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WO2021192726A1 - Inhibiteur d'absorption de choline, inducteur d'apoptose, médicament anticancéreux, et utilisation associée - Google Patents

Inhibiteur d'absorption de choline, inducteur d'apoptose, médicament anticancéreux, et utilisation associée Download PDF

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Publication number
WO2021192726A1
WO2021192726A1 PCT/JP2021/005541 JP2021005541W WO2021192726A1 WO 2021192726 A1 WO2021192726 A1 WO 2021192726A1 JP 2021005541 W JP2021005541 W JP 2021005541W WO 2021192726 A1 WO2021192726 A1 WO 2021192726A1
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cancer
uptake inhibitor
present
choline
compound
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Japanese (ja)
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正人 稲津
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Tokyo Medical University
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Tokyo Medical University
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a choline uptake inhibitor, a cell death inducer, an anticancer agent, and its use.
  • anticancer drugs are a very important development target. Then, various kinds of anticancer agents such as small molecule compounds, antibodies, and nucleic acids are being tried to be put into practical use.
  • an object of the present invention is to provide a new drug that can be used as an anticancer drug.
  • the choline uptake inhibitor of the present invention is an inhibitor that suppresses the uptake of choline into cells, and is characterized by containing an isoquinoline compound represented by the following formula (1) or a derivative thereof. do.
  • the cell death inducer of the present invention is characterized by containing the choline uptake inhibitor of the present invention.
  • the anticancer agent of the present invention is characterized by containing the choline uptake inhibitor of the present invention.
  • the method for suppressing cholinergic uptake of the present invention is characterized by including a step of adding the cholinergic uptake inhibitor of the present invention to cancer cells.
  • the method for inducing cell death of the present invention is characterized by including a step of adding the choline uptake inhibitor of the present invention to cancer cells.
  • the method for treating cancer of the present invention is characterized by comprising a step of administering the choline uptake inhibitor of the present invention to a patient.
  • cell death of cancer cells can be induced by suppressing the uptake of choline by cancer cells.
  • many of the anticancer agents having a plant-derived compound as an active ingredient have been clinically applied, and various compounds in the present invention have a plant-derived compound as a skeleton. Therefore, it is highly possible that the present invention will be clinically applied as a very useful anticancer agent as well as an anticancer agent containing a plant-derived compound as an active ingredient, which has already been clinically applied. Therefore, it can be said that the present invention is very useful in the medical field, for example.
  • FIG. 1 is a graph showing the relationship between the amount of choline uptake in tongue cancer cells and the compound concentration.
  • FIG. 2 (A) is a graph showing the relationship between the survival rate of tongue cancer cells (HCS-3), the compound concentration, and the treatment time with the compound, and FIG. 2 (B) is the survival of tongue cancer cells. It is a graph which shows the rate, and FIG. 2C is a graph which shows the caspase-3 / 7 activity of tongue cancer cells.
  • FIG. 3 is a graph showing the relationship between the amount of choline uptake and the compound concentration in glioma cells (U251MG) and pancreatic cancer cells (MIA PaCa-2).
  • FIG. 3 is a graph showing the relationship between the amount of choline uptake and the compound concentration in glioma cells (U251MG) and pancreatic cancer cells (MIA PaCa-2).
  • FIG. 3 is a graph showing the relationship between the amount of choline uptake and the compound concentration in glioma cells
  • FIG. 4 is a graph showing the relationship between the survival rate of glioma cells (U251MG) or pancreatic cancer cells (MIA PaCa-2) and the compound concentration.
  • FIG. 5 is a graph showing the relationship between the survival rate of various cancer cells and the compound concentration when compound # 1 is added.
  • FIG. 6 is a graph showing the relationship between the survival rate of various cancer cells and the compound concentration when compound # 16 is added.
  • FIG. 7 (A) shows the results of cell viability and caspase-3 / 7 activity using compound # 1 in the two graphs on the left for glioma cells (U251MG), and the two graphs on the right are the results. , Cell viability with compound # 16 and results of caspase-3 / 7 activity.
