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WO2009108926A1 - Inhibiteurs de glycolyse utiles dans le traitement de tumeurs du cerveau - Google Patents

Inhibiteurs de glycolyse utiles dans le traitement de tumeurs du cerveau Download PDF

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WO2009108926A1
WO2009108926A1 PCT/US2009/035702 US2009035702W WO2009108926A1 WO 2009108926 A1 WO2009108926 A1 WO 2009108926A1 US 2009035702 W US2009035702 W US 2009035702W WO 2009108926 A1 WO2009108926 A1 WO 2009108926A1
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group
alkyl
dfg
glycolysis
glucose
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Waldemar Priebe
Charles Conrad
Timothy Madden
Izabela Fokt
Slawomir Szymanski
Leposav Antonovic
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University of Texas System
University of Texas at Austin
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University of Texas System
University of Texas at Austin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

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  • a serious disadvantage of treating glioblastoma is the harmful effects on normal cells and tissue. Furthermore, the mutagenic potential of certain anti-neoplastic therapies often promotes tumor resistance and can initiate other malignancies. A need exists, therefore, for cancer treatments to be developed for highly glycolytic cancer cells such as glioblastoma with little or no toxicity towards normal cells.
  • Rl is selected from the group consisting of alkyl, lower alkyl, substituted alkyl, cycloalkyl, hydroxyl, alkoxy, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, acylamino, carbamate, 0-carbamyl, N-carbamyl, carbonyl, carboxy, carboxylate, ester, ether, halogen, haloalkoxy, haloalkyl, heteroalkyl, hydrazinyl, hydroxyalkyl, isocyanato, isothiocyanato, mercaptyl, nitro, oxy, NH 2 , NR 3 R 4 , and NHCOR 5 ;
  • R3 and R4 are selected from the group consisting of hydrogen, alkyl, lower alkyl, substituted alkyl, cycloalkyl, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, haloalkyl, heteroalkyl, hydrazinyl, and hydroxyalkyl; and
  • R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, haloalkyl, and heteroalkyl.
  • R2 is selected from the group consisting of alkyl, lower alkyl, substituted alkyl, cycloalkyl, hydroxyl, alkoxy, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, acylamino, carbamate, O-carbamyl, N-carbamyl, carbonyl, carboxy, carboxylate, ester, ether, halogen, haloalkoxy, haloalkyl, heteroalkyl, hydrazinyl, hydroxyalkyl, isocyanato, isothiocyanato, mercaptyl, nitro, oxy, NH 2 , NR 3 R 4 , and NHCOR 5 ;
  • R3 and R4 are selected from the group consisting of hydrogen, alkyl, lower alkyl, substituted alkyl, cycloalkyl, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, haloalkyl, heteroalkyl, hydrazinyl, and hydroxyalkyl; and
  • R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, haloalkyl, and heteroalkyl.
  • compositions comprising one or more compounds together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions are provided.
  • FIG. 1 shows a schematic diagram of various metabolic pathways in a eukaryotic cell.
  • FIG. 2 shows a schematic diagram of various glycolytic pathways in a eukaryotic cell.
  • FIG. 3 shows a schematic diagram of the Krebs cycle in a eukaryotic cell.
  • FIG. 4 shows a schematic diagram of various steps in oxidative phosphorylation in a eukaryotic cell.
  • FIGS. 5a and 5b shows comparisons of DFG treatment in U87 GBM brain tumor cell line under normoxia and hypoxia performed in three independent experiments.
  • FIGS. 6a and 6b shows comparisons of 2-DG treatment in U87 GBM brain tumor cell line under normoxia and hypoxia performed in three independent experiments.
  • FIG. 7a shows U87 GBM brain tumor sensitivity to DFG alone and in the presence of increased concentration of D-glucose (GLC) under normoxia. D-Glucose protects moderately U87 glioblastoma from DFG-inhibited glycolysis in a dose dependent manner in normoxic conditions.
  • LPC D-glucose
  • FIG. 7b shows U87 GBM brain tumor sensitivity in vitro to DFG alone and in the presence of increased concentrations of D-glucose (GLC) under hypoxia.
  • D-Glucose protects U87 glioblastoma from DFG-inhibited glycolysis in a dose-dependent manner in hypoxic conditions to a greater extent than in normoxic conditions. Note the significant shift OfIC 50 f° r DFG when D-Glucose is present.
  • FIG. 8a shows U87 GBM brain tumor sensitivity in vitro to 2-DG alone and in the presence of increased concentration of D-glucose (GLC) under normoxia.
  • D-Glucose protects U87 glioblastoma from 2-DG-inhibited glycolysis in a dose-dependent manner in normoxic conditions. Note the significant increase of ICs 0 for 2-DG when D-glucose is present.
  • FIG. 8b shows U87 GBM brain tumor sensitivity in vitro to 2-DG alone and in the presence of increased concentration of D-glucose (GLC) under hypoxia.
  • D-Glucose protects U87 glioblastoma from 2-DG-inhibited glycolysis in a dose-dependent manner in hypoxic conditions to a greater extent than in normoxic conditions. Note the significant increase of IC50 for 2-DG when D-glucose is present.
