WO2012011741A2 - 신규한 푸사리세틴 화합물 및 이의 용도 - Google Patents
신규한 푸사리세틴 화합물 및 이의 용도 Download PDFInfo
- Publication number
- WO2012011741A2 WO2012011741A2 PCT/KR2011/005348 KR2011005348W WO2012011741A2 WO 2012011741 A2 WO2012011741 A2 WO 2012011741A2 KR 2011005348 W KR2011005348 W KR 2011005348W WO 2012011741 A2 WO2012011741 A2 WO 2012011741A2
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- cancer
- fusaricetin
- pharmaceutically acceptable
- present
- Prior art date
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- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000001965 potato dextrose agar Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical compound CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 125000002456 taxol group Chemical group 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940033203 vitamin b6 0.5 mg Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- 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
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L31/00—Edible extracts or preparations of fungi; Preparation or treatment thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention is a bear light isolated from the soil having anticancer activity, a compound having cancer cell proliferation inhibitory activity and cancer cell metastasis inhibitory activity produced from the fungus, an anticancer composition comprising the compound as an active ingredient, and the compound It is about the separation method.
- Cancer is the leading cause of mortality in modern society, and despite many studies to date, there is no technological treatment.
- Representative cancer treatments of modern medicine include surgical surgery, biotherapy, radiation therapy, and chemotherapy with chemotherapy.
- Chemotherapy is a method of treating cancer that has been metastasized by oral or injection of anticancer drugs to suppress the proliferation of cancer cells.
- Chemotherapy is currently used as a standard therapy for the treatment of metastatic cancer.
- chemotherapy can not cure cancer, but it plays an important role in relieving symptoms and extending lifespan.
- anticancer agents derived from natural products the most commonly used anticancer agent is taxol, which is used to treat breast cancer and ovarian cancer.
- these chemotherapeutic agents have problems such as side effects and anticancer drug expression, and many studies on cancer have been conducted so far, but due to the diversity of cancer itself and various pathogenesis mechanisms, it is possible to overcome less side effects and resistance. New anticancer drugs are needed.
- the inventors of the present invention while searching for metabolites of soil microorganisms for a substance having excellent anticancer activity, fungus strain Fusarium to produce a substance having excellent anticancer activity from soil samples.
- sp.) FN080326 was screened and purified from the new structure of the fusarisetin compound.
- the fusaricetin compounds were used to treat cancer cells such as breast cancer cells, liver cancer cells, and myeloid leukemia cells.
- the present invention was completed by confirming that the cancer cell proliferation inhibitory and cancer cell metastasis inhibiting activity.
- An object of the present invention is the fusarisetin (fusarisetin) having the activity of inhibiting cancer cell proliferation and cancer cell metastasis produced from the fungus of Fusarium ⁇ U isarium sp.
- a compound is provided.
- Another object of the present invention is to provide a method for producing the fusaricetin compound according to the present invention.
- Another object of the present invention is to provide a new strain for producing a fusaricetin compound according to the present invention.
- Another object of the present invention is to provide an anticancer composition comprising the fusaricetin compound according to the present invention.
- Another object of the present invention is to provide a method for preventing or treating cancer using the fusaricetin compound according to the present invention.
- the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof: ⁇ 17> [Tue 1]
- Rl, R2, R3, R4, R5 and R6 may each have hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetyl, benzyl, halogen atoms, hydroxyl groups or carboxyl groups And includes isomers in all asymmetric carbons.
- the present invention provides a pharmaceutical composition for preventing and treating cancer containing the compound as an active ingredient.
- the present invention provides a health food for preventing and improving cancer containing the compound as an active ingredient.
- the present invention provides a method for producing the compound.
- the present invention also provides the Fusarium sp. FN080326 strain producing the compound, deposited under accession number KCTC11985BP.
- the present invention also provides a method for treating cancer, comprising administering a pharmaceutically effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject with cancer.
