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WO2025178159A1 - Nouveaux composés thioamides, leur procédé de production et leurs utilisations - Google Patents

Nouveaux composés thioamides, leur procédé de production et leurs utilisations

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Publication number
WO2025178159A1
WO2025178159A1 PCT/KR2024/002598 KR2024002598W WO2025178159A1 WO 2025178159 A1 WO2025178159 A1 WO 2025178159A1 KR 2024002598 W KR2024002598 W KR 2024002598W WO 2025178159 A1 WO2025178159 A1 WO 2025178159A1
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WO
WIPO (PCT)
Prior art keywords
cancer
group
pharmaceutically acceptable
solvate
stereoisomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2024/002598
Other languages
English (en)
Korean (ko)
Inventor
오동찬
이상국
두영은
배은서
박수연
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SNU R&DB Foundation
Original Assignee
Seoul National University R&DB Foundation
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Filing date
Publication date
Application filed by Seoul National University R&DB Foundation filed Critical Seoul National University R&DB Foundation
Publication of WO2025178159A1 publication Critical patent/WO2025178159A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/195—Proteins from microorganisms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces

Definitions

  • the present invention relates to a novel thioamide compound, a method for producing the same, and a use thereof.
  • Cancer is a leading cause of death worldwide, and in Korea, it is the leading cause of death, with 161.1 deaths per 100,000 people as of 2022. While the five-year survival rate for cancer patients is increasing due to increased early diagnosis and improved treatments, cancer incidence and mortality rates are also on the rise, with cancer deaths in Korea in particular experiencing a significant increase.
  • the global anticancer drug market is expected to grow rapidly, from $193 billion in 2022 to $377 billion in 2027, at a compound annual growth rate of 13-16%.
  • Natural products are becoming increasingly important as a source of biologically active drug candidates. Natural products account for 23.5% of all approved and used drugs worldwide over the past 40 years, and synthetic drugs with pharmacokinetic groups derived from natural products account for approximately 14% of the total, highlighting the importance of research on natural product medicines.
  • Another aspect provides a method for preparing a compound of formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of: 1) culturing a strain of Streptomyces sp. GC5 (Accession No.: KCTC15723BP); and 2) isolating a compound of formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof from the strain, a lysate thereof, a culture medium thereof, or an extract of the culture medium.
  • Another aspect provides a pharmaceutical composition for preventing or treating cancer, comprising a compound represented by the above chemical formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  • Another aspect provides a method for preventing or treating cancer, comprising administering to a subject a pharmaceutical composition for preventing or treating cancer.
  • Another aspect provides the use of a compound represented by the above formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, for use in preventing or treating cancer.
  • One aspect is to provide a compound represented by the formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
  • R a is hydrogen, a substituted or unsubstituted C1-C20 alkyl group, a substituted or unsubstituted C1-C20 alkoxy group, a substituted or unsubstituted C2-C20 alkenyl group, a substituted or unsubstituted C2-C20 alkynyl group, a substituted or unsubstituted C2-C20 alkylene oxide group, a substituted or unsubstituted C3-C30 cycloalkyl group, a substituted or unsubstituted C3-C30 heterocycloalkyl group, a substituted or unsubstituted C3-C30 cycloalkenyl group, a substituted or unsubstituted C3-C30 heterocycloalkenyl group, a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted C6-C30 aryloxy group,
  • R 11 of the above chemical formula 1 may be hydrogen or a hydroxy group.
  • At least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 and R 13 of the above chemical formula 1 may be a substituted or unsubstituted C 1 to C 10 alkyl group, and specifically, may be a substituted or unsubstituted C 1 to C 5 alkyl group.
  • At least one of R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 12 and R 13 of the chemical formula 1 may be a substituted or unsubstituted methyl group, and specifically, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 12 and R 13 may be a methyl group.
  • the compound of formula 2 may be named Thiogochangamide A
  • the compound of formula 3 may be named Thiogochangamide B.
  • halogen as used in chemical formulas includes atoms such as fluorine, bromine, chlorine, and iodine.
