-2-deoxy-α/β-D-gluco-/mannopyranoside:When isopropanol instead of methanol was used as a solvent the compound obtained was isopropyl 2-bromo-2-deoxy-α/β-D-gluco/mannopyranoside, ¹H NMR (200 MHz, D₂O): δ 1.10-1.30 (m, 6H, 2×CH₃) 2.80 (s, 4H, —CO(CH₂)₂CO—NH—), 3.60-4.60 (m 8H,H-2,3,4,5,6,6′, CH₂) 4.40, 5,30 (2s, 1H, H-1, α/β.EXAMPLE 3A mixture of D-glucal (64.6 g), methanol (400 ml), N-bromosuccinimide (79 g) were stirred at 15° C. for 6 h. The reaction mixture was hydrogenated in a Parr apparatus in presence of 60 g of Raney nickel catalyst (a 50% slurry in methanol) and triethylamine (62 ml). After 8-9 h, the reaction mixture was filtered on a Celite filter pad. The Celite pad was washed with methanol. The washings and filtrate were combined, concentrated to a thick heavy syrup, dissolve in chloroform (500 ml), pyridine (400 ml) and acetic anhydride (251 ml) was added while stirring, maintaining the temperature between 5-10° C. After 12 hours, the reaction mixture was diluted with CHCl₃ (500 ml) transferred to a separating funnel and organic phase was washed with water. The organic phase was separated, dried (Na₂SO₄) and concentrated to obtain methyl 2-deoxy-3,4,6-tri-O-acetyl-2 deoxy-α/β-D-glucopyranoside as a syrup (163.43 g, 87%). [α]_D+65.0° (c 1.0, CHCl₃) ¹H NMR (200 MHz, CDCl₃): δ 1.55-1.90 (m, 2H, H-22′), 2.01, 2.04, 2.11, 2.15, (4s, 9H, 3×OCOCH₃), 2.18, 3.40 (2s, 3H, OCH₃), 3.45-50 (m, 3H, H-5, 6,6′) 4.80-5.40 (m, 3H,H-1,3,4). The syrup was dissolved in methanol (600 ml) 1N NaOMe in methanol (25 ml) was added and left at room temperature. After 6-10 h, dry CO₂ gas was passed into the reaction mixture, solvent was evaporated to obtain a syrupy residue. The residue was once again extracted into dry methanol and concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside as syrup. Quantity obtained 81 g (92%).EXAMPLE 4A 500 ml round bottom flask equipped with magnetic stir bar was charged with a solution of D-glucal (323 g) in methanol (175 ml), cooled to 15° C., N-bromosuccinimide (NIBS) (39.4 g) was added and stirred or 6 hours at 15° C., The reaction mixture was concentrated to half the volume, cooled to 0° C. and separated succinimide, was removed by filtration. To the filtrate was added a slurry of 30 g Raney nickel (a 50% slurry in Methanol) Et₃N (32 ml) and hydrogenated in a Parr apparatus at 120 psi. After 7-8 hours, the reaction mixture was filtered through a Celite filter pad, and washed with MeOH. The washings and filtrate were combined and triturate with hexane to separate and remove by filtration insoluble triethylamine hydrobromide and succinimide. The filtrate was concentrated to a residue, dissolved in methanol and triturated with hexane to remove most of the triethylamine hydrobromide and succinimide. The filtrate was concentrated to obtain methyl 2-deoxy-α/β-D-glucopyranoside (85%).EXAMPLE 5To a stirred solution of methyl 3,4,6-tri-O-acetyl-2-deoxy-α/β-D-glucopyranoside (47 g) (from example 3) in acetic acid (40 ml) and acetic anhydride (110 ml) was added concentrated sulphuric acid (0.94 ml) at 0°. The reaction mixture was brought to room temperature and stirred. After 2 hours the reaction mixture was diluted with water (50 ml) and extracted into CH₂Cl₂ (3×150 ml). The organic phase was separated, washed with saturated NaHCO₃ solution H₂O dried over Na₂SO₄ and concentrated to obtain 2-deoxy-1,3,4,6-tetra-O-acetyl-α/β-D-glucopyranoside as a crystalline compound. mp. 115-118° C. Quantity obtained 44.5 g (86%). [α]_D+21.5° (c 1.0, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ 1.50-2.45 (m, 14H, H-2,2′, 4×OCOCH₃), 3.85-5.40, (m, 5H, H-3,4,5,6,6′), 5.75-6.20 (m, 1H, H-1, α/β). To a heterogeneous mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) in water (100 ml) was added acetyl chloride (10 ml) and heated to 80° C. After 6 hours the reaction mixture was cooled to room temperature, neutralised with saturated aq. Ba(OH)₂, concentrated to half the volume and filtered on a Celite pad, Filtrate was concentrated on a rotary evaporator and dried over anhydrous P₂O₅ to obtain a residue which was dissolved in hot isopropyl alcohol and filtered on a pad of Celite to obtain a clear filtrate. The filtrate was concentrated to a residue, dissolved in hot isopropyl alcohol (50 ml), acetone (75 ml) and seeded with a few crystals of 2-deoxy-D-glucose. After 15-18 hours at 5° C. crystalline title product was filtered. Quantity obtained 3.21 g (64.9%) m.p. 148-149° C.EXAMPLE 6A heterogeneous mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (9 g) (from example 5), water (30 ml) and 11% aq. H₂SO₄ (0.3 ml) was stirred at 85° C. for 7 h to obtain a homogenous solution. The reaction mixture was cooled, neutralised with aq. Ba(OH)₂ solution and filtered. The filtrate obtained was concentrated to half the volume and solids separated were filtered. To the filtrate was added activated carbon (1 g) and filtered. The filtrate was concentrated on a rotary evaporator and dried over P₂O₅ to obtain 2-deoxy-D-glucose that was crystallized from methyl alcohol (27 ml) and acetone (54 ml). Quantity obtained 2.4 g. mp. 146-149° C.,EXAMPLE 7A heterogeneous mixture of 1,3,4,tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (25 g) (from example 5), H₂O (250 ml), toluene (250 ml) and glacial acetic acid (1.25 ml) was heated to reflux for 10-12 hours, while it was connected to a Dean-Stark azeotropic distillation apparatus. An azeotropic mixture of acetic acid, toluene was collected to remove acetic acid and every one hour fresh toluene (50 ml) was introduced. After completion of the reaction, toluene was removed by distillation from the reaction mixture to obtain a residue that was dissolved in methanol, treated with charcoal and filtered. Be filtrate was separated, concentrated to a residue and crystallized from isopropyl alcohol and acetone to obtain 2-deoxy-D-glucose (7.33 g, 59%). mp. 148-151° C.EXAMPLE 8A heterogeneous mixture of 1,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) (tom example 5), H₂O (200 ml) conc. HCl (0.3 ml) and glacial acetic acid (0.5 ml) was heated to 85° C. After 6 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)₂ and filtered on a pad of Celite. Filtrate was separated, treated with charcoal and filtered. The filtrate was concentrated to a residue and crystallized from MeOH, acetone to obtain the product. Quantity obtained 275 g. mp. 147-148° C.EXAMPLE 9A heterogeneous mixture of 1,3,4,5-tetra-O-acetyl-2-deoxy-α/β-D-glucopyranoside (10 g) (from example 3) water (100 ml) and conc. HCl (0.5 ml) was heated to 80° C. After 2-5 hours the reaction mixture was cooled to room temperature, neutralized with aq. Ba(OH)₂ and filtered on a pad of Celite. The filtrate was concentrated to a residue, dissolved in ethanol, treated with charcoal and filtered. The filtrate was concentrated to a solid residue and crystallized from methanol-acetone to obtain the title product. Quantity obtained 3.15 g mp. 148-151° C.,EXAMPLE 10A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30 g) (from example 2) water (15 ml) and conc. HCl (1.5 ml) was heated to 80-85° C. After 3-5 hours the reaction mixture was cooled to room temperature, neutralize with aq. Ba(OH)₂ and filtered to remove insoluble salts. The filtrate was concentrated to a residue, crystallized from MeOH, acetone and hexane to obtain 2-deoxy-D-glucose (11.77 g) mp. 149-151° C.EXAMPLE 11A solution of methyl 2-deoxy-α/β-D-glucopyranoside (30 g) (form example 2) water (195 ml) and conc. H₂SO₄ (5.9 ml) was heated to 80° C. After 2-3 hours the reaction mixture was cooled, neutralized with aq. Ba(OH)₂ and filtered. The filtrate was separated, treated with charcoal and filtrate. The Filtrate was concentrated to a residue and crystallized from isopropyl alcohol to obtain the title product. Quantity obtained 5.2 g. mp. 152-154° C.EXAMPLE 12A mixture of methyl 2-deoxy-α/β-D-glucopyranoside (24 g) (from example 2) water (125 ml) and IR 120H+resin (7.5 ml) was heated to 90-95° C. for 2 h. The reaction mixture was cooled to room temperature, filtered and the resin was washed with water (20 ml). The filtrate was concentrated to residue and crystallized from ethanol to obtain 2-deoxy-D-glucose (8.8 g), mp. 150-152° C.CLIP

