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WO2025178157A1 - Nouveau composé d'oxazolomycine, son procédé de production et son utilisation - Google Patents

Nouveau composé d'oxazolomycine, son procédé de production et son utilisation

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Publication number
WO2025178157A1
WO2025178157A1 PCT/KR2024/002537 KR2024002537W WO2025178157A1 WO 2025178157 A1 WO2025178157 A1 WO 2025178157A1 KR 2024002537 W KR2024002537 W KR 2024002537W WO 2025178157 A1 WO2025178157 A1 WO 2025178157A1
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WIPO (PCT)
Prior art keywords
group
unsubstituted
substituted
chemical formula
stereoisomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/KR2024/002537
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English (en)
Korean (ko)
Inventor
오동찬
이상국
박지윤
문동현
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SNU R&DB Foundation
Original Assignee
Seoul National University R&DB Foundation
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Filing date
Publication date
Application filed by Seoul National University R&DB Foundation filed Critical Seoul National University R&DB Foundation
Publication of WO2025178157A1 publication Critical patent/WO2025178157A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • 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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • 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

  • This patent application relates to a novel oxazolomycin compound, a method for producing the same, and uses thereof.
  • This patent application claims priority to Republic of Korea Patent Application No. 10-2024-026030, filed with the Korean Intellectual Property Office on February 22, 2024, the disclosure of which is incorporated herein by reference.
  • Cancer or malignant tumors, are a long-standing enemy of civilization, and despite the constant advancement of medicine, they are the most common cause of death in modern times. Cancer is a disease in which cells ignore the normal cycle of cell death and proliferate uncontrollably, disrupting bodily functions. Because cancer has diverse causes, symptoms, and pathogenesis vary greatly depending on the organ in which it develops, complete cure is extremely difficult. Furthermore, depending on the progression of the cancer, metastasis (the spread of cancer cells to other organs through bodily fluids like blood or lymph) can occur, making even treatment deemed successful the risk of recurrence undeniable. While mortality rates for diseases like rabies and Ebola hemorrhagic fever are higher than cancer, cancer is a cosmic disease because it is so common, yet it can be contracted at any time and in any place, and it is impossible to completely prevent it.
  • R may be selected from a hydroxy group, a substituted or unsubstituted C 1 to C 20 alkyl group, or a substituted or unsubstituted C 1 to C 20 alkoxy.
  • R may be hydrogen
  • the geometric structure of the double bond portion between carbons 10 to 15 and carbons 15 to 18 can be changed between E or Z structures.
  • the bond between the amide portion and carbon 14 can be changed to a structure in which it is broken.
  • the compound represented by the above chemical formula I may be a methyl-oxazolomycin compound.
  • methyl-oxazolomycin may refer to an oxazolomycin compound having a methyl group bonded to carbon 1.
  • the compound represented by the above chemical formula I may be a compound represented by chemical formula II.
  • the compound represented by the above chemical formula I may be a compound represented by chemical formula III.
  • the compound represented by the above chemical formula II may be methyl-oxazolomycin B.
  • halogen atoms include fluorine, bromine, chlorine, iodine, etc.
  • alkyl refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon.
  • the alkyl is C 1 It can be an alkyl group having C 20 , C 1 to C 15 , C 1 to C 10 , or C 1 to C 5 .
  • 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.
  • cycloalkyl group refers to a saturated or partially unsaturated non-aromatic monocyclic, bicyclic or tricyclic hydrocarbon group.
  • heterocyclic group refers to a non-aromatic organic compound that is a group (ring) containing one or more heteroatoms selected from N, O, P and S, and the remaining ring atoms are carbon.
  • the heterocyclic group is, for example, tetrahydropyran or tetrahydropyridine.
  • aryl refers to an aromatic system comprising one or more rings, and also includes groups in which an aromatic ring is fused to one or more carbon rings.
  • the C 6 -C 30 aryl group may be an aryl group having a carbon atom of C 6 to C 15 , or a carbon atom of C 6 to C 10 .
  • the aryl group is, for example, phenyl, naphthyl, or tetrahydronaphthyl.
  • heteroaryl group refers to a monocyclic or bicyclic organic compound containing one or more heteroatoms selected from the group consisting of N, O, P, and S, with the remaining ring atoms being carbon.
  • the heteroaryl group may contain 1 to 5 heteroatoms and may contain 5 to 10 ring members.
  • the S or N may be oxidized to have multiple oxidation states.
  • isomers in “stereoisomer” refers to compounds that have the same molecular formula but different connection methods or spatial arrangements of the constituent atoms within the molecule.
  • Isomers include, for example, structural isomers and stereoisomers.
  • the stereoisomers can be diastereomers or enantiomers.
  • Enantiomers are isomers that do not overlap with their mirror images, like the relationship between left and right hands, and are also called optical isomers. Enantiomers are distinguished as R (Rectus: clockwise) and S (Sinister: counterclockwise) when four or more substituents are different on the chiral center carbon.