  • FIG. 1 shows the results of cell viability with compound # 16 and results of caspase-3 / 7 activity.
  • FIG. 7 shows pancreatic cancer cells (MIA PaCa-2), and the two graphs on the left are the results of cell viability and caspase-3 / 7 activity using compound # 1, and the right. The two graphs are the results of cell viability and caspase-3 / 7 activity with compound # 16.
  • FIG. 8 shows the results of administration of the compound # 1 (Compound X) to a model mouse transplanted with glioma cells (U251MG), and the graph of (A) shows the number of days after administration and the tumor volume (mm) of the model mouse.
  • FIG. 9 shows the results of administration of the compound # 1 or # 16 to a model mouse transplanted with pancreatic cancer cells (MIAPaCa-2), and the graph of (A) shows the number of days after administration and the tumor of the model mouse.
  • the relationship with the volume (mm 3 / mouse) is shown, the graph in (B) shows the total tumor volume from the 0th day to the 11th day after administration, and the graph in (C) shows the number of days after administration.
  • FIG. 10 shows the results of administration of the compound # 2 to a model mouse transplanted with tongue cancer cells (HSC-3), and the graph of (A) shows the number of days after administration and the tumor volume (mm) of the model mouse. The relationship with 3 / mouse) is shown, the graph in (B) shows the total tumor volume from the 0th day to the 17th day after administration, and the graph in (C) shows the number of days after administration and the model mouse. The relationship with the weight of the mouse is shown.
  • HSC-3 tongue cancer cells
  • the choline uptake inhibitor of the present invention is characterized by containing an isoquinoline compound represented by the above formula (1) or a derivative thereof.
  • the compound of the formula (1) and a derivative thereof are collectively referred to as a drug in the present invention.
  • the choline uptake inhibitor of the present invention is characterized by containing the above-mentioned agent, and other configurations and conditions are not particularly limited.
  • the choline uptake inhibitor of the present invention cell death of cancer cells can be induced by suppressing the uptake of choline in cancer cells. Therefore, the cholinergic uptake inhibitor of the present invention can be used, for example, as a cell death inducer as described later.
  • the mode of cell death of cancer cells is not particularly limited, and examples thereof include apoptosis. Therefore, the cholinergic uptake inhibitor of the present invention can also be referred to as, for example, a cell death inducer, specifically, for example, an apoptosis inducer.
  • the choline uptake inhibitor that suppresses choline uptake in cancer cells can be read as, for example, a cell death inducer or an apoptosis inducer, and the cell death inducement effect can be read as, for example, the apoptosis inducer effect. Is.
  • the agent in the present invention is the isoquinoline compound (# 1) represented by the above formula (1) or a derivative thereof.
  • the derivative is not particularly limited, and the structure of the isoquinoline ring in the derivative is represented by, for example, any of the following formulas (A1) to (A4) in Table 2. Further, in the derivative, the substituent R of the isoquinoline ring is represented by, for example, any of the following structures (B1) to (B18) in Table 3. The structure of the derivative is, for example, a combination of the isoquinoline ring of the following formula (A1) and the substituent R of any of the following formulas (B1) to (B18), the isoquinoline ring of the following formula (A2) and the following formula (B1).
  • Tables 4, 5, and 6 show specific examples of the derivatives.
  • Derivatives # 2 in Table 4 are combinations of formulas (A2) and (B2)
  • derivatives # 3 to # 10 in Table 5 are combinations of formulas (A1) and formulas (B3) to (B10).
  • the derivatives # 11, # 12, # 14 to # 16 are combinations of the formula (A1) and the formulas (B11), (B12), (B14) to (B16)
  • the derivatives # 13 and # 17 are a combination of the formula (A3) and the formula (B13) or (B17)
  • the derivative # 18 is a combination of the formula (A4) and the formula (B18).
