WO2021225363A1 - Composition anti-inflammatoire ou antidiabétique comprenant un métabolite du champignon d'origine marine penicillium glabrum sf-7123 - Google Patents

Composition anti-inflammatoire ou antidiabétique comprenant un métabolite du champignon d'origine marine penicillium glabrum sf-7123 Download PDF

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WO2021225363A1
WO2021225363A1 PCT/KR2021/005622 KR2021005622W WO2021225363A1 WO 2021225363 A1 WO2021225363 A1 WO 2021225363A1 KR 2021005622 W KR2021005622 W KR 2021005622W WO 2021225363 A1 WO2021225363 A1 WO 2021225363A1
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formula
inflammatory
present
pharmaceutical composition
compound
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Korean (ko)
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임정한
김일찬
한세종
오현철
손재학
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한국해양과학기술원
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    • 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
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to an anti-inflammatory or anti-diabetic composition comprising a metabolite of the marine-derived fungus Penicillium glabrum SF-7123, and more particularly, to an anti-inflammatory or anti-diabetic composition comprising the metabolite It relates to a pharmaceutical composition for use, a food for improving inflammation or diabetes, and a method for isolating the metabolite.
  • Inflammation is an essential immune response of the body to injury or infection.
  • Macrophages and microglia resident macrophage-like cells of the central nervous system
  • They are activated in response to various stimuli and cause phagocytosis of damaged macrophages and nerve cells to protect tissues and prevent damage to the brain and body.
  • pro-inflammatory mediators including NO, prostaglandin E 2 (PGE 2 ), tumor necrosis factor (TNF)- ⁇ , interleukin (IL)-1 ⁇ and IL-6 ( Lappas, M., et al., Biol. Reprod . 2002 , 67 , 668-673.; Amor, S., et al., Immunology 2010 , 129 , 154-169.). Therefore, inhibiting the production of pro-inflammatory mediators can be considered as a major target for the prevention or treatment of inflammatory diseases.
  • iNOS inducible nitric oxide enzyme
  • COX- 2 cyclooxygenase-2
  • pro-inflammatory mediators including NO, prostaglandin E 2 (PGE 2 ), tumor necrosis factor (TNF)- ⁇ , interleukin (IL)-1 ⁇ and IL-6 ( Lappas, M., et al., Biol. Reprod . 2002 , 67 , 668-673.; Amor, S.
  • the RAW 264.7 cell line (Abelson murine leukemia virus-transformed macrophages derived from male BALB/c mice) has been widely used as an in vitro model for examining cells.
  • BV2 cells raf/myc-immortalized murine microglia
  • BV2 cells have been frequently used to model the response of microglia in vivo.
  • PTP1B Protein tyrosine phosphatase 1B
  • marine-derived fungi have been proposed as a unique source of biologically active secondary metabolites (Ebada, SS; Proksch, ed. Springer Berlin Heidelberg, Berlin, Heidelberg, Chapter 32; pp 759-788; 2015.).
  • biologically active compounds including polyketides (40%), alkaloids (20%), peptides (15%), terpenoids (15%), a variety of novel metabolites consisting of prenylated polyketides (7%) and shikimates (2%) and lipids (1%) were explored (Rateb, ME, Ebel, R. Nat. Prod. Rep . 2011 , 28 , 290-344).
  • studies on metabolites having an effect of inhibiting the production of pro-inflammatory mediators and PTP1B have not been reported.
  • the present inventors made diligent efforts to screen metabolites with excellent anti-inflammatory or antidiabetic activity.
  • metabolites of the marine-derived fungus Penicillium glabrum (SF-7123) were detected by LPS in RAW264.7 macrophages and BV2 microglia. It was confirmed that it has an anti-inflammatory effect and an anti-diabetic effect on the induced inflammatory response, and the present invention was completed.
  • An object of the present invention is to provide an anti-inflammatory or anti-diabetic pharmaceutical composition comprising a metabolite of Penicillium glabrum SF-7123 and a food for improving inflammation or diabetes, which has excellent anti-inflammatory or anti-diabetic activity have.
  • Another object of the present invention is to provide a method for isolating the metabolite.
  • Another object of the present invention is to provide a method for preventing or treating an inflammatory disease or diabetes comprising administering the metabolite or the pharmaceutical composition.