- the present invention provides a method for preventing cancer, comprising administering to a subject a pharmaceutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
- the present invention provides the compound or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition for preventing and treating cancer.
- the present invention provides the compound or a pharmaceutically acceptable salt thereof for use as a health food for preventing and improving cancer.
- the present invention provides a compound represented by the following [Formula 1] or a pharmaceutically acceptable salt thereof: ⁇ One]
- Rl, R2, R3, R4, R5 and R6 may each have hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, acetyl, benzyl, halogen atoms, hydroxyl groups or carboxyl groups, all asymmetric Isomers at carbon.
- the compound represented by [Formula 1] is preferably a fusa risetin A compound represented by the following [Formula 2], but is not limited thereto.
- the compound represented by the above [Formula 1] is preferably, but not limited to, a fusa risen B compound represented by the following [Formula 3]:
- the fusaricetin compound is preferably, but not limited to, polarized light from Fusarium ⁇ Fusariwn sp.) FN080326.
- the fusaricetin compound preferably has proliferative and metastatic inhibitory activity against cancer cells such as breast cancer cells, liver cancer cells or myeloid leukemia cells.
- the cancer is preferably breast cancer, liver cancer or myeloid leukemia, and more preferably breast cancer, but is not limited thereto.
- the present invention includes not only the fusaricetin compound represented by the above [Formula 1] or a pharmaceutically acceptable salt thereof, but also all possible solvates and hydrates that can be prepared therefrom.
- the fusaricetin compound of Formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as a salt.
- Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
- These pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate , Succinate, suverate, sebacate, fumarate, maleate, butine-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzo Ate, hydroxybenzoate, hydroxybenzoate, phthalate, terephthalate, Benzenesulfonate, toluenesulfonate, chlorobenz
- Acid addition salts according to the present invention can be prepared by conventional methods, for example, by dissolving the fusaricetin compound of formula (1) in an excess of aqueous solution of an acid and dissolving the salt with a miscible organic solvent such as methanol and ethanol. It may be prepared by precipitation with acetone or acetonitrile. An equivalent amount of the fusaricetin compound of Formula 1 and an acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be prepared by suction filtration.
- bases may be used to make pharmaceutically acceptable metal salts.
- Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the compound salt unintentionally, and evaporating and drying the filtrate.
- the metal salt it is pharmaceutically suitable to prepare sodium, potassium, or champ salt.
- Corresponding silver salts are also obtained by reacting alkali metal or alkaline earth metal salts with a suitable silver salt (eg silver nitrate).
- the molecular weight and the molecular formula of Compounds 1 and 2 isolated from the culture of Fusarium FN080326 were determined using an ESI mass spectrometer (Electrospray Ionization mass spectrometer). In addition, through nuclear magnetic resonance (NMR) analysis
- HMBC Multiple—Quantum Coherence
- HMBC Het eronuc 1 ear Multiple-Bond Coherence
- DEPT Distort ionless Enhancement by Polarization
- NOS Nuclear Overhauser effect spectroscopy
- human breast cancer cell line MDA-MB-231 cell
- mouse fibroblast cell line 3Y1 cell
- human liver cancer cell line Hep3B
- K562 cells human chronic myeloid leukemia cell line
- HL-60 cells human promyelocytic leukemia cell line
- the fusaricetin A and B of the present invention were concentration-dependent IC 50 values, 50% proliferation inhibitory concentration for all MDA-MB-231 cells, 3Y1 cells, Hep3B cells, K562 cells and HL-60 cell lines, respectively. Reduction (see FIGS. 7 and 8). Therefore, it can be seen that the fusaricetin A and B of the present invention have excellent cancer cell proliferation activity.
- the fusaricetin A and B of the present invention in order to determine whether the cancer cell metastasis activity of fusaricetin A and B, human breast cancer cells (MDA-MB-231 cells) cultured in a medium to which the addition of fusaricetin A and B at various concentrations After that, the degree of metastasis of the cells was measured using a transwell chamber.