  • ketone refers to a functional group consisting of one carbonyl group bonded to two hydrocarbon groups.
  • cyano refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.
  • alkyl refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon group.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, and the like.
  • One or more hydrogen atoms of the above “alkyl” may be substituted with a halogen, a C1-C20 alkyl group substituted with a halogen (e.g., CCF 3 , CHCF 2 , CH 2 F, CCl 3 , etc.), a C1-C20 alkoxy group, a C2-C20 alkoxyalkyl group, a hydroxy group, a nitro group, a cyano group, an amino group, or a C1-C20 alkyl group, a C2-C20 alkenyl group, a C2-C20 alkynyl group, a C1-C20 heteroalkyl group, a C6-C20 aryl group, a C6-C20 arylalkyl group, a C6-C20 heteroaryl group, a C7-C20 heteroarylalkyl group, a C6-C20 heteroaryloxy group, or a C6-C20 heteroaryloxyal
  • alkoxy used in chemical formulas represents alkyl-O-, wherein the alkyl is as described above.
  • Non-limiting examples of the alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropoxy, cyclohexyloxy, etc.
  • At least one hydrogen atom in the alkoxy group may be replaced with the same substituent as in the case of the alkyl group described above.
  • aryloxy used in chemical formulas means O-aryl, and examples of aryloxy include phenoxy, etc.
  • One or more hydrogen atoms in the “aryloxy” may be replaced with a substituent similar to the alkyl group described above.
  • heteroaryl refers to a monocyclic or bicyclic organic compound containing one or more heteroatoms selected from N, O, P, or S, with the remaining ring atoms being carbon.
  • the heteroaryl group may contain, for example, 1 to 5 heteroatoms and 5 to 10 ring members.
  • the S or N may be oxidized to have various oxidation states.
  • One or more hydrogen atoms in the above “heteroaryl” can be substituted with a substituent similar to that in the case of the above-described alkyl group.
  • heteroarylalkyl means alkyl substituted with heteroaryl.
  • heteroaryloxy refers to an -O-heteroaryl moiety.
  • One or more hydrogen atoms in the heteroaryloxy may be replaced with a substituent similar to that for the alkyl group described above.
  • heteroaryloxy means alkyl substituted with heteroaryl.
  • One or more hydrogen atoms in the heteroaryloxyalkyl may be replaced with a substituent similar to that in the case of the alkyl group described above.
  • amino group refers to a nitrogen atom covalently bonded to at least one carbon or heteroatom.
  • the amino group includes, for example, -NH 2 and substituted moieties.
  • amino group includes alkylamino groups in which the nitrogen is bonded to at least one additional alkyl group, arylamino groups in which the nitrogen is bonded to at least one or more independently selected aryl groups, and diarylamino groups.
  • substitution in the above "substituted or unsubstituted” refers to a case where one or more hydrogen atoms in an organic compound are replaced with another atomic group to form a derivative, and the substituent refers to the introduced atomic group.
  • the substituent may be a halogen atom, a hydroxy group, a nitro group, a cyano group, an amino group, an amidino group, an acetamino group, a hydrazine, a hydrazone, a carboxyl group, a sulfonyl group, a sulfamoyl group, a sulfonic acid group, a phosphoric acid, a C 1 to C 5 alkyl group, a C 1 to C 5 alkoxy group, a C 2 to C 5 alkenyl group, a C 2 to C 5 alkynyl group, a C 3 to C 10 cycloalkyl group, a C 6 to C 10 aryl group, a C 6 to C 10 heteroaryl group, a C 6 to C 20 arylalkyl group, a C 6 to C 20 heteroarylalkyl group, or a combination thereof.
  • isomer in “stereoisomer” used herein refers to a compound that has the same molecular formula but has different connection methods or spatial arrangements of the constituent atoms within the compound.
  • Isomers include, for example, structural isomers and stereoisomers.
  • the stereoisomers may be diastereomers or enantiomers.
