WO2022103103A1 - Novel lipid peptide compound, production method therefor, and use thereof - Google Patents

Novel lipid peptide compound, production method therefor, and use thereof Download PDF

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Publication number
WO2022103103A1
WO2022103103A1 PCT/KR2021/016155 KR2021016155W WO2022103103A1 WO 2022103103 A1 WO2022103103 A1 WO 2022103103A1 KR 2021016155 W KR2021016155 W KR 2021016155W WO 2022103103 A1 WO2022103103 A1 WO 2022103103A1
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Prior art keywords
solvate
stereoisomer
cancer
pharmaceutically acceptable
acceptable salt
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PCT/KR2021/016155
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French (fr)
Korean (ko)
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오동찬
최진성
이상국
신종헌
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서울대학교산학협력단
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Publication of WO2022103103A1 publication Critical patent/WO2022103103A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • 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

  • Physiologically active substances derived from microorganisms have generally been the source of antibiotics, antifungals, and anticancer drugs, and have been developed as new drugs for the treatment of various diseases including these, or as a template for the development of new drugs.
  • Antibiotics derived from microorganisms are representative of, for example, amphotericin, erythromycin, streptomycin, tetracycline, and vancomycin. Also, in 2003, daptomycin isolated from the actinomycete Streptomyces was approved by the US Food and Drug Administration (FDA) as a next-generation antibiotic.
  • FDA US Food and Drug Administration
  • anticancer agents derived from bacteria for example, doxorubicin (doxorubicin), bleomycin (bleomycin), misramycin (mithramycin), neocarzinostatin (neocarzinostatin), pentostatin (pentostatin), and epothilone (epothilone)
  • doxorubicin doxorubicin
  • bleomycin bleomycin
  • mithramycin mithramycin
  • neocarzinostatin neocarzinostatin
  • pentostatin pentostatin
  • epothilone epothilone
  • Patent Document 1 KR 10-1723649 B1
  • lipopeptide compounds are provided, stereoisomers, solvates, or pharmaceutically acceptable salts thereof.
  • a method for producing a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof is provided.
  • compositions for preventing or treating cancer comprising a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  • a method for preventing or treating cancer using a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof is provided.
  • a lipopeptide compound for use in the manufacture of a medicament for the prevention or treatment of cancer.
  • a lipopeptide compound for use in preventing or treating cancer.
  • One aspect provides a compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
  • Ser means serine (S).
  • Thr stands for threonine (T).
  • Ala means Alanine (A).
  • Pro stands for Proline (P).
  • Gly means glycine (G).
  • Leu means leucine (L).
  • X may be glycine (Glyine; Gly or G) substituted with C 1 to C 10 alkylacetamide.
  • the C 1 to C 10 alkylacetamide may be a C 1 to C 5 alkylacetamide.
  • the C 1 to C 10 alkylacetamide may be n-ethylacetamide (ethylacetmaide).
  • X may be glycine substituted with n-ethylacetamide.
  • R 1 may be a saturated or unsaturated hydrocarbon chain.
  • hydrocarbon refers to an organic compound composed of carbon and hydrogen.
  • the hydrocarbon may be an aliphatic saturated hydrocarbon, an aliphatic unsaturated hydrocarbon, an alicyclic hydrocarbon, or an aromatic hydrocarbon.
  • the saturated hydrocarbon refers to a hydrocarbon composed of a single bond.
  • the unsaturated hydrocarbon refers to a hydrocarbon containing one or more double bonds or triple bonds.
  • R 1 is a substituted or unsubstituted C 1 to C 30 alkyl group, a substituted or unsubstituted C 2 to C 30 alkenyl group, a substituted or unsubstituted C 2 to C 30 alkynyl group, or a combination thereof can be selected.
  • the R 1 may be substituted (ie, branched) with a C 1 to C 10 alkyl group (eg, a methyl group).
  • the R 1 may be a C 1 to C 30 alkyl group including one or more alkenyl groups.
  • the R 1 may be 9-methyl-1-decene.
  • R 2 is absent, or a substituted or unsubstituted C 1 to C 20 alkyl group, a substituted or unsubstituted C 1 to C 20 alkenyl group, or a substituted or unsubstituted C 1 to C 20 alkynyl group can In the absence of R 2 , Ser-R 2 in Formula 1 may be serine. The R 2 may be a substituted or unsubstituted C 1 to C 20 alkyl group. The R 2 may be a methyl group.
  • the compound may be referred to as a lipopeptide compound or a lipopeptide.
  • lipopeptide refers to a substance comprising a lipid conjugated to a peptide.
  • the lipid of the lipopeptide may be a saturated or unsaturated hydrocarbon.
  • the lipid may be an acyl group or an acyl chain.
  • the peptide of the lipopeptide is a compound in which two or more amino acids are linked by a peptide bond between a carboxyl group and an amino group.
  • the peptide may comprise 2 to 50, 2 to 40, 2 to 30, 2 to 20, or 2 to 10 amino acids.
  • the amino acid is a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amine group, an amidino group, an acetamino group, hydrazine, hydrazone, a carboxyl group, a sulfonyl group, a sulfamoyl group, a sulfonic acid group, phosphoric acid, C 1 to C 10 Alkyl group, C 1 To C 10 Alkoxy group, C 2 To C 10 Alkenyl group, C 2 To C 10 Alkynyl group, C 3 To C 10 Cycloalkyl group, C 6 To C 10 Aryl group, C It may be substituted with a 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.
  • the compound includes a derivative of the compound represented by Formula 1 above.
  • derivative refers to a compound obtained by substituting another atom or group of atoms for a part of the structure of the compound.
  • the compound represented by Formula 1 may be a compound represented by Formula 2 or Formula 3:
  • the compound represented by Formula 1 may be a compound represented by Formula 4 or Formula 5:
  • substitution in the above "unsubstituted” or “substituted” refers to introduced instead of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and the substituent refers to an introduced atomic group .
  • the substituent is a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amine group, an amidino group, an acetamino group, hydrazine, hydrazone, a carboxyl group, a sulfonyl group, a sulfamoyl group, a sulfonic acid group, phosphoric acid, C 1 to C 10 Alkyl group, C 1 To C 10 Alkoxy group, C 2 To C 10 Alkenyl group, C 2 To C 10 Alkynyl group, C 3 To C 10 Cycloalkyl group, C 6 To C 10 Aryl group, C It may be a 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.
  • alkyl refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon.
  • the alkyl is C 1 to C 30 , C 1 to C 20 , C 1 to C 15 , C 1 to C 10 , or C 1 to C 5 It may be an alkyl group.
  • the alkyl is, for example, 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, or n-heptyl.
  • alkenyl refers to a branched or unbranched hydrocarbon having one or more carbon-carbon double bonds.
  • the alkenyl group may be a C 2 to C 30 , C 2 to C 20 , C 2 to C 15 , C 2 to C 10 , or C 2 to C 5 alkenyl group.
  • the alkenyl group is, for example, vinyl, allyl, butenyl, isopropenyl, or isobutenyl.
  • alkynyl refers to a branched or unbranched hydrocarbon having at least one carbon-carbon triple bond.
  • the alkynyl group may be a C 2 to C 30 , C 2 to C 20 , C 2 to C 15 , C 2 to C 10 , or C 2 to C 5 alkynyl group.
  • the alkynyl is, for example, ethynyl, butynyl, isobutynyl, or isopropynyl.
  • acetamide may also be referred to as ethanamide.
  • the acetamide may be CH 3 CONH-.
  • halogen refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, bromine, chlorine, iodine and the like.
  • hydroxy refers to a -OH functional group (hydroxyl group).
  • the hydroxyalkyl group may be an alkyl group substituted with a hydroxy group.
  • cyano refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.
  • amine refers to a functional group in which one or more hydrogens are substituted with an alkyl or aromatic ring in ammonia (NH 3 ).
  • the amine group may be, for example, an amino group (—NH 2 ) and an alkylamine group.
  • alkoxy refers to an alkyl single bonded to an oxygen atom. Said alkoxy is, for example, methoxy, ethoxy, or butoxy.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon group.
  • aryl refers to an aromatic system comprising one or more rings, including groups in which the aromatic ring is fused to one or more carbon rings.
  • the C 6 to C 30 aryl group may be a C 6 to C 15 , or C 6 to C 10 aryl group.
  • the aryl is, for example, phenyl, naphthyl, or tetrahydronaphthyl.
  • heteroaryl refers to a monocyclic or bicyclic organic compound containing one or more heteroatoms selected from the group consisting of N, O, P and S, and the remaining ring atoms are carbon.
  • the heteroaryl group may include 1 to 5 heteroatoms, and 5 to 10 ring members.
  • the S or N may be oxidized to have several oxidation states.
  • the term "isomer” of the term “stereoisomer” refers to a compound that has the same molecular formula but does not have the same spatial arrangement or connection mode of constituent atoms in the molecule.
  • Isomers include, for example, structural isomers, and stereoisomers.
  • the stereoisomer may be a diasteromer or an enantiomer.
  • An enantiomer refers to an isomer that does not overlap its mirror image as in the relationship between the left hand and the right hand, and is also called an optical isomer. Enantiomers are divided into R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents differ from each other at the chiral central carbon.
  • Diastereomers refer to stereoisomers that are not in a mirror image relationship, and are isomers resulting from a different spatial arrangement of atoms.
  • the diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.
  • solvate refers to a compound solvated in an organic or inorganic solvent.
  • the solvate is, for example, a hydrate.
  • salt refers to the inorganic and organic acid addition salts of compounds.
  • the pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • the inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate.
  • the organic acid salts include formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate It may be an acid.
  • the metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.
  • Another aspect provides a Streptomyces sp. AMD43 strain (Accession No.: KCTC14317BP) for producing a compound represented by Formula 1 according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof do.
  • Streptomyces sp. AMD43 strain (accession number: KCTC14317BP) may be a marine-derived bacterium.
  • the Streptomyces genus ( Streptomyces sp.) bacteria are Gram-positive bacteria belonging to the Actinomycetes family (Streptomycetaceae).
  • the strain may produce a compound represented by Formula 1 according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt.
  • the strain may produce a compound represented by Formula 1 or a stereoisomer thereof according to an aspect.
  • the strain includes variants thereof.
  • a variant may be, for example, a variant caused by natural mutation or artificial mutation.
  • Artificial mutations may be caused by physical mutagens such as ultraviolet rays, or chemical mutagens such as basic compounds.
  • the strain includes spores, cells, or cultures of the strain.
  • Streptomyces genus Streptomyces sp.
  • AMD43 strain accesion Number: KCTC14317BP
  • a compound according to an aspect comprising the step of isolating a compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture medium in which the strain is cultured, a stereoisomer thereof, a solvate, or a pharmaceutical
  • a method for producing a chemically acceptable salt comprising the step of isolating a compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture medium in which the strain is cultured, a stereoisomer thereof, a solvate, or a pharmaceutical
  • a method for producing a chemically acceptable salt comprising the step of isolating a compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture medium in which the strain is cultured, a stereoisomer thereof, a solvate, or a pharmaceutical
  • Streptomyces sp. AMD43 strain the compound represented by Formula 1, stereoisomers, solvates, and salts are as described above.
  • the method includes the step of culturing Streptomyces sp. AMD43 strain (accession number: KCTC14317BP).
  • the culturing step may be culturing the strain in a liquid medium or a solid medium.
  • the medium may contain, for example, glucose, starch syrup, dextrin, starch, molasses, animal oil, or vegetable oil as a carbon source.
  • the medium may contain, for example, bran, soybean meal, wheat, malt, cottonseed meal, fish meal, cornstarch, broth, yeast extract, malt extract, ammonium sulfate, sodium nitrate, or urea as a nitrogen source.
  • the culture may be cultured while shaking or standing still under aerobic conditions.
  • the incubation temperature may be, for example, from about 20°C to about 40°C, from about 25°C to about 37°C, from about 28°C to about 35°C, or about 30°C.