- the fusaricetin A and B of the present invention significantly reduced the ED 100 , which shows 100% metastasis inhibition concentration to MDA-MB-231 cells, respectively. Therefore, it can be seen that the fusaricetin A and B of the present invention have cancer metastasis inhibitory activity against cancer cells.
- fusaricetin A and B inhibit the metastasis of cells induced by 10% fetal bovine serum (FBS), a group of factors involved in cancer cell metastasis, such as Integrin. It can be seen that it inhibits Matrix metal loproteinases (MNPs), Heparanase, Fibroblast Growth Factor (FGF) and the like.
- FBS fetal bovine serum
- MNPs Matrix metal loproteinases
- Heparanase Heparanase
- FGF Fibroblast Growth Factor
- the present invention provides a Fusarium sp. FN080326 strain, which produces the fusaricetin A or B compound, deposited under accession number KCTC11985BP.
- the present invention provides a method for separating the fusaricetin A or B compounds from the Fusarium sp. FN080326 strain of the present invention.
- ⁇ 6i> 2 separating the fusaricetin compound from the strain culture obtained in step 1) It provides a method for separating the fusaricetin compound according to the invention, comprising the step. In the embodiment of the present invention.
- step 3 separating the ethyl acetate extract obtained in step 2) by column chromatography.
- step 1) is a step of culturing the fungus Fusarium sp. FN080326 strain, wherein the strain is a Fusarium sp. FN080326 strain deposited with accession number KCTC11985BP. desirable.
- Strain cultures can be cultured in a medium containing nutrients that can be used by conventional microorganisms.
- a nutrient source the well-known nutrient source conventionally used for the cultivation of a bear bear can be used.
- the carbon source may be glucose, starch syrup, textine, starch, molasses, animal oil, vegetable oil, etc.
- the nitrogen source may be bran, soybean meal, wheat, malt, cottonseed meal, fishmeal, cornspicker, or juicy.
- Yeast extract, ammonium sulfate, nitric oxide, urea and the like can be used.
- shaking culture or stationary culture is preferable but not limited to aerobic conditions.
- the incubation temperature is slightly different depending on the conditions when incubated in each of the above conditions, it is usually preferred to incubate at 20 ⁇ 37 ° C, it is more preferable to incubate at 25 ⁇ 30 ° C It is not limited to this.
- step 2) is a step of extracting the strain culture obtained in step 1) with ethyl acetate, wherein the fusaricetin A or B compound of the present invention is applied to the mycelium part as well as the culture medium of the strain. May exist. Therefore, it is preferable to add an organic solvent such as ethyl acetate to the culture medium and mycelium of the strain to extract the active ingredient from the culture medium and the mycelium, and then concentrate the extract obtained by a reduced pressure evaporation method.
- an organic solvent such as ethyl acetate
- step 3) is a step of separating the fusaricetin A or B compound of the present invention, the ethyl acetate concentrate obtained in step 2) using a methane: water mixed solvent flash column After chromatography, high-performance liquid chromatography can be purified by blood separation.
- the present invention provides a pharmaceutical composition for preventing and treating cancer, which contains the fusaricetin A or B compound of the present invention as an active ingredient.
- the fusaricetin A or B compound of the present invention has proliferation inhibitory and metastatic inhibitory activity against cancer cells such as breast cancer cells, liver cancer cells or myeloid leukemia cells, It can be seen that it can be usefully used as an active ingredient of anticancer drugs.
- composition containing fusaricetin A or B, or a pharmaceutically acceptable salt thereof, according to the present invention as an active ingredient may be used in the form of a general pharmaceutical preparation.
- the fusaricetin A or B of the present invention may be administered in various formulations, oral and parenteral, in actual clinical administration.
- it when formulated, it may be prepared by including one or more pharmaceutically acceptable carriers in addition to fusaricetin A or B as an active ingredient.
- Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, saturated saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary.
- other conventional additives such as a complete liquid, bacteriostatic agent, can be added.
- Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, and the like, which may comprise at least one excipient such as, for example, starch, Calcium carbonate, sucrose or lactose, gelatin and the like are mixed and prepared.
- excipients such as, for example, starch, Calcium carbonate, sucrose or lactose, gelatin and the like are mixed and prepared.
- lubricants such as magnesium styrate talc are also used.
- liquid preparations for oral administration include suspending agents, liquid solutions, emulsions, and syrups.
- various excipients such as wetting agents, sweeteners, Fragrances, preservatives and the like.
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers and suppositories.
- non-aqueous solvent and the suspending solvent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used.
- As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
- the pharmaceutical composition of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection.
- parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection.
- the fusaricetin A or B is mixed in water with a stabilizer or laxative to prepare a solution or suspension, which is formulated in unit doses of 3/4 vials.
- Fusaricetin A or B according to the present invention is preferably included in 0.1 to 50% by weight relative to the total weight of the composition.
- the composition as described above is not necessarily limited thereto, and may vary according to the condition of the patient, the type of disease, and the degree of progression.
- the preferred dosage of fusaricetin A or B according to the present invention depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, it is preferable to administer at 0.01 mg / kg to 10 g / k g per day, preferably 1 mg / kg to 1 g / kg. Administration may be administered once a day or may be divided several times. Therefore, the above dosage does not limit the scope of the present invention in any aspect.
- the present invention provides a health food for cancer prevention and improvement comprising the fusaricetin A or B compound of the present invention as an active ingredient.
- the fusaricetin A or B compound of the present invention has proliferation inhibitory and metastatic inhibitory activity against cancer cells such as breast cancer cells, liver cancer cells or myeloid leukemia cells, It can be seen that it can be usefully used as an active ingredient of anti-cancer health food.
- Examples of foods to which the substance may be added include beverages, gums, vitamin complexes, or health supplements, and include all health foods in the conventional sense.
- the beverage composition of the present invention may contain various flavors, natural carbohydrates, and the like as additional components, like ordinary beverages.
- the above-mentioned natural carbohydrates include glucose, monosaccharides such as fructose, malsaccharides such as maltose, disaccharides such as sucrose, polysaccharides such as textine, and cyclodextrin, xylly, sorbitol, and erythritol. to be.
- natural sweeteners such as tautin, stevia extract, synthetic sweeteners such as saccharin, aspartame, and the like can be used.
- the proportion of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02-0.03 g per 100 m of the composition of the present invention.
- composition of the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH Regulators, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like.
- composition of the present invention may contain a flesh for preparing natural fruit juices, fruit juice drinks and vegetable drinks. These components can be used independently or in combination. The proportion of such additives is not critical but is usually selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.
- the present invention provides a method for treating cancer, comprising administering to a subject with cancer a pharmaceutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
- the present invention provides a method for preventing cancer, comprising administering to a subject a pharmaceutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
- the fusaricetin A or B compound of the present invention has proliferative and metastatic inhibitory activity against cancer cells such as breast cancer cells, liver cancer cells or myeloid leukemia cells, the fusaricetin A or B compounds are It can be seen that it can be usefully used for the prevention or treatment of cancer.
- the present invention provides the compound or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition for preventing and treating cancer.
- the present invention provides the compound or a pharmaceutically acceptable salt thereof for use as a health food for preventing and improving cancer.
- the fusaricetin A or B compound of the present invention has proliferation inhibitory and metastatic inhibitory activity against cancer cells such as breast cancer cells, liver cancer cells or myeloid leukemia cells, It can be seen that it can be usefully used as an active ingredient in the production of anticancer drugs.
- Examples of foods to which the substance may be added include beverages, gums, vitamin complexes or health supplements, and include all health foods in the conventional sense.
- novel fusaricetin compound of the present invention exhibits excellent proliferation inhibition and cancer cell metastasis inhibiting activity against various cancer cells, and thus the fusaricetin compound can be usefully used as an anticancer agent.