  • Another object of the present invention is to provide an anti-inflammatory or anti-diabetic use of the metabolite.
  • Another object of the present invention is to provide the use of the metabolite for the prevention or treatment of inflammatory diseases or diabetes.
  • Another object of the present invention is to provide the use of said metabolite in the manufacture of a medicament for the treatment of inflammatory diseases or diabetes.
  • the present invention provides an anti-inflammatory or anti-diabetic pharmaceutical composition
  • an extract of Penicillium glabrum SF-7123 comprising an extract of Penicillium glabrum SF-7123.
  • the present invention also provides a food for improving inflammation or diabetes containing the extract.
  • the present invention also comprises the steps of (a) culturing Penicillium glabrum (Penicillium glabrum) SF-7123; (b) extracting the strain culture obtained in step (a) with ethyl acetate (EtOAc); and (c) separating the ethyl acetate (EtOAc) extract obtained in step (b) by column chromatography.
  • R 1 to R 9 are each independently H, linear or branched C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 is aryl.
  • the present invention also provides an anti-inflammatory or anti-diabetic pharmaceutical composition
  • an anti-inflammatory or anti-diabetic pharmaceutical composition comprising one or more metabolites selected from the group consisting of the following Chemical Formulas 1 to 4:
  • R 1 to R 9 are each independently H, linear or branched C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 is aryl.
  • the present invention also provides a food for improving inflammation or diabetes comprising one or more metabolites selected from the group consisting of the following Chemical Formulas 1 to 4:
  • R 1 to R 9 are each independently H, linear or branched C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 is aryl.
  • the present invention also provides a method for preventing or treating an inflammatory disease or diabetes comprising administering the extract, the metabolite, or the pharmaceutical composition.
  • the present invention also provides the use of said extract or said metabolite for anti-inflammatory or anti-diabetic use.
  • the present invention also provides the use of said extract or said metabolite for the prevention or treatment of inflammatory diseases or diabetes.
  • the present invention also provides the use of said extract or said metabolite in the manufacture of a medicament for the treatment of an inflammatory disease or diabetes.
  • the present invention also provides the use of the extract or the metabolite in the manufacture of a functional food for the prevention or amelioration of inflammatory diseases or diabetes.
  • R 1 shows the effect of compound 1 in which R 1 is H on the mRNA expression of pro-inflammatory cytokines in LPS-induced BV2 cells.
  • Cells were pretreated with compound 1 with R 1 of H at the indicated concentration for 3 hours, followed by stimulation with LPS (1 ⁇ g/mL) for 24 hours.
  • Data represent mean values of three experiments ⁇ SD ( * p ⁇ 0.05; ** p ⁇ 0.01; *** p ⁇ 0.001 compared to LPS treated group).
  • FIG. 2 shows the effect of compound 1, wherein R 1 is H, on protein expression of iNOS and COX-2 in LPS-induced BV2 cells (A) and RAW264.7 cells (B).
  • Cells were pretreated with Compound 1 (1.0, 2.0 and 4.0 ⁇ M) in which R 1 is H for 3 hours, followed by treatment with LPS (1 ⁇ g/mL) for 24 hours.
  • Western blot analysis was performed for iNOS and COX-2 expression and representative blots of three independent experiments are shown. Band intensities were quantified by densitometry and normalized to ⁇ -actin ( ** p ⁇ 0.01; *** p ⁇ 0.001 compared to LPS treated group).
  • 3A to 3H show the effect of Compound 1, wherein R 1 is H, on NF- ⁇ B activation in LPS-induced BV2 and RAW264.7 cells.
  • Cells were pretreated with compound 1 (1.0, 2.0 and 4.0 ⁇ M) with R 1 of H for 3 h, followed by stimulation with LPS for 1 h (* p ⁇ 0.05; ** p ⁇ 0.01; *** p ⁇ 0.001). compared to the LPS-treated group).
  • 3A-3F show the results of Western blot analysis using specific anti-I ⁇ B- ⁇ , anti-p-I ⁇ B- ⁇ , anti-p65 and anti-p50 antibodies. Representative blots of three independent experiments are shown. Band intensities were quantified by densitometry and normalized to ⁇ -actin in the cytoplasmic fraction and PCNA in the nuclear fraction.