  • the agent may be, for example, a salt, hydrate, solvate, isomer, etc. of the compound of the formula (1), a salt, hydrate, solvate, isomer, etc. of the derivative. ..
  • the isomer include a stereoisomer and a tautomer.
  • the choline uptake inhibitor of the present invention contains the above-mentioned drug as an active ingredient.
  • the choline uptake inhibitor of the present invention may be composed of, for example, only the active ingredient, or may contain the active ingredient and other ingredients.
  • the active ingredient may be composed of, for example, only the drug, or may contain the drug and other active ingredients.
  • the drug contained as the active ingredient may contain, for example, only one type or two or more types.
  • the other component is, for example, a pharmaceutically acceptable additive.
  • the cholinergic uptake inhibitor of the present invention may be used, for example, in vivo or in vitro.
  • the cholinergic uptake inhibitor of the present invention can be used, for example, as a research reagent, or can be used as a pharmaceutical product or a quasi-drug.
  • the target of addition of the choline uptake inhibitor of the present invention is not particularly limited, and is, for example, a cell, a tissue, an organ containing the cell, a living body, or the like.
  • the addition target may be, for example, a cancerous target, a normal non-cancerous target, or a target for which it is unknown whether or not the addition is cancerous.
  • the organism from which the addition target is derived is not particularly limited, and examples thereof include humans and non-human animals other than humans. Examples of the non-human animal include non-human mammals such as mice, rats, rabbits, dogs, sheep, horses, cats, goats, monkeys, guinea pigs, and cows.
  • the method of adding the choline uptake inhibitor of the present invention is not particularly limited.
  • the form of addition may be, for example, oral administration or parenteral administration.
  • the form of the choline uptake inhibitor of the present invention is not particularly limited, and can be appropriately set depending on, for example, the addition target and the addition method.
  • Examples of the form include liquids, emulsions, creams, gels, ointments and the like.
  • the cholinergic uptake inhibitor of the present invention may contain the above-mentioned other components as appropriate, for example, depending on these forms.
  • the cholinergic uptake inhibitor of the present invention when the cholinergic uptake inhibitor of the present invention is added to cancer cells, the cholinergic uptake inhibitor (the agent) in 10,000 cells / 1 mL (medium) / well in one culture is used.
  • the lower limit of the concentration in the medium is, for example, 0.001 mg / mL, 0.01 mg / mL, 0.1 mg / mL, the upper limit thereof is, for example, 10 mg / mL, and the range is, for example, It is 0.001 to 10 mg / mL, 0.01 to 10 mg / mL, and 0.1 to 10 mg / mL.
  • the cell death inducer of the present invention is characterized by containing the choline uptake inhibitor of the present invention.
  • the cell death inducer of the present invention is characterized by containing the choline uptake inhibitor of the present invention, and other configurations and conditions are not particularly limited.
  • the cell death inducer of the present invention can be said to be, for example, an apoptosis inducer.
  • the description of the choline uptake inhibitor of the present invention and the like can be incorporated.
  • cell death inducer of the present invention cell death of cancer cells can be induced by suppressing the uptake of choline.
  • the anticancer agent of the present invention is characterized by containing the choline uptake agent of the present invention.
  • the anticancer agent of the present invention is characterized by containing the cholinergic uptake inhibitor of the present invention, and other configurations and conditions are not particularly limited.
  • the anticancer agent of the present invention the description of the choline uptake inhibitor of the present invention and the cell death inducer of the present invention can be incorporated.
  • cancer can be treated by suppressing the uptake of choline in cancer cells and inducing cell death of cancer cells.
  • the treatment of cancer also includes, for example, the meaning of so-called actions for alleviating the progression of cancer, curing cancer, and the like.
  • the anticancer agent of the present invention may be used, for example, for any one purpose, or may be used for two or more purposes.
  • the anticancer agent of the present invention may contain, for example, a pharmaceutically acceptable additive in addition to the above-mentioned agent in the choline uptake inhibitor of the present invention.