  • Diastereoisomers are stereoisomers that are not mirror images, and can be divided into cis-trans isomers that are created by different spatial arrangements of atoms.
  • solvate refers to a compound that is solvated in an organic or inorganic solvent.
  • the solvate is, for example, a hydrate.
  • salt refers to inorganic and organic acid addition salts of a compound.
  • the pharmaceutically acceptable salt may be a salt that does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.
  • the inorganic acid salt may be a hydrochloride, a bromate, a phosphate, a sulfate, or a disulfate.
  • the organic acid salt may be a formate, an acetate, an acetate, a propionate, a lactate, an oxalate, a tartrate, a malate, a maleate, a citrate, a fumarate, a besylate, a camsylate, an edisyl salt, a trichloroacetic acid, a trifluoroacetic acid, a benzoate, a gluconate, a methanesulfonate, a glycolate, a succinate, a 4-toluenesulfonate, a galacturonate, an embronate, a glutamate, a methanesulfonic acid, an ethanesulfonic acid, a benzenesulfonic acid, a p-toluenesulfonic acid, or an aspartate.
  • the above metal salt may be a calcium salt, a sodium salt, a
  • Another aspect provides a strain of Streptomyces sp. AH05 (accession number: KCTC15725BP) producing a compound or a stereoisomer thereof according to one aspect.
  • the 16S rRNA base sequence of the Streptomyces sp. AH05 strain may be the base sequence represented by SEQ ID NO: 1.
  • the strain may have a 16S rRNA gene having a sequence identity of 98% or more, 99% or more, 99.5% or more, or 99.5% or more with SEQ ID NO: 1.
  • a Streptomyces sp. AH05 strain having a 16rRNA gene including a base sequence represented by sequence number 1 was isolated and extracted from tidal flat sediments of Anmyeondo Island through analysis and identification using a molecular genetic method based on 16rRNA sequence search, and a compound was obtained.
  • the above strain includes spores, mycelia, or cultures of the strain.
  • the above strain may be isolated or derived from the sediment of Anmyeondo tidal flat.
  • Another aspect is the step of culturing Streptomyces sp. AH05 strain (Accession number: KCTC15725BP); and
  • a method for producing a compound according to one aspect or a stereoisomer thereof comprising a step of isolating the compound according to one aspect or a stereoisomer thereof from a culture of the strain.
  • the above method includes a step of culturing Streptomyces sp. AH05 strain (Accession number: KCTC15725BP).
  • the step of culturing the above Streptomyces sp. AH05 strain may be culturing the strain in a liquid medium or a solid medium.
  • the medium may include, as a carbon source, for example, glucose, corn syrup, dextrin, starch, molasses, animal oil, or vegetable oil.
  • the medium may include, as a nitrogen source, for example, wheat bran, soybean meal, wheat, malt, cottonseed meal, fish meal, corn syrup, meat juice, yeast extract, ammonium sulfate, sodium nitrate, or urea.
  • Cultivation may be performed under aerobic conditions with shaking or standing.
  • the culture temperature may be, for example, about 20°C to about 40°C, about 25°C to about 37°C, about 28°C to about 35°C, or about 30°C.
  • the culture time may be, for example, about 1 day to about 2 months, about 1 day to about 6 weeks, about 1 day to about 1 month, about 1 day to about 2 weeks, or about 1 day to about 1 week.
  • the method comprises a step of isolating a compound represented by any one of Chemical Formulas I to III or a stereoisomer thereof from a culture of the strain.
  • the separation step may include concentrating, centrifuging, filtering, or performing chromatography on the culture medium.
  • the chromatography may be, for example, column chromatography, planar chromatography, paper chromatography, or thin-layer 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 or 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 a compound according to one aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  • Solid cancers refer to tumors that develop in organs such as the liver, lungs, breasts, or skin.
  • Non-solid cancers originate in the blood and are also called hematologic cancers.
  • the cancer may be breast cancer.
  • the above breast cancer is classified into types based on the presence (positive) or absence (negative) of estrogen receptors (ER), progesterone receptors (PR), and epidermal growth factor receptors (HER2).
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 epidermal growth factor receptors
  • Estrogen binds to estrogen receptors, and the homodimerized estrogen receptors induce the transcription of various growth factors, such as cyclin D1, c-myc, and CDK4, in the nucleus.
  • the breast cancer may be HER2 negative breast cancer.
  • the compound according to one aspect has selective anticancer activity against ER+, PR+, and HER2- breast cancer cell lines and can be used as an effective ingredient for treating and preventing HER2-negative breast cancer.
  • prevention refers to any action that suppresses or delays the onset of a disease by administering a composition.
  • treatment refers to any action that improves or beneficially alters the symptoms of a disease by administering a composition.
  • the pharmaceutical composition may further comprise a known active ingredient having anticancer activity.
  • the known active ingredient having anticancer activity may be an anticancer agent.
  • the anticancer agent may be 5-fluorouracil, irinotecan, etoposide, oxaliplatin, leucovorin, capecitabine, or a combination thereof.
  • the compound represented by Chemical Formula I, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and the anticancer agent may be a single or separate composition for simultaneous or sequential administration.
