Glucose derivatives and anticancer agents using the same

Abstract

Provided are novel glucose derivatives and an anticancer agent using the same. The glucose derivatives according to the present invention consist of an L-glucose derivative represented by general formula (1) and a D-glucose derivative represented by general formula (2). In formula (1): XL2 represents an -SAuRL2 group; and XL1, XL3, XL4 and XL5 independently represent an -ORL1 group, an -NH2 group or a fluorine atom. RL2 represents a ligand, and RL1 represents a hydrogen atom or an organic group. In formula (2): XD2 represents an -SAuRD2 group; and XD1, XD3, XD4 and XD5 independently represent an -ORD1 group, an -NH2 group or a fluorine atom. RD2 represents a ligand, and RD1 represents a hydrogen atom or an organic group. The anticancer agent according to the present invention comprises at least one of the aforesaid glucose derivatives.

Description

[Technical field]

[0001] The present invention relates to a glucose derivative and an anticancer agent using the same. [Background technology]

[0002] One of the common cancer treatment methods is the use of anticancer drugs. In general, anticancer drugs act not only on cancer cells but also on normal cells, resulting in strong side effects. How to reduce these side effects has become an issue in cancer treatment. In response to this, molecular targeted drugs that identify molecules specifically expressed in cancer cells and suppress the proliferation and metastasis of cancer cells have attracted attention. Molecular targeted drugs are expected to suppress the side effects caused by classical anticancer drugs. However, in reality, molecules that are said to be specifically expressed in cancer cells are also expressed in normal cells, and molecular targeted drugs act on molecules that are different from those expected, resulting in more than a few side effects. Needless to say, the human body is a collection of cells. As long as they are cells, they require a carbon source for their activity and proliferation. Therefore, a method of identifying cancer by labeling the molecules that are taken up by cells, rather than targeting specific proteins or molecules in our body, has been attracting renewed attention in recent years (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Ono K. et al., Cancers, 12: 850, 2020 Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention relates to a novel glucose derivative. The present invention also provides the novel glucose derivative. The present invention aims to provide an anticancer agent using the above compound. [Means for solving the problem]

[0005] The present inventors have conducted extensive research to solve the above problems. As a result, they have found a novel glucose derivative that is taken up by cancer cells and is toxic to the cancer cells, and have completed the present invention. Specifically, the present invention provides the following.

[0006] A first aspect of the present invention is a glucose derivative selected from the group consisting of an L-glucose derivative represented by the following general formula (1) and a D-glucose derivative represented by the following general formula (2). [ka] [In formula (1), X L2 -SAuR L2 represents a group, and X L1 , X L3 , X L4 , and X L5 are each independently: -OR L1 R represents a group, an -NH2 group, or a fluorine atom. L2 indicates a ligand, R L1 represents a hydrogen atom or an organic group. [ka] [In formula (2), X D2 -SAuR D2 represents a group, and X D1 , X D3 , X D4 , and X D5 are each independently: -OR D1 R represents a group, an -NH2 group, or a fluorine atom. D2 indicates a ligand, R D1 represents a hydrogen atom or an organic group.

[0007] Since the glucose derivative according to the first aspect of the present invention contains a gold atom (Au) in the molecule, when the glucose derivative is taken up into a cancer cell, the gold atom may exhibit significant toxicity to the cancer cell.

[0008] A second aspect of the present invention is an anticancer agent comprising at least one glucose derivative according to the first aspect of the present invention. Effect of the Invention

[0009] According to the present invention, it is possible to provide a novel glucose derivative and an anticancer agent using the same. The glucose derivative is taken up by cancer cells and is toxic to the cancer cells. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the results of administering E2-ADG or E2-ALG at a concentration of 1000 μM for 10 or 30 minutes to mouse insulinoma MIN6 cells (Miyazaki J. et al., Endocrinology 127: 126-132, 1990) cultured for 5 days in vitro (DIV), and evaluating the activity of live cells based on the fluorescence intensity of the fluorescent marker Calcein. Error bars indicate standard deviation. * indicates p<0.001 (Bonferroni-Dunn test). [Diagram 2] 2 shows the results of administering D-glucose analog DGG and L-glucose analog LGG, in which the hydrogen atom of the OH group at position 1 of glucose is replaced with a -SAuP(C2H5)3 group, at a concentration of 1000 μM for 10 or 30 minutes to MIN6 cells at 5 DIV, and evaluating the occurrence of cell death based on the intensity of the positive signal of the dead cell marker propidium iodide (hereinafter referred to as "PI"). The horizontal axis indicates the diameter of each cell. [Diagram 3] FIG. 3 shows the percentage of dead cells as a PI value when E2-ADG or E2-ALG was administered at a concentration of 1000 μM for 90 minutes to MIN6 cells at 11 days of culture in the presence or absence of 150 μM phloretin (hereinafter referred to as "PHT"). Error bars indicate standard deviation. * indicates p<0.001 (Bonferroni-Dunn test). [Figure 4]Figure 4 shows the results of evaluating the activity of live cells by the fluorescence intensity of the fluorescent marker Calcein when M2-ADG or M2-ALG was administered for 30 minutes at the indicated concentrations to MIN6 cells 4 days after culture. Error bars indicate standard deviation. * indicates p<0.001 (Bonferroni-Dunn test). [Diagram 5] Figure 5 shows the percentage of dead cells as a PI value when M2-ADG or M2-ALG was administered for 30 minutes at the indicated concentrations to MIN6 cells 4 days into culture. Error bars indicate standard deviation. * indicates p<0.001 (Bonferroni-Dunn test). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Preferred embodiments of the present invention will be described in detail below. However, the present invention is not limited to the following embodiments. The relationship between the abbreviations and compound names used in the present specification, including the examples, is shown below. Ac: Acetyl group Ac2O: acetic anhydride AcONa: Sodium acetate DBU: Diazabicycloundecene DCM: dichloromethane DMF: N,N-dimethylformamide Et: Ethyl group Et3PAuCl: Chloro(triethylphosphine)gold(I) HClO4: perchloric acid HOBt: 1-hydroxybenzotriazole IPE: Diisopropyl ether KSAc: Potassium thioacetate Me: Methyl group MeCN: Acetonitrile MeOH: Methanol Me3PAuCl: Chloro(trimethylphosphine)gold(I) NaOMe: Sodium methoxide NIS: N-iodosuccinimide PBr3: Phosphorus tribromide Piv: Pivaloyl group PivCl: Pivaloyl chloride TCEP·HCl: Tris(2-carboxyethyl)phosphine hydrochloride Tf: Trifluoromethylsulfonyl group TfO: Trifluoromethanesulfonic anhydride Trt: Trityl group TrtCl: Trityl chloride

[0012] The glucose derivative of the present embodiment has a structure represented by the following general formula (1) or a structure represented by the following general formula (2).