  • FIG. 9a shows U87 GBM brain tumor sensitivity in vitro to DFG alone and in the presence of increased concentration of D-mannose (MAN) under normoxia.
  • D-Mannose has only a small effect on DFG inhibition of U87 cell line growth under normoxic conditions. Such an effect was noted at low level exposure (0.1 mM) but did not increase at a 10 fold greater concentration (1 mM).
  • FIG. 9b shows U87 GBM brain tumor sensitivity in vitro to DFG alone and in the presence of increased concentration of D-mannose (MAN) under hypoxia.
  • D-Mannose has no effect on DFG inhibition of U87 cell line growth under hypoxic conditions.
  • DFG inhibits glycolysis selectively and therefore targets selectively highly glycolytic tumor cells.
  • FIG. 10a shows U87 GBM brain tumor sensitivity in vitro to 2-DG alone and in the presence of increased concentration of D-mannose (MAN) under normoxia.
  • D- Mannose offers significant protection to U87 glioblastoma from 2-DG-mediated growth inhibition in a non-dose dependent manner under normoxic conditions.
  • D- glucose protection even low level D-Mannose exposure (0.1 mM) provides an equivalent degree of protection to 1 mM exposures. This is in contrast to DFG treatment where D- mannose effect was low.
  • FIG. 10b shows U87 GBM brain tumor sensitivity in vitro to 2-DG alone and in the presence of increased concentration of D-mannose (MAN) under hypoxia.
  • D-Mannose offers noticeable protection to U87 glioblastoma from 2-DG-mediated growth inhibition under hypoxic conditions, but this protection is significantly lower than that observed under normoxic conditions as shown in Fig. 10a.
  • FIG. 11a shows U87 GBM brain tumor sensitivity in vitro to DFG alone and in the presence of increased concentration of D-galactose (GAL) under normoxia.
  • D- Galactose supplementation has no impact on the survival of U87 glioblastoma cell from DFG-inhibited glycolysis, regardless of dose under normoxic conditions. Note that the IC5 0 for DFG is unchanged and the curves are virtually super-imposable across the D-galactose concentration range.
  • FIG. 1 Ib shows U87 GBM brain tumor sensitivity in vitro to DFG alone and in the presence of increased concentration of D-galactose (GAL) under hypoxia.
  • GAL D-galactose
  • FIG. 12a shows U87 GBM brain tumor sensitivity in vitro to 2-DG alone and in the presence of increased concentration of D-galactose (GAL) under normoxia.
  • D- Galactose supplementation has no impact on the survival of U87 glioblastoma cell from 2- DG-inhibited glycolysis, regardless of dose under normoxic conditions. Note that the IC 5O for DFG is unchanged and the curves are virtually super-imposable across the D-galactose concentration range.
  • FIG. 12b shows U87 GBM brain tumor sensitivity in vitro to 2-DG alone and in the presence of increased concentration of D-galactose (GAL) under hypoxia.
  • GAL D-galactose
  • FIG. 13a shows the results of 2 DFG activity of 72 h normoxia treatment of
  • FIG. 13b shows the results of 2 DFG activity of 72 h hypoxia treatment of
  • FIGS. 14a through 14f provide the quantification of 2-DFG induced autophagy in U87 glioma cells after 72h of normoxia treatment in 5.6 mM low glucose media using acridine orange-acid vesicular organelles (AVO) straining assay.
  • AVO vesicular organelles
  • FIGS. 15a through 15f provide the quantification of 2-DFG induced autophagy in U87 glioma cells after 72h of hypoxia treatment in 5.6 mM low glucose media using acridine orange-acid vesicular organelles (AVO) straining assay.
  • AVO acridine orange-acid vesicular organelles
  • FIGS. 16a through 16d provides electron micrographs of 2-DFG induced autophagy in U87 cells (5 mM, 72h treatment, 5.6 mM low glucose media).
  • FIG. 17 shows the effect of 2-DFG (5 mM) on cell cycle distribution of U87 cells determined after 72h treatment using cell cycle analysis.
  • gliomas primary tumors
  • gliomas high-grade gliomas
  • secondary brain tumors such as metastatic brain tumors
  • Rl is selected from the group consisting of alkyl, lower alkyl, substituted alkyl, cycloalkyl, hydroxyl, alkoxy, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, acylamino, carbamate, O-carbamyl, N-carbamyl, carbonyl, carboxy, carboxylate, ester, ether, halogen, haloalkoxy, haloalkyl, heteroalkyl, hydrazinyl, hydroxyalkyl, isocyanato, isothiocyanato, mercaptyl, nitro, oxy, NH 2 , NR 3 R 4 , and NHCOR 5 ;
  • R3 and R4 are selected from the group consisting of hydrogen, alkyl, lower alkyl, substituted alkyl, cycloalkyl, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, haloalkyl, heteroalkyl, hydrazinyl, and hydroxyalkyl; and
  • R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, haloalkyl, and heteroalkyl.