  • the additives include, for example, excipients, stabilizers, surfactants, preservatives, antioxidants, pH adjusters, thickeners, chelating agents, coloring agents, flavoring agents, moisturizing ingredients, vitamins, amino acids. kind etc. can be mentioned.
  • the blending amount of the additive is not particularly limited, and may not interfere with the function of the choline uptake inhibitor, for example.
  • the administration method of the anticancer agent of the present invention is not particularly limited, and examples thereof include parenteral administration and oral administration, which can be appropriately set according to, for example, the purpose of treatment, the target site, the degree of cancer progression, and the like.
  • the administration site may be, for example, a treatment site, that is, a site that has become cancerous, or a site that can deliver the active ingredient of the anticancer agent of the present invention to the site that has become cancerous.
  • the parenteral administration method include affected area injection, intravenous injection, subcutaneous injection, intradermal injection, drip injection, and transdermal administration.
  • the dosage form is not particularly limited and can be appropriately determined depending on the administration method. For example, it may be liquid, creamy, gel or the like, and the medium and the drug in the choline uptake inhibitor of the present invention may be used. It can be prepared by mixing.
  • the aqueous solvent is, for example, physiological saline, isotonic solution, etc.
  • the oily solvent is, for example, soybean oil, etc.
  • the emulsifying solvent is, for example, a mixed solution thereof.
  • the parenteral administration agent may further contain, for example, alcohol, polyalcohol, surfactant and the like.
  • the anticancer agent of the present invention may include, for example, a DDS agent for effectively delivering the drug in the choline uptake inhibitor of the present invention from a treatment site other than the treatment site to the treatment site. Among the treatment sites, DDS for effective delivery to cancer cells may be included.
  • examples of the dosage form of the oral administration agent include tablets, pills, granules, powders, capsules, syrups and the like.
  • the orally administered agent may contain, for example, a diluent, an excipient, a carrier and the like.
  • excipient examples include polyhydric alcohols such as glycerin and polyethylene glycol, or derivatives thereof.
  • the stabilizers include, for example, paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; timerosal; dehydroacetic acid. ; Sorbic acid and the like can be mentioned.
  • Examples of the surfactant include W / O type emulsifiers such as glycerin monostearate and sorbitan monostearate; and O / W type emulsifiers such as polyoxyethylene hydrogenated castor oil 60 and polysorbate 60.
  • Examples of the preservative include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol, thymol and the like.
  • Examples of the antioxidant include sodium bisulfite, ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium edetate hydrate, benzotriazole and the like.
  • Examples of the pH adjuster include citric acid hydrate, sodium citrate hydrate, lactic acid, diisopropanolamine, acetic acid, sodium acetate hydrate and the like.
  • the administration conditions of the anticancer agent of the present invention are not particularly limited, and for example, the administration time, administration period, dose and the like can be appropriately set according to the type, gender, age, administration site and the like of the administration target. ..
  • the total daily dose of the drug is, for example, 0.001 to 1000 mg, 0.01 to 1000 mg, 0.1 to 1000 mg.
  • the administration period is, for example, 1 to 14 days, the number of administrations per day is, for example, 1 to 5 times, and the administration interval is, for example, every 3 to 7 days.
  • the method for suppressing cholinergic uptake of the present invention is a method for suppressing cholinergic uptake of cancer cells, and is characterized by including a step of adding the cholinergic uptake inhibitor of the present invention to cancer cells.
  • the present invention is characterized by including a step of adding the choline uptake inhibitor of the present invention, and other steps and conditions are not particularly limited.
  • the choline uptake inhibitor of the present invention is as described above.
  • the conditions for adding the choline uptake inhibitor of the present invention are not particularly limited, and are the same as those described in the choline uptake inhibitor of the present invention, for example.
  • the cell death-inducing method of the present invention is a method of inducing cell death of cancer cells, and is characterized by including a step of adding the choline uptake inhibitor of the present invention to cancer cells.