[0013] [ka]

[0014] In formula (1), X L2 -SAuR L1 represents a group, and X L1 , X L3 , X L4 , and X L5 are each independently: -OR L1 R represents a group, an -NH2 group, or a fluorine atom. L2 indicates a ligand, R L1 represents a hydrogen atom or an organic group.

[0015] [ka]

[0016] In formula (2), X D2 -SAuR D2 represents a group, and X D1 , X D3 , X D4 , and X D5 are each independently: -OR D1 R represents a group, an -NH2 group, or a fluorine atom. D2 indicates a ligand, R D1 represents a hydrogen atom or an organic group.

[0017] Glucose derivatives exist in D- and L-forms, and the structure represented by general formula (1) is an L-form glucose derivative, and the structure represented by general formula (2) is a D-form glucose derivative. Glucose derivatives also include anomeric isomers, i.e., X L1 Or X D1 Anomers with X facing equatorial direction L1 Or X D1 In the present embodiment, the L-glucose derivative or D-glucose derivative may be a mixture of these anomers.

[0018] R L2 or R D2 Examples of the ligand in R include a phosphine ligand, a thiolate ligand, and an olefin ligand. L2 or R D2 is preferably a phosphine ligand, more preferably a trialkylphosphine ligand, even more preferably a trimethylphosphine ligand or a triethylphosphine ligand, and especially preferably a triethylphosphine ligand.

[0019] R L1 or R D1 In the above, examples of the organic group include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an acyl group. These groups may further have another substituent. The number of carbon atoms in the organic group may be, for example, 1 to 10, preferably 1 to 5, and more preferably 1 to 3.

[0020] R L1 or R D1 is preferably a hydrogen atom, an alkyl group, or an acyl group, more preferably a hydrogen atom or an acyl group, and even more preferably a hydrogen atom or an acetyl group.

[0021] X L1 , X L3 , X L4 , X L5 , X D1, X D3 , X D4 , or X D5 The isotope of the fluorine atom in is not particularly limited, and for example, is a radioisotope. 18 F, a stable isotope 19 F and the like. The isotope of the fluorine atom is 18 When the isotope of the fluorine atom is F, the glucose derivative of the present embodiment can be suitably used, for example, as a PET reagent. 19 When X is F, the glucose derivative of the present embodiment can be suitably used, for example, as a cancer treatment drug. From the viewpoint of making the above-mentioned PET reagent or cancer treatment drug use more suitable, in the general formula (1), L4 Or X L5 is preferably a fluorine atom, and in the general formula (2), X D4 Or X D5 is preferably a fluorine atom.

[0022] From the viewpoint of ease of synthesis or activity of glucose derivatives, X L1 , X L3 , X L4 , and X L5 are each independently: -OR L1 is preferably a group, and X D1 , X D3 , X D4 , and X D5 are each independently: -OR D1 It is preferable that the aryl group is a group.

[0023] The L-glucose derivative represented by the general formula (1) can be synthesized, for example, from an L-sugar or a derivative thereof. The D-glucose derivative represented by the general formula (2) can be synthesized, for example, from a D-sugar or a derivative thereof. Specific examples of L-sugar or a derivative thereof include L-glucose, L-mannose, L-galactose, 1,2:5,6-di-O-isopropylidene-α-L-glucofuranose, etc. Specific examples of D-sugar or a derivative thereof include D-glucose, D-mannose, D-galactose, 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, etc.

[0024] Examples of a method for synthesizing an L-glucose derivative represented by general formula (1) from an L-sugar or a derivative thereof, and a method for synthesizing a D-glucose derivative represented by general formula (2) from a D-sugar or a derivative thereof include the methods described in the Examples. Various derivatives can be synthesized by appropriately combining the steps of the methods described in the Examples or by introducing a substituent by a conventionally known method.

[0025] Methods other than those described in the Examples are not particularly limited, and examples thereof include the following methods.

[0026] X L2 represents the -SAuP(C2H5)3 group, and X L1 , X L3 , and X L4 represents an -OH group, and X L5 A glucose derivative having a structure represented by general formula (1), in which represents a fluorine atom, can be synthesized from L-mannose as a starting material according to the following reaction formula, as compound 11. In compound 11, the OH group at the 6-position of glucose is substituted with a fluorine atom. [ka]

[0027] X L2 represents the -SAuP(CH3)3 group, and X L1 , X L3, and X L4 represents an -OH group, and X L5 A glucose derivative having a structure represented by general formula (1) in which represents a fluorine atom can be synthesized according to the above reaction scheme in which Et is replaced by Me in the reactions from compound 9 to compound 11.

[0028] X L2 represents the -SAuP(C2H5)3 group, and X L1 , X L3 , and X L5 represents an -OH group, and X L4 A glucose derivative having a structure represented by general formula (1) in which represents a fluorine atom can be synthesized as compound 20 from compound 12 as a starting material according to the following reaction formula. In compound 20, the OH group at the 4-position of glucose is substituted with a fluorine atom. Compound 12 is compound 5L in the examples described later.

[0029] [ka]

[0030] X L2 represents the -SAuP(CH3)3 group, and X L1 , X L3 , and X L5 represents an -OH group, and X L4 A glucose derivative having a structure represented by general formula (1) in which represents a fluorine atom can be synthesized according to the above reaction scheme in which Et is replaced by Me in the reactions from compound 18 to compound 20.

[0031] By using the glucose derivative of this embodiment, it is possible to effectively treat cancer, particularly various cancers such as pancreatic cancer, brain tumor, breast cancer, stomach cancer, gastroesophageal junction cancer, oral cancer, biliary tract cancer, lung cancer, ovarian cancer, uterine cancer, and other adenocarcinomas, and sarcomas. Therefore, the glucose derivative of this embodiment can be suitably used as an anticancer agent.