- FIG. I is a diagram showing HPLC chromatograms of Compounds 1 and 2 (fusaricetin A and B) isolated from the present invention.
- FIG. 2 is an NMR spectrum of Compound 1 (fusaricetin A) isolated from the present invention.
- FIG. 3 is a 13 C NMR spectrum of Compound 1 (Fusaricetin A) isolated from the present invention.
- FIG. 5 is a 13 C NMR spectrum of Compound 2 (Fusaricetin B) isolated from the present invention
- Figure 6 is a picture showing a micrograph of the Fusarium sp. FN080326 isolated in the present invention.
- FIG. 7 is a diagram showing the cancer cell proliferation inhibitory activity of Compound 1 (fusaricetin A) isolated from the present invention.
- FIG. 8 is a diagram showing the cancer cell proliferation inhibitory activity of Compound 2 (fusaricetin B) isolated from the present invention.
- FIG. 9 is a diagram showing the cancer cell metastasis inhibitory activity of the compounds 1 and 2 (fusaricetin A and B) isolated from the present invention.
- CCCAGAGAGGTGG (MCTACCACTCAG n: GGA GCTCTC (SEQ ID NO: 3)
- GenBank search results of the nucleotide sequences obtained through the sequencing analysis showed that fusarium ox cisporum 0 sar / iw oxysporum) (DQ916150) 99%, and fusarium incanatum 0 s / 1 ⁇ 2? 99% homology.
- the strain was identified as Fusarium and named as Fusarium isarium sp.) FN080362, and was deposited on July 18, 2011 to the Korea Institute of Bioscience and Biotechnology (KCTC) (Accession Number: KCTC11985BP).
- Compounds 1 and 2 isolated from the culture medium of FN080326 were determined molecular weight and molecular formula using an ESI mass spectrometer (ESI).
- ESI mass spectrometer
- NMR, 13 C NMR, COSYCCorrelat ion Spectroscopy (HMRQC), 1H-Detected heteronuclear Multiple—Quantum Coherence (HMQC), Hetronron 1 ear Multiple—Bon Coherence (HMBC), and DPT (Distort ionless) Enhancement by Polarization) and NOESY (Nuclear Overhauser effect spectroscopy) spectra were obtained and the molecular structure of the compound was determined (FIGS. 2, 3, 4 and 5).
- Fusaricetin A and B were obtained by HRESIMS analysis and NMR analysis. It was confirmed that the C 22 H 31 N0 5 , and the compound having the same molecular weight and molecular formula confirmed that the compound 1 and 2 are two different properties of the three-dimensional configuration of carbon 5 from the binding constant value of H ⁇ and N0ESY results.
- H, 3 ⁇ 4 NMR data is shown in Table 1 below; HRESIMS mlz 412.2085 [M + Na] + (calcd for C 22 H 31 N05Na, 412.2100).
- Fusarisetin B (Compound 2): white powder; [a] D +84.9 (c 0.2,
- human breast cancer cell line MDA-MB-231 cells, 5.0xi0 3 C ells per well
- mouse fibroblast Cell lines (3Y1 cells, 5.0 ⁇ 10 cells per well)
- human liver cancer cell lines Hep3B, 5.0 ⁇ 10 eel Is per well
- DMEM medium Dulbeccos modification of Eagles medium, containing 10% fetal bovine serum
- human chronic myeloid leukemia cell line K562 cells, 3.0xi0 4 cells per well
- human promyelocytic leukemia cell line HL— 60 cells, 1.0X
- IC 50 values of 503 ⁇ 4 inhibition of growth for MDA-MB-231 cells, 3Y1 cells, Hep3B cells, K562 cells and HL-60 cell lines were 69.5 ⁇ g / m ⁇ , 67.5 g / ml, 34.7 / g / ml, Concentrations of 61.3 // g / ml and 57.7 / g / ml.