  • 3G and 3H show the results of measuring the NF- ⁇ B binding activity in the nuclear fraction using the NF- ⁇ B ELISA kit (Active Motif).
  • Figure 4 shows the effect of compound 1 in which R 1 is H on the activation of the MAPK pathway in LPS-induced BV2 and RAW264.7 cells.
  • Cells were pretreated with compound 1 (1.0, 2.0 and 4.0 ⁇ M) with R 1 of H for 3 h, followed by stimulation with LPS for 1 h.
  • the levels of phosphorylated-ERK (p-ERK), phosphorylated-JNK (p-JNK) and phosphorylated-p38 MAPK (p-p38 MAPK) were determined by Western blot analysis. Representative blots of three independent experiments are shown. Band intensities were quantified by densitometry and normalized to ⁇ -actin ( *** p ⁇ 0.001 compared to LPS treated group).
  • FIG. 5 shows Lineweaver-Burk plots for compound 3 (A) and compound 4 (B) in inhibition of PTP1B. Data represent mean ⁇ SD of three experiments. Concentrations ( ⁇ M) of compound 3 and compound 4 are indicated.
  • the metabolites of compounds 1 to 4 were isolated from the extract of the marine-derived fungus Penicillium glabrum SF-7123 (Accession No.: KCTC 14169BP), and the structures thereof were confirmed.
  • the metabolites (Compounds 1 to 4) were NO, prostaglandin E 2 (PGE 2 ), inducible nitric oxide enzyme (iNOS) and cyclooxygenase-2 (COX) in RAW264.7 macrophages and BV2 microglia. -2), and the like, by inhibiting the production of pro-inflammatory mediators and the expression of PTP1B, it was confirmed that it has a preventive or therapeutic effect on inflammatory diseases or diabetes.
  • the present invention in one aspect relates to a pharmaceutical composition for anti-inflammatory or antidiabetic comprising an extract of Penicillium glabrum SF-7123.
  • the extract relates to an anti-inflammatory or anti-diabetic pharmaceutical composition
  • an anti-inflammatory or anti-diabetic pharmaceutical composition comprising one or more metabolites selected from the group consisting of the following Chemical Formulas 1 to 4.
  • R 1 to R 9 are each independently H, linear or branched C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 aryl, preferably H, CH 3 or CH 2 CH 3 .
  • C 1-10 alkyl group means a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl , n-pentyl, n-hexyl, 1-ethylpropyl, 2,2-dimethylpropyl, and the like.
  • C 1-10 alkoxy group means a linear or branched alkyloxy group having 1*10 carbon atoms, for example, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2- oxy, methylprop-2-oxy, isopropoxy, tert-butoxy, and the like.
  • C 3-10 cycloalkyl group means a saturated hydrocarbon ring having 3 * 10 carbon atoms, and in addition to monocycloalkyl groups exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, polycycloalkyl groups, such as For example, a bicycloalkyl group, tricycloalkyl group, etc.
  • the bicycloalkyl group includes norbornyl, for example, exo-2-norbornyl, endo-2-norbornyl, 3-pinanyl, bi A cyclo[3.1.0]hexyl group, a bicyclo[2.2.1]heptyl group, a bicyclo[2.2.2]octo-2-yl group, etc., a tricycloalkyl group includes adamantyl, for example 1-adaman A tyl group, 2-adamantyl, etc. are mentioned.
  • a C 2-10 alkenyl group contains at least one double bond and is a straight or branched chain hydrocarbon radical having from 2 to 10 carbon atoms, for example, ethenyl, 2-propenyl, 3-butenyl, 2-part tenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl and the like.
  • the C 6-10 aryl group means an aryl group having 6*10 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
  • R 1 is CH 3 Metabolites of the formula (1) 9- O - is defined as methyl, New chroman menin (9- O -methylneuchromenin), the R 1 is H
  • the metabolite of Formula 1 is defined as neuchromenin, and the term "Compound 1" refers to a metabolite in which R 1 is CH 3 or H in Formula 1 above.
  • metabolites of R 2 to the formula II R 4 is CH 3, respectively, asterisks acid is defined as (asterric acid), the term "compound 2" the metabolic the R 2 to R 4 CH 3, respectively in the above formula (2) means body.