  • R2 is selected from the group consisting of alkyl, lower alkyl, substituted alkyl, cycloalkyl, hydroxyl, alkoxy, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, acylamino, carbamate, O-carbamyl, N-carbamyl, carbonyl, carboxy, carboxylate, ester, ether, halogen, haloalkoxy, haloalkyl, heteroalkyl, hydrazinyl, hydroxyalkyl, isocyanato, isothiocyanato, mercaptyl, nitro, oxy, NH 2 , NR 3 R 4 , and NHCOR 5 ;
  • R3 and R4 are selected from the group consisting of hydrogen, alkyl, lower alkyl, substituted alkyl, cycloalkyl, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, haloalkyl, heteroalkyl, hydrazinyl, and hydroxyalkyl; and R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, haloalkyl, and heteroalkyl.
  • ATP adenosine 5 '-triphosphate
  • ATP adenosine 5 '-triphosphate
  • carbohydrates are first hydrolyzed into monosacharrides (e.g., glucose), and lipids are hydrolyzed into fatty acids and glycerol.
  • proteins are hydrolyzed into amino acids. The energy in the chemical bonds of these hydrolyzed molecules are then released and harnessed by the cell to form ATP molecules through numerous catabolic pathways.
  • glucose is a simple sugar or monosaccharide, and the primary source of energy for animals.
  • Glucose is an important sugar in human metabolism having a normal concentration of about 0.1% in human blood except in persons suffering from diabetes.
  • oxidation of glucose contributes to a series of complex biochemical reactions which provide the energy needed by cells.
  • glucose produces carbon dioxide, water and certain nitrogen compounds.
  • Energy from glucose oxidation is used to convert ADP to adenosine 5 '-triphosphate ("ATP"), a multifunctional nucleotide that is known as "molecular currency” of intracellular energy transfer.
  • ATP adenosine 5 '-triphosphate
  • ATP produced as an energy source during cellular respiration is consumed by different enzymes and cellular process including biosynthetic reactions, motility and cell division.
  • ATP is the substrate by which kinases phosphorylate proteins and lipids and adenylate cyclase produces cyclic AMP.
  • ATP is an unstable molecule that tends to be hydrolyzed in water.
  • ATP and ADP are allowed to come into chemical equilibrium, almost all the ATP will be converted to ADP.
  • Cells maintain ATP to ADP at a point ten orders of magnitude from equilibrium, with ATP concentrations a thousand fold higher than the concentration of ADP. This displacement from equilibrium means that the hydrolysis of ATP in the cell releases a lot of energy.
  • Nicholls D.G. & Ferguson SJ. (2002) Bioenergetics Academic Press 3 rd Ed. ATP concentration inside the cell is typically 1-10 mM. Beis L 5 & Newsholme E.A. (1975) Biochem J 152, 23-32.
  • ATP is produced by redox reactions using simple sugars (e.g., glucose), complex sugars (carbohydrates), lipids and proteins.
  • carbohydrates are hydrolyzed into simple sugars such as glucose, or fats (triglycerides) are hydrolyzed to give fatty acids and glycerol.
  • proteins are hydrolyzed to give amino acids.
  • Cellular respiration is the process of oxidizing these hydrolyzed molecules to carbon dioxide to generate ATP. For instance, up to 36 molecules of ATP can be produced from a single molecule of glucose. Lodish, H., et al, Molecular Cell Biology, 5 th Ed. New York (2004).
  • the three main pathways to generate energy in eukaryotic organisms are: glycolysis, the Krebs Cycle (also known as the citric acid cycle), and oxidative phosphosylation.
  • the main source of energy for living organisms is glucose.
  • breaking down glucose the energy in the glucose molecule's chemical bonds is released and can be harnessed by the cell to form ATP molecules.
  • the process by which this occurs consists of several stages. The first is called glycolysis (the prefix glyco refers to glucose, and lysis means to split), in which the glucose molecule is broken down into two smaller molecules called pyruvic acid.
  • glycolysis the prefix glyco refers to glucose
  • lysis means to split the glucose molecule is broken down into two smaller molecules called pyruvic acid.
  • the next stages are different for anaerobes and aerobes.
  • glycolysis glucose and glycerol are metabolized to pyruvate via the glycolytic pathway shown in Figure 2. In most organisms, glycolysis occurs in the cytosol. During this process, two ATP molecules are generated. Two molecules of NADH are also produced, which can be further oxidized via the electron transport chain and result in the generation of additional ATP molecules.
  • Glycolysis is the first stage in the release of energy from the glucose molecule.
  • Glycolysis involves the breaking down of glucose into two smaller molecules of pyruvic acid, each pyruvic acid molecule having three carbon atoms, or half of the carbons in a glucose molecule.
  • two ATP molecules are necessary. As shown in Figure 2, the first ATP molecule releases a phosphate group which then joins to the glucose molecule to form glucose phosphate. Then, the second ATP molecule contributes a phosphate group, forming a molecule called fructose diphosphate.
  • the fructose diphosphate molecule splits into two molecules of glyceraldehyde phosphate "PGAL.” Each PGAL molecule then releases electrons to a coen2yme NAD+ (nicotinamide adenine dinucleotide) and phosphate groups and energy to ADP.
  • coen2yme NAD+ nicotinamide adenine dinucleotide
  • Glycolysis has been correlated with disease progression in certain cancers.
  • the Warburg effect recognizes that tumor cells rely on anaerobic glycolysis rather than on oxidative phosphorylation or the Krebs cycle (otherwise referred to as "aerobic respiration") for ATP generation, even when sufficient oxygen is available.