  • Enantiomers are isomers that do not overlap with their mirror images, like the relationship between left and right hands, and are also called optical isomers. Enantiomers are distinguished as R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents are different at the chiral center carbon.
  • Diastereoisomers are stereoisomers that are not mirror images, and can be divided into cis-trans isomers due to the different spatial arrangement of atoms.
  • solvate refers to a compound solvated in an organic or inorganic solvent.
  • the solvate is, for example, a hydrate.
  • the organic acid salt may be a formate, an acetate, a propionate, a lactate, an oxalate, a tartrate, a malate, a maleate, a citrate, a fumarate, a besylate, a camsylate, an edisyl salt, a trichloroacetic acid, a trifluoroacetate, a benzoate, a gluconate, a methanesulfonate, a glycolate, a succinate, a 4-toluenesulfonate, a galacturonate, an embronate, a glutamate, an ethanesulfonate, a benzenesulfonate, a p-toluenesulfonate, or an aspartate.
  • the above metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.
  • the compound represented by the above chemical formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof may be isolated from Streptomyces sp., and specifically, may be isolated from Streptomyces sp. GC2 strain (Accession No.: KCTC15723BP), a lysate thereof, a culture medium thereof, and/or an extract of the culture medium.
  • the above strain includes spores, mycelia, or cultures of the strain.
  • a method may be used, including a step of culturing a strain of Streptomyces sp. GC2 (Accession No.: KCTC15723BP) to produce a compound represented by the chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof; and a step of isolating the compound represented by the chemical formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof from the strain, a lysate thereof, a culture medium thereof, and/or an extract of the culture medium.
  • the step of separating may include a step of concentrating, centrifuging, filtering, or performing chromatography on the strain, its lysate, its culture medium, and/or the extract of the culture medium.
  • the chromatography may be, for example, column chromatography, planar chromatography, paper chromatography, or thin-layer chromatography, depending on the form of the stationary phase.
  • the chromatography may be, for example, gas chromatography, liquid chromatography, or affinity chromatography, depending on the physical properties of the mobile phase.
  • the liquid chromatography may be, for example, high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • the chromatography may be, for example, ion exchange chromatography, size-exclusion chromatography, depending on the separation method.
  • the chromatography may be, for example, normal phase chromatography or reverse phase chromatography.
  • the pharmaceutical composition may further comprise a known active ingredient having anticancer activity.
  • the known active ingredient having anticancer activity may be an anticancer agent.
  • the anticancer agent may be 5-fluorouracil, irinotecan, etoposide, gemcitabine, paclitaxel, oxaliplatin, leucovorin, capecitabine, or a combination thereof.
  • the compound represented by the above chemical formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, and the anticancer agent may be a single or separate composition for simultaneous or sequential administration.
  • the compound represented by the above chemical formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof can improve and/or enhance the effect of cancer treatment by reducing the resistance of cancer or cancer cells to anticancer drugs or increasing the sensitivity/sensitivity to anticancer drugs.
  • Non-limiting examples of the above carriers include lactose, dextrose, maltodextrin, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, glycerol, ethanol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, saline solution, sterile water, Ringer's solution, buffered saline, albumin injection solution, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
  • the pharmaceutical composition may be prepared as an oral formulation or a parenteral formulation according to the route of administration by a conventional method known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient.
  • the above pharmaceutical composition can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions, each according to a conventional method.
  • the above pharmaceutical composition may be prepared using a diluent or excipient such as a generally used filler, bulking agent, binder, wetting agent, disintegrant, or surfactant, but may not be limited thereto.
  • a diluent or excipient such as a generally used filler, bulking agent, binder, wetting agent, disintegrant, or surfactant, but may not be limited thereto.
  • the above pharmaceutical composition When the above pharmaceutical composition is manufactured into an oral dosage form, it can be manufactured into a dosage form such as powder, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, wafers, etc., using a suitable carrier according to a method known in the art.
  • suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, xylitol, etc.; starches such as corn starch, potato starch, and wheat starch; celluloses such as cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, and hydroxypropylmethylcellulose; polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyols, and vegetable oils.