  • the incubation time may be, for example, from about 1 day to about 4 months, from about 1 day to about 2 months, from about 1 day to about 6 weeks, from about 1 day to about 1 month, from about 1 day to about 2 weeks, or about 1 day. to about 1 week.
  • the method includes isolating the compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture solution.
  • Separation may include performing concentration, centrifugation, filtration, or chromatography of the culture solution.
  • the chromatography may be, for example, column chromatography, planar chromatography, paper chromatography or thin film chromatography depending on the type of 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.
  • Another aspect provides a pharmaceutical composition for preventing or treating cancer, comprising the compound according to the aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  • the compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof may be cytotoxic to cancer cells.
  • the compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof may be used as an anticancer agent.
  • the cancer is, for example, intrahepatic cholangiocarcinoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, mycosis fungoides, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, basal cell carcinoma , ovarian epithelial cancer, ovarian germ cell tumor, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, Non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain tumor, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningio
  • prevention refers to any action that suppresses or delays the onset of a disease by administration of the composition.
  • treatment refers to any act of improving or beneficially changing the symptoms of a disease by administering the composition.
  • the pharmaceutical composition may include the compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition may further include a known active ingredient having anticancer activity.
  • the pharmaceutical composition may further include a carrier, excipient or diluent.
  • Carriers, excipients and diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
  • the pharmaceutical composition may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively.
  • oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively.
  • a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
  • the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule.
  • the solid formulation may further include an excipient.
  • the excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin.
  • the solid formulation may further include a lubricant such as magnesium stearate or talc.
  • the oral liquid formulation may be a suspension, an oral solution, an emulsion, or a syrup.
  • the liquid formulation may contain water or liquid paraffin.
  • the liquid formulation may contain excipients, for example, wetting agents, sweetening agents, perfuming agents, or preservatives.
  • the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solution, suspension, emulsion, freeze-dried or suppository.
  • the non-aqueous solvent or suspending agent may include vegetable oil or ester.
  • the vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil.
  • the ester may be, for example, ethyl oleate.
  • the base of the suppository may be witepsol, macrogol, tween 61, cacao butter, laurin, or glycerogelatin.
  • the preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the individual, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art.
  • the compound, isomer, derivative, solvate, or pharmaceutically acceptable salt thereof may be, for example, from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg.
  • the amount may be administered in divided doses from 1 to 24 times a day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per 1 month to 12 months.
  • the compound, isomer, derivative, solvate, or pharmaceutically acceptable salt thereof is present in an amount of from about 0.0001% to about 10% by weight, or from about 0.001% to about 1% by weight, based on the total weight of the composition. may be included.
  • the administration method may be oral or parenteral administration.
  • the method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes.
  • the compositions may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.
  • Another aspect is a method for preventing or treating cancer, comprising administering to an individual a pharmaceutical composition for preventing or treating cancer comprising a compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof provides
  • the subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat or cat.
  • the subject may be suffering from, or likely to have, cancer.
  • the administration method may be oral or parenteral administration.
  • the method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes.
  • the pharmaceutical composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.
  • the preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art.
  • the dosage is, for example, in the range of from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, or from about 0.1 mg/kg to about 1 mg/kg on an adult basis.
  • the administration may be administered once a day, multiple times a day, or once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks to once a year.
  • a lipopeptide compound for use in the manufacture of a medicament for the prevention or treatment of cancer.
  • a lipopeptide compound for use in preventing or treating cancer.
  • novel lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof has cytotoxicity to cancer cells, it can be used to prevent or treat various types of cancer.
  • FIG. 1 is a photograph of a strain of Streptomyces sp. AMD43 cultured in a solid medium.
  • AMD43 strain was isolated from the sediments of tidal flat samples collected in Anmyeondo, Korea in 2019. AMD43 strain was isolated by inoculating the YEME solid medium (10 g of malt extract per 1 L of water, 4 g of yeast, 4 g of glucose, and 18 g of agar) and culturing at 28° C. for about 7 days (FIG. 1).
  • the AMD43 strain was identified as being of the genus Streptomyces sp. This strain was named Streptomyces sp. AMD43 strain, and the strain was deposited with the Korea Research Institute of Bioscience and Biotechnology on September 21, 2020 (accession number: KCTC14317BP).
  • AMD43 strain of Streptomyces genus was inoculated in YEME solid medium and cultured at 30° C. for several days.
  • the cultured AMD43 strain spores were inoculated into 50 mL of YEME liquid medium (10 g of malt extract per 1 L of water, 4 g of yeast, and 4 g of glucose), and cultured for about 4 days while shaking at 200 rpm at a temperature of 30°C. .
  • the EtOAc layer was stored separately in a clean flask, and 100 g of Anhydrous Sodium Sulfate (Daejeong Hwa Gold Co., Ltd.) was added to remove the water remaining in the culture, and passed through several layers of clean gauze to remove foreign substances. was removed.
  • the EtOAc layer from which the water was removed was transferred back to a 3 L round flask, and then dried under reduced pressure using a vacuum dryer. About 2.5 g of crude extract was obtained from a total of 18 L of strain culture.
  • the obtained extract was divided into thirds, and the three-divided extract was fractionated with a Sephadex LH-20 column (mobile phase: methanol).
  • LC/MS was used in which Agilent technologies' 1200 series LC and 6130 series mass spectrometer were connected. Using LC/MS, it was confirmed that the 7th fraction (fraction 7) and 8th fraction (fraction 8) contained new substances taeanamide A and taeanamide B.
  • Fractions 7 and 8 were dissolved together in methanol and concentrated by evaporation. Fractions were purified by chromatography. Fraction 7 and Fraction 8 were injected into high-performance liquid chromatography (HPLC) using a Kromasil column (100-5-C18, 10 x 250 mm), 45% aqueous CH 3 CN (detection: UV 210 nm, flow rate: Chromatography was performed under isocratic conditions of 2 mL/min). Taeanamide A (20 mg) and Taeanamide B (40 mg) were eluted at about 19 minutes and about 28 minutes, respectively.
  • HPLC high-performance liquid chromatography
  • Taeanamide A and Taeanamide B were confirmed based on 1D and 2D nuclear magnetic resonance (NMR) spectra.
  • a nuclear magnetic resonance spectrum ( 1 H NMR, 13 C NMR) was 800 MHz NMR manufactured by Bruker, and DMSO-d 6 was used as the solvent.
  • Table 1 shows the structural positioning of Taeanamide A and Taeanamide B by nuclear magnetic resonance spectra.
  • Taeanamide A (1) C/H ⁇ C , type ⁇ H , mult ( J in Hz) One 171.4, C 2 54.2, CH 4.50, m 2-NH 8.18, m 3a 61.4, CH 2 3.89, (dd, 11.0, 4.5) 3b 3.62, m 4 171.8, C 5 50.3, CH 4.51, m 5-NH 7.67, (d, 8.0) 6 41.7, CH 2 1.41, m 7 23.8, CH 1.53, m 8 21.3, CH 3 0.82, (d, 6.5) 9 23.3, CH 3 0.80, (d, 6.5) 10 171.4, C 11 48.6, C 4.22, m 11-NH 8.33, (d, 7.0) 12 18.0, CH 3 1.22, (d, 7.0) 13 171.0, C 14 51.1, CH 4.19, m 14-NH 8.15, (d, 6.5) 15a 31.2, CH 2 1.77, m 15b 1.64, (td, 14.0, 7.5) 16 35.5, CH 2
  • Taeanamide B (2) C/H ⁇ C , type ⁇ H , mult ( J in Hz) One 172.5, C 2 56.7, CH 5.11, m 2-NH 9.35, (d, 6.5) 3a 63.0, CH 2 4.36, m 3b 4.22, m 3-OH 6.84, (t, 5.5) 4 174.3, C 5 52.6, CH 5.25, m 5-NH 8.84, (d, 9.5) 6 41.9, CH 2 2.02, m 7 25.4, CH 1.94, m 8 23.9, CH 3 0.90, (d, 6.5) 9 19.8, CH 3 0.83, (d, 6.5) 10 174.0, C 11 50.7, C 5.04, m 11-NH 9.41, (d, 6.5) 12 18.7, CH 3 1.70, (d, 7.0) 13 173.6, C 14 52.9, CH 4.97, m 14-NH 8.67, (d, 7.0) 15a 32.8, CH 2 2.59, (td, 13.5, 6.5) 15b 2.35,
  • Human lung cancer cell line A-549, human colorectal cancer cell line HCT116, human gastric cancer cell line SNU638, human liver cancer cell line SK-HEP-1, breast cancer cell line MDA-MB-231, and leukemia cell line K562 were prepared from the Korean Cell Line Bank, Korea. ) was purchased from
  • Cell cultures were prepared using 10% (v/v) heat-inactivated fetal bovine serum (FBS) and an antibacterial-antimycobacterial solution (100 units/mL penicillin G sodium, 100 ⁇ g/mL streptomycin, and Medium containing 250 ng/mL amphotericin B) (RPMI-1640 medium for A549, HCT116, SNU638, and K562 cells; DMEM (Dulbecco's modified) for MDA-MB-231 and SK-HEP-1 Eagle's medium); and minimal essential medium for MRC-5) were used.
  • FBS heat-inactivated fetal bovine serum
  • an antibacterial-antimycobacterial solution 100 units/mL penicillin G sodium, 100 ⁇ g/mL streptomycin, and Medium containing 250 ng/mL amphotericin B
  • RPMI-1640 medium for A549, HCT116, SNU638, and K562 cells
  • DMEM Dulbecco's modified for MDA-MB-2
  • SRB sulforhodamine B
  • Taeanamide A did not show a cell growth inhibitory effect, but Taeanamide B showed a relatively high cell growth inhibitory activity against all six types of cancer cells.

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Abstract

Provided are: a novel lipid peptide compound, and a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof; a method for producing same; and an anticancer use thereof. The lipid peptide compound, and a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof have cytotoxicity against cancer cells, and can be used for preventing or treating various types of cancer.

Description

신규한 지질펩티드 화합물, 이의 생산 방법, 및 이의 용도Novel lipopeptide compounds, methods for their production, and uses thereof
신규한 지질펩티드 화합물, 이를 생산하는 방법, 및 이의 항암 용도에 관한 것이다.It relates to novel lipopeptide compounds, methods for their production, and their anti-cancer uses.
미생물로부터 유래한 생리 활성 물질은 대체로 항생제, 항진균, 항암제의 원천이었으며 이를 비롯한 다양한 질병 치료를 위한 신약으로 개발되거나 신약 개발의 바탕(template)이 되어 왔다. 미생물로부터 유래한 항생제는 예를 들면, 암포테리신(amphotericin), 에리트로마이신(erythromycin), 스트렙토마이신(streptomycin), 테트라사이클린(tetracycline), 및 반코마이신(vancomycin)이 대표적이다. 또한, 2003년에는 방선균인 스트렙토마이세스(Streptomyces)에서 분리된 댑토마이신(daptomycin)이 차세대 항생제로서 미국 식품의약안전청(FDA)의 승인을 받은 바 있다. 한편, 세균으로부터 유래한 항암제는 예를 들면, 독소루비신(doxorubicin), 블레오마이신(bleomycin), 미스라마이신(mithramycin), 네오카르지노스타틴(neocarzinostatin), 펜토스타틴(pentostatin), 및 에포틸론(epothilone)이 있다. 이와 같이, 세균 유래 생리 활성 물질의 연구는 항균제, 항진균제, 및 항암제 개발에서 매우 중요하다.Physiologically active substances derived from microorganisms have generally been the source of antibiotics, antifungals, and anticancer drugs, and have been developed as new drugs for the treatment of various diseases including these, or as a template for the development of new drugs. Antibiotics derived from microorganisms are representative of, for example, amphotericin, erythromycin, streptomycin, tetracycline, and vancomycin. Also, in 2003, daptomycin isolated from the actinomycete Streptomyces was approved by the US Food and Drug Administration (FDA) as a next-generation antibiotic. On the other hand, anticancer agents derived from bacteria, for example, doxorubicin (doxorubicin), bleomycin (bleomycin), misramycin (mithramycin), neocarzinostatin (neocarzinostatin), pentostatin (pentostatin), and epothilone (epothilone) There is this. As such, the study of bioactive substances derived from bacteria is very important in the development of antibacterial agents, antifungal agents, and anticancer agents.