References

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The Drugs Controller General of India (DCGI) has given permission for the emergency use of drug 2-deoxy-D-glucose (2-DG) as an adjunct therapy in moderate to severe Covid-19 cases, said Defence Research and Development Organisation on Saturday.

“Being a generic molecule and analogue of glucose, it can be easily produced and made available in plenty,” said the DRDO in a statement.

An adjunct therapy refers to an alternative treatment that is used together with the primary treatment. Its purpose is to assist the primary treatment.

“The drug has been developed by DRDO lab Institute of Nuclear Medicine and Allied Sciences in collaboration with Dr Reddy’s Laboratories. Clinical trial have shown that this molecule helps in faster recovery of hospitalized patients and reduces supplemental oxygen dependence,” the statement read.

According to DRDO, the patients treated with 2-DG showed faster symptomatic cure than Standard of Care (SoC) on various endpoints in the efficacy trends.

“A significantly favourable trend (2.5 days difference) was seen in terms of the median time to achieving normalization of specific vital signs parameters when compared to SOC,” it said.

The drug comes in powder form in sachets, which is taken orally by dissolving it in water.

“It accumulates in the virus-infected cells and prevents virus growth by stopping viral synthesis and energy production,” said the DRDO.

In April 2020, during the first wave of the Covid-19 pandemic, INMAS-DRDO scientists conducted laboratory experiments of 2-DG with the help of the Centre for Cellular and Molecular Biology (CCMB), Hyderabad.

They found that this molecule works effectively against the SARS-CoV-2 virus and inhibits viral growth.

Based on the results, the DCGI had in May 2020 permitted Phase-II clinical trial of 2-DG in Covid-19 patients.

In Phase-II trials (including dose-ranging) conducted from May to October 2020, the drug was found to be safe and showed significant improvement in the patients’ recovery.

“Phase IIa was conducted in 6 hospitals and Phase IIb (dose-ranging) clinical trial was conducted at 11 hospitals all over the country. Phase-II trial was conducted on 110 patients,” said the DRDO.

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