  • the present invention is characterized by including a step of adding the choline uptake inhibitor of the present invention or the cell death inducer of the present invention, and other steps and conditions are not particularly limited.
  • the choline uptake inhibitor and cell death inducer of the present invention are as described above.
  • the conditions for adding the choline uptake inhibitor and the cell death inducer of the present invention are not particularly limited, and are the same as those described in the choline uptake inhibitor and the cell death inducer of the present invention, for example.
  • the method for treating cancer of the present invention is characterized by comprising a step of administering the choline uptake inhibitor of the present invention to a patient.
  • the present invention is characterized by including the step of administering the choline uptake inhibitor, the cell death inducer, or the anticancer agent of the present invention, and other steps and conditions are not particularly limited.
  • the choline uptake inhibitor, cell death inducer, or anticancer agent of the present invention is as described above.
  • the administration conditions of the choline uptake inhibitor, cell death inducer, or anticancer agent of the present invention are not particularly limited, and for example, in the choline uptake inhibitor, cell death inducer, or anticancer agent of the present invention. It is the same as the description.
  • the present invention is the use of an isoquinoline compound represented by the above formula (1) or a derivative thereof (the drug) for use in suppressing choline uptake of cancer cells, inducing cell death, or treating cancer.
  • the present invention is the use of said agents for the production of cholinergic uptake inhibitors, cell death inducers, or anticancer agents.
  • the present invention can refer to, for example, the description of the choline uptake inhibitor, cell death inducer, anticancer agent, cholinergic uptake inhibitory method, cell death induction method, and cancer treatment method of the present invention.
  • Human pancreatic cancer cell line MIA PaCa-2 (RCB2094: RIKEN BioResource Center) was cultured in D-MEM medium containing 10% fetal bovine serum FBS, 100 units / mL penicillin, and 100 ⁇ g / mL streptomycin. ..
  • D-MEM medium containing 10% FBS was used.
  • Culturing of human tongue cancer cell line (HCS-3: JCRB cell bank) was confirmed using PMI-1640 medium.
  • HASTR / ci35 Immortalized human normal astrocytes (HASTR / ci35) cells with a choline transporter (CTL1) -mediated uptake mechanism were used.
  • the cells were seeded on a 24-well plate at 1x10 5 cells / well, and 24 hours later, a [ 3 H] choline uptake experiment was performed.
  • uptake buffer (125 mmol / L NaCl, 4.8 mmol / L KCl, 1.2 mmol / L CaCl 2 , 1.2 mmol / L KH 2 PO 4 , 5.6 mmol / L glucose.
  • the cells were washed with 1.2 mmol / L EDTA 4 and 25 mmol / L HEPES, pH 7.4).
  • [3 H] choline was added so that the final concentration reached 10 ⁇ mol / L, and uptake was started.
  • Caspase-3 / 7 activity measurement Caspase-3 / 7 activity, an indicator of apoptosis, was measured using Caspase-Glo® 3/7 activity (Promega). Then, the number of viable cells was measured at the same time as the measurement of caspase-3 / 7 activity, and evaluated as the activity per unit viable cell number.
  • Example 1 The drug of the present invention was confirmed to have an inhibitory effect on choline uptake and an antitumor effect on various cancers.
  • the compounds # 1 to # 18 were added to immortalized human normal astrocytes (HASTR / ci35), and the amount of choline uptake was measured.
  • the compounds # 1 to # 18 were added to the human pancreatic cancer cell line MIA PaCa-2, the human glioma cell line U251MG, and the human tongue cancer cell line (HCS-3), and the cell viability was measured. These results are shown in Table 7. Both compounds were able to suppress the uptake of choline and further suppress the survival rate of cancer cells. Among them, compounds # 1 and # 16 showed effective suppression of survival in all cancer cells.
  • Example 2 Among the agents of the present invention, compound # 2 (GPN000316 / Amb544925) was confirmed to have an inhibitory effect on choline uptake and an antitumor effect on tongue cancer cells.