  • Hypoxia- inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis, J. Bio. Chem. Vol. 277, No. 26, 23111 (2002).
  • glycolysis occurs in the cytoplasm and involves many enzyme-catalyzed steps that break down glucose (and other monosacharrides) into 2 pyruvate molecules.
  • the pathway leads to the generation of a sum of 2 ATP molecules.
  • the pyruvate molecules generated from the glycolytic pathway enter the mitochondria from the cytosol.
  • the molecules are then converted to acetyl co-enzyme A (Acetyl-CoA) for entry into the Krebs cycle.
  • the Krebs cycle consists of the bonding of acetyl coenzyme- A with oxaloacetate to form citrate.
  • the formed citrate is then broken down through a series of enzyme-catalyzed steps to generate additional ATP molecules.
  • Fatty acids, glycerols and amino acids can also enter the Krebs cycle after they are converted to acetyl-CoA. However, unlike glucose and other monosacharrides, such molecules can by-pass the glycolytic pathway. For instance, fatty acids can be converted to acetyl-CoA through a four-step enzyme-catalyzed pathway known as ⁇ -oxidation.
  • ketogenesis Another noteworthy metabolic pathway is ketogenesis. As illustrated in
  • ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown.
  • acetyl-CoA generated in fatty-acid ⁇ - oxidation challenge the processing capacity of the Krebs cycle, or if the activity in the Krebs cycle is low due to low amounts of intermediates such as oxaloacetate, then acetyl-CoA is used in the biosynthesis of ketone bodies.
  • Ketogenesis is also associated with low carbohydrate levels in the blood.
  • a switch occurs from utilization of carbohydrates as the main source of energy to using fatty acid stores in the liver as a primary source of energy.
  • Ketones produced as a result of the fatty acid oxidation serves as the main source of energy in such circumstances.
  • Mechanisms and conditions inducing ketogenesis would include starvation and a zero carbohydrate diet (Dietary-induced Ketogenesis).
  • Krebs cycle also generate electrons that become stored in the form of reduced co-enzymes, such as NADH and FADH2. As shown in Figure 3, these co-enzymes participate in oxidative phosphorylation, where their electrons pass through an electron transport chain across the mitochondrial membrane. During this process, the protons from NADH and FADH2 enter the mitochondrial intermembrane space. Consequently, the electron transport chain leads to the formation of a proton gradient within the intermembrane space. Finally, the protons flux from the intermembrane space to the mitochondrial matrix through specific proton channels that catalyze the synthesis of additional ATP molecules.
  • cancer cells Like normal cells, cancer cells also utilize metabolic pathways to generate
  • malignant gliomas and pancreatic cancer are intrinsically resistant to conventional therapies and represent significant therapeutic challenges.
  • Malignant gliomas have an annual incidence of 6.4 cases per 100,000 (Central Brain Tumor Registry of the United States, 2002-2003) and are the most common subtype of primary brain tumors and the deadliest human cancers.
  • GBM glioblastoma multiforme
  • the median survival duration for patients ranges from 9 to 12 months, despite maximum treatment efforts.
  • approximately one-third of patients with GBM their tumors will continue to grow despite treatment with radiation and chemotherapy.
  • the prognosis for pancreatic cancer is generally regarded as poor, with few victims still alive 5 years after diagnosis, and complete remission rare.
  • Another problem in treating malignant tumors is the toxicity of the treatment to normal tissues unaffected by disease. Often chemotherapy is targeted at killing rapidly-dividing cells regardless of whether those cells are normal or malignant. However, widespread cell death and the associated side effects of cancer treatments may not be necessary for tumor suppression if the growth control pathways of tumors can be disabled.
  • therapy sensitization i.e. using low dose of a standard treatment in combination with a drug that specifically targets crucial processes in the tumor cell, increasing the effects of the other drug.
  • the glycolytic pathway has become a potential target for the selective inhibition of many tumor cells, particularly glioblastomas and pancreatic cancers and other highly glycolytically sustained tumors.
  • the inhibition of glycolysis would be selective for such tumor cells because normal cells in aerobic conditions would be able to survive such inhibition by generating energy through other pathways (e.g., the Krebs cycle, and oxidative phosphorylation).
  • other pathways e.g., the Krebs cycle, and oxidative phosphorylation
  • glycolysis is blocked in glycolytic tumor cells, the tumor cells would die because of an inability to utilize the aforementioned pathways.
  • current glycolytic inhibition approaches for cancer treatment present various challenges. For instance, many such treatments are not specific for the hypoxic environment of tumor cells. More importantly, current treatments are not selective inhibitors of glycolysis.
  • glycoproteins are essential for maintaining the structural integrity of cell membrane.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
  • inhibitor(s) of glycolysis are intended to refer to compounds or compositions that substantially inhibit or interfere with the activity of one or more enzymes involved in glycolysis.
  • inhibiting glycolysis is intended to refer to a decrease in glycolytic activity, a reduction in glycolytic activity, or the elimination of glycolytic activity.