  • the metabolite of Formula 3 in which R 5 is CH 3 is defined as myxotrichin C (myxotrichin C), and the term “Compound 3” refers to a metabolite in which R 5 is CH 3 in Formula 3 above.
  • R 6 to R of 9 is CH 3
  • each metabolite of formula (4) is to be defined by the oxy Fu Nikon (deoxyfunicone)
  • the term "compound 4" is a metabolic
  • R 6 to R 9 is CH 3 respectively in the above formula (4) means body.
  • anti-inflammatory refers to the action of inhibiting or reducing inflammation.
  • the term "inflammation” is one of the defensive responses of biological tissues to certain stimuli, and is a biological defense mechanism that seeks to recover to its original state by removing injuries caused by various harmful stimuli.
  • Inflammation stimuli include infection or chemical and physical stimuli, and the inflammatory process can be divided into acute and chronic inflammation.
  • Acute inflammation is a short-term reaction within a few days, and plasma components or blood cells are involved in the removal of foreign substances by opening the microcirculation system.
  • Chronic inflammation has a long duration, and tissue proliferation is seen.
  • the anti-inflammatory or anti-diabetic pharmaceutical composition can be used for prevention, treatment or improvement of inflammatory diseases by having anti-inflammatory activity.
  • inflammatory disease is a generic term for diseases in which inflammation is the main lesion.
  • the term "extract” refers to a substance having anti-inflammatory activity isolated from the Penicillium glabrum SF-7123.
  • the extract is used in the sense of including not only the extract but also its dry powder or all forms formulated using the same.
  • the extract may be extracted using polar, non-polar, water, an organic solvent, or a mixed solvent thereof, and preferably may be extracted using an organic solvent.
  • the extracted liquid may be used in liquid form or may be used after concentration and/or drying.
  • the organic solvent is an anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, isopropanol, butanol, etc.), ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N, N-dimethylform Amide (DMF), dimethyl sulfoxide (DMSO), 1,3-butylene glycol, propylene glycol, or a mixture thereof can be used, and the extract is extracted by heating at room temperature or under conditions in which the active ingredient of the extract is not destroyed or minimized. can do.
  • methanol, ethanol, isopropanol, butanol, etc. ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N, N-dimethylform Amide (DMF), dimethyl sulfoxide (DMSO
  • the degree of extraction and loss of the active ingredient of the extract may be different, so an appropriate organic solvent should be selected and used.
  • the extraction method is not particularly limited, and examples thereof include cold extraction, ultrasonic extraction, and reflux cooling extraction.
  • Filtration is a process of removing suspended solid particles from the extract, and may use cotton, nylon, etc. to filter out particles, ultrafiltration, cryofiltration, centrifugation, etc., but is not limited thereto.
  • a separation process by various chromatography chromatography according to size, charge, hydrophobicity or affinity may be further included.
  • Drying the filtrate includes, but is not limited to, freeze drying, vacuum drying, hot air drying, spray drying, reduced pressure drying, foam drying, high frequency drying, infrared drying, and the like. In some cases, a process of pulverizing the final dried extract may be added.
  • the anti-inflammatory or anti-diabetic pharmaceutical composition may be characterized in having one or more of the following characteristics.
  • NO nitric oxide
  • PGE 2 prostaglandin E 2
  • NF- ⁇ B nuclear factor kappa B
  • MAPK mitogen-activated protein kinase
  • the anti-inflammatory or anti-diabetic pharmaceutical composition is nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) It may be characterized in that it has a production inhibitory property.
  • NO is a small molecule that is an intracellular mediator produced by various immune cells and plays a pivotal role in the physiological and pathological conditions of inflammatory conditions.
  • PGE 2 can modulate immune and inflammatory responses.
  • nitric oxide is a substance whose amount is increased by nitric oxide synthase when inducing an inflammatory reaction in a cell, and is a molecule that is an indicator of the inflammatory response.
  • NOS nervous system nitric oxide synthase
  • the synthesized nitric oxide increases the production of cGMP in brain cells, thereby performing a function of storing information recognized from the outside for a long time.
  • NO is a free radical and is known to be involved in physiological and pathological processes.
  • NO is synthesized by L-Arginine oxidation by nitric oxide synthase (Atkan, et al., 75: 639-653, 2004).