[0032] The anticancer agent of the present embodiment comprises at least one glucose derivative of the present embodiment. The target of application of the anticancer agent is not particularly limited, and examples thereof include various cancers such as pancreatic cancer, brain tumor, breast cancer, stomach cancer, gastroesophageal junction cancer, oral cancer, biliary tract cancer, lung cancer, ovarian cancer, and uterine cancer, and adenocarcinoma, and sarcoma.

[0033] The glucose derivative of this embodiment or the anticancer agent of this embodiment can be administered, for example, in the form of an oral agent (tablet, granule, powder, capsule, syrup, etc.), a sublingual tablet, or an injection (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, intra-articular administration, epidural administration, etc.), or by direct application to a local area such as the cervix, oral cavity, or skin. EXAMPLES

[0034] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. The structures of the synthesized compounds were analyzed by UPLC-MS, 1 H-NMR, 13 The specific rotation was determined by using C-NMR etc. In each example, the specific rotation was measured five times at 20.00°C using a cell with a cell length of 100 mm for the sample for specific rotation measurement, and the average value calculated for the five measurement results was used.

[0035] Four types of 2-thio-glucose derivatives with trialkylphosphine gold bonded were synthesized. First, compound A (M2-ADG) in which the sugar moiety is D-glucose and trimethylphosphine gold is bonded to the thiol group at the 2nd position, second, compound B (E2-ADG) in which the sugar moiety is D-glucose and triethylphosphine gold is bonded to the thiol group at the 2nd position, third, compound C (M2-ALG) in which the sugar moiety is L-glucose and trimethylphosphine gold is bonded to the thiol group at the 2nd position, and fourth, compound D (E2-ALG) in which the sugar moiety is L-glucose and triethylphosphine gold is bonded to the thiol group at the 2nd position.

[0036] [Example 1] ·Compound A (M2-ADG) Compound A (M2-ADG) was synthesized using D-mannose (compound 1D) as a starting material according to the following reaction scheme. [ka]

[0037] Synthesis of Compound 1D to Compound 4D Compound 4D was obtained according to the procedure reported in the paper (J. Am. Chem. Soc. 2010, 132, 7405-7417).

[0038] Synthesis of compound 6D The process of obtaining compound 6D from compound 4D via compound 5D was based on the paper (J. Org. Chem. 2017, 82, 12613-12623), in which disulfide dimer 5D was formed by oxidation, and then reduced to selectively remove the S-acetyl group to obtain compound 6D.

[0039] ·Synthesis of compound 2D [ka]

[0040] In a 1L flask, acetic anhydride (95mL, 1.0mol), 50mg of D-mannose (compound 1D), and 70% by mass HClO4 (0.50mL) were added and heated to 40℃. The remaining D-mannose (24.95g, 138.5mmol) was then added in portions at the same temperature and stirred overnight at room temperature. The reaction vessel was then cooled in an ice bath, PBr3 (19.8mL, 139mmol) was added dropwise, and cold water (13.6mL) was added dropwise at 27℃ or less. After the addition was completed, the reaction solution was returned to room temperature and stirred for 1 hour. The reaction solution was cooled again in an ice bath, and an aqueous solution of sodium acetate (45.6g, 556mmol) and water (57mL) was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was poured into 83mL of cold water and extracted twice with dichloromethane. The mixture was then washed twice with cold saturated sodium bicarbonate water, re-extracted with dichloromethane, and dried over Na2SO4. The desiccant was filtered off, and the crude product containing 2D was concentrated under reduced pressure. Diethyl ether (225 mL) was added to the crude product, which contained 2D, to precipitate a white solid. The solid was filtered off and washed with cold diethyl ether to obtain 8.4 g of 2D (yield 17%).

[0041] Compound 4D synthesis [ka]

[0042] Under an argon atmosphere, 2D (8.4 g, 24.1 mmol), dehydrated dichloromethane (252 mL), and dehydrated pyridine (4.3 mL, 53.1 mmol) were added to a 500 mL Kolben and cooled to an internal temperature of -20°C. Tf2O (8.7 mL, 53.1 mmol) was then added so that the internal temperature did not exceed -20°C, and the mixture was stirred at the same temperature. After the reaction was completed, the reaction solution was poured into cold water, washed with cold saturated sodium bicarbonate water (340 mL), dried with Na2SO4, filtered, and concentrated to obtain a crude product of 3D as a brown oil. This was carried to the next step without further purification.

[0043] Under an argon atmosphere, 3D (11.6 g, 24.1 mmol), DMF (440 mL), and KSAc (27.6 g, 241 mmol) were added to a 1 L Kolben and stirred at room temperature. After the reaction was completed, extraction was performed with water / dichloromethane (volume ratio: 1 / 3), washed with brine, and concentrated under reduced pressure. The resulting residue containing 4D was purified with silica gel (216 g). Ethyl acetate / heptane (volume ratio: 1 / 3) was used as the developing solvent. The fraction containing the target product was concentrated to obtain 9.4 g of crude 4D. This crude product was recrystallized with ethyl acetate / heptane (volume ratio: 1 / 2) to obtain 5.8 g of 4D (yield 66%).

[0044] Synthesis of compound 5D [ka]

[0045] This reaction was carried out in four batches. Under an argon atmosphere, 4D (1.0 g, 2.5 mmol), dehydrated acetonitrile (15 mL), iodine (1.6 g, 6.2 mmol), and NIS (1.4 g, 6.2 mmol) were added and stirred at room temperature for 5 hours. (The same operation was carried out for three more batches using 1.0 g of 4D.) The reaction solution was then poured into water / dichloromethane (volume ratio: 1 / 3), and the organic layer was washed with a 5% by mass aqueous solution of sodium thiosulfate and brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue containing 5D was purified with silica gel (106 g). Ethyl acetate / heptane (volume ratio: 1 / 2) was used as the developing solvent. The fraction containing the target product was concentrated to obtain 1.7 g of crude 5D. Diisopropyl ether IPE (34 mL) was then added to the resulting crude product at room temperature to precipitate a solid. The solid was filtered and dried to obtain 1.5 g of 5D (yield 41%).

[0046] Synthesis of compound 7D [ka]

[0047] In a 20 mL eggplant flask, 5D (371 mg, 511 μmol), DMF (3.7 mL), and TCEP·HCl (192 mg, 766 μmol) were added under an argon atmosphere. After stirring at room temperature for 1 hour, the mixture was extracted with water / dichloromethane (volume ratio: 1 / 3), washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. Azeotropy was then performed with toluene to obtain crude 6D. This was carried out to the next step without further purification.