  • IC 5 o is intended to refer to the concentration of a compound or composition that reduces the viability of cells to half the original level. In broader terms, ICs 0 can refer to half the maximal inhibitory concentration of a substance for inhibiting various biological processes.
  • reference to "therapeutically effective” is intended to qualify the amount of active ingredients that is used in the treatment of a disease or disorder described in the present disclosure. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
  • treatment of a patient is intended to refer to procedures or applications of the methods of the present invention to a patient in order to temporarily or permanently cure, reduce, mitigate, or ameliorate a condition or disorder described in the present disclosure.
  • patient is intended to refer to all mammals including but not limited to humans, cows, dogs, cats, goats, sheep, pigs, and rabbits.
  • patient is a human.
  • inhibition of cell viability is intended to refer to the reduction or elimination of cell division by various mechanisms, including but not limited to apoptosis, autophagy, and necrosis.
  • hypooxic is intended to refer to a condition characterized by low oxygen supply.
  • normoxic is intended to refer to a condition characterized by adequate oxygen supply.
  • DFG 2-Deoxy-2,2- difluoro-D-arabino-hexopyranose, including any salt, ester or solvate thereof.
  • Rl is selected from the group consisting of alkyl, lower alkyl, substituted alkyl, cycloalkyl, hydroxyl, alkoxy, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, acylamino, carbamate, O-carbamyl, N-carbamyl, carbonyl, carboxy, carboxylate, ester, ether, halogen, haloalkoxy, haloalkyl, heteroalkyl, hydrazinyl, hydroxyalkyl, isocyanato, isothiocyanato, mercaptyl, nitro, oxy, NH 2 , NR 3 R 4 , and NHCOR 5 ;
  • R3 and R4 are selected from the group consisting of hydrogen, alkyl, lower alkyl, substituted alkyl, cycloalkyl, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, haloalkyl, heteroalkyl, hydrazinyl, and hydroxyalkyl; and
  • R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, haloalkyl, and heteroalkyl.
  • R2 is selected from the group consisting of alkyl, lower alkyl, substituted alkyl, cycloalkyl, hydroxyl, alkoxy, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, acylamino, carbamate, O-carbamyl, N-carbamyl, carbonyl, carboxy, carboxylate, ester, ether, halogen, haloalkoxy, haloalkyl, heteroalkyl, hydrazinyl, hydroxyalkyl, isocyanato, isothiocyanato, mercaptyl, nitro, oxy, NH 2 , NR 3 R 4 , and NHCOR 5 ;
  • R3 and R4 are selected from the group consisting of hydrogen, alkyl, lower alkyl, substituted alkyl, cycloalkyl, acyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, haloalkyl, heteroalkyl, hydrazinyl, and hydroxyalkyl; and
  • R5 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, alkenyl, alkylene, alkylamino, alkylthio, alkylidene, alkynyl, amido, carbamoyl, haloalkyl, and heteroalkyl.
  • acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon.
  • An “acetyl” group refers to a -C(O)CH 3 group.
  • An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
  • alkenyl refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20, preferably 2 to 6, carbon atoms.
  • suitable alkenyl radicals include ethenyl, propenyl, 2- methylpropenyl, 1 ,4-butadienyl and the like.
  • alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below.
  • suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
  • alkyl refers to a straight- chain or branched-chain alkyl radical containing from 1 to and including 20, preferably 1 to 10, and more preferably 1 to 6, carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like.
  • alkylene as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH 2 -).
  • alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N- methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.
  • alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
  • alkylthio refers to an alkyl thioether (R-S-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
  • suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec- butylthio, tert-butylthio, methanesulfonyl, ethanesulfmyl, and the like.
  • alkynyl refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20, preferably from 2 to 6, more preferably from 2 to 4, carbon atoms.
  • Alkynylene refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C ⁇ C-).
  • alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like.
  • acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group.
  • An example of an “acylamino” group is acetylamino (CH 3 C(O)NH-).
  • amino refers to — NRR , wherein R and R are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted.
  • aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl.
  • arylalkenyl or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
  • arylalkoxy or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
  • arylalkyl or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
  • arylalkynyl or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
  • arylalkanoyl or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4- phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxy.
  • carbamate refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
  • O-carbamyl refers to a
  • N-carbamyl as used herein, alone or in combination, refers to a
  • carbonyl when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.
  • Carboxylate anion, such as is in a carboxylic acid salt.
  • An "O-carboxy” group refers to a RC(O)O- group, where R is as defined herein.
  • a “C-carboxy” group refers to a -C(O)OR groups where R is as defined herein.
  • cyano as used herein, alone or in combination, refers to -CN.
  • cycloalkyl or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12, preferably five to seven, carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
  • cycloalkyl radicals examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3- dihydro-lH-indenyl, adamantyl and the like.
  • "Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydonapthalene, octahydronapthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type.
  • the latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane.
  • esters refers to a carboxy group bridging two moieties linked at carbon atoms.
  • ether refers to an oxy group bridging two moieties linked at carbon atoms.
  • halo or halogen
  • haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • "Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difiuoromethylene (-CF 2 -), chloromethylene (-CHC1-) and the like.
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 .