  • PGE 2 prostaglandin E 2
  • COX-2 COX-2
  • PGE 2 is an inflammatory mediator produced at the site of inflammation by COX-2 called prostaglandin endoperoxide synthetase.
  • PGE 2 is associated with many cardiovascular diseases, arthritis, inflammatory bowel disease and chronic inflammatory diseases including chronic gastric ulcer (St-Onge, M. et al., Biochim. Biophys. Acta. 1771:1235-1245, 2007).
  • St-Onge M. et al., Biochim. Biophys. Acta. 1771:1235-1245, 2007.
  • Turini ME et al., Annu. Rev. Med. 53:35-57, 2002
  • Singh VP et al., Pharmacology 72:77-84, 2004).
  • the anti-inflammatory or anti-diabetic pharmaceutical composition may be characterized in that it inactivates NF- ⁇ B (nuclear factor kappa B) and MAPK (mitogen-activated protein kinase).
  • NF- ⁇ B nuclear factor kappa B
  • MAPK mitogen-activated protein kinase
  • nuclear factor-kappa B nuclear factor-kappa B
  • mitogen-activated protein kinase MAPK
  • NF- ⁇ B nuclear factor-kappa B
  • MAPK mitogen-activated protein kinase
  • I ⁇ B is phosphorylated and translocates NF- ⁇ B dimers (p50 and p65) to the nucleus, resulting in iNOS, COX-2, NO, PGE 2 , TNF- ⁇ , IL-1 ⁇ and IL It results in the transcription of inflammatory genes such as -6.
  • FIGS. 3G and 3H decreased the DNA binding activity of the p65 subunit in LPS-stimulated BV2 and RAW264.7 cells.
  • MAPK is a major signal transduction system that regulates cell growth and differentiation by transmitting this signal from the cell membrane to the nucleus in order to activate a receptor located on the cell membrane, such as a growth factor.
  • MAPKs play important roles in a variety of cellular conditions, such as apoptosis, cell growth, differentiation, proliferation and immune responses (Liu, Y., et al., Nat. Rev. Immunol . 2007 , 7 , 202-212.).
  • MAPK consists of three major signaling pathways, including extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2), c-Jun N-terminal kinase (JNK) and p38 MAPK.
  • p38 MAPK is one of the MAPKs regulating the inflammatory response, so it is considered a target for anti-inflammatory treatment.
  • Pre-treatment with compound 1 in which R 1 is H inhibited LPS-induced p38 MAPK phosphorylation in BV2 and RAW264.7 cells, but did not affect ERK and JNK MAPK ( FIG. 4 ).
  • the anti-inflammatory or anti-diabetic pharmaceutical composition is characterized in that it has an expression inhibitory property of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).
  • iNOS inducible nitric oxide synthase
  • COX-2 cyclooxygenase-2
  • compound 1 in which R 1 is H attenuated the protein expression of iNOS and COX-2 in a dose-dependent manner in both BV2 and RAW264.7 cells stimulated with LPS ( FIG. 2 ).
  • iNOS and COX-2 are pro-inflammatory mediators, iNOS is an inflammatory molecule that produces NO, and COX-2 produces PGE 2 . Excessive increased activity of iNOS and COX-2 may be the etiology of various inflammatory diseases.
  • COX-2 is an enzyme involved in the production of prostaglandin, a protein related to an inflammatory response, and an increase in intracellular COX-2 expression level can be an indicator indicating that an inflammatory response is in progress. have.
  • the anti-inflammatory or anti-diabetic pharmaceutical composition may be characterized in that it has the properties of inhibiting the expression of IL-1 ⁇ , IL-6 and TNF- ⁇ .
  • compound 1 wherein R 1 is H effectively inhibits the mRNA expression of IL-1 ⁇ , TNF- ⁇ and IL-6 when BV2 cells are activated with LPS (1 ⁇ g/mL) for 12 hours. decreased (Fig. 1).
  • the anti-inflammatory or anti-diabetic pharmaceutical composition may be characterized in that it has a property of inhibiting the expression of PTP1B.
  • compounds 3 and 4 were shown to inhibit the active PTP1B enzyme in a dose-dependent manner with IC 50 values of 19.2 ⁇ M and 24.3 ⁇ M, respectively (Table 3).
  • the pharmaceutical composition may be characterized in that it further comprises a pharmaceutically acceptable carrier, excipient or diluent.