[0048] In an argon atmosphere, 6D, dehydrated dichloromethane (3.7mL), and Me3PAuCl (283mg, 916μmol) were added to a 20mL eggplant flask. Then, DBU (182μL, 1.2mmol) was dissolved in dehydrated dichloromethane (927μL) and added dropwise to the reaction solution. After confirming the completion of the reaction, the mixture was filtered through Celite and concentrated under reduced pressure. The resulting residue containing 7D was purified using NH silica gel (20g). Ethyl acetate / heptane (volume ratio: 1 / 1) was used as the developing solvent. The fraction containing the target product was concentrated to obtain 367mg of 7D (yield 56%).

[0049] Synthesis of compound A (M2-ADG) [ka]

[0050] In an argon atmosphere, 7D (360 mg, 566 μmol) and methanol (5.5 mL) were added to a 20 mL eggplant flask, and the flask was cooled to an internal temperature of -20°C. Then, 5M NaOMe methanol solution (136 μL, 679 μmol) was added dropwise, and the flask was stirred at the same temperature. After confirming the completion of the reaction, Amberlite IR120 (H + After adding 1,000 mL of ethyl acetate (foam) to adjust the pH to 6-7, the mixture was filtered and concentrated under reduced pressure. The resulting residue containing M2-ADG was purified with DIOL silica gel (15 g). Chloroform / methanol (volume ratio: 100 / 0 → 98 / 2 → 96 / 4) was used as the developing solvent. The fraction containing the target substance was concentrated and freeze-dried to obtain 127 mg of M2-ADG (yield 47%).

[0051] ·Specific rotation measurement Compound A (M2-ADG) was dissolved in water to a concentration of 0.9408 (g / dL) to obtain a sample for specific rotation measurement. The specific rotation was +30.41 degrees.

[0052] [Example 2] ·Compound B (E2-ADG) Compound B (E2-ADG) was synthesized according to the following reaction scheme using compound 5D of Example 1 as a starting material. [ka]

[0053] Synthesis of compound 8D [ka]

[0054] In a 30 mL eggplant flask, 5D (1.0 g, 1.4 mmol), DMF (10.4 mL), and TCEP·HCl (540 mg, 2.1 mmol) were added under an argon atmosphere. After stirring at room temperature for 1 hour, the mixture was extracted with water / dichloromethane (volume ratio: 1 / 3), washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. Azeotropy was then performed with toluene to obtain crude 6D. This was carried to the next step without further purification.

[0055] Under an argon atmosphere, 6D, dehydrated dichloromethane (10.4 mL), and Et3PAuCl (900 mg, 2.6 mmol) were added to a 50 mL Kolben. Then, DBU (512 μL, 3.4 mmol) was dissolved in dehydrated dichloromethane (2.6 mL) and added dropwise to the reaction solution. After confirming the completion of the reaction, the solution was concentrated under reduced pressure. The resulting residue containing 8D was purified using NH silica gel (62 g). Ethyl acetate / heptane (volume ratio: 1 / 1) was used as the developing solvent. The fraction containing the target product was concentrated to obtain 1.6 g of 8D (yield 85%).

[0056] Synthesis of compound B (E2-ADG) [ka]

[0057] In an argon atmosphere, 8D (1.63 g, 2.4 mmol) and methanol (24 mL) were added to a 100 mL Kolben, and the mixture was cooled to an internal temperature of -20°C. Then, 5 M NaOMe methanol solution (577 μL, 2.8 mmol) was added dropwise, and the mixture was stirred at the same temperature. After confirming the completion of the reaction, Amberlite IR120 (H + After adding ethyl acetate (foam) and adjusting the pH to 6-7, the mixture was filtered and concentrated under reduced pressure. The resulting residue containing E2-ADG was purified using DIOL silica gel (15 g). Chloroform / methanol (volume ratio: 100 / 0 → 98 / 2 → 96 / 4) was used as the developing solvent. The fraction containing the target substance was concentrated and freeze-dried to obtain 136 mg of E2-ADG (yield 11%).

[0058] ·Specific rotation measurement Compound B (E2-ADG) was dissolved in water to a concentration of 0.9410 (g / dL) to obtain a sample for specific rotation measurement. The specific rotation was +34.01 degrees.

[0059] [Example 3] ·Compound C (M2-ALG) Compound C (M2-ALG) was synthesized using L-mannose (compound 1L) as a starting material according to the following reaction scheme. [ka]

[0060] Synthesis of compound 2L [ka]

[0061] In a 1L flask, acetic anhydride (62g, 0.60mol), L-mannose (compound 1L) 50mg, and 70% by mass HClO4 (0.30mL) were added and heated to 40℃. The remaining L-mannose (14.95g, 83mmol) was then added in portions at the same temperature and stirred at room temperature for 17h. The reaction vessel was then cooled in an ice bath, PBr3 (22.5g, 83mmol) was added dropwise, and cold water (13.6mL) was added dropwise at 27℃ or less. After the addition was completed, the reaction solution was returned to room temperature and stirred for 1.5 hours. After checking the progress of the reaction by TLC, it was cooled again in an ice bath, and an aqueous solution of sodium acetate (27.3g, 333mmol) and water (34mL) was added dropwise. After stirring at room temperature for 20 minutes, the reaction solution was poured into 50mL of an ice bath and extracted twice with dichloromethane. The mixture was then washed twice with cold saturated sodium bicarbonate water, re-extracted with dichloromethane, and dried with Na2SO4. The desiccant was filtered off, and the mixture was concentrated under reduced pressure. 150 mL of diethyl ether was added to precipitate a white solid. The solid was filtered off and washed with cold diethyl ether to obtain 6.5 g of 2L (yield 23%).

[0062] Synthesis of compound 4L [ka]

[0063] Under an argon atmosphere, 2L (18.8g, 2.6mmol), dehydrated pyridine (3.33mL, 41.2mmol), and dehydrated dichloromethane (196mL) were added to a 500mL Kolben and cooled to an internal temperature of -20℃. Then, Tf2O (6.76mL, 41.2mmol) was added so that the internal temperature did not exceed -20℃, and the mixture was stirred at the same temperature. After the reaction was completed, the reaction solution was poured into cold water, washed with cold saturated sodium bicarbonate water (150mL), dried with Na2SO4, filtered, and concentrated to obtain 10.1g of a crude product of 3L as a brown oil. This was carried to the next step without further purification.