  • the formulation may include diluents and/or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants, as needed.
  • suitable carriers include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof, and preferably, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, sterile water for injection, and isotonic solutions such as 5% dextrose can be used.
  • PBS phosphate buffered saline
  • the pharmaceutical composition may be administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount refers to an amount sufficient to treat or prevent a disease at a reasonable benefit/risk ratio applicable to medical treatment or prevention, and the effective dosage level may be determined based on factors including the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the excretion rate, the treatment period, drugs used in combination or simultaneously with the composition of the present invention used, and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered alone or in combination with a component known to exhibit a therapeutic effect on a known cancer disease. It is important to take all of the above factors into consideration and administer an amount that can achieve the maximum effect with the minimum amount without side effects.
  • the dosage of the pharmaceutical composition may be determined by a person skilled in the art in consideration of the intended use, the degree of toxicity of the disease, the patient's age, weight, sex, medical history, or the type of substance used as the active ingredient.
  • the pharmaceutical composition of the present invention may be administered at about 0.1 ng to about 1,000 mg/kg, preferably 1 ng to about 100 mg/kg, per adult, and the frequency of administration of the composition of the present disclosure is not particularly limited thereto, but may be administered once a day or administered in divided doses several times.
  • the dosage or frequency of administration does not limit the scope of the present disclosure in any way.
  • Another aspect provides a method for treating or preventing cancer, comprising administering to a subject a pharmaceutical composition for treating or preventing cancer.
  • a method for treating or preventing cancer comprising administering to a subject a pharmaceutical composition for treating or preventing cancer.
  • the same principles as described above apply to the method.
  • the pharmaceutical composition described above may be administered in single or multiple doses in a pharmaceutically effective amount.
  • the composition may be formulated and administered in the form of a liquid, powder, aerosol, injection, infusion solution (Ringel), capsule, pill, tablet, suppository, or patch.
  • the pharmaceutical composition for cancer prevention or treatment may be administered via any conventional route, as long as it can reach the target tissue.
  • Another aspect provides a food composition for preventing or improving cancer, comprising a compound represented by the above chemical formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  • a food composition for preventing or improving cancer comprising a compound represented by the above chemical formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  • the same parts as described above also apply to the composition.
  • the above food can be manufactured by a method commonly used in the art, and can be manufactured by adding raw materials and ingredients commonly added in the art during the manufacturing process.
  • the formulation of the food can be manufactured without limitation as long as it is a formulation recognized as a food.
  • the food composition can be manufactured in various forms of formulation, and unlike general drugs, it has the advantage of not having side effects that may occur with long-term use of drugs because it uses food as a raw material, and is highly portable, so the food composition of the present invention can be taken as a supplement to enhance the effect of improving cancer.
  • the above food composition can be used very usefully because it can be consumed on a daily basis and is expected to be highly effective in improving cancer.
  • the food composition may further comprise a physiologically acceptable carrier, and the type of the carrier is not particularly limited, and any carrier commonly used in the art may be used.
  • the food composition may comprise additional ingredients commonly used in food compositions to improve odor, taste, sight, etc.
  • the food composition may comprise vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, etc.
  • the food composition may comprise minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr).
  • the food composition may comprise amino acids such as lysine, tryptophan, cysteine, and valine.
  • the food composition may include food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), bactericides (bleaching powder and high-purity bleaching powder, sodium hypochlorite, etc.), antioxidants (butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.), colorants (tar colorants, etc.), color developers (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG, monosodium glutamate, etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), leavening agents (alum, D-potassium hydrogen tartrate, etc.), reinforcing agents, emulsifiers, thickeners (glucose fillers), film-forming agents, gum-forming agents, gum
  • the health beverage composition may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, or carbonating agents.
  • it may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, or vegetable drinks.
  • These ingredients may be used independently or in combination.
  • the proportion of these additives is not particularly important, but is typically selected within the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the health beverage composition of the present invention.