  • FIG. 1 is a graph showing the relationship between the amount of choline uptake and the compound concentration.
  • the unit (% of vehicle) of the choline uptake amount was shown as a relative value with the choline uptake amount of the negative control (DMSO added) as 100%.
  • the compound # 2 was able to inhibit choline uptake in tongue cancer cells in a concentration-dependent manner.
  • FIG. 2A is a graph showing the relationship between the survival rate, the compound concentration, and the treatment time with the compound.
  • the unit of survival rate (% of vehicle) was shown as a relative value with the number of viable cells of the negative control (DMSO added) as 100%.
  • DMSO added negative control
  • FIGS. 2 (B) and 2 (C) are shown in FIGS. 2 (B) and 2 (C).
  • (B) is a graph showing the viability of tongue cancer cells treated with compound # 2
  • (C) is the result of caspase-3 / 7 activity of tongue cancer cells treated with compound # 2. ..
  • the "DMSO" in each graph is the result of negative control.
  • the addition of the compound # 2 to the tongue cancer cells showed a significant increase in caspase-3 / 7 activity and a significant suppression of the cell rate as compared with the negative control. confirmed. From these results, it is considered that compound # 2 exhibits antitumor activity by causing cell death due to induction of apoptosis.
  • Example 3 Among the agents of the present invention, compound # 1 (Amb4269951) and compound # 16 (Amb4269675) were confirmed to have an inhibitory effect on choline uptake and an antitumor effect on various cancer cells.
  • the graph (A) is a graph showing the relationship between the choline uptake amount and the compound concentration in the glioma cells
  • the graph (B) is the relationship between the choline uptake amount and the compound concentration in the pancreatic cancer cells.
  • the left is the result of compound # 1
  • the right is the result of compound # 16.
  • the unit (% of vehicle) of the choline uptake amount was shown as a relative value with the choline uptake amount of the negative control (DMSO added) as 100%.
  • both compounds were able to inhibit choline uptake in glioma cells and pancreatic cancer cells in a concentration-dependent manner.
  • Each IC 50 values for glioma cells (U251MG), Compound # 1 is 2.4 ⁇ mol / L, compound # 16 is 3.6 ⁇ mol / L, relative to pancreatic cancer cells (MIA PaCa-2) Compound # 1 was 2.4 ⁇ mol / L and compound # 16 was 6.0 ⁇ mol / L.
  • the graph of (A) is a graph showing the relationship between the survival rate of glioma cells and the compound concentration
  • the graph of (B) is the survival rate of pancreatic cancer cells and the compound concentration for each treatment time.
  • the left is the result of compound # 1
  • the right is the result of compound # 16.
  • the unit of survival rate (% of vehicle) was shown as a relative value with the number of viable cells of the negative control (DMSO added) as 100%.
  • both compounds were able to suppress the cell survival of glioma cells and pancreatic cancer cells in a concentration-dependent and time-dependent manner. From this, it is considered that both compounds # 1 and # 16 suppress cell survival in a cell cycle-dependent manner.
  • the cancer cells are human esophageal squamous cell carcinoma cell (KYSE450), human pancreatic adenocarcinoma cell (PANC-1), human breast adenocarcinoma cell (MCF-7), and human gestational chorionic villus cancer cell (JEG-3).
  • Human prostate cancer cells PC-3
  • human oral squamous cell carcinoma cells HSC-3
  • human colon adenocarcinoma cells H69
  • humans Malignant melanoma cells MeWo
  • human neuroblastoma cells SH-SY5Y
  • human hepatoma cells HepG2
  • human prostate cancer cells LNCaP
  • human cervical cancer cells HeLa
  • FIGS. 5 and 6 each graph is a graph showing the relationship between the cell viability and the compound concentration
  • FIG. 5 is the result of the compound # 1
  • FIG. 6 is the result of the compound # 16.