[0064] Under an argon atmosphere, 3L (9.0g, 18.7mmol), DMF (342mL), and KSAc (21.4g, 187mmol) were added to a 1L Kolben and stirred at room temperature. After the reaction was completed, extraction was performed with water / ethyl acetate (volume ratio: 1 / 3), washed with brine, and concentrated under reduced pressure. The resulting residue containing 4L was purified with silica gel (272g). Ethyl acetate / heptane (volume ratio: 1 / 3) was used as the developing solvent. The fraction containing the target substance was concentrated to obtain 7.8g of crude 4L. This crude material was recrystallized with ethyl acetate / heptane (volume ratio: 1 / 2) to obtain 5.0g of 4L (yield 66%).

[0065] Synthesis of compound 5L [ka]

[0066] This reaction was carried out in two batches. Under an argon atmosphere, 4L (1.5g, 3.7mmol), dehydrated acetonitrile (30mL), iodine (2.3g, 9.2mmol), and NIS (2.1g, 9.2mmol) were added and stirred at room temperature for 6 hours. (The same operation was carried out in another batch using 1.5g of 4L.) The reaction solution was then poured into water / dichloromethane (volume ratio: 1 / 3), and the organic layer was washed with 5% by mass sodium thiosulfate aqueous solution and brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue containing 5L was purified using silica gel (55g). Ethyl acetate / heptane (volume ratio: 1 / 1) was used as the developing solvent. The fraction containing the target product was concentrated to obtain 1.5g of crude product of 5L. Next, diisopropyl ether IPE (15mL) was added to the obtained crude product at room temperature to precipitate a solid. The solid was filtered and dried to obtain 993 mg of 5L (yield 31%).

[0067] Synthesis of compound 7L [ka]

[0068] In an argon atmosphere, 5L (335mg, 0.461mmol), DMF (3.3mL), and TCEP·HCl (198mg, 0.690mmol) were added to a 30mL flask. After stirring at room temperature for 2 hours, the mixture was extracted with water / dichloromethane (volume ratio: 1 / 3), washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. Azeotropy was then performed with toluene to obtain 6L of crude material (light yellow oil). This was carried to the next step without further purification.

[0069] In an argon atmosphere, 6L, dehydrated dichloromethane (3.4mL), and Me3PAuCl (281mg, 0.910mmol) were added to a 10mL flask. DBU (168mg, 1.10mmol) was then dissolved in dehydrated dichloromethane (0.84mL) and added dropwise to the reaction solution. After confirming the completion of the reaction, the mixture was filtered through Celite and concentrated under reduced pressure. The resulting residue containing 7L was purified using NH silica gel (1.8g). Ethyl acetate / heptane (volume ratio: 1 / 1) was used as the developing solvent. The fraction containing the target product was concentrated to obtain 430mg of 7L (yield 73%).

[0070] Synthesis of compound M2-ALG [ka]

[0071] Under an argon atmosphere, 7L (373 mg, 0.59 mmol) and methanol (5.6 mL) were added to a 10 mL flask and cooled to an internal temperature of -20°C. Then, 5M NaOMe methanol solution (0.14 mL, 0.70 mmol) was added dropwise and stirred at the same temperature. After confirming the completion of the reaction, Amberlite IR120 (H + After adding ethyl acetate (foam) and adjusting the pH to 6-7, the mixture was filtered and concentrated under reduced pressure. The resulting residue containing M2-ALG was purified with DIOL silica gel (10 g). Chloroform / methanol (volume ratio: 100 / 0 → 98 / 2 → 96 / 4) was used as the developing solvent. The fraction containing the target substance was concentrated and freeze-dried to obtain 136 mg of M2-ALG (yield 50%).

[0072] ·Specific rotation measurement Compound C (M2-ALG) was dissolved in water to a concentration of 0.6224 (g / dL) to obtain a sample for specific rotation measurement. The specific rotation was −31.65 degrees.

[0073] [Example 4] ·Compound D(E2-ALG) Compound D (E2-ALG) was synthesized according to the following reaction scheme using compound 5L of Example 3 as a starting material. [ka]

[0074] Synthesis of compound 8L [ka]

[0075] In an argon atmosphere, 5L (444mg, 0.61mmol), DMF (4.4mL), and TCEP·HCl (263mg, 0.92mmol) were added to a 30mL flask. After stirring at room temperature for 2 hours, the mixture was extracted with water / dichloromethane (volume ratio: 1 / 3), washed with brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. Azeotropy was then performed with toluene to obtain 6L of crude material. This was carried to the next step without further purification.

[0076] In an argon atmosphere, 6L, dehydrated dichloromethane (4.4mL), and Et3PAuCl (423mg, 1.21mmol) were added to a 100mL eggplant flask. Then, DBU (223mg, 1.5mmol) was dissolved in dehydrated dichloromethane (1.0mL) and added dropwise to the reaction solution. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure. The resulting residue containing 8L was purified using NH silica gel (24.4g). Ethyl acetate / heptane (volume ratio: 1 / 1) was used as the developing solvent. The fraction containing the target product was concentrated to obtain 541mg of 8L (yield 65%).

[0077] Synthesis of compound E2-ALG [Chemistry]

[0078] Under an argon atmosphere, 8L (541 mg, 0.797 mmol) and methanol (8.1 mL) were added to 30 mL of corben, and the mixture was cooled so that the internal temperature reached -20°C. Then, a 5M NaOMe methanol solution (0.19 mL, 0.96 mmol) was added dropwise, and the mixture was stirred at the same temperature. After confirming the completion of the reaction, Amberlite IR120 (H + form) was added to adjust the pH to 6 - 7, followed by filtration and concentration under reduced pressure. The residue containing E2-ALG obtained was purified using DIOL silica gel (10 g). Chloroform / methanol (volume ratio: 100 / 0 → 98 / 2 → 96 / 4) was used as the developing solvent. The fraction containing the target product was concentrated and lyophilized to obtain 185 mg of E2-ALG (yield 46%).

[0079] ·Specific rotation measurement Compound D (E2-ALG) was dissolved in water to a concentration of 0.6430 (g / dL) to obtain a sample for specific rotation measurement. The specific rotation was -32.12 degrees.