  • the above food composition may contain the compound of the present invention in various weight % if it can exhibit an effect of improving or preventing cancer, and specifically may contain 0.00001 to 100 weight % or 0.01 to 80 weight % relative to the total weight of the food composition, but is not limited thereto.
  • Figure 1 is a drawing showing a photograph of a medium in which Streptomyces sp. GC2 strain (accession number: KCTC15723BP) spread on an agar plate was cultured.
  • Figure 3 is a diagram showing the tumor inhibition efficacy in a PANC-GR cell line tumor xenograft animal model by combined administration of thioguanamide B and gemcitabine.
  • the adsorbate was loaded onto a C18 reversed-phase open column (34 x 150 mm), and 20%, 40%, 60%, 80%, and 100% MeOH solutions (500 mL each) were applied to generate five fractions (repeated five times since a total of 50 g of extract was collected). Analysis of 10 ⁇ L aliquots of each fraction by LC/MS confirmed that thioguanamides A and B were detected in the 80% and 100% MeOH-H 2 O fractions, respectively.
  • MeOH-H 2 O fractions were evaporated and redissolved in MeOH and subjected to reversed-phase chromatography.
  • the conditions for the first-step reversed-phase chromatography were as follows: (Column used: Kromasil C18, 5 ⁇ m, 250 ⁇ 10 mm, Flow rate: 2 mL/min, Detection UV: 270 nm, Solvent system of 30% to 60% CH 3 CN-H 2 O containing 0.1 formic acid over 40 min). Thioguanamides A and B eluted at 29 and 31 min, respectively.
  • human lung cancer A549), colon cancer (HCT116), gastric cancer (SNU638), liver cancer (SK-HEP-1), and breast cancer (MDA-MB-231) cells were provided by the Korea Cell Line Bank.
  • Cell proliferation(%) (average absorbance sample - average absorbance zeroday ) / (average absorbance control - average absorbance zeroday ) x 100
  • Example 1 In order to confirm the anticancer activity of thioguanamide obtained in Example 1 above against resistant cancer, an anticancer drug resistance model was constructed and its anticancer efficacy was evaluated.
  • the PANC-1 pancreatic cancer cell line was purchased from the Korean Cell Line Bank (Seoul, Korea) and cultured in DMEM medium supplemented with 10% heat-inactivated FBS (Gibco, Grand Island, NY), 100 units/mL penicillin, and 100 ⁇ g/mL streptomycin.
  • the gemcitabine-resistant cell line, PANC-GR was established by culturing PANC-1 cells with increasing doses of gemcitabine (0.1–2 ⁇ M). Cells were passaged 2–3 times per week in a 37°C incubator under 5% CO2 conditions.
  • Gemcitabine used was purchased from Sigma-Aldrich (St. Louis, MO, USA).
  • thioguanamide B The anticancer efficacy of thioguanamide B and gemcitabine was evaluated against the PANC-1 pancreatic cancer cell line and the gemcitabine-resistant cell line PANC-GR, respectively.
  • Thioguanamide B exhibited anticancer efficacy against PANC-1 (IC 50 : 1.23 ⁇ M) and PANC-GR (IC 50 : 0.48 ⁇ M) cells
  • gemcitabine exhibited anticancer efficacy only against PANC-1 cells (IC 50 : 2.1 ⁇ M) and did not exhibit anticancer effect against the resistant cell line PANC-GR cells (IC 50 : > 50 ⁇ M) (Table 3). Based on the above results, it can be seen that thioguanamide B can overcome gemcitabine resistance acquired in pancreatic cancer.
  • the PANC-GR cell line contracted above was subcutaneously injected into BALB/c-nude mice (6-week-old, male) at a cell concentration of 1x107 /mL.
  • thioguanamide B (1 mg/kg) and gemcitabine (20 mg/kg) were administered intraperitoneally three times a week at a fixed concentration, and a combination of gemcitabine and thioguanamide B (gemcitabine 20 mg/kg; thioguanamide B 1 mg/kg) was co-administered three times a week.