  • the pharmaceutical composition may further comprise a carrier, excipient or diluent.
  • the carrier, excipient and diluent may include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
  • compositions 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 injectable solutions, respectively, according to conventional methods.
  • oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods.
  • the compositions may be prepared using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.
  • the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule.
  • the solid preparation may further include an excipient.
  • the excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin.
  • the solid preparation may further include a lubricant such as magnesium stearate or talc.
  • the liquid preparation for oral administration may be a suspension, an oral solution, an emulsion, or a syrup.
  • the liquid preparation may include water or liquid paraffin.
  • the liquid preparation may include an excipient such as a wetting agent, a sweetener, a flavoring agent, or a preservative.
  • the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solvent, suspension, emulsion, lyophilized product, or suppository.
  • the non-aqueous solvent or suspension may contain a 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, cocoa butter, laurin butter, or glycerogelatin.
  • the preferred dosage of the pharmaceutical composition above varies depending on the condition and body weight of the subject, the degree of the disease, the drug form, the route and period of administration, and can be appropriately selected by those skilled in the art.
  • the compound, its isomer, derivative, solvate, or pharmaceutically acceptable salt may be administered in an amount of, for example, about 0.0001 mg/kg to about 100 mg/kg, or about 0.001 mg/kg to about 100 mg/kg, once to 24 times a day, once to 7 times every 2 days to 1 week, or once to 24 times every 1 month to 12 months.
  • the compound, its isomer, derivative, solvate, or pharmaceutically acceptable salt may be included in an amount of about 0.0001 wt% to about 10 wt%, or about 0.001 wt% to about 1 wt%, based on the total weight of the entire composition.
  • Administration may be oral or parenteral.
  • the route of administration may be oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal.
  • the composition may be administered systemically or locally, and may be administered alone or in combination with other pharmaceutically active compounds.
  • Another aspect provides a health functional food for preventing or improving cancer, comprising a compound according to one aspect, a stereoisomer, a solvate, or a salt thereof.
  • the above health functional food can be used as a functional food or added to various foods by formulating the compound represented by Chemical Formula I, its stereoisomer, solvate, or salt into an encapsulated form, powdered form, or suspension.
  • the above foods include, for example, meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, functional foods, and health foods.
  • Another aspect provides a method of preventing or treating cancer, comprising administering to a subject a compound according to one aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  • the subject may be a mammal, such as a human, cow, horse, pig, dog, sheep, goat, or cat.
  • the subject may be diagnosed with cancer or may be at a high risk of being diagnosed with cancer.
  • the route of administration may be oral or parenteral.
  • the route of administration may be oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal.
  • the pharmaceutical composition may be administered systemically or locally, and may be administered alone or in combination with other pharmaceutically active compounds.
  • the preferred dosage of the pharmaceutical composition may vary depending on the patient's condition and weight, the extent of the disease, the drug form, the route and duration of administration, and may be appropriately selected by those skilled in the art.
  • the dosage may be in the range of about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg for adults.
  • the administration may be administered once a day, multiple times a day, or once a week, once every two weeks, once every three weeks, or once every four weeks, or once a year.
  • Another aspect provides the use of the compound, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for preventing or treating cancer.
  • novel oxazolomycin compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof uses, and methods for producing the same. Since the compounds have anticancer activity, the compounds, stereoisomers, solvates, or pharmaceutically acceptable salts thereof can be used to prevent or treat cancer.
  • Figure 1 is a photograph of a medium in which Streptomyces sp. AH05 strain was cultured.
  • Figure 2a is a diagram showing the level of estrogen receptor expression in the MCF-7 cell line confirmed by Western blot.
  • Figure 2b is a diagram showing the level of estrogen receptor expression in the T-47D cell line confirmed by Western blot.
  • Figure 3a is a diagram showing the results of inhibition of estrogen receptor synthesis by cyclohexamide treatment in MCF-7 cell lines.
  • Figure 3b is a graph showing the half-life of the estrogen receptor after treatment with 0.16 ⁇ M methyl-oxazolomycin A in MCF-7 cells. *p ⁇ 0.05
  • Figure 4a is a diagram showing the results of inhibition of estrogen receptor degradation by treatment with MG132, a proteasome inhibitor, in MCF-7 cell lines.
  • Figure 4b is a graph showing the relative intensity of estrogen receptor expression after MG132 treatment in MCF-7 cell lines.