구조적으로 기존의 물질과는 판이하게 다른 생리활성물질을 탐색하기 위하여 최근 천연물 연구 중 하나의 전략은 지리적, 계통분류학적으로 특이한 환경에서 천연물을 연구하는 것이다. 손쉽게 접근이 가능한 토양 서식 미생물이나 육상식물들은 오랜 기간에 걸쳐서 천연물 획득을 위하여 깊게 연구되었지만, 해양 기원의 미생물에 대한 연구는 상대적으로 활발하게 이루어지지 않았다. 해양은 지구 표면의 70%를 차지하고 있고 그 자체가 대부분 탐사되지 않은 기회의 공간으로 제시되고 있다. 해양 미생물은 그 다양성에 대하여 정확하게 파악되지 않고 있지만 현재까지 해양 미생물 중 단지 1%만이 배양되거나 동정된 것으로 추정될 정도로 이 분야의 연구가 미진한 상황이다.In order to search for physiologically active substances that are structurally different from existing substances, one of the recent natural product research strategies is to study natural products in a geographically and phylogenetically unique environment. Although easily accessible soil-dwelling microorganisms and terrestrial plants have been studied in depth to acquire natural products over a long period of time, studies on microorganisms of marine origin have not been conducted relatively actively. The ocean occupies 70% of the Earth's surface and is presented as a space of opportunity that is largely unexplored. Although the diversity of marine microorganisms is not accurately understood, research in this field is insufficient so far that only 1% of marine microorganisms have been cultured or identified.
따라서, 구조적으로 새로운 항생제 및 항암제의 개발을 위하여, 유용한 생리 활성 물질을 생산하는 해양 미생물을 선별하고, 이들이 생산하는 신규 화합물을 탐색, 발굴하는 것이 필요하다.Therefore, for the development of structurally novel antibiotics and anticancer drugs, it is necessary to select marine microorganisms that produce useful physiologically active substances, and to search for and discover new compounds produced by them.
(특허문헌 1) KR 10-1723649 B1(Patent Document 1) KR 10-1723649 B1
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 제공한다.Provided are lipopeptide compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 세균을 제공한다.Bacteria that produce lipopeptide compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof are provided.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 방법을 제공한다.A method for producing a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof is provided.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.Provided is a pharmaceutical composition for preventing or treating cancer comprising a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 이용하여 암을 예방 또는 치료하는 방법을 제공한다.Provided is a method for preventing or treating cancer using a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
암 예방 또는 치료용 약제의 제조에 사용하기 위한, 지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도를 제공한다.Provided is the use of a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention or treatment of cancer.
암을 예방 또는 치료하는 데 사용하기 위한, 지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도를 제공한다.Provided is the use of a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, for use in preventing or treating cancer.
일 양상은 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 제공한다:One aspect provides a compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
[식 1][Equation 1]
R1-(C=O)-Ser-Thr-Ala-Thr-Pro-Gly-X-Ala-Leu-Ser-R2.R 1 -(C=O)-Ser-Thr-Ala-Thr-Pro-Gly-X-Ala-Leu-Ser-R 2 .
상기 식 1에서, C=O는 1개의 산소 원자에 이중결합된 1개의 탄소원자로 이루어진 기능기 즉, 카르보닐(carbonyl)기를 의미한다.In Formula 1, C=O means a functional group consisting of one carbon atom double bonded to one oxygen atom, that is, a carbonyl group.
상기 식 1에서, Ser은 세린(Serine: S)을 의미한다. Thr은 트레오닌(Shreonine: T)을 의미한다. Ala은 알라닌(Alanine: A)을 의미한다. Pro은 프롤린(Proline: P)을 의미한다. Gly은 글리신(Glycine: G)을 의미한다. Leu은 류신(Leucine: L)을 의미한다.In Formula 1, Ser means serine (S). Thr stands for threonine (T). Ala means Alanine (A). Pro stands for Proline (P). Gly means glycine (G). Leu means leucine (L).
상기 식 1에서, X는 C1 내지 C10 알킬아세트아미드로 치환된 글리신(Glyine; Gly 또는 G)일 수 있다. 상기 C1 내지 C10 알킬아세트아미드는 C1 내지 C5 알킬아세트아미드일 수 있다. 상기 C1 내지 C10 알킬아세트아미드는 n-에틸아세트아미드(ethylacetmaide)일 수 있다. 상기 X는 n-에틸아세트아미드로 치환된 글리신일 수 있다.In Formula 1, X may be glycine (Glyine; Gly or G) substituted with C 1 to C 10 alkylacetamide. The C 1 to C 10 alkylacetamide may be a C 1 to C 5 alkylacetamide. The C 1 to C 10 alkylacetamide may be n-ethylacetamide (ethylacetmaide). X may be glycine substituted with n-ethylacetamide.
상기 식 1에서, R1은 포화 또는 불포화된 탄화수소 사슬일 수 있다. 용어 "탄화수소(hydrocarbon)"는 탄소와 수소로 이루어진 유기 화합물을 말한다. 상기 탄화수소는 지방족 포화 탄화수소, 지방족 불포화 탄화수소, 지방족 고리 탄화수소, 또는 방향족 탄화수소일 수 있다. 상기 포화 탄화수소는 단일 결합으로 구성된 탄화수소를 말한다. 상기 불포화 탄화수소는 하나 이상의 이중결합 또는 삼중 결합을 포함하는 탄화수소를 말한다. 상기 R1은 치환 또는 비치환된 C1 내지 C30의 알킬기, 치환 또는 비치환된 C2 내지 C30의 알케닐기, 치환 또는 비치환된 C2 내지 C30의 알키닐기, 또는 이들의 조합으로부터 선택될 수 있다. 상기 R1은 C1 내지 C10의 알킬기(예, 메틸기)로 치환된(즉, 분지된) 것일 수 있다. 상기 R1은 1개 이상의 알케닐기를 포함하는 C1 내지 C30의 알킬기일 수 있다. 상기 R1은 9-메틸-1-데센(9-methyl-1-decene)일 수 있다.In Formula 1, R 1 may be a saturated or unsaturated hydrocarbon chain. The term “hydrocarbon” refers to an organic compound composed of carbon and hydrogen. The hydrocarbon may be an aliphatic saturated hydrocarbon, an aliphatic unsaturated hydrocarbon, an alicyclic hydrocarbon, or an aromatic hydrocarbon. The saturated hydrocarbon refers to a hydrocarbon composed of a single bond. The unsaturated hydrocarbon refers to a hydrocarbon containing one or more double bonds or triple bonds. Wherein R 1 is a substituted or unsubstituted C 1 to C 30 alkyl group, a substituted or unsubstituted C 2 to C 30 alkenyl group, a substituted or unsubstituted C 2 to C 30 alkynyl group, or a combination thereof can be selected. The R 1 may be substituted (ie, branched) with a C 1 to C 10 alkyl group (eg, a methyl group). The R 1 may be a C 1 to C 30 alkyl group including one or more alkenyl groups. The R 1 may be 9-methyl-1-decene.
상기 식 1에서, R2는 없거나, 또는 치환 또는 비치환된 C1 내지 C20 알킬기, 치환 또는 비치환된 C1 내지 C20 알케닐기, 또는 치환 또는 비치환된 C1 내지 C20 알키닐기일 수 있다. 상기 R2가 없는 경우, 식 1 중 Ser-R2는 세린일 수 있다. 상기 R2는 치환 또는 비치환된 C1 내지 C20 알킬기일 수 있다. 상기 R2는 메틸기일 수 있다.In Formula 1, R 2 is absent, or a substituted or unsubstituted C 1 to C 20 alkyl group, a substituted or unsubstituted C 1 to C 20 alkenyl group, or a substituted or unsubstituted C 1 to C 20 alkynyl group can In the absence of R 2 , Ser-R 2 in Formula 1 may be serine. The R 2 may be a substituted or unsubstituted C 1 to C 20 alkyl group. The R 2 may be a methyl group.
상기 화합물은 지질펩티드(lipopeptide) 화합물 또는 리포펩티드로 불릴 수 있다. 용어 "지질펩티드(lipopeptide)"는 펩티드에 접합된 지질을 포함하는 물질을 말한다. 상기 지질펩티드의 지질은 포화 또는 불포화된 탄화수소일 수 있다. 상기 지질은 아실(acyl) 기 또는 아실 사슬일 수 있다. 상기 지질펩티드의 펩티드는 펩티드(peptide)는 두개 이상의 아미노산이 카르복시기와 아미노기 간의 펩티드 결합으로 연결된 형태의 화합물이다. 구성 아미노산의 수에 따라 디펩티드(dipeptide), 트리펩티드(tripeptide), 테트라펩티드(tetrapeptide) 등이라 하고, 약 10개 이하의 펩티드 결합이 있는 것을 올리고펩티드(oligopeptide), 다수의 펩티드 결합이 있는 것을 폴리펩티드(polypeptide)라고 한다. 상기 펩티드는 2개 내지 50개, 2개 내지 40개, 2개 내지 30개, 2개 내지 20개, 또는 2개 내지 10개의 아미노산을 포함할 수 있다. 상기 아미노산은 할로겐 원자, 히드록시기, 니트로기, 시아노기, 아민기, 아미디노기, 아세트아미노기, 히드라진, 히드라존, 카르복실기, 술포닐기, 술파모일(sulfamoyl)기, 술폰산기, 인산, C1 내지 C10의 알킬기, C1 내지 C10의 알콕시기, C2 내지 C10의 알케닐기, C2 내지 C10의 알키닐기, C3 내지 C10의 시클로알킬기, C6 내지 C10의 아릴기, C6 내지 C10의 헤테로아릴기, C6 내지 C20의 아릴알킬기, C6 내지 C20의 헤테로아릴알킬기, 또는 이들의 조합으로 치환될 수 있다.The compound may be referred to as a lipopeptide compound or a lipopeptide. The term “lipopeptide” refers to a substance comprising a lipid conjugated to a peptide. The lipid of the lipopeptide may be a saturated or unsaturated hydrocarbon. The lipid may be an acyl group or an acyl chain. The peptide of the lipopeptide is a compound in which two or more amino acids are linked by a peptide bond between a carboxyl group and an amino group. Depending on the number of constituent amino acids, they are called dipeptide, tripeptide, tetrapeptide, etc., and those with about 10 or less peptide bonds are called oligopeptides, and those with multiple peptide bonds are called oligopeptides. It is called a polypeptide. The peptide may comprise 2 to 50, 2 to 40, 2 to 30, 2 to 20, or 2 to 10 amino acids. The amino acid is a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amine group, an amidino group, an acetamino group, hydrazine, hydrazone, a carboxyl group, a sulfonyl group, a sulfamoyl group, a sulfonic acid group, phosphoric acid, C 1 to C 10 Alkyl group, C 1 To C 10 Alkoxy group, C 2 To C 10 Alkenyl group, C 2 To C 10 Alkynyl group, C 3 To C 10 Cycloalkyl group, C 6 To C 10 Aryl group, C It may be substituted with a 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.
상기 화합물은 상기 식 1로 표시되는 화합물의 유도체를 포함한다. 용어 "유도체(derivative)"는 상기 화합물의 구조 일부를 다른 원자나 원자단으로 치환하여 얻어지는 화합물을 말한다.The compound includes a derivative of the compound represented by Formula 1 above. The term "derivative" refers to a compound obtained by substituting another atom or group of atoms for a part of the structure of the compound.
상기 식 1로 표시되는 화합물은 식 2 또는 식 3으로 표시되는 화합물 일 수 있다:The compound represented by Formula 1 may be a compound represented by Formula 2 or Formula 3:
[식 2][Equation 2]
Figure PCTKR2021016155-appb-I000001
; 및
Figure PCTKR2021016155-appb-I000001
; and
[식 3][Equation 3]
Figure PCTKR2021016155-appb-I000002
.
Figure PCTKR2021016155-appb-I000002
.