  • the unit of survival rate (% of vehicle) was shown as a relative value with the number of viable cells of the negative control (DMSO added) as 100%.
  • DMSO added negative control
  • FIG. 7 (A) is for glioma cells (U251MG), the two graphs on the left are the results of cell viability and caspase-3 / 7 activity using compound # 1, and the two on the right. The graph shows the results of cell viability and caspase-3 / 7 activity with compound # 16.
  • (B) is for pancreatic cancer cells (MIAPaCa-2), and the two graphs on the left are the results of cell viability and caspase-3 / 7 activity using compound # 1, and the right. The two graphs are the results of cell viability and caspase-3 / 7 activity with compound # 16.
  • the left bar “DMSO” of each graph is the result of negative control, and the concentration ( ⁇ M) of the right bar is the addition concentration of each of the above compounds.
  • concentration ( ⁇ M) of the right bar is the addition concentration of each of the above compounds.
  • FIG. 7 when either compound was used, a significant increase in caspase-3 / 7 activity was observed for both glioma cells and pancreatic cancer cells as compared to the negative control, and the cell rate. Significant suppression of was confirmed. From these results, it is considered that Compound # 1 and Compound # 16 exhibit antitumor activity by causing cell death due to induction of apoptosis.
  • Example 4 The antitumor activity of the agent of the present invention against various cancers in vivo was confirmed.
  • Compound # 1 (Amb4269951) was used as the glioma drug.
  • the compound # 1 was intraperitoneally administered to human cancer cell xenograft model mice transplanted with glioma cells (U251MG) under the condition of 10 mg / kg. Administration was performed once a day on Day 0 (experiment start date), 3, 7, 10, 15, and 18.
  • DMSO was administered instead of each of the above compounds. Then, the tumor volume and body weight were measured over time.
  • FIG. 8 (A) is a graph showing the relationship between the number of days from the experiment start date (Day 0) and the tumor volume (mm 3 / mouse) of the model mouse, and (B) is the 0th day (experiment). It is a graph which shows the total tumor volume from the start date Day 0) to the 18th day (Day 18) by the area (AUC; Area Under the Curve), and (C) is the number of days from the experiment start date (Day 0) and It is a graph which shows the relationship with the weight of a model mouse.
  • Pancreatic cancer Compound # 1 (Amb4269951) and Compound # 16 (Amb4269675) were used as drugs.
  • the above compound # 1 or compound # 16 was intraperitoneally administered under the condition of 10 mg / kg to human cancer cell xenograft model mice transplanted with pancreatic cancer cells (MIAPaCa-2). Administration was performed once daily on Day 0 (experiment start date) -4 and Day 7-11.
  • MIAPaCa-2 pancreatic cancer cells
  • DMSO was administered instead of each of the above compounds. Then, the tumor volume and body weight were measured over time.
  • FIG. 9 (A) is a graph showing the relationship between the number of days from the experiment start date (Day 0) and the tumor volume (mm 3 / mouse) of the model mouse, and (B) is the 0th day (experiment). It is a graph which shows the total tumor volume from the start date (Day 0) to the 11th day (Day 11) by the area (AUC), and (C) shows the number of days from the experiment start date (Day 0) and the weight of the model mouse. It is a graph which shows the relationship of.
  • Model mice to which either Compound # 1 or # 16 was administered also significantly suppressed the increase in tumor volume as shown in FIGS. 9 (A) and 9 (B), while the increase in tumor volume was significantly suppressed as compared with the negative control.
  • 9 (C) no weight loss was observed. From this, it was found that compounds # 1 and # 16 have low toxicity leading to body weight loss and exhibit an antitumor effect.
  • Tongue cancer Compound # 2 (GPN000316 / Amb544925) was used as the drug.
  • the compound # 2 was intraperitoneally administered to human cancer cell xenograft model mice transplanted with tongue cancer cells (HSC-3) under the condition of 10 mg / kg. The administration was performed once a day on Days 1-8, with the start date of the experiment as Day 0.