- compound 2 showed concentrations of 76.5 / g / ml, 62.2 / g / ml, 27.2 ⁇ g / m ⁇ , 49.3 g / ml and 29.4 // g / ml for each cell line (FIGS. 7 and 8) . Therefore, it can be seen that the compounds 1 and 2 of the present invention have cancer cell proliferation activity.
- Human breast cancer cells (MDA-MB-231 cells) were applied at the concentration of 1.0 ⁇ 10 5 cells per well on the top of the chamber.
- the medium used was DMEM medium (Dulbeccos modification of Eagles medium, serum-free), and 30 / zg / ml, 10 // g / ml, 3 // g Each was added at a concentration of / ml.
- FBS fetal bovine serum
- FBS fetal bovine serum
- the cells were induced with 10% concentration fetal bovine serum at the bottom of the chamber and transferred through the porous membrane with 100% MeOH, and then stained with a light stain reagent. Three stained and transferred using a microscope Catcher was calculated.
- the ED 100 representing the 100% metastasis inhibition concentration of the human breast cancer cell line (MDA-MB-231 cells) in FIG. 9 was found to be 10 // g / ml each (FIG. 9).
- FBS fetal bovine serum
- Compounds 1 and 2 of the present invention have cancer metastasis inhibiting activity against cancer cells.
- the powders are prepared by mixing the above ingredients and filling them in airtight cloths.
- the above components are mixed and layered in a gelatin capsule to prepare a 3 ⁇ 4 capsule.
- Purified water is added to each of the components in accordance with the conventional method for preparing a liquid solution, the lemon flavor is added appropriately, and then the above components are mixed and purified water is added.
- Vitamin A Acetate 70 ⁇
- composition ratio of the vitamin and mineral mixtures described above is a relatively suitable composition suitable for health foods in a preferred embodiment, but the composition ratio may be arbitrarily modified, and according to the conventional health food manufacturing method After mixing, the granules may be prepared and used for preparing a health food composition according to a conventional method.
- the resulting solution is filtered and obtained in a sterilized 2 £ container and sealed sterilized It is then refrigerated and then used to prepare a healthy beverage composition of the present invention.
- composition ratio is a relatively suitable composition for a preferred beverage in a preferred embodiment
- the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, use.
- FN080326 strain can be used to mass produce the novel fusaricetin compound of the present invention, and the novel fusaricetin compound of the present invention can be used for anticancer drugs or anti-cancer health foods. Can be used to develop
- Pcr / KRaon / ooKwa Accumulated microorganisms a are other ⁇
- ⁇ indicator is designated by 3 ⁇ 4 and 3 ⁇ 4 is supported by other countries.
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JP2013520651A JP5728576B2 (ja) | 2010-07-20 | 2011-07-20 | 新規なフサリセチン化合物およびその用途 |
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CN111196815B (zh) * | 2019-05-08 | 2022-04-29 | 中国农业科学院烟草研究所 | 一种海洋真菌来源新型fusarisetin类除草剂、制备方法及应用 |
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Non-Patent Citations (4)
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BEZUIDENHOUT, S.C. ET AL.: 'Structure elucidation of the fumonisins, mycotoxins from Fusarium moniliforme.' J. CHEM. SOC., CHEM. COMMUN. vol. 11, 1988, pages 743 - 745 * |
BURKE,L.T. ET AL.: 'A short stereoselective total synthesis of the fusarium toxin equisetin.' ORGANIC LETTERS. vol. 2, no. 23, 2000, pages 3611 - 3613 * |
GELDERBLOM,W.C. ET AL.: 'Fumonisins - novel mycotoxins with cancer-promoting activity produced by Fusarium moniliforme.' APPLIED & ENVIRONMENTAL MICROBIOLOGY. vol. 54, no. 7, 1988, pages 1806 - 1811 * |
PEREIRA,C. ET AL.: 'Total synthesis of the sphingolipid biosynthesis inhibitor fumonisin Bl.' J. AM. CHEM. SOC. vol. 131, 2009, pages 6066 - 6067 * |
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