상기 식 1로 표시되는 화합물은 식 4 또는 식 5로 표시되는 화합물 일 수 있다:The compound represented by Formula 1 may be a compound represented by Formula 4 or Formula 5:
[식 4][Equation 4]
Figure PCTKR2021016155-appb-I000003
; 및
Figure PCTKR2021016155-appb-I000003
; and
[식 5][Equation 5]
Figure PCTKR2021016155-appb-I000004
.
Figure PCTKR2021016155-appb-I000004
.
상기 "비치환" 또는 "치환"에서의 용어 "치환"은 유기 화합물 중의 하나 이상의 수소 원자를 다른 원자단으로 치환하여 유도체를 형성한 경우 수소 원자 대신에 도입되는 것을 말하고, 치환기는 도입된 원자단을 말한다. 상기 치환기는 할로겐 원자, 히드록시기, 니트로기, 시아노기, 아민기, 아미디노기, 아세트아미노기, 히드라진, 히드라존, 카르복실기, 술포닐기, 술파모일(sulfamoyl)기, 술폰산기, 인산, C1 내지 C10의 알킬기, C1 내지 C10의 알콕시기, C2 내지 C10의 알케닐기, C2 내지 C10의 알키닐기, C3 내지 C10의 시클로알킬기, C6 내지 C10의 아릴기, C6 내지 C10의 헤테로아릴기, C6 내지 C20의 아릴알킬기, C6 내지 C20의 헤테로아릴알킬기, 또는 이들의 조합일 수 있다.The term "substitution" in the above "unsubstituted" or "substituted" refers to introduced instead of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and the substituent refers to an introduced atomic group . The substituent is a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amine group, an amidino group, an acetamino group, hydrazine, hydrazone, a carboxyl group, a sulfonyl group, a sulfamoyl group, a sulfonic acid group, phosphoric acid, C 1 to C 10 Alkyl group, C 1 To C 10 Alkoxy group, C 2 To C 10 Alkenyl group, C 2 To C 10 Alkynyl group, C 3 To C 10 Cycloalkyl group, C 6 To C 10 Aryl group, C It may be a 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.
용어 "알킬(alkyl)"은 완전 포화된 분지형 또는 비분지형 (또는, 직쇄 또는 선형) 탄화수소를 말한다. 상기 알킬은 C1 내지 C30, C1 내지 C20, C1 내지 C15, C1 내지 C10, 또는 C1 내지 C5인 알킬기일 수 있다. 상기 알킬은 예를 들어, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, 2차 부틸(sec-butyl), n-펜틸, 이소펜틸, 네오펜틸, iso-아밀, n-헥실, 3-메틸헥실, 2,2-디메틸펜틸, 2,3-디메틸펜틸, 또는 n-헵틸이다.The term “alkyl” refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon. The alkyl is C 1 to C 30 , C 1 to C 20 , C 1 to C 15 , C 1 to C 10 , or C 1 to C 5 It may be an alkyl group. The alkyl is, for example, 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, or n-heptyl.
용어 "알케닐(alkenyl)"은 하나 이상의 탄소-탄소 이중결합을 갖는 분지형 또는 비분지형 탄화수소를 말한다. 상기 알케닐기는 C2 내지 C30, C2 내지 C20, C2 내지 C15, C2 내지 C10, 또는 C2 내지 C5인 알케닐기일 수 있다. 상기 알케닐기는 예를 들어, 비닐, 알릴, 부테닐, 이소프로페닐, 또는 이소부테닐이다.The term “alkenyl” refers to a branched or unbranched hydrocarbon having one or more carbon-carbon double bonds. The alkenyl group may be a C 2 to C 30 , C 2 to C 20 , C 2 to C 15 , C 2 to C 10 , or C 2 to C 5 alkenyl group. The alkenyl group is, for example, vinyl, allyl, butenyl, isopropenyl, or isobutenyl.
용어 "알키닐(alkynyl)"은 적어도 하나의 탄소-탄소 삼중결합을 갖는 분지형 또는 비분지형 탄화수소를 말한다. 상기 알키닐기는 C2 내지 C30, C2 내지 C20, C2 내지 C15, C2 내지 C10, 또는 C2 내지 C5인 알키닐기일 수 있다. 상기 알키닐은 예를 들어, 에티닐, 부티닐, 이소부티닐, 또는 이소프로피닐이다.The term "alkynyl" refers to a branched or unbranched hydrocarbon having at least one carbon-carbon triple bond. The alkynyl group may be a C 2 to C 30 , C 2 to C 20 , C 2 to C 15 , C 2 to C 10 , or C 2 to C 5 alkynyl group. The alkynyl is, for example, ethynyl, butynyl, isobutynyl, or isopropynyl.
상기 알킬아세트아미드 중 아세트아미드(acetamide)는 에탄아미드(ethanamide)로도 불릴 수 있다. 상기 아세트아미드는 CH3CONH-일 수 있다.Among the alkylacetamides, acetamide may also be referred to as ethanamide. The acetamide may be CH 3 CONH-.
용어 "할로겐(halogen)" 원자는 주기율표의 17족에 속하는 원자를 말한다. 할로겐 원자는 불소, 브롬, 염소, 요오드 등을 포함한다.The term "halogen" atom refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, bromine, chlorine, iodine and the like.
용어 "히드록시(hydroxy)"는 -OH 기능기(수산기)를 말한다. 상기 히드록시알킬기는 히드록시기로 치환된 알킬기일 수 있다.The term "hydroxy" refers to a -OH functional group (hydroxyl group). The hydroxyalkyl group may be an alkyl group substituted with a hydroxy group.
용어 "시아노(cyano)"는 탄소 원자와 질소 원자 사이에 삼중결합으로 이루어진 기능기를 말한다.The term "cyano" refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.
용어 "아민(amine)"은 암모니아(NH3)에서 하나 이상의 수소가 알킬 또는 방향족 고리로 치환된 기능기를 말한다. 상기 아민기는 예를 들어, 아미노기(-NH2) 및 알킬아민기(alkylamine)일 수 있다.The term “amine” refers to a functional group in which one or more hydrogens are substituted with an alkyl or aromatic ring in ammonia (NH 3 ). The amine group may be, for example, an amino group (—NH 2 ) and an alkylamine group.
용어 "알콕시(alkoxy)"는 산소 원자에 단일 결합된 알킬을 말한다. 상기 알콕시는 예를 들어 메톡시, 에톡시, 또는 부톡시이다.The term “alkoxy” refers to an alkyl single bonded to an oxygen atom. Said alkoxy is, for example, methoxy, ethoxy, or butoxy.
용어 "시클로알킬(cycloalkyl)"는 포화 또는 부분적으로 불포화된 비방향족(non-aromatic) 모노시클릭, 바이시클릭 또는 트리시클릭 탄화수소기를 말한다.The term “cycloalkyl” refers to a saturated or partially unsaturated non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon group.
용어 "아릴(aryl)"은 단독 또는 조합하여 사용되어, 하나 이상의 고리를 포함하는 방향족 시스템을 말하고, 방향족 고리가 하나 이상의 탄소 고리에 융합된 그룹도 포함한다. 상기 C6 내지 C30의 아릴기는 C6 내지 C15, 또는 C6 내지 C10인 아릴기일 수 있다. 상기 아릴은 예를 들어, 페닐, 나프틸, 또는 테트라히드로나프틸이다.The term "aryl", used alone or in combination, refers to an aromatic system comprising one or more rings, including groups in which the aromatic ring is fused to one or more carbon rings. The C 6 to C 30 aryl group may be a C 6 to C 15 , or C 6 to C 10 aryl group. The aryl is, for example, phenyl, naphthyl, or tetrahydronaphthyl.
용어 "헤테로아릴(heteroaryl)"은 N, O, P 및 S로 이루어진 군으로부터 선택된 하나 이상의 헤테로원자를 포함하고, 나머지 고리원자가 탄소인 모노시클릭(monocyclic) 또는 바이시클릭(bicyclic) 유기 화합물을 말한다. 상기 헤테로아릴기는 1 내지 5개의 헤테로원자를 포함할 수 있고, 5 내지 10 고리 멤버(ring member)를 포함할 수 있다. 상기 S 또는 N은 산화되어 여러 산화 상태를 가질 수 있다.The term "heteroaryl" refers to a monocyclic or bicyclic organic compound containing one or more heteroatoms selected from the group consisting of N, O, P and S, and the remaining ring atoms are carbon. say The heteroaryl group may include 1 to 5 heteroatoms, and 5 to 10 ring members. The S or N may be oxidized to have several oxidation states.
용어 "입체이성질체"의 "이성질체(isomer)"는 분자식은 같지만 분자 내에 있는 구성 원자의 연결 방식이나 공간 배열이 동일하지 않은 화합물을 말한다. 이성질체는 예를 들면, 구조 이성질체(structural isomers), 및 입체이성질체(stereoisomer)를 포함한다. 상기 입체이성질체는 부분입체 이성질체(diasteromer) 또는 거울상이성질체(enantiomer)일 수 있다. 거울상이성질체는 왼손과 오른손의 관계처럼 그 거울상과 겹쳐지지 않는 이성질체를 말하고, 광학 이성질체(optical isomer)라고도 한다. 거울상 이성질체는 키랄 중심 탄소에 4개 이상의 치환기가 서로 다른 경우 R(Rectus: 시계 방향) 및 S(Sinister: 반시계 방향)로 구분한다. 부분입체이성질체는 거울상 관계가 아닌 입체 이성질체를 말하고, 원자의 공간 배열이 달라 생기는 이성질체이다. 상기 부분입체이성질체는 시스(cis)-트랜스(trans) 이성질체 및 형태 이성질체(conformational isomer 또는 conformer) 로 나뉠 수 있다.The term "isomer" of the term "stereoisomer" refers to a compound that has the same molecular formula but does not have the same spatial arrangement or connection mode of constituent atoms in the molecule. Isomers include, for example, structural isomers, and stereoisomers. The stereoisomer may be a diasteromer or an enantiomer. An enantiomer refers to an isomer that does not overlap its mirror image as in the relationship between the left hand and the right hand, and is also called an optical isomer. Enantiomers are divided into R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents differ from each other at the chiral central carbon. Diastereomers refer to stereoisomers that are not in a mirror image relationship, and are isomers resulting from a different spatial arrangement of atoms. The diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.
용어 "용매화물(solvate)"은 유기 또는 무기 용매에 용매화된 화합물을 말한다. 상기 용매화물은 예를 들어 수화물이다.The term “solvate” refers to a compound solvated in an organic or inorganic solvent. The solvate is, for example, a hydrate.
용어 "염(salt)"은 화합물의 무기 및 유기산 부가염을 말한다. 상기 약학적으로 허용가능한 염은 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 염일 수 있다. 상기 무기산염은 염산염, 브롬산염, 인산염, 황산염, 또는 이황산염일 수 있다. 상기 유기산염은 포름산염, 아세트산염, 프로피온산염, 젖산염, 옥살산염, 주석산염, 말산염, 말레인산염, 구연산염, 푸마르산염, 베실산염, 캠실산염, 에디실염, 트리클로로아세트산, 트리플루오로아세트산염, 벤조산염, 글루콘산염, 메탄술폰산염, 글리콜산염, 숙신산염, 4-톨루엔술폰산염, 갈룩투론산염, 엠본산염, 글루탐산염, 에탄술폰산염, 벤젠술폰산염, p-톨루엔술폰산염, 또는 아스파르트산염일 수 있다. 상기 금속염은 칼슘염, 나트륨염, 마그네슘염, 스트론튬염, 또는 칼륨염일 수 있다.The term "salt" refers to the inorganic and organic acid addition salts of compounds. The pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate. The organic acid salts include formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate It may be an acid. The metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.
다른 양상은 일 양상에 따른 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)를 제공한다.Another aspect provides a Streptomyces sp. AMD43 strain (Accession No.: KCTC14317BP) for producing a compound represented by Formula 1 according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof do.
식 1로 표시되는 화합물, 입체이성질체, 용매화물, 및 염은 전술한 바와 같다.The compound, stereoisomer, solvate, and salt represented by Formula 1 are as described above.