[0080] <Administration test using E2-ADG or E2-ALG> [Example 5-1] Administration to MIN6 cells at an early stage after the start of culture The effects of E2-ADG (synthesized in Example 2) and E2-ALG (synthesized in Example 4) on cell proliferation were investigated. As the cells, a mouse pancreatic β-cell line (insulinoma) MIN6 (Miyazaki J. et al., Endocrinology 127: 126-132, 1990) was used, and all experiments were performed using early passage cells with a passage number of 10 or less.

[0081] MIN6 cells are one of the most widely used and reliable cells in the world as a normal pancreatic β-cell line of the islets of Langerhans that secrete insulin (Miyazaki J. et al., Endocrinology 127: 126-132, 1990). During the period from the start of culture to approximately 6 DIV, the uptake of fluorescent D-glucose 2-NBDG into the cells is mainly mediated by the glucose transporter GLUT (Yamada, K. et al., J. Biol. Chem. 275: 22278-83, 2000; Yamada, K. Nature Protocols 2: 753-62, 2007; Sasaki, A. et al., Human Cell 2016, 29, 37-45).

[0082] Previous studies have shown that when fluorescent D-glucose 2-NBDG is applied to MIN6 cells with passage number 10 or less at a time younger than 6 DIV, uptake via GLUT is observed, whereas uptake of fluorescent L-glucose 2-NBDLG is occasionally observed slightly but is generally very weak; after 7 DIV of culture, a small proportion of MIN6 cells clearly show uptake of 2-NBDLG into the cells; after 9 DIV of culture, uptake of 2-NBDLG into MIN6 cells becomes evident, with maximum uptake of 2-NBDLG being observed at 10-15 DIV (Sasaki, A. et al., Human Cell 2016, 29, 37-45). Furthermore, it has been reported that the uptake of 2-NBDLG into MIN6 cells at 10-15 DIV is not mediated by glucose transporters such as GLUTs, but by a "channel-like transport mechanism that does not distinguish between D-glucose and L-glucose" (Sasaki, A. et al., Human Cell 2016, 29, 37-45); furthermore, it has been reported that this "channel-like transport mechanism that does not distinguish between D-glucose and L-glucose" is selectively inhibited by 150 μM phloretin, and that in the presence of this concentration of phloretin, uptake into MIN6 cells is almost completely eliminated (Sasaki, A. et al., Human Cell 2016, 29, 37-45).

[0083] Based on these findings, we predicted that if E2-ALG does not pass through GLUTs and is taken up into MIN6 cells via the channel-like transport mechanism described above, as in the case of application of 2-NBDLG, then E2-ALG would hardly be taken up by MIN6 cells up to 6 DIV from the start of culture, and the effect of E2-ALG on cell proliferation would be minimal.

[0084] In the experiment, approximately 3000 MIN6 cells were seeded in each well of a 96-well plate, and after 5 DIV had elapsed since the start of culture, wells to be administered with E2-ALG and wells to be administered with E2-ADG were placed in the same plate to minimize external disturbance, and administration was performed according to a previously established method (Sasaki, A. et al., Human Cell 2016, 29, 37-45). E2-ALG was dissolved in buffer to a concentration of 1000 μM, and administered to MIN6 cells for 10 or 30 minutes, and then washed out with a buffer solution that did not contain E2-ALG. Meanwhile, E2-ADG was administered in the same manner at a concentration of 1000 μM. To exclude uptake via hemichannels or gap junctions, carbenoxolone was pre-dissolved in the buffer solution (Sasaki, A. et al., Human Cell 2016, 29, 37-45).

[0085] Changes in cellular activity were evaluated using the live cell marker Calcein-AM. Calcein-AM is cell membrane permeable, and after entering the cell, the AM is cleaved by the esterase activity of the cell, resulting in calcein that emits green fluorescence. Calcein-AM was applied to MIN6 cells in the usual manner, and the green fluorescence emitted by the cells was quantitatively measured using a Yokogawa confocal quantitative image cytometer CellVoyager CQ1. Image analysis was performed using the software provided with the CQ1, and the differences between the E2-ALG and E2-ADG groups were statistically compared using Stat View 5.0. The Bonferroni-Dunn test was used for statistical comparison. In addition, the values ​​of MIN6 cells in Krebs-Ringer buffer (KRB) solution without E2-ALG or E2-ADG at the same time were used as a negative control.

[0086] The degree of cell death was evaluated using propidium iodide (PI), a red dye impermeable to cell membranes. PI was applied to MIN6 cells simultaneously with Calcein-AM. The principle of cell death evaluation using PI is as follows. In cells with healthy cell membranes, PI does not enter the cells and does not emit fluorescence. However, when the integrity of the cell membrane is lost due to deterioration of the cell condition, PI nonspecifically enters the cells, and the nucleus emits red fluorescence as a result of binding to the nucleus. The degree of this red fluorescence was quantitatively measured using CellVoyager CQ1, and image analysis was performed using the software provided with the CQ1. The degree of cell death was evaluated by statistically comparing the control group and the treatment group, or the E2-ALG treatment group and the E2-ADG treatment group.

[0087] First, the effect of E2-ALG on MIN6 cells at 5 DIV was examined using the green fluorescence of Calcein, which indicates cell activity. The results showed that when E2-ALG was administered for 10 minutes, the average cell activity was slightly lower than that of the negative control group, but there was no statistically significant difference between the negative control and E2-ALG (Figure 1). When E2-ALG was administered for 30 minutes, cell activity was clearly lower than that of the negative control, and this decrease was statistically significant (Figure 1).

[0088] At the same time, evaluation of cell death using the dead cell marker propidium iodide (PI) showed that the average values ​​were higher than those in the negative control KRB, but there was also a large variability, and no statistically significant differences were observed between the negative control group and E2-ALG, between the negative control group and E2-ADG, or between E2-ALG and E2-ADG in either the 10-minute or 30-minute administration groups (data not shown).

[0089] However, when comparing the cytotoxicity of E2-ADG administered for 10 min to that of E2-ALG administered for 10 min to MIN6 cells at 5 DIV, contrary to our expectations, the average cellular activity indicated by calcein intensity was slightly lower in the case of E2-ADG than in the case of E2-ALG, but no statistically significant difference was observed between the two (Figure 1). Similar results were obtained after administration for 30 min (Figure 1). These results were completely unexpected.