  • Figure 5a is a diagram showing the results of inhibiting the degradation of estrogen receptors by treatment with MG132, a proteasome inhibitor, in the T-47D cell line.
  • Figure 5b is a graph showing the relative intensity of estrogen receptor expression after MG132 treatment in the T-47D cell line.
  • Figure 6a is a diagram showing the results of flow cytometry analysis according to the concentration of methyl-oxazolomycin A in the MCF-7 cell line.
  • Figure 6b is a graph showing the cell cycle distribution according to the concentration of methyl-oxazolomycin A in the MCF-7 cell line.
  • Figure 7a is a diagram showing the results of flow cytometry analysis according to the concentration of methyl-oxazolomycin A in the T-47D cell line.
  • Figure 7b is a graph showing the cell cycle distribution according to the concentration of methyl-oxazolomycin A in the T-47D cell line.
  • Figure 8a is a diagram showing the level of breast cancer cell growth factor expression in the MCF-7 cell line confirmed by Western blot.
  • Figure 8b is a diagram showing the expression level of breast cancer cell growth-related factors in the T-47D cell line using Western blot.
  • yeast extract-malt extract medium (4 g of yeast extract, 10 g of malt extract, 4 g of glucose, 16 g of agar powder, and 28 g of artificial sea salt per 1 L of distilled water) was used (Fig. 1).
  • the strain was identified as Streptomyces sp.
  • the strain was named Streptomyces sp. AH05 and deposited with the Korea Center for Microbial Resources (KCTC) (Accession No.: KCTC15725BP).
  • KCTC Korea Center for Microbial Resources
  • the 16s rRNA sequence of the Streptomyces sp. AH05 strain is indicated as sequence number 1.
  • GLY liquid medium (20 g of glycerol, 10 g of lactose, 5 g of malt extract, 5 g of yeast extract, 1 g of calcium carbonate, 28 g of artificial sea salt per 1 L of distilled water) and tertiary culture was performed at 180 rpm and 30°C for 3-4 days.
  • organic extraction was performed by mixing ethyl acetate (EtOAc) corresponding to 1.5 to 2 times the amount of the culture medium.
  • EtOAc ethyl acetate
  • the mixed culture medium and EtOAc were sufficiently shaken using a separatory funnel, and the aqueous layer and organic layer were allowed to sufficiently separate (upper layer: organic layer/lower layer: aqueous layer) and then the aqueous layer was removed. After removing the aqueous layer, the remaining moisture in the organic layer was removed with anhydrous sodium sulfate. Thereafter, the ethyl acetate layer in the organic layer was dried under reduced pressure. As a result, a total of 80 L of culture was cultured to obtain 20 g of extract.
  • EtOAc ethyl acetate
  • Example 3 Isolation and purification of methyl-oxazolomycin A and B from extracts of Streptomyces sp. AH05 strain.
  • Methyl-oxazolomycin A and B were isolated and purified from the extract of Streptomyces sp. AH05 strain of Example 2. Specifically, methanol and Celite were added to the dried extract of Example 2, and the extract was adsorbed onto Celite after drying under reduced pressure. Subsequently, fractionation was performed using solvents prepared in 20%, 40%, 60%, 80%, and 100% (methanol/water) compositions sequentially on an open column packed with ODS (C 18 ) resin. As a result, methyl-oxazolomycin A and B were isolated in the 80% MeOH-H 2 O fraction, which was confirmed through LC/MS.
  • methyl-oxazolomycin A was eluted in 20 minutes, and methyl-oxazolomycin B was eluted in 22 minutes, respectively.
  • methyl-oxazolomycin A was purified in 44 minutes, and methyl-oxazolomycin B was purified in 46 minutes.
  • Example 4 Identification of the double bond structure and physicochemical properties of methyl-oxazolomycin A and B.
  • a sulforhodamine B (SRB) assay was performed. Specifically, the triple-negative breast cancer (ER-, PR-, HER-) MDA-MB-231 cell line, and the ER+, PR+, HER2- breast cancer MCF-7 cell line and T-47D cell line were prepared. The prepared cells were seeded at a density of 5-7 ⁇ 10 4 cells/mL in 96-well culture plates and cultured with methyl-oxazolomycin for 72 hours. After incubation, the plates were fixed with a 10% trichloroacetic acid solution for 30 minutes at 4°C.
  • both methyl-oxazolomycin A and B had no activity in the MDA-MB-231 cell line with IC 50 values of 20 ⁇ M or higher.
  • both methyl-oxazolomycin A and B showed strong cell growth inhibition in ER+, PR+, and HER2- breast cancer cell lines.
  • the above results confirmed that both methyl-oxazolomycin A and B have selective anticancer activity in ER+, PR+, and HER2- breast cancer cell lines.
  • MCF-7 and T-47D cell lines were treated with concentrations of 0, 0.02, 0.04, 0.08, and 0.16 ⁇ M for 24 h. Then, 2x sample loading buffer (250 mM Tris-HCl (pH 6.8), 4% SDS, 10% glycerol, 0.006% bromophenol blue, 2% ⁇ -mercaptoethanol, 50 mM sodium fluoride, and 5 mM sodium orthovanadate) was added to disrupt the cells and incubated at 100°C for 15 minutes. After cooling, the samples were stored at -20°C and thawed at room temperature just before use to perform Western blotting.
  • 2x sample loading buffer 250 mM Tris-HCl (pH 6.8), 4% SDS, 10% glycerol, 0.006% bromophenol blue, 2% ⁇ -mercaptoethanol, 50 mM sodium fluoride, and 5 mM sodium orthovanadate
  • MCF-7 and T-47D cells were seeded at 24 X 10 4 cells/well in 60 mm petri dishes, and the cell cycle was synchronized with 1% FBS medium after 24 hours. After 24 hours, the cell lines were treated with methyl-oxazolomycin A at concentrations of 0, 0.02, 0.04, 0.08, and 0.16 ⁇ M. After 24 hours, the cells were collected, stained with propidium iodide (PI), and the cell cycle distribution was analyzed using a flow cytometer.
  • PI propidium iodide