스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)는 해양 유래 세균일 수 있다. 상기 스트렙토마이세스 속(Streptomyces sp.) 세균은 방선균과(Streptomycetaceae)에 속하는 그람양성(Gram-positive) 세균이다. Streptomyces sp. AMD43 strain (accession number: KCTC14317BP) may be a marine-derived bacterium. The Streptomyces genus ( Streptomyces sp.) bacteria are Gram-positive bacteria belonging to the Actinomycetes family (Streptomycetaceae).
상기 균주는 일 양상에 따른 식 1로 표시되는 화합물, 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산할 수 있다. 상기 균주는 일 양상에 따른 식 1로 표시되는 화합물 또는 이의 입체이성질체를 생산할 수 있다.The strain may produce a compound represented by Formula 1 according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt. The strain may produce a compound represented by Formula 1 or a stereoisomer thereof according to an aspect.
상기 균주는 그의 변이체를 포함한다. 변이체는 예를 들면, 자연 돌연변이 또는 인위적 돌연변이에 의해 생긴 변이체일 수 있다. 인위적 돌연변이는 자외선 등 물리적 돌연변이원, 또는 염기 화합물 등 화학적 돌연변이원에 의해 발생할 수 있다.The strain includes variants thereof. A variant may be, for example, a variant caused by natural mutation or artificial mutation. Artificial mutations may be caused by physical mutagens such as ultraviolet rays, or chemical mutagens such as basic compounds.
상기 균주는 균주의 포자, 균체, 또는 이것의 배양물을 포함한다.The strain includes spores, cells, or cultures of the strain.
다른 양상은 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)를 배양하는 단계; 및Another aspect is Streptomyces genus ( Streptomyces sp.) culturing the AMD43 strain (Accession Number: KCTC14317BP); and
상기 균주를 배양한 배양액으로부터 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 분리하는 단계를 포함하는, 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 방법을 제공한다.A compound according to an aspect, comprising the step of isolating a compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture medium in which the strain is cultured, a stereoisomer thereof, a solvate, or a pharmaceutical Provided is a method for producing a chemically acceptable salt.
스트렙토마이세스 속(Streptomyces sp.) AMD43 균주, 식 1로 표시되는 화합물, 입체이성질체, 용매화물, 및 염은 전술한 바와 같다. Streptomyces sp. AMD43 strain, the compound represented by Formula 1, stereoisomers, solvates, and salts are as described above.
상기 방법은 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)를 배양하는 단계를 포함한다. 배양하는 단계는 액체 배지 또는 고체 배지에서 균주를 배양하는 것일 수 있다. 배지는 탄소원으로서 예를 들면, 포도당, 물엿, 덱스트린, 전분, 당밀, 동물유, 또는 식물유를 포함할 수 있다. 배지는 질소원으로서 예를 들면, 밀기울, 대두박, 소맥, 맥아, 면실박, 어박, 콘스팁리커, 육즙, 효모 추출물, 맥아 추출물, 황산암모늄, 질산소다, 또는 요소를 포함할 수 있다.The method includes the step of culturing Streptomyces sp. AMD43 strain (accession number: KCTC14317BP). The culturing step may be culturing the strain in a liquid medium or a solid medium. The medium may contain, for example, glucose, starch syrup, dextrin, starch, molasses, animal oil, or vegetable oil as a carbon source. The medium may contain, for example, bran, soybean meal, wheat, malt, cottonseed meal, fish meal, cornstarch, broth, yeast extract, malt extract, ammonium sulfate, sodium nitrate, or urea as a nitrogen source.
배양은 호기성 조건에서 진탕 또는 정치하면서 배양하는 것일 수 있다. 배양 온도는 예를 들어 약 20℃ 내지 약 40℃, 약 25℃ 내지 약 37℃, 약 28℃ 내지 약 35℃, 또는 약 30℃일 수 있다. 배양 시간은 예를 들어 약 1일 내지 약 4개월, 약 1일 내지 약 2개월, 약 1일 내지 약 6주, 약 1일 내지 약 1개월, 약 1일 내지 약 2주, 또는 약 1일 내지 약 1주일 수 있다.The culture may be cultured while shaking or standing still under aerobic conditions. The incubation temperature may be, for example, from about 20°C to about 40°C, from about 25°C to about 37°C, from about 28°C to about 35°C, or about 30°C. The incubation time may be, for example, from about 1 day to about 4 months, from about 1 day to about 2 months, from about 1 day to about 6 weeks, from about 1 day to about 1 month, from about 1 day to about 2 weeks, or about 1 day. to about 1 week.
상기 방법은 배양액으로부터 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 분리하는 단계를 포함한다.The method includes isolating the compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture solution.
분리하는 단계는 배양액을 농축, 원심분리, 여과, 또는 크로마토그래피를 수행하는 단계를 포함할 수 있다. 크로마토그래피는 예를 들면, 정지상의 형태에 따라 컬럼 크로마토그래피, 평판 크로마토그래피(planar chromatography), 종이 크로마토그래피 또는 얇은 막 크로마토그래피일 수 있다. 크로마토그래피는 예를 들면, 이동상의 물리적 특성에 따라, 기체 크로마토그래피, 액체 크로마토그래피, 또는 친화 크로마토그래피일 수 있다. 액체 크로마토그래피는 예를 들면 고성능 액체 크로마토그래피(HPLC)일 수 있다. 크로마토그래피는 예를 들면, 분리 방법에 따라, 이온 교환 크로마토그래피, 크기-배제 크로마토그래피일 수 있다. 크로마토그래피는 예를 들면, 정상 크로마토그래피 또는 역상 크로마토그래피일 수 있다.Separation may include performing concentration, centrifugation, filtration, or chromatography of the culture solution. The chromatography may be, for example, column chromatography, planar chromatography, paper chromatography or thin film chromatography depending on the type of 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). 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.
다른 양상은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect provides a pharmaceutical composition for preventing or treating cancer, comprising the compound according to the aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
식 1로 표시되는 화합물, 입체이성질체, 용매화물, 및 염은 전술한 바와 같다.The compound, stereoisomer, solvate, and salt represented by Formula 1 are as described above.
상기 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 암세포에 대해 세포독성을 가질 수 있다. 상기 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 항암제로 사용될 수 있다.The compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof may be cytotoxic to cancer cells. The compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof may be used as an anticancer agent.
상기 암은 예를 들면 간내 담관암, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 균상식육종, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구 백혈병, 기저세포암, 난소 상피암, 난소 생식 세포 종양, 남성 유방암, 뇌종양, 뇌하수체선종, 다발성 골수종, 담낭암, 담도암, 대장암, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아 뇌종양, 소아 림프종, 소아 백혈병, 소장암, 수막종, 식도암, 신경교종, 신경모세포종, 신우요관암, 신장암, 악성 연부 조직 종양, 악성 골종양, 악성 림프종, 악성 중피종, 악성 흑색종, 안종양, 외음부암, 요도암, 원발부위 불명암, 위림프종, 위암, 위유암종, 위장관 간질 종양, 윌름 종양, 유방암, 육종, 음경암, 인두암, 임신 융모 질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 뇌종양, 직장암, 직장유암종, 질암, 척수종양, 청신경초종, 췌장암, 침샘암, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 후두암 또는 이들의 조합일 수 있다. 상기 암은 폐암, 대장암, 위암, 혈액암, 간암, 또는 유방암일 수 있다.The cancer is, for example, intrahepatic cholangiocarcinoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, mycosis fungoides, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, basal cell carcinoma , ovarian epithelial cancer, ovarian germ cell tumor, male breast cancer, brain tumor, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, Non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain tumor, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, neuroblastoma, pelvic ureter cancer, renal cancer, malignant soft tissue tumor, malignant bone tumor, malignancy Lymphoma, malignant mesothelioma, malignant melanoma, eye tumor, vulvar cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal tumor, Wilms tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, pregnancy villi Disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic brain tumor, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord tumor, acoustic schwannoma, pancreatic cancer, salivary gland cancer, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung It may be squamous cell carcinoma, skin cancer, anal cancer, laryngeal cancer, or a combination thereof. The cancer may be lung cancer, colon cancer, stomach cancer, blood cancer, liver cancer, or breast cancer.
용어 "예방"은 조성물의 투여에 의해 질병을 억제시키거나 발병을 지연시키는 모든 행위를 말한다. 용어 "치료"는 조성물의 투여에 의해 질병의 증세가 호전되거나 이롭게 변경하는 모든 행위를 말한다.The term "prevention" refers to any action that suppresses or delays the onset of a disease by administration of the composition. The term "treatment" refers to any act of improving or beneficially changing the symptoms of a disease by administering the composition.
상기 약학적 조성물은 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 유효 성분으로 포함할 수 있다. 상기 약학적 조성물은 항암 활성을 갖는 공지의 유효 성분을 더 포함할 수 있다.The pharmaceutical composition may include the compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition may further include a known active ingredient having anticancer activity.
상기 약학적 조성물은 담체, 부형제 또는 희석제를 더 포함할 수 있다. 담체, 부형제 및 희석제는 예를 들면, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로스, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 또는 광물유를 포함할 수 있다.The pharmaceutical composition may further include a carrier, excipient or diluent. Carriers, excipients and diluents include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
상기 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.The pharmaceutical composition may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
상기 약학적 조성물에 있어서, 경구 투여를 위한 고형 제제는 정제, 환제, 산제, 과립제, 또는 캡슐제일 수 있다. 상기 고형 제제는 부형제를 더 포함할 수 있다. 부형제는 예를 들면, 전분, 칼슘 카르보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 또는 젤라틴일 수 있다. 또한, 상기 고형 제제는 마그네슘 스테아레이트, 또는 탈크와 같은 윤활제를 더 포함할 수 있다. 상기 약학적 조성물에 있어서, 경구를 위한 액상 제제는 현탁제, 내용액제, 유제, 또는 시럽제일 수 있다. 상기 액상 제제는 물, 또는 리퀴드 파라핀을 포함할 수 있다. 상기 액상 제제는 부형제, 예를 들면 습윤제, 감미제, 방향제, 또는 보존제를 포함할 수 있다. 상기 약학적 조성물에 있어서, 비경구 투여를 위한 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 또는 및 좌제일 수 있다. 비수성용제 또는 현탁제는 식물성 기름 또는 에스테르를 포함할 수 있다. 식물성 기름은 예를 들면, 프로필렌 글리콜(propylene glycol), 폴리에틸렌 글리콜, 또는 올리브 오일일 수 있다. 에스테르는 예를 들면 에틸올레이트일 수 있다. 좌제의 기제는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 또는 글리세로젤라틴일 수 있다.In the pharmaceutical composition, the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule. The solid formulation may further include an excipient. The excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, the solid formulation may further include a lubricant such as magnesium stearate or talc. In the pharmaceutical composition, the oral liquid formulation may be a suspension, an oral solution, an emulsion, or a syrup. The liquid formulation may contain water or liquid paraffin. The liquid formulation may contain excipients, for example, wetting agents, sweetening agents, perfuming agents, or preservatives. In the pharmaceutical composition, the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solution, suspension, emulsion, freeze-dried or suppository. The non-aqueous solvent or suspending agent may include vegetable oil or ester. The vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil. The ester may be, for example, ethyl oleate. The base of the suppository may be witepsol, macrogol, tween 61, cacao butter, laurin, or glycerogelatin.
상기 약학적 조성물의 바람직한 투여량은 개체의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 상기 화합물, 이의 이성질체, 유도체, 용매화물, 또는 약학적으로 허용가능한 염은 예를 들면, 약 0.0001 ㎎/㎏ 내지 약 100 ㎎/㎏, 또는 약 0.001 ㎎/㎏ 내지 약 100 ㎎/㎏의 양을 일일 1회 내지 24회, 2일 내지 1주에 1 내지 7회, 또는 1개월 내지 12개월에 1 내지 24회로 나누어 투여할 수 있다. 상기 약학적 조성물에서 화합물, 이의 이성질체, 유도체, 용매화물, 또는 약학적으로 허용가능한 염은 전체 조성물 총 중량에 대하여 약 0.0001 중량% 내지 약 10 중량%, 또는 약 0.001 중량% 내지 약 1 중량%로 포함될 수 있다.The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the individual, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, the compound, isomer, derivative, solvate, or pharmaceutically acceptable salt thereof may be, for example, from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg. The amount may be administered in divided doses from 1 to 24 times a day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times per 1 month to 12 months. In the pharmaceutical composition, the compound, isomer, derivative, solvate, or pharmaceutically acceptable salt thereof is present in an amount of from about 0.0001% to about 10% by weight, or from about 0.001% to about 1% by weight, based on the total weight of the composition. may be included.