[0090] In fact, the above experimental results are completely different from the results shown in FIG. 2, in which D-glucose analog DGG and L-glucose analog LGG (Yamaguchi E. et al., PCT / JP2021 / 013857), in which the hydrogen atom of the 1-OH group of glucose is replaced with the same -SAuP(C2H5)3 group as in the present invention, were administered to MIN6 cells at 5 DIV as in the present invention at a concentration of 1000 μM for 30 minutes. DGG caused clear PI-positive cell death, while LGG showed only PI-positive cell death almost the same as that of the negative control group. Even when administered at 1000 μM for 10 minutes, DGG caused PI-positive cell death exceeding that of the negative control, while the PI-positive cell death shown by LGG was the same as that of the negative control group (FIG. 2).

[0091] The results of administering DGG or LGG show that DGG exhibits cytotoxicity by penetrating MIN6 cells at a stage when there are few cells showing characteristics of malignant tumor cells such as nuclear atypia via a protein that selectively interacts with D-glucose, such as a glucose transporter, while LGG, which cannot pass through the glucose transporter, does not exhibit cytotoxicity to these cells under the same conditions. These results are clearly different from the results of the present invention, in which not only E2-ADG but also E2-ALG were administered to the same MIN6 cells at the same concentration and time as above, and both caused a clear decrease in cell activity, and no statistically significant difference was observed between the D type and the L type.

[0092] These results of administering E2-ADG or E2-ALG at a concentration of 1000 μM for 10 or 30 minutes to MIN6 cells at 5 DIV may be explained by assuming that "neither E2-ALG nor E2-ADG can pass through the glucose transporter GLUT expressed in MIN6 cells at 5 DIV," but that both E2-ADG and E2-ALG strongly penetrate into cells via a "channel-like transport mechanism that does not distinguish between D-glucose and L-glucose," which is also expressed in very small amounts in MIN6 cells at 5 DIV, and clearly reduce the activity of the cells that they penetrated, although they did not consistently induce cell death as assessed by PI-positive cells. Therefore, to verify this hypothesis, the following experiment was further performed.

[0093] [Example 5-2] Administration to MIN6 cells 10 DIV or later from the start of culture MIN6 cells were used with 10 or fewer passages, and E2-ALG or E2-ADG was applied to the MIN6 cells at a concentration of 1000 μM for 90 minutes at 11 DIV, which is the time when spheroids with a diameter of 100 μm or more are usually formed. Specifically, about 1000 MIN6 cells were seeded in each well of a 96-well plate, and E2-ALG was dissolved in a buffer to a concentration of 10 μM or 1000 μM and administered to the MIN6 cells for 90 minutes at 11 DIV, and then quickly washed off with a buffer solution that did not contain E2-ALG. Similarly, E2-ADG was simultaneously applied to another well in the same plate. Statistical comparisons were made between the control group and the treatment group, or between the E2-ALG treatment group and the E2-ADG treatment group using the cell death marker PI (Figure 3).

[0094] As a result of the experiment, both E2-ALG and E2-ADG caused a significant increase in the percentage of dead cells, as indicated by the PI value, in MIN6 cells at 11 DIV, and caused strong cytotoxicity, as compared with the negative control of KRB solution alone without E2-ALG or E2-ADG (Figure 3). Furthermore, the degree of effect on cells was slightly lower in E2-ALG than in E2-ADG on average, but no statistically significant difference was observed between the two (Figure 3). At a concentration of 10 μM, the effect of E2-ALG or E2-ADG on cells was greater on average than the negative control of KRB solution alone, but was not significantly different, and there was no significant difference between E2-ALG and E2-ADG (not shown).

[0095] Previously, the inventors have reported that fluorescent L-glucose such as 2-NBDLG and CLG is taken up into mouse pancreatic tumor cells and human osteosarcoma cells, which show malignant characteristics of unequal nuclei, via a specific transport mechanism inhibited by PHT, the aglycone of polyphenol phlorizin contained in some plants of the Rosaceae family, such as apple skin and seeds, or cherry leaves (see Human Cell 29: 37-45, 2016; Human Cell 34: 634-643, 2021; Org. Lett. 18: 1338-1341, 2016). In addition, the results of the inventors' previous experiments suggest that the transport mechanism of these fluorescent L-glucose into cells is a non-transporter type, possibly a channel-like mechanism, that does not distinguish between D-glucose derivatives and L-glucose derivatives (Human Cell 29: 37-45, 2016). Such a channel-like mechanism may be specifically expressed in the cell membrane of malignant tumor cells found in patients with intractable cancer, and in fact, fluorescent L-glucose such as 2-NBDLG (Human Cell 29: 37-45, 2016) and CLG is hardly taken up by normal cells or tumor cells showing benign characteristics (US10001487B2, US10509041B2, EP3130596B1, Patent No. 6566348, ZL201580030346.9). Therefore, the following experiments were further carried out.

[0096] We analyzed whether the cell death caused by E2-ALG and E2-ADG in MIN6 cells was mediated by a specific transport mechanism inhibited by PHT on the same plate. Specifically, 1000 μM E2-ALG was applied to MIN6 cells for 90 minutes in the presence or absence of 150 μM PHT, and statistically examined whether the cytotoxicity caused by E2-ALG, i.e., the percentage of dead cells as indicated by the PI value, was significantly reduced by PHT. The same experiment was also performed on the same plate with E2-ADG, and both were compared with the control.

[0097] As a result of the experiment, about 75% of the cytotoxicity of E2-ALG and E2-ADG against MIN6 cells at 11 DIV, i.e., MIN6 cells at the stage when cells showing the characteristics of malignant tumors have increased, was eliminated by PHT (Figure 3). It was a completely unexpected result that the uptake of E2-ALG and E2-ADG into tumor cells was inhibited by PHT with such high specificity in a realistic administration time of 90 minutes applied in clinical practice. The present invention overturns the conventional wisdom based on fluorescently labeled D-glucose that has been established so far.

[0098] To the best of the inventors' knowledge, E2-ALG and E2-ADG are a pair of glucose derivatives that are enantiomers of each other, of which the D-form has no strong preference for glucose transporters, and are the first examples of molecules that are selectively taken up by tumor cells that exhibit characteristics of malignant tumor cells via a non-glucose transporter pathway that is specifically inhibited by phloretin, and selectively induce significant cell death in these cells.