  • the change in tumor size and body weight were measured twice a week.
  • the tumor size was measured using a caliper, and the tumor volume was calculated using the following mathematical formula:
  • Tumor volume (mm 3 ) (width) x (length) x (height) x ⁇ /6
  • the antitumor activity of thioguanamide B was confirmed by single administration three times a week for 23 days and in combination with gemcitabine.
  • the tumor size in the thioguanamide B group was reduced by 52.21% compared to the gemcitabine monotherapy group with low sensitivity, and in the combination therapy group, the tumor size was reduced by 65.09%, confirming excellent antitumor activity (Figs. 3 and 4).

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Abstract

La présente invention concerne un nouveau composé thioamide, son procédé de production et ses utilisations. Le nouveau composé thioamide, les stéréoisomères de celui-ci, les solvates ou les sels pharmaceutiquement acceptables selon la présente invention présentent non seulement une efficacité anticancéreuse contre divers carcinomes, mais ont également une excellente activité anticancéreuse contre des cancers résistant aux médicaments anticancéreux, et peuvent ainsi être utilisés pour la prévention ou le traitement de divers types de cancers.
PCT/KR2024/002598 2024-02-22 2024-02-28 Nouveaux composés thioamides, leur procédé de production et leurs utilisations Pending WO2025178159A1 (fr)

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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
EYLES TOM H., VIOR NATALIA M., LACRET RODNEY, TRUMAN ANDREW W.: "Understanding thioamitide biosynthesis using pathway engineering and untargeted metabolomics", CHEMICAL SCIENCE, vol. 12, no. 20, 1 January 2021 (2021-01-01), United Kingdom , pages 7138 - 7150, XP093347589, ISSN: 2041-6520, DOI: 10.1039/D0SC06835G *
FRATTARUOLO LUCA, LACRET RODNEY, CAPPELLO ANNA RITA, TRUMAN ANDREW W.: "A Genomics-Based Approach Identifies a Thioviridamide-Like Compound with Selective Anticancer Activity", ACS CHEMICAL BIOLOGY, vol. 12, no. 11, 17 November 2017 (2017-11-17), pages 2815 - 2822, XP093347598, ISSN: 1554-8929, DOI: 10.1021/acschembio.7b00677 *
KAWAHARA TEPPEI, IZUMIKAWA MIHO, KOZONE IKUKO, HASHIMOTO JUNKO, KAGAYA NORITAKA, KOIWAI HANAE, KOMATSU MAMORU, FUJIE MANABU, SATO : "Neothioviridamide, a Polythioamide Compound Produced by Heterologous Expression of a Streptomyces sp. Cryptic RiPP Biosynthetic Gene Cluster", JOURNAL OF NATURAL PRODUCTS, vol. 81, no. 2, 23 February 2018 (2018-02-23), US , pages 264 - 269, XP093347605, ISSN: 0163-3864, DOI: 10.1021/acs.jnatprod.7b00607 *
KUDO KEI, KOIWAI HANAE, KAGAYA NORITAKA, NISHIYAMA MAKOTO, KUZUYAMA TOMOHISA, SHIN-YA KAZUO, IKEDA HARUO: "Comprehensive Derivatization of Thioviridamides by Heterologous Expression", ACS CHEMICAL BIOLOGY, vol. 14, no. 6, 21 June 2019 (2019-06-21), pages 1135 - 1140, XP093347600, ISSN: 1554-8929, DOI: 10.1021/acschembio.9b00330 *
SIKANDAR ASFANDYAR, LOPATNIUK MARIA, LUZHETSKYY ANDRIY, KOEHNKE JESKO: "Non-Heme Monooxygenase ThoJ Catalyzes Thioholgamide β-Hydroxylation", ACS CHEMICAL BIOLOGY, vol. 15, no. 10, 16 October 2020 (2020-10-16), pages 2815 - 2819, XP093347593, ISSN: 1554-8929, DOI: 10.1021/acschembio.0c00637 *

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