투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The compositions may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.
다른 양상은 일 양상에 따른 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 암 예방 또는 치료용 약학적 조성물을 개체에게 투여하는 단계를 포함하는 암을 예방 또는 치료하는 방법을 제공한다.Another aspect is a method for preventing or treating cancer, comprising administering to an individual a pharmaceutical composition for preventing or treating cancer comprising a compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof provides
식 1로 표시되는 화합물, 입체이성질체, 용매화물, 염, 암, 예방, 치료, 및 약학적 조성물은 전술한 바와 같다.The compound, stereoisomer, solvate, salt, cancer, prevention, treatment, and pharmaceutical composition represented by Formula 1 are as described above.
상기 개체는 포유동물, 예를 들면, 인간, 마우스, 래트, 소, 말, 돼지, 개, 원숭이, 양, 염소 또는 고양이일 수 있다. 상기 개체는 암을 앓고 있거나, 앓을 가능성이 큰 개체일 수 있다.The subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat or cat. The subject may be suffering from, or likely to have, cancer.
투여 방법은 경구, 또는 비경구 투여일 수 있다. 투여 방법은 예를 들어, 경구, 경피, 피하, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 국소, 코안(intranasal), 기관내(intratracheal), 또는 피내 경로일 수 있다. 상기 약학적 조성물은 전신적으로 또는 국부적으로 투여될 수 있고, 단독으로 또는 다른 약학적 활성 화합물과 함께 투여될 수 있다.The administration method may be oral or parenteral administration. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes. The pharmaceutical composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.
상기 약학적 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물 형태, 투여 경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 상기 투여량은 예를 들어, 성인 기준으로 약 0.001 ㎎/kg 내지 약 100 ㎎/kg, 약 0.01 ㎎/kg 내지 약 10 ㎎/kg, 또는 약 0.1 ㎎/kg 내지 약 1 ㎎/kg의 범위 내 일 수 있다. 상기 투여는 1일 1회, 1일 다회, 또는 1주일에 1회, 2주일에 1회, 3주일에 1회, 또는 4주일에 1회 내지 1년에 1회 투여될 수 있다.The preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. The dosage is, for example, in the range of from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, or from about 0.1 mg/kg to about 1 mg/kg on an adult basis. can be The administration may be administered once a day, multiple times a day, or once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks to once a year.
암 예방 또는 치료용 약제의 제조에 사용하기 위한, 지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도를 제공한다.Provided is the use of a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the prevention or treatment of cancer.
암을 예방 또는 치료하는 데 사용하기 위한, 지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염의 용도를 제공한다.Provided is the use of a lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, for use in preventing or treating cancer.
신규한 지질펩티드 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염은 암세포에 대해 세포독성을 가지므로, 다양한 종류의 암을 예방 또는 치료하는데 사용할 수 있다.Since the novel lipopeptide compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof has cytotoxicity to cancer cells, it can be used to prevent or treat various types of cancer.
도 1은 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주를 고체 배지에서 배양한 균주의 사진이다.1 is a photograph of a strain of Streptomyces sp. AMD43 cultured in a solid medium.
이하 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, it will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예 1. 태안아미드의 분리 및 구조의 확인Example 1. Isolation of Taeanamide and Confirmation of Structure
1-1. 태안아미드 생산 균주의 분리1-1. Isolation of Taeanamide-producing strain
2019년 한국 안면도에서 채집한 갯벌 시료의 침전물로부터 AMD43 균주를 분리하였다. AMD43 균주는 YEME 고체 배지(물 1L 당 맥아 추출물 10 g, 효모 4 g, 포도당 4 g, 및 한천 18 g)에 접종하여 28℃에서 약 7일 동안 배양하여 분리하였다(도 1).AMD43 strain was isolated from the sediments of tidal flat samples collected in Anmyeondo, Korea in 2019. AMD43 strain was isolated by inoculating the YEME solid medium (10 g of malt extract per 1 L of water, 4 g of yeast, 4 g of glucose, and 18 g of agar) and culturing at 28° C. for about 7 days (FIG. 1).
16S rDNA 염기서열 분석 결과에 기반하여, AMD43 균주는 스트렙토마이세스 속(Streptomyces sp.)인 것으로 동정되었다. 이 균주를 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주로 명명하고, 상기 균주를 2020년 9월 21일자로 한국생명공학연구원에 기탁하였다(수탁번호: KCTC14317BP).Based on the results of 16S rDNA sequencing, the AMD43 strain was identified as being of the genus Streptomyces sp. This strain was named Streptomyces sp. AMD43 strain, and the strain was deposited with the Korea Research Institute of Bioscience and Biotechnology on September 21, 2020 (accession number: KCTC14317BP).
1-2. 스트렙토마이세스 속 AMD43 균주의 배양1-2. Culture of Streptomyces genus AMD43 strain
스트렙토마이세스 속 AMD43 균주를 YEME 고체 배지에 접종하고 30℃에서 수일간 배양하였다.AMD43 strain of Streptomyces genus was inoculated in YEME solid medium and cultured at 30° C. for several days.
배양된 AMD43 균주의 포자를 50 mL의 YEME 액체 배지(물 1L 당 맥아 추출물 10 g, 효모 4 g, 및 포도당 4 g)에 접종하고, 30℃의 온도에서 200 rpm으로 진탕하면서 약 4일간 배양하였다.The cultured AMD43 strain spores were inoculated into 50 mL of YEME liquid medium (10 g of malt extract per 1 L of water, 4 g of yeast, and 4 g of glucose), and cultured for about 4 days while shaking at 200 rpm at a temperature of 30°C. .
10 mL의 AMD43 균주의 배양액을 200 mL의 YEME 액체 배지에 접종하고, 30℃의 온도에서 160 rpm으로 진탕하면서 약 4일간 배양하였다.10 mL of the AMD43 strain culture was inoculated into 200 mL of YEME liquid medium, and cultured for about 4 days while shaking at a temperature of 30° C. at 160 rpm.
그 후, 25 mL의 AMD43 균주의 배양액을 1 L의 YEME 액체 배지에 접종하고, 30℃의 온도에서 160 rpm으로 진탕하면서 약 4일간 배양하였다.Thereafter, 25 mL of the culture solution of the AMD43 strain was inoculated into 1 L of YEME liquid medium, and cultured for about 4 days while shaking at a temperature of 30° C. at 160 rpm.
1-3. 태안아미드 A 및 B의 분리 빛 정제1-3. Separation light purification of Taeanamide A and B
실시예 1-2에 기재된 바와 같이 배양한 스트렙토마이세스 속 AMD43 균주의 배양물을 수득하였다.A culture of the Streptomyces genus AMD43 strain cultured as described in Example 1-2 was obtained.
스탠드에 거치된 분별깔때기에 배양이 끝난 AMD43 균주 1 L와 약 2.5 L 부피의 에틸 아세테이트(EtOAc, 대정화금주식회사)를 넣어 준 뒤 마개를 막고 상하좌우로 3분간 흔들어 1차 추출을 진행하였다. 이후 다시 스탠드에 거치하여 물 층과 EtOAc 층이 완전히 나누어진 후 분별깔때기의 밸브를 열어 물 층을 제거하였다. 물층에 새로운 EtOAc를 첨가하고, 같은 방식으로 반복 추출을 진행하였다. EtOAc 층은 깨끗한 플라스크에 따로 받아 보관하였고, 100 g의 무수 소듐 설페이트(Anhydrous Sodium Sulfate)(대정화금주식회사)를 첨가하여 배양물에 남아있는 물을 제거하고, 여러 겹의 깨끗한 거즈를 통과시켜 이물질을 제거하였다. 물기가 제거된 EtOAc 층을 다시 3 L 부피의 둥근 플라스크로 옮겨 담은 후 감압건조기를 사용하여 감압 건조하였다. 총 18 L의 균주 배양으로부터 약 2.5 g의 조(crude) 추출물을 얻을 수 있었다.1 L of the cultured AMD43 strain and about 2.5 L of ethyl acetate (EtOAc, Daejeong Hwa-Geum Co., Ltd.) were put into a separatory funnel mounted on a stand, and the stopper was closed and shaken up, down, left, and right for 3 minutes to perform primary extraction. After that, it was mounted on a stand again, and after the water layer and the EtOAc layer were completely divided, the valve of the separatory funnel was opened to remove the water layer. Fresh EtOAc was added to the aqueous layer, and repeated extraction was performed in the same manner. The EtOAc layer was stored separately in a clean flask, and 100 g of Anhydrous Sodium Sulfate (Daejeong Hwa Gold Co., Ltd.) was added to remove the water remaining in the culture, and passed through several layers of clean gauze to remove foreign substances. was removed. The EtOAc layer from which the water was removed was transferred back to a 3 L round flask, and then dried under reduced pressure using a vacuum dryer. About 2.5 g of crude extract was obtained from a total of 18 L of strain culture.
수득된 추출물을 3등분하고 3등분한 추출물을 Sephadex LH-20 컬럼으로 분획하였다(이동상: 메탄올). 분획물의 조성 확인은 아질런트(Agilent technologies) 사의 1200 시리즈 LC와 6130 시리즈 질량분석기를 연결한 LC/MS를 사용하였다. LC/MS를 사용하여 7번째 분획(분획물 7) 및 8번째 분획(분획물 8)에서 신규 물질인 태안아미드(taeanamide) A와 태안아미드 B를 함유하는 것을 확인하였다.The obtained extract was divided into thirds, and the three-divided extract was fractionated with a Sephadex LH-20 column (mobile phase: methanol). To confirm the composition of the fraction, LC/MS was used in which Agilent technologies' 1200 series LC and 6130 series mass spectrometer were connected. Using LC/MS, it was confirmed that the 7th fraction (fraction 7) and 8th fraction (fraction 8) contained new substances taeanamide A and taeanamide B.
분획물 7과 분획물 8을 함께 메탄올에 용해시키고 증발시켜 농축하였다. 분획물은 크로마토그래피로 정제하였다. 분획물 7과 분획물 8을 Kromasil 컬럼(100-5-C18, 10 x 250 mm)을 사용하고 HPLC(high-performance liquid chromatography)에 주입하여, 45% 수용액 CH3CN (검출: UV 210 nm, 유속: 2 mL/분)의 등용매(isocratic) 조건 하에서 크로마토그래피를 수행하였다. 태안아미드 A(20 mg)와 태안아미드 B(40 mg)는 각각 약 19분 및 약 28분 분획에서 용출되었다.Fractions 7 and 8 were dissolved together in methanol and concentrated by evaporation. Fractions were purified by chromatography. Fraction 7 and Fraction 8 were injected into high-performance liquid chromatography (HPLC) using a Kromasil column (100-5-C18, 10 x 250 mm), 45% aqueous CH 3 CN (detection: UV 210 nm, flow rate: Chromatography was performed under isocratic conditions of 2 mL/min). Taeanamide A (20 mg) and Taeanamide B (40 mg) were eluted at about 19 minutes and about 28 minutes, respectively.
1-4. 태안아미드 A 및 태안아미드 B의 화학구조의 확인1-4. Identification of the chemical structures of Taeanamide A and Taeanamide B
태안아미드 A와 태안아미드 B의 구조는 1D 및 2D 핵자기 공명 스펙트럼(nuclear magnetic resonance: NMR) 스펙트럼을 기반으로 확인하였다. 핵자기 공명 스펙트럼(1H NMR, 13C NMR)은 브루커(Bruker) 사의 800 MHz NMR을, 용매는 DMSO-d6를 사용하였다.The structures of Taeanamide A and Taeanamide B were confirmed based on 1D and 2D nuclear magnetic resonance (NMR) spectra. A nuclear magnetic resonance spectrum ( 1 H NMR, 13 C NMR) was 800 MHz NMR manufactured by Bruker, and DMSO-d 6 was used as the solvent.