[0099] [Consideration] These results indicate that E2-ALG and E2-ADG were selectively taken up by cells exhibiting characteristics of malignant tumors through a specific mechanism inhibited by PHT, and induced strong cell death within 90 minutes. Administration for 30 minutes had a smaller effect on cells than administration for 90 minutes. In addition, looking at the relationship between administration concentration and effect, in this short-term single administration, the cytotoxic mechanism became apparent at concentrations between 100 and 1000 μM, but it is possible that cytotoxic effects may be induced at lower concentrations if observations are performed over a long period of time.

[0100] In E2-ALG and E2-ADG, the -SAuP(C2H5)3 group attached to the 2nd position of L- and D-glucose is the same group attached to the 1st position of D-glucose in Auranofin, which is FDA-approved as an antirheumatic drug. Auranofin further has a structure in which all hydrogen atoms in the OH group of glucose are replaced with acetyl groups. Auranofin has relatively few side effects, and has been reported to have anticancer effects against ovarian cancer, breast cancer, non-small cell lung cancer, acute lymphocytic leukemia, osteosarcoma, and various other cancers. However, there are many unknowns about the mechanism of action, and clinical trials are being repeatedly conducted as drug repositioning. Recent research has shown that Et3PAuCl is effective against nutrient-deficient pancreatic cancer cells (Onodera, T. et al., J. Biol. Chem. 295, 16678-16690, 2020), and there are also reports that Et3PAuCl alone exhibits cytotoxicity against colon cancer cells (ACS Med.Chem. Lett. 8: 997-1001,2017).

[0101] As far as the inventors know, glucose analog molecules in a mirror-image relationship in which the 2-position of D-glucose and the 2-position of L-glucose are substituted in the same way with the same cytotoxic substituents have been applied to mammalian cells, and after comparing the passage characteristics of glucose transporters and channel-like transport mechanisms (non-glucose transporter type), the D-glucose analog substituted at the 2-position does not show a statistically significant difference from its mirror image isomer, the L-glucose analog, in the degree of cell death, and the D-glucose analog does not pass through the glucose transporter. There are also no reports of experiments arguing that both these D-glucose analogs and L-glucose analogs show cytotoxicity by passing through the channel-like transport mechanism. In other words, E2-ADG and its mirror image isomer, E2-ALG, are expected to be a never-before-seen type of glucose analog that can minimize toxicity to non-cancer cells by both passing through the channel-like transport mechanism in the same way and not passing through the glucose transporters widely expressed in normal cells. In particular, if E2-ADG, a D-glucose analog, does not pass through GLUT widely expressed in almost all normal cells in the body, it can greatly reduce side effects on normal cells compared to D-glucose analogs that pass through GLUT, and since it is a D-glucose analog, it may be supplied at a relatively low cost, and medical economic advantages are expected. On the other hand, E2-ALG, an analog of L-glucose that does not bind to membrane proteins having a D-glucose binding site, may ensure higher safety and effectively shrink cancer even when used at a higher concentration than D-glucose analogs.

[0102] <Administration test using M2-ADG or M2-ALG> [Example 6-1] Administration to MIN6 cells at an early stage after the start of culture An administration test was carried out in the same manner as in Example 5-1, except that M2-ADG (synthesized in Example 1) was used instead of E2-ADG, and M2-ALG (synthesized in Example 3) was used instead of E2-ALG in Example 5-1. However, M2-ADG or M2-ALG was administered for 30 minutes 4 DIV after the start of culture, and the concentrations of M2-ADG or M2-ALG were 10 μM, 100 μM, or 1000 μM.

[0103] As a result, first, as in Example 5-1, no statistically significant difference was observed between the M2-ADG administration group and the M2-ALG administration group at any concentration in terms of cell activity evaluated by calcein (Figure 4). In particular, when the concentration was 10 μM or 100 μM, the average cell activity was only slightly decreased compared to the negative control of KRB alone, regardless of whether M2-ADG or M2-ALG was administered, and there was no significant difference between the negative control and the KRB alone, and there was no significant difference in cell activity between M2-ADG and M2-ALG. However, at a concentration of 1000 μM, a significant decrease in cell activity was observed when either M2-ADG or M2-ALG was administered, and there was no significant difference between the cell activity decrease effects of the two administration groups (Figure 4).

[0104] On the other hand, the results of evaluating the occurrence of cell death by administration of M2-ADG or M2-ALG to MIN6 cells using the cell death marker PI are shown in FIG. 5. In both M2-ADG and M2-ALG administration groups, when the administration concentration was 10 μM, there was no difference in the degree of cell death compared to the negative control (FIG. 5). When the administration concentration was 100 μM, the average value increased, but there was still no significant difference with the negative control (FIG. 5). However, at a concentration of 1000 μM, as can be seen from FIG. 5, clear cell death was observed. These results are clearly different from the results when E2-ALG or E2-ADG was administered for the same 30 minutes (Example 5-1). At any of the above administration concentrations, no statistically significant difference was observed between the M2-ADG administration group and the M2-ALG administration group (FIG. 5).

Claims

1. A glucose derivative selected from the group consisting of an L-glucose derivative represented by the following general formula (1) and a D-glucose derivative represented by the following general formula (2): 【Chemistry 1】 [In formula (1), X Ｌ２ Ha-SAuR Ｌ２ represents a group, and X Ｌ１ , X Ｌ３ , X Ｌ４ , and X Ｌ５ Each independently represents -OR Ｌ１ group, -NH ２ R represents a group or a fluorine atom. Ｌ２ represents a ligand, R Ｌ１ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an acyl group. 【Chemistry 2】 [In formula (2), X Ｄ２ Ha-SAuR Ｄ２ represents a group, and X Ｄ１ , X Ｄ３ , X Ｄ４ , and X Ｄ５ Each independently represents -OR Ｄ１ group, -NH ２ R represents a group or a fluorine atom. Ｄ２ represents a ligand, R Ｄ１ represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, or an acyl group.

2. X Ｌ１ , X Ｌ３ , X Ｌ４ , and X Ｌ５ Each independently represents -OR Ｌ１ is a group, and X Ｄ１ , X Ｄ３ , X Ｄ４ , and X Ｄ５ Each independently represents -OR Ｄ１ The glucose derivative according to claim 1, which is a group.

3. R Ｌ２ and R Ｄ２ The glucose derivative according to claim 1 or 2, wherein each of the is independently a trialkylphosphine ligand.

4. The glucose derivative according to claim 1 or 2, which is an L-glucose derivative.

5. An anticancer agent comprising at least one glucose derivative according to claim 1 or 2.

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