  • heteroaryl refers to 3 to 7 membered, preferably 5 to 7 membered, unsaturated heteromonocyclic rings, or fused polycyclic rings in which at least one of the fused rings is unsaturated, wherein at least one atom is selected from the group consisting of O, S, and N.
  • the term also embraces fused polycyclic groups wherein heterocyclic radicals are fused with aryl radicals, wherein heteroaryl radicals are fused with other heteroaryl radicals, or wherein heteroaryl radicals are fused with cycloalkyl radicals.
  • heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl,
  • Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
  • heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one, preferably 1 to 4, and more preferably 1 to 2 heteroatoms as ring members, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8 ring members in each ring, more preferably 3 to 7 ring members in each ring, and most preferably 5 to 6 ring members in each ring.
  • Heterocycloalkyl and “heterocycle” are intended to include sulfones, sulfoxides, N- oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
  • Heterocycle groups of the invention are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5- b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
  • the heterocycle groups may be optionally substituted unless specifically prohibited.
  • hydrazinyl as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
  • hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
  • isothiocyanato refers to a -NCS group.
  • linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
  • lower means containing from 1 to and including 6 carbon atoms.
  • nitro refers to -NO 2 .
  • perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
  • perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
  • sulfonate refers the -SO 3 H group and its anion as the sulfonic acid is used in salt formation.
  • thia and thio refer to a
  • thia and thio an ether wherein the oxygen is replaced with sulfur.
  • the oxidized derivatives of the thio group namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
  • thiol as used herein, alone or in combination, refers to an -SH group.
  • N-thiocarbamyl refers to an ROC(S)NR'- group, with R and R' as defined herein.
  • O-thiocarbamyl refers to a -OC(S)NRR', group with R and R'as defined herein.
  • thiocyanato refers to a -CNS group.
  • trihalomethanesulfonamido refers to a X 3 CS(O) 2 NR- group with
  • X is a halogen and R as defined herein.
  • trihalomethanesulfonyl refers to a X 3 CS(O) 2 - group where X is a halogen.
  • trihalomethoxy refers to a X 3 CO- group where X is a halogen.
  • trimethysilyl as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.
  • any definition herein may be used in combination with any other definition to describe a composite structural group.
  • the trailing element of any such definition is that which attaches to the parent moiety.
  • the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
  • the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
  • the substituents of an "optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxy
  • Two substituents may be joined together to form a fused five-, six-, or seven- membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
  • An optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., - CH 2 CH 2 F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH 2 CF 3 ).
  • R or the term R' refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted.
  • aryl, heterocycle, R, etc. occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence.
  • certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written.
  • an unsymmetrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.
  • Asymmetric centers exist in the compounds of the present invention. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
  • the compounds of the present invention may exist as geometric isomers.
  • the present invention includes all cis, trans, syn, anti,
  • compounds may exist as tautomers; all tautomeric isomers are provided by this invention.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • bond refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • a bond may be single, double, or triple unless otherwise specified.
  • a dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
  • gliomas can grow in a predominately infiltrative fashion with little to no contrast enhancement seen on MRI scans versus more rapidly growing contrast enhancing mass lesions.
  • gliomas can grow in a predominately infiltrative fashion with little to no contrast enhancement seen on MRI scans versus more rapidly growing contrast enhancing mass lesions.
  • Many studies have indicated that these different types of growth patterns also represent various degrees of hypoxic regions within individual tumors. Relative hypoxic areas can be seen both in the center of the rapidly growing tumor mass, which often has regions of necrosis associated with this, as well as some relatively hypoxic regions within the infiltrative component of the tumor as well. Accordingl y, some of these relatively hypoxic regions may have cells, which are cycling at a slower rate and may therefore be more resistant to many chemotherapy agents.
  • DFG 2-Deoxy-2,2-difluoro-D-arabino-hexopyranose
  • DFG 2-Deoxy-2,2-difluoro-D-arabino-hexopyranose
  • IC 50 values generally correspond to 2-DG or DFG concentrations that inhibited the viability of U87 glioblastoma cells to half their original level (i.e., 50%).
  • Mannose did not significantly affect the viability of glioblastoma cells against DFG activity under hypoxic or normoxic conditions, as demonstrated by an insignificant shift in IC 5O values after co-treatment with D-mannose.
  • the graphs for such assays are shown in Figure 9.
  • D-glucose offers protection to glioblastoma cells against 2-DG and
  • DFG because both molecules compete with D-glucose as substrates for one or more enzymes in the glycolytic pathway, indicating that both molecules are inhibitors of glycolysis.
  • D-mannose offers protection to glioblastoma cells against 2- DG activity indicates that 2-DG also competes with D-mannose as a substrate for one or more enzymes in glycosylation, further affirming that 2-DG is a non-selective inhibitor of glycolysis.
  • D-mannose does not offer protection to glioblastoma cells against DFG activity, it is envisioned that DFG is not an inhibitor of glycosylation and a substantially selective inhibitor of the glycolytic pathway.