  • HSC-3 tongue cancer cells
  • DMSO was administered instead of each of the above compounds. Then, the tumor volume and body weight were measured over time.
  • FIG. 10 (A) is a graph showing the relationship between the number of days from the experiment start date (Day 0) and the tumor volume (mm 3 / mouse) of the model mouse, and (B) is the 0th day (experiment). It is a graph which shows the total tumor volume from the start date Day0) to the 17th day (Day17) by the area (AUC), and (C) is the number of days from the experiment start date (Day0) and the weight of the model mouse. It is a graph which shows the relationship with.
  • cell death of cancer cells can be induced by suppressing the uptake of choline by cancer cells.
  • many of the anticancer agents having a plant-derived compound as an active ingredient have been clinically applied, and various compounds in the present invention have a plant-derived compound as a skeleton. Therefore, it is highly possible that the present invention will be clinically applied as a very useful anticancer agent as well as an anticancer agent containing a plant-derived compound as an active ingredient, which has already been clinically applied. Therefore, it can be said that the present invention is very useful in the medical field, for example.

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Abstract

La présente invention décrit un nouveau médicament qui peut être utilisé comme médicament anticancéreux.　Cet inhibiteur d'absorption de choline supprime l'absorption de choline dans des cellules, et est caractérisé en ce qu'il contient un composé isoquinoléine représenté par la formule (1) ou un dérivé de celui-ci.
PCT/JP2021/005541 2020-03-24 2021-02-15 Inhibiteur d'absorption de choline, inducteur d'apoptose, médicament anticancéreux, et utilisation associée Ceased WO2021192726A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001055117A1 (fr) * 2000-01-28 2001-08-02 Les Laboratoires Servier Nouveaux derives d'isoquinoleines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US20070078144A1 (en) * 2003-01-29 2007-04-05 Stockwell Brent R Agents for treating neurodegenerative diseases
JP2013049646A (ja) * 2011-08-30 2013-03-14 Tokyo Medical Univ 癌治療剤
WO2015054027A1 (fr) * 2013-10-08 2015-04-16 Pain Therapeutics, Inc. Procédé pour inhiber la croissance de cellules cancéreuses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001055117A1 (fr) * 2000-01-28 2001-08-02 Les Laboratoires Servier Nouveaux derives d'isoquinoleines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US20070078144A1 (en) * 2003-01-29 2007-04-05 Stockwell Brent R Agents for treating neurodegenerative diseases
JP2013049646A (ja) * 2011-08-30 2013-03-14 Tokyo Medical Univ 癌治療剤
WO2015054027A1 (fr) * 2013-10-08 2015-04-16 Pain Therapeutics, Inc. Procédé pour inhiber la croissance de cellules cancéreuses

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANDREU, I ET AL.: "An efficient method for the preparation of antitumoral a-keto-imines benzyldihydroisoquinolines by selective benzylic oxidation with C/Pd in acetonitrile", TETRAHEDRON LETTERS, vol. 43, no. 5, 2002, pages 757 - 759, XP004332801, DOI: 10.1016/S0040-4039(01)02257-2 *
HIRAI, K. ET AL.: "Molecular and Functional Analysis of Choline Transporters and Antitumor Effects of Choline Transporter-Like Protein 1 Inhibitors in Human Pancreatic Cancer Cells", INT J MOL SCI, vol. 21, no. 15, 31 July 2020 (2020-07-31), XP055863220 *
NAM, K. Y. ET AL.: "Identification of chalcones as potent and selective PDE5A1 inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 12, 2012, pages 3983 - 3987, XP029121587, DOI: 10.1016/j.bmcl.2012.04.094 *
WATANABE, S ET AL.: "Anticancer Activity of Amb4269951, a Choline Transporter-Like Protein 1 Inhibitor, in Human Glioma Cells", PHARMACEUTICALS, vol. 13, no. 5, 31 May 2020 (2020-05-31), XP055863223 *

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