핵자기공명 스펙트럼에 의한 태안아미드 A와 태안아미드 B의 구조 위치 지정을 표 1에 나타내었다.Table 1 shows the structural positioning of Taeanamide A and Taeanamide B by nuclear magnetic resonance spectra.
[태안아미드 A(Taeanamide A)][Taeanamide A]
(1) 분자식: C51H87N11O17 (1) Molecular formula: C 51 H 87 N 11 O 17
(2) 분자량: 1126(2) molecular weight: 1126
(3) 색: 흰색(3) Color: white
(4) 1H-NMR (DMSO-d6, 800 MHz): 표 1 참조(4) 1 H-NMR (DMSO-d 6 , 800 MHz): see Table 1
(5) 13C-NMR (DMSO-d6, 200 MHz): 표 1 참조(5) 13 C-NMR (DMSO-d 6 , 200 MHz): see Table 1
[태안아미드 B(Taeanamide B)][Taeanamide B]
(1) 분자식: C52H89N11O17 (1) Molecular formula: C 52 H 89 N 11 O 17
(2) 분자량: 1140(2) molecular weight: 1140
(3) 색: 흰색(3) Color: white
(4) 1H-NMR (pyridine-d5, 800 MHz): 표 2 참조(4) 1 H-NMR (pyridine-d5, 800 MHz): see Table 2
(5) 13C-NMR (pyridine-d5, 200 MHz): 표 2 참조(5) 13 C-NMR (pyridine-d5, 200 MHz): see Table 2
Taeanamide A (1)Taeanamide A (1)
C/HC/H δ C, type δ C , type δ H, mult (J in Hz) δ H , mult ( J in Hz)
1One 171.4, C171.4, C
22 54.2, CH54.2, CH 4.50, m4.50, m
2-NH2-NH 8.18, m8.18, m
3a3a 61.4, CH2 61.4, CH 2 3.89, (dd, 11.0, 4.5)3.89, (dd, 11.0, 4.5)
3b3b 3.62, m3.62, m
44 171.8, C171.8, C
55 50.3, CH50.3, CH 4.51, m4.51, m
5-NH5-NH 7.67, (d, 8.0)7.67, (d, 8.0)
66 41.7, CH2 41.7, CH 2 1.41, m1.41, m
77 23.8, CH23.8, CH 1.53, m1.53, m
88 21.3, CH3 21.3, CH 3 0.82, (d, 6.5)0.82, (d, 6.5)
99 23.3, CH3 23.3, CH 3 0.80, (d, 6.5)0.80, (d, 6.5)
1010 171.4, C171.4, C
1111 48.6, C 48.6, C 4.22, m4.22, m
11-NH11-NH 8.33, (d, 7.0)8.33, (d, 7.0)
1212 18.0, CH3 18.0, CH 3 1.22, (d, 7.0)1.22, (d, 7.0)
1313 171.0, C171.0, C
1414 51.1, CH51.1, CH 4.19, m4.19, m
14-NH14-NH 8.15, (d, 6.5)8.15, (d, 6.5)
15a15a 31.2, CH2 31.2, CH 2 1.77, m1.77, m
15b15b 1.64, (td, 14.0, 7.5)1.64, (td, 14.0, 7.5)
1616 35.5, CH2 35.5, CH 2 3.03, m3.03, m
16-NH16-NH 7.81, (t, 5.5)7.81, (t, 5.5)
1717 169.2, C169.2, C
1818 22.6, CH3 22.6, CH 3 1.79, m1.79, m
1919 168.4, C168.4, C
20a20a 41.9, CH2 41.9, CH 2 3.85, (dd, 17.0, 6.0)3.85, (dd, 17.0, 6.0)
20b20b 3,55, (dd, 17.0, 3.5)3,55, (dd, 17.0, 3.5)
20-NH20-NH 7.67, (d, 8.0)7.67, (d, 8.0)
2121 171.5, C171.5, C
2222 60.3, CH60.3, CH 4.26, m4.26, m
23a23a 29.0, CH2 29.0, CH 2 1.98, m1.98, m
23b23b 1.78, m1.78, m
24a24a 24.3, CH2 24.3, CH 2 1.79, m1.79, m
24b24b 1.73, m1.73, m
25a25a 46.8, CH2 46.8, CH 2 3.43, m3.43, m
25b25b 3.59, m3.59, m
2626 169.8, C169.8, C
2727 55.3, CH55.3, CH 4.53, m4.53, m
27-NH27-NH 8.08, (d, 8.5)8.08, (d, 8.5)
2828 66.5, CH66.5, CH 3.92, m3.92, m
2929 19.3, CH3 19.3, CH 3 1.02, (d, 6.5)1.02, (d, 6.5)
3030 172.1, C172.1, C
3131 48.8, CH48.8, CH 4.28, m4.28, m
31-NH31-NH 7.76, (d, 6.5)7.76, (d, 6.5)
3232 17.9, CH3 17.9, CH 3 1.23, (d, 7.0)1.23, (d, 7.0)
3333 168.4, C168.4, C
3434 55.70, CH55.70, CH 4.43, (dd, 9.0, 2.5)4.43, (dd, 9.0, 2.5)
34-NH34-NH 8.26, (d, 9.0)8.26, (d, 9.0)
3535 70.2, CH70.2, CH 5.34, m5.34, m
3636 16.1, CH3 16.1, CH 3 1.08, (d, 6.5)1.08, (d, 6.5)
3737 171.4, C171.4, C
3838 55.7, CH55.7, CH 4.50, m4.50, m
38-NH38-NH 8.17, m8.17, m
3939 61,4, CH2 61,4, CH 2 3.63, m3.63, m
4040 165.4, C165.4, C
4141 123.8, CH123.8, CH 6.06, (d, 15.0)6.06, (d, 15.0)
4242 143.5, CH143.5, CH 6.65, (dt, 15.0, 7.0)6.65, (dt, 15.0, 7.0)
4343 31.2, CH2 31.2, CH 2 2.14, (dd, 14.0, 7.0)2.14, (dd, 14.0, 7.0)
4444 27.8, CH2 27.8, CH 2 1.38, m1.38, m
4545 29.1, CH2 29.1, CH 2 1.25, m1.25, m
4646 28.7, CH2 28.7, CH 2 1.27, m1.27, m
4747 26.5, CH2 26.5, CH 2 1.24, m1.24, m
4848 38.5, CH2 38.5, CH 2 1.13, m1.13, m
4949 27.4, CH27.4, CH 1.50, m1.50, m
5050 22.5, CH3 22.5, CH 3 0.84, (d, 6.5)0.84, (d, 6.5)
5151 22.5, CH3 22.5, CH 3 0.84, (d, 6.5)0.84, (d, 6.5)
Taeanamide B (2)Taeanamide B (2)
C/HC/H δ C, type δ C , type δ H, mult (J in Hz) δ H , mult ( J in Hz)
1One 172.5, C172.5, C
22 56.7, CH56.7, CH 5.11, m5.11, m
2-NH2-NH 9.35, (d, 6.5)9.35, (d, 6.5)
3a3a 63.0, CH2 63.0, CH 2 4.36, m4.36, m
3b3b 4.22, m4.22, m
3-OH3-OH 6.84, (t, 5.5)6.84, (t, 5.5)
44 174.3, C174.3, C
55 52.6, CH52.6, CH 5.25, m5.25, m
5-NH5-NH 8.84, (d, 9.5)8.84, (d, 9.5)
66 41.9, CH2 41.9, CH 2 2.02, m2.02, m
77 25.4, CH25.4, CH 1.94, m1.94, m
88 23.9, CH3 23.9, CH 3 0.90, (d, 6.5)0.90, (d, 6.5)
99 19.8, CH3 19.8, CH 3 0.83, (d, 6.5)0.83, (d, 6.5)
1010 174.0, C174.0, C
1111 50.7, C50.7, C 5.04, m5.04, m
11-NH11-NH 9.41, (d, 6.5)9.41, (d, 6.5)
1212 18.7, CH3 18.7, CH 3 1.70, (d, 7.0)1.70, (d, 7.0)
1313 173.6, C173.6, C
1414 52.9, CH52.9, CH 4.97, m4.97, m
14-NH14-NH 8.67, (d, 7.0)8.67, (d, 7.0)
15a15a 32.8, CH2 32.8, CH 2 2.59, (td, 13.5, 6.5)2.59, (td, 13.5, 6.5)
15b15b 2.35, (td, 13.5, 7.0)2.35, (td, 13.5, 7.0)
16a16a 37.3, CH2 37.3, CH 2 3.85, m3.85, m
16b16b 3.55, m3.55, m
16-NH16-NH 8.58, (t, 6.0)8.58, (t, 6.0)
1717 171.5, C171.5, C
1818 23.6, CH3 23.6, CH 3 2.01, s2.01, s
1919 170.8, C170.8, C
20a20a 44.3, CH2 44.3, CH 2 4.40, m4.40, m
20b20b 4.04, (dd, 17.0, 5.0)4.04, (dd, 17.0, 5.0)
20-NH20-NH 9.25, (t, 6.0)9.25, (t, 6.0)
2121 174.0174.0
2222 62.3, CH62.3, CH 4.69, (t, 7.5)4.69, (t, 7.5)
2323 30.2, CH2 30.2, CH 2 2.15, m2.15, m
2424 26.1, CH2 26.1, CH 2 1.94, m1.94, m
2525 48.8, CH2 48.8, CH 2
2626 171.7, C171.7, C
2727 57.8, CH57.8, CH 5.22, (dd, 8.5, 4.5)5.22, (dd, 8.5, 4.5)
27-NH27-NH 8.55, (d, 8.5)8.55, (d, 8.5)
2828 68.5, CH68.5, CH 4.58, m4.58, m
28-OH28-OH 6.49, (d, 5.0)6.49, (d, 5.0)
2929 20.8, CH3 20.8, CH 3 1.58, (d, 6.5)1.58, (d, 6.5)
3030 174.1, C174.1, C
3131 51.0, CH51.0, CH 5.03, m5.03, m
31-NH31-NH 9.07, (d, 6.5)9.07, (d, 6.5)
3232 18.7, CH3 18.7, CH 3 1.70, (d, 7.0)1.70, (d, 7.0)
3333 172.5, C172.5, C
3434 60.6, CH60.6, CH 5.06, m5.06, m
34-NH34-NH 9.05, (d, 8.0)9.05, (d, 8.0)
3535 67.8, CH67.8, CH 4.92, m4.92, m
35-OH35-OH 6.53, (d, 3.5)6.53, (d, 3.5)
3636 20.8, CH3 20.8, CH 3 1.48, (d, 6.5)1.48, (d, 6.5)
3737 173.1, C173.1, C
3838 58.2, CH58.2, CH 5.32, (dd, 12.0, 6.0)5.32, (dd, 12.0, 6.0)
38-NH38-NH 9.22, (d, 6.0)9.22, (d, 6.0)
39a39a 63.3, CH2 63.3, CH 2 4.46, m4.46, m
39b39b 4.36, m4.36, m
39-OH39-OH 7.00, (t, 5.5)7.00, (t, 5.5)
4040 167.6, C167.6, C
4141 124.9, CH124.9, CH 6.35, (d, 15.5)6.35, (d, 15.5)
4242 145.4, CH145.4, CH 7.15, m7.15, m
4343 32.7, CH2 32.7, CH 2 2.09, m2.09, m
4444 29.1, CH2 29.1, CH 2 1.30, m1.30, m
4545 30.0, CH2 30.0, CH 2 1.19, m1.19, m
4646 30.5, CH2 30.5, CH 2 1.15, m1.15, m
47a47a 37.3, CH2 37.3, CH 2 1.02, m1.02, m
47b47b 1.22, m1.22, m
4848 30.2, CH2 30.2, CH 2 1.30, m1.30, m
4949 35.1, CH2 35.1, CH 2 1.24, m1.24, m
5050 12.1, CH3 12.1, CH 3 0.86, (d, 7.5)0.86, (d, 7.5)
5151 22.1, CH3 22.1, CH 3 0.83, (d, 7.5)0.83, (d, 7.5)
5252 52.5, CH3 52.5, CH 3 3.63, s3.63, s
핵자기공명 스펙트럼 자료로부터 분석된 태안아미드 A의 화학구조식을 하기에 나타내었다.The chemical structural formula of Taeanamide A analyzed from nuclear magnetic resonance spectrum data is shown below.