  • the schematic diagram in Figure 11 illustrates a model that provides a theoretical mechanism for the aforementioned DFG activity. As shown in the schematic, it can be envisioned that DFG only interferes with various glycolytic pathways, whereas 2-DG interferes with both glycolytic and glycosylation pathways. [0149] Additional experiments confirmed that DFG is a substantially selective inhibitor of glycolysis. For instance, as shown in Figure 11, the addition of various concentrations of D-galactose did not significantly affect the viability of glioblastoma cells against DFG activity under hypoxic and normoxic conditions. Similar results were obtained with 2-DG (Fig. 12). The table below summarizes these results.
  • DFG exerts the aforementioned effects primarily by eliciting autophagy rather than apoptosis.
  • Autophagy is a regulated process in which portions of the cytoplasm are first sequestered with double- membrane vesicles known as autophagosomes. Klionsky, D.J., et al., Autophagy as a Regulated Pathway of Cellular Degradation, Science, 2000, 290:1717-1721. These autophagosomes then fuse with lysosomes to become autolysosomes or degradative autophagic vacuoles, after which the sequestered contents are degraded by lysosomal hydrolases. Autophagy leads to the extensive degradation of organelles, including mitochondria, which precedes nuclear destruction.
  • Autophagy is induced in various cell conditions; for example, it is responsible for the degradation of normal proteins in response to nutrient deprivation, differentiation, aging, transformation, and cancer. Cuervo, A.M., Autophagy: In Sickness and in Health, Trends Cell Biol, 2004, 14: 70-77; Shintani, T., et al., Autophagy in Health and Disease: A Double-Edged Sword, Science, 2004, 306: 990-995. In cancer research, autophagy is a novel concept, and its role remains unclear. In general, cancer cells show less autophagic degradation than normal cells. Bursch, W., et al., Programmed Cell Death (PCD). Apoptosis, Autophagic PCD, or Others?
  • PCD Programmed Cell Death
  • DG are able to stimulate the process of autophagy in U87 Glioblastoma cells, as determined by the detection of autophagosomes in the cells after treatment.
  • DFG also exerts its effects by autophagy.
  • the compounds presented herein can be used to treat glioma. These compounds can be used to treat other highly glycolytic forms of cancer, including but not limited to pancreatic cancer.
  • the methods provided herein can be used in various forms of treatment.
  • the compounds can be administered as a raw chemical, it is also possible to present it as a pharmaceutical formulation.
  • the subject invention can include a pharmaceutical formulation comprising the compound or a pharmaceutically acceptable salt, ester, or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compound ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the compounds may also be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen-free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for parenteral administration include aqueous and non-aqueous
  • sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of DFGs to allow for the preparation of highly concentrated solutions.
  • Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.
  • the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds presented herein may be administered orally or via injection at a dose of from 0.1 to 4 g/kg per day.
  • the dose range for adult humans is generally from 5 mg to 4 g/kg per day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 100 mg, usually around lO mg to 1O g.
  • the amount of the compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity.
  • the compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
  • any one of the aforementioned modes of treatment can occur by providing clinicians with a kit that contains a therapeutically effective amount of compound in any of the aforementioned forms along with instructions on how to administer treatment to patients.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • the benefit of experienced by a patient may be increased by administering one of compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • increased therapeutic benefit may result by also providing the patient with another therapeutic agent for diabetes.
  • the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • the multiple therapeutic agents may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.
  • DFG was synthesized using the following general synthetic procedure set forth below.
  • Step 1 Synthesis of l,2:5,6-di-O-isopropylidene-D-glucofuranose
  • Zinc bromide (%) and P 2 O 5 (2Og) were added to the previously prepared suspension of D-glucose (100 g) in acetone (2L) and stirred overnight at room temperature.
  • the pH of the reaction mixture was adjusted to 7 by addition of saturated water solution of sodium carbonate.
  • Inorganic salts were filtered off and washed with acetone.
  • Acetone solutions were combined and acetone was removed by evaporation.
  • the resulting aqueous residue was extracted with ether (3x10OmL). Extracts were then pooled together and dried over Na 2 SO 4 . Drying agent and solvent were removed to give 85 g of l,2:5,6-di-O-isopropylidene-D-glucofuranose. (Yield 60%). Additional information about this step appears in the Journal of the American Chemical Society, 1938, 60:1507. The entire article is incorporated herein by reference.
  • Step 2 Synthesis of 3-O-benzyl-l,2;5,6-di-O-isopropylidene-D-glucofuranose
  • Benzyl bromide 25 mL was added, and the reaction mixture was heated to 50 0 C and stirred at that temperature for 2 hours.
  • Step 4 Synthesis of l,2A6-tetra-O-acetyl-3-O-benzyl-a-D-glucopyranose
  • Step 6 Synthesis of benzyl 2A6-tri-O-acetyl-4-O-benzyl- ⁇ -D-glucopyranoside
  • Step 8 Synthesis of benzyl 3-O-benzyl-4,6-O-benzylidene- ⁇ -D-glucopyranoside
  • Step 9 Synthesis of benzyl 4,6-O-benzylidene-3-O-benzyl- ⁇ -D-arabino-hexapyranosis-2- ulose
  • Step 9 (6 g), DMF (120 mL), DMSO (60 mL), and phosphorus pentoxide (6 g) was prepared and stirred at 40°C for 24 hours. The reaction mixture was then cooled down. Next, dichloromethane (200 mL) was added. The obtained solution was washed with saturated sodium bicarbonate and then with water until it was neutral. The solution was subsequently dried over sodium sulfate. The drying agent was then filtered off, and the solvent was evaporated. Finally, the product was purified by crystallization from ethanol. (Yield 3.8g). Additional information about this step appears in Carbohydrate Research, 1977, 59:268-273. The entire article is incorporated herein by reference.