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé d'oxazolomycine, un stéréoisomère, un solvate ou un sel pharmaceutiquement acceptable de celui-ci, une utilisation de celui-ci, et son procédé de production. Le composé présente une activité anticancéreuse et, par conséquent, le composé, un stéréoisomère, un solvate ou un sel pharmaceutiquement acceptable de celui-ci peut être utilisé pour prévenir ou traiter le cancer.
PCT/KR2024/002537 2024-02-22 2024-02-27 Nouveau composé d'oxazolomycine, son procédé de production et son utilisation Pending WO2025178157A1 (fr)

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KR10-2024-0026030 2024-02-22
KR1020240026030A KR20250129852A (ko) 2024-02-22 2024-02-22 신규한 옥사졸로마이신 화합물, 이의 생산 방법 및 용도

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WO2025178157A1 true WO2025178157A1 (fr) 2025-08-28

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KR102342772B1 (ko) * 2019-05-02 2021-12-23 서울대학교산학협력단 매크로라이드계 유도체 화합물, 이의 생산 방법 및 용도
KR102389725B1 (ko) * 2020-02-14 2022-04-25 서울대학교산학협력단 피페라진산을 함유하는 사이클릭 펩티드 화합물, 이의 생산 방법, 및 이의 용도

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KR102342772B1 (ko) * 2019-05-02 2021-12-23 서울대학교산학협력단 매크로라이드계 유도체 화합물, 이의 생산 방법 및 용도
KR102389725B1 (ko) * 2020-02-14 2022-04-25 서울대학교산학협력단 피페라진산을 함유하는 사이클릭 펩티드 화합물, 이의 생산 방법, 및 이의 용도

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