[태안아미드 A][Taeanamide A]
Figure PCTKR2021016155-appb-I000005
Figure PCTKR2021016155-appb-I000005
핵자기공명 스펙트럼 자료로부터 분석된 태안아미드 B의 화학구조식을 하기에 나타내었다.The chemical structural formula of Taeanamide B analyzed from nuclear magnetic resonance spectrum data is shown below.
[태안아미드 B][Taeanamide B]
Figure PCTKR2021016155-appb-I000006
Figure PCTKR2021016155-appb-I000006
실시예 2. 태안아미드 A 및 B의 항암 활성의 확인Example 2. Confirmation of anticancer activity of Taeanamide A and B
태안아미드 A 및 B의 생물학적 활성을 확인하기 위해, 다양한 인간 암 세포에 대한 세포독성을 확인하였다.In order to confirm the biological activity of Taeanamide A and B, the cytotoxicity to various human cancer cells was confirmed.
인간 폐암 세포주 A-549, 인간 대장암 세포주 HCT116, 인간 위암 세포주 SNU638, 인간 간암 세포주 SK-HEP-1, 유방암 세포주 MDA-MB-231, 및 백혈병 세포주 K562를 한국 세포주 은행(Korean Cell Line Bank, Korea)로부터 구입하였다.Human lung cancer cell line A-549, human colorectal cancer cell line HCT116, human gastric cancer cell line SNU638, human liver cancer cell line SK-HEP-1, breast cancer cell line MDA-MB-231, and leukemia cell line K562 were prepared from the Korean Cell Line Bank, Korea. ) was purchased from
세포의 배양액은 10%(v/v) 열-불활성화 우태아 혈청(fetal bovine serum: FBS) 및 항균-항마이코박테라이 용액(100 units/mL 페니실린 G 소듐, 100 ㎍/mL 스트렙토마이신, 및 250 ng/mL 암포테리신(amphotericin) B)을 함유한 배지(A549, HCT116, SNU638, 및 K562 세포에 대해 RPMI-1640 배지; MDA-MB-231 및 SK-HEP-1에 대해 DMEM (Dulbecco's modified Eagle's medium); 및 MRC-5에 대해 minimal essential medium)를 사용하였다.Cell cultures were prepared using 10% (v/v) heat-inactivated fetal bovine serum (FBS) and an antibacterial-antimycobacterial solution (100 units/mL penicillin G sodium, 100 μg/mL streptomycin, and Medium containing 250 ng/mL amphotericin B) (RPMI-1640 medium for A549, HCT116, SNU638, and K562 cells; DMEM (Dulbecco's modified) for MDA-MB-231 and SK-HEP-1 Eagle's medium); and minimal essential medium for MRC-5) were used.
세포 증식은 술포로다민(sulforhodamine B: SRB) 분석법으로 측정하였다. 간단히, 배양 중인 세포를 96-웰 플레이트에 접종하고, 30분 동안 인큐베이션하거나(제0일, 음성 대조군) 또는 정해진 시간에 화합물을 처리하였다. 비교군으로 에토포시드(etoposide)를 사용하였다. 인큐베이션 후, 세포를 고정하고, 건조시킨 후, 1%(v/v) 아세트산 중 0.4(w/v) SRB로 염색하였다. 부착되지 않은 염료는 세척하여 제거하고, 염색된 세포를 10mM Tris (pH 10.0)에 현탁하였다. 515 nm에서 흡광도를 측정하고, 세포 증식을 측정하였다. TableCurve 2D v5.01 소프트웨어(Systant Software Inc., Richmond, CA, USA)를 이용한 비선형 회귀분석법으로 50%의 세포 성장을 억제하는 화합물의 농도, 즉 IC50(50% inhibition concentration)을 산출하였다. 모든 시약은 Sigma-Aldrich에서 구입하였다. 산출된 IC50를 하기 표 3에 나타내었다. 양성 대조군으로서 에토포시드(etoposide)(Sigma Aldrich)를 사용하였다.Cell proliferation was measured by sulforhodamine B (SRB) assay. Briefly, cells in culture were seeded in 96-well plates and incubated for 30 min (day 0, negative control) or treated with compounds at set times. As a comparison group, etoposide was used. After incubation, cells were fixed, dried and stained with 0.4 (w/v) SRB in 1% (v/v) acetic acid. Non-adherent dye was removed by washing, and the stained cells were suspended in 10 mM Tris (pH 10.0). Absorbance was measured at 515 nm and cell proliferation was measured. By nonlinear regression analysis using TableCurve 2D v5.01 software (Systant Software Inc., Richmond, CA, USA), the concentration of the compound that inhibits 50% of cell growth, ie, IC 50 (50% inhibition concentration), was calculated. All reagents were purchased from Sigma-Aldrich. The calculated IC 50 is shown in Table 3 below. Etoposide (Sigma Aldrich) was used as a positive control.
태안아미드 A 및 태안아미드 B의 세포 성장 억제 농도(IC50, μM)Cell growth inhibitory concentrations of Taeanamide A and Taeanamide B (IC 50 , μM)
IC50 (μM)IC 50 (μM) A549A549 HCT116HCT116 MCF-7MCF-7 MDA-MB-231MDA-MB-231 SK-Hep-1SK-Hep-1 SNU638SNU638
태안아미드 ATaeanamide A >20>20 >20>20 >20>20 >20>20 >20>20 >20>20
태안아미드 BTaeanamide B 0.930.93 0.270.27 1.591.59 1.571.57 1.431.43 0.340.34
에토포시드etoposide 0.210.21 0.660.66 0.860.86 5.915.91 6.556.55 0.460.46
표 3에 나타난 바와 같이, 태안아미드 A는 세포 성장 억제 효과가 나타나지 않았으나, 태안아미드 B는 모든 6종의 암세포에 대해 비교적 높은 세포 성장 억제 활성을 나타내었다.As shown in Table 3, Taeanamide A did not show a cell growth inhibitory effect, but Taeanamide B showed a relatively high cell growth inhibitory activity against all six types of cancer cells.
Figure PCTKR2021016155-appb-I000007
Figure PCTKR2021016155-appb-I000007

Claims (13)

  1. 식 1로 표시되는 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염:A compound represented by Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
    [식 1][Equation 1]
    R1-(C=O)-Ser-Thr-Ala-Thr-Pro-Gly-X-Ala-Leu-Ser-R2,R 1 -(C=O)-Ser-Thr-Ala-Thr-Pro-Gly-X-Ala-Leu-Ser-R 2 ,
    식 1에서, X는 C1 내지 C10 알킬아세트아미드로 치환된 글리신(Glyine; Gly 또는 G)이고,In Formula 1, X is glycine (Glyine; Gly or G) substituted with C 1 to C 10 alkylacetamide,
    R1은 포화 또는 불포화된 탄화수소 사슬이고,R 1 is a saturated or unsaturated hydrocarbon chain,
    R2는 없거나, 또는 치환 또는 비치환된 C1 내지 C20 알킬기, 치환 또는 비치환된 C1 내지 C20 알케닐기, 또는 치환 또는 비치환된 C1 내지 C20 알키닐기이다.R 2 is absent, or is a substituted or unsubstituted C 1 to C 20 alkyl group, a substituted or unsubstituted C 1 to C 20 alkenyl group, or a substituted or unsubstituted C 1 to C 20 alkynyl group.
  2. 청구항 1에 있어서, 상기 식 1 중 X는 n-에틸아세트아미드로 치환된 글리신인 것인 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염.The compound according to claim 1, wherein X in Formula 1 is glycine substituted with n-ethylacetamide, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  3. 청구항 1에 있어서, 상기 식 1 중 R1은 치환 또는 비치환된 C1 내지 C30의 알킬기, 치환 또는 비치환된 C2 내지 C30의 알케닐기, 치환 또는 비치환된 C2 내지 C30의 알키닐기, 또는 이들의 조합으로부터 선택된 것인 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염.The method according to claim 1, R 1 in Formula 1 is a substituted or unsubstituted C 1 to C 30 alkyl group, a substituted or unsubstituted C 2 to C 30 alkenyl group, or a substituted or unsubstituted C 2 to C 30 A compound selected from an alkynyl group, or a combination thereof, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  4. 청구항 1에 있어서, 상기 식 1 중 R1은 9-메틸-1-데센(9-methyl-1-decene)인 것인 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염.The compound according to claim 1, wherein R 1 in Formula 1 is 9-methyl-1-decene, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  5. 청구항 1에 있어서, 상기 식 1 중 R2는 치환 또는 비치환된 C1 내지 C20 알킬기인 것인 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염.The compound according to claim 1, wherein R 2 in Formula 1 is a substituted or unsubstituted C 1 to C 20 alkyl group, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  6. 청구항 5에 있어서, 상기 식 1 중 R2는 메틸기인 것인 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염.The compound according to claim 5, wherein R 2 in Formula 1 is a methyl group, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  7. 청구항 1에 있어서, 상기 식 1로 표시되는 화합물은 식 2 또는 식 3으로 표시되는 것인 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염:The method according to claim 1, wherein the compound represented by Formula 1 is a compound represented by Formula 2 or Formula 3, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
    [식 2][Equation 2]
    Figure PCTKR2021016155-appb-I000008
    ; 및
    Figure PCTKR2021016155-appb-I000008
    ; and
    [식 3][Equation 3]
    Figure PCTKR2021016155-appb-I000009
    .
    Figure PCTKR2021016155-appb-I000009
    .
  8. 청구항 1에 있어서, 상기 식 1로 표시되는 화합물은 식 4 또는 식 5로 표시되는 것인 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염:The method according to claim 1, wherein the compound represented by Formula 1 is a compound represented by Formula 4 or Formula 5, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
    [식 4][Equation 4]
    Figure PCTKR2021016155-appb-I000010
    ; 및
    Figure PCTKR2021016155-appb-I000010
    ; and
    [식 5][Equation 5]
    Figure PCTKR2021016155-appb-I000011
    .
    Figure PCTKR2021016155-appb-I000011
    .
  9. 청구항 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP).A Streptomyces sp. AMD43 strain (Accession No.: KCTC14317BP) that produces the compound of claim 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  10. 스트렙토마이세스 속(Streptomyces sp.) AMD43 균주(수탁번호: KCTC14317BP)를 배양하는 단계; 및Streptomyces genus ( Streptomyces sp.) culturing the AMD43 strain (accession number: KCTC14317BP); and
    상기 균주를 배양한 배양액으로부터 청구항 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 분리하는 단계를 포함하는,Comprising the step of isolating the compound of claim 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof from the culture solution of the strain,
    청구항 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 생산하는 방법.A method for producing the compound of claim 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.
  11. 청구항 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 암 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, comprising the compound of claim 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  12. 청구항 11에 있어서, 상기 암은 폐암, 대장암, 위암, 혈액암, 간암, 또는 유방암인 것인 약학적 조성물.The pharmaceutical composition of claim 11, wherein the cancer is lung cancer, colorectal cancer, stomach cancer, blood cancer, liver cancer, or breast cancer.
  13. 청구항 1의 화합물, 이의 입체이성질체, 용매화물, 또는 약학적으로 허용가능한 염을 포함하는 암 예방 또는 치료용 약학적 조성물을 개체에게 투여하는 단계를 포함하는 암을 예방 또는 치료하는 방법.A method for preventing or treating cancer, comprising administering to an individual a pharmaceutical composition for preventing or treating cancer comprising the compound of claim 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
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