  • Step 10 Synthesis of benzyl-3-O-benzyl-4,6-O-benzylidene-2-deoxy-2,2-difluoro-D-arabino hexopyranoside
  • DFG acts primarily through the inhibition of glycolysis, in contrast to 2-DG, which exerts its action by targeting biological effects of D-glucose and D-mannose.
  • cells were treated with increasing concentration (1 to 10 mM) of 2-difluoro-D-glucose (DFG) for 72 hours in normoxic (21% O 2 ) or hypoxic (approximately 0.1% O 2 ) conditions.
  • DFG 2-difluoro-D-glucose
  • the cells were also treated with increasing concentration of the glucose (5, 10, and 20 mM), galactose (5, 10, and 20 mM) or mannose (0.1, 1, and 5 mM).
  • Glycolysis is the major energy producing pathway for fast growing, glycolytically depended tumors, such as gliomas. Blocking glycolysis is therefore an important therapeutic strategy when used alone or in combination therapy to enhance the effects of chemotherapy in energy starved tumors.
  • D-glucose antimetabolites 2-deoxy-D-glucose (2-DG), 2-fluoro-2-deoxy-D-glucose (2-FG) and 2- fluoro-2-deoxy-D-mannose (2-FM) and confirmed their ability to block glycolysis and discovered their ability to induce autophagic cell death in vitro and established that their antitumor activity in vivo in orthotopic glioma model was comparable to that of temozolomide, the standard of care therapy.
  • 2-DFG is an equally potent inhibitor of cell proliferation and a potent inducer of autophagic cell death in gliomas as are 2-DG, 2-FG, and 2-FM. Therefore, targeting the energetic metabolism of cancer cells and the autophagic survival response using inhibitors of glycolysis is a promising therapeutic approach for the treatment of cancers that are dependent on glycolysis for survival.
  • Electron microscopy data indicate extensive presence of autophagosomes (a marker of autophagic cell death) after 72h treatment of 5 mM 2-DFG under normoxia.
  • Cell cycle experiments in U87 cells treated with 5 mM of 2-DFG show significant increase in G2/M phase with no significant increase in Sub G0/G1 phase indicating that the cell death is not mediated by apoptosis.
  • these results demonstrate that 2-DFG is a potent inhibitor of glycolysis and inducer of autophagy and potentially promising novel antitumor agent for high grade gliomas and other cancers highly dependent on glycolysis.

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Abstract

L'invention concerne des procédés de traitement de tumeur du cerveau par administration d'une quantité thérapeutiquement efficace d'un composé de formule I ou II à un patient le nécessitant.
PCT/US2009/035702 2006-04-27 2009-03-02 Inhibiteurs de glycolyse utiles dans le traitement de tumeurs du cerveau Ceased WO2009108926A1 (fr)

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WO2021188586A1 (fr) 2020-03-16 2021-09-23 Board Of Regents, The University Of Texas System Procédé de traitement d'infections virales avec des monosaccharides de type hexoses et leurs analogues
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US10302630B2 (en) 2012-10-09 2019-05-28 The Procter & Gamble Company Method of identifying or evaluating beneficial actives and compositions containing the same
US9726663B2 (en) 2012-10-09 2017-08-08 The Procter & Gamble Company Method of identifying or evaluating synergistic combinations of actives and compositions containing the same
US11137387B2 (en) 2012-10-09 2021-10-05 The Procter & Gamble Company Method of identifying or evaluating synergistic combinations of actives and compositions containing the same
CN102875608A (zh) * 2012-10-12 2013-01-16 兰溪市苏格生物技术有限公司 葡萄糖丙酮化合物的制备方法
US11471394B2 (en) 2013-03-15 2022-10-18 Colgate-Palmolive Company Oral care compositions containing deoxy sugar antimetabolites
US10201554B2 (en) 2013-04-05 2019-02-12 Board Of Regents, The University Of Texas System Esters of 2-deoxy-monosacharides with anti proliferative activity
US11026960B2 (en) 2013-04-05 2021-06-08 Board Of Regents, The University Of Texas System Esters of 2-deoxy-monosaccharides with anti proliferative activity
EP3939595A1 (fr) 2013-04-05 2022-01-19 Board of Regents, The University of Texas System Esters de 2-désoxy-monosaccharides ayant une activité antiproliférative
WO2014165736A2 (fr) 2013-04-05 2014-10-09 Board Of Regents, The University Of Texas System Esters de 2-désoxy-monosaccharides ayant une activité antiproliférative
US11925654B2 (en) 2013-04-05 2024-03-12 Board Of Regents, The University Of Texas System Esters of 2-deoxy-monosaccharides with anti proliferative activity
WO2021188586A1 (fr) 2020-03-16 2021-09-23 Board Of Regents, The University Of Texas System Procédé de traitement d'infections virales avec des monosaccharides de type hexoses et leurs analogues

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