  • Carriers, excipients and diluents that may be included in the composition include, but are not limited to, 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, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate and mineral oil.
  • a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
  • the pharmaceutical composition according to the present invention may be formulated and used in various forms according to conventional methods. Suitable dosage forms include tablets, pills, powders, granules, dragees, hard or soft capsules, solutions, suspensions or emulsions, injections, oral dosage forms such as aerosols, external preparations, suppositories, and sterile injection solutions.
  • Suitable dosage forms include tablets, pills, powders, granules, dragees, hard or soft capsules, solutions, suspensions or emulsions, injections, oral dosage forms such as aerosols, external preparations, suppositories, and sterile injection solutions.
  • the present invention is not limited thereto.
  • the pharmaceutical composition according to the present invention can be prepared in a suitable dosage form using a pharmaceutically inert organic or inorganic carrier. That is, when the formulation is a tablet, a coated tablet, a dragee, and a hard capsule, it may contain lactose, sucrose, starch or derivatives thereof, talc, calcium carbonate, gelatin, stearic acid or a pharmaceutically acceptable salt thereof. In addition, when the formulation is a soft capsule, it may contain vegetable oils, waxes, fats, semi-solid and liquid polyols. In addition, when the formulation is in the form of a solution or syrup, water, polyol, glycerol, and vegetable oil may be included.
  • the "pharmaceutically acceptable salt” refers to a formulation of a compound 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 pharmaceutical salt is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc., tartaric acid, formic acid, citric acid , organic carbonic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • acid addition salts formed with phonic acid and the like are included.
  • pharmaceutically acceptable salts of carboxylic acids include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, and guanidine, dicyclohexylamine, N organic salts such as -methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine, and the like.
  • Acids such as oxalic acid are not pharmaceutically acceptable, but can be used in the preparation of useful salts as intermediates for obtaining pharmaceutically acceptable salts.
  • the pharmaceutical composition according to the present invention may further include a preservative, a stabilizer, a wetting agent, an emulsifier, a solubilizing agent, a sweetener, a colorant, an osmotic pressure regulator, an antioxidant, and the like, in addition to the carrier described above.
  • the pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and drug activity of the patient. , sensitivity to drugs, administration time, administration route and excretion rate, duration of treatment, factors including concurrent drugs, and other factors well known in the medical field.
  • the pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple. In consideration of all of the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, which can be easily determined by those skilled in the art.
  • composition of the present invention can be used in combination with a pharmaceutical composition for treatment of inflammatory diseases, such as immunotherapy, chemotherapy, and radiation therapy, and pharmaceutical compositions for the treatment of other inflammatory diseases, which can be recognized by those skilled in the art as being effective in the prevention or treatment of inflammatory diseases. .
  • inflammatory diseases such as immunotherapy, chemotherapy, and radiation therapy
  • pharmaceutical compositions for the treatment of other inflammatory diseases which can be recognized by those skilled in the art as being effective in the prevention or treatment of inflammatory diseases.
  • the pharmaceutical composition of the present invention may be administered to an individual by various routes.
  • the mode of administration can be, for example, by subcutaneous, intravenous, intramuscular or intrauterine intrathecal or intracerebrovascular injection.
  • the pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient, along with several related factors such as the disease to be treated, the route of administration, the age, sex and weight of the patient, and the severity of the disease.
  • the present invention relates to a food for improving inflammation or diabetes comprising an extract of Penicillium glabrum SF-7123.
  • the extract relates to a food for improving inflammation or diabetes containing one or more metabolites selected from the group consisting of the following Chemical Formulas 1 to 4.
  • R 1 to R 9 are each independently H, linear or branched C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 aryl, preferably H, CH 3 or CH 2 CH 3 .
  • the term "food” refers to meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, There are vitamin complexes, health functional foods, and health foods, and includes all foods in the ordinary sense.
  • the functional food is the same term as food for special health use (FoSHU), and in addition to supplying nutrition, it is processed to efficiently exhibit bioregulatory functions and has high medical effects.
  • function (sex) means to obtain a useful effect for health purposes such as regulating nutrients or physiological action with respect to the structure and function of the human body.
  • the food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art.
  • the formulation of the food may be manufactured without limitation as long as it is a formulation recognized as a food, and the health functional food according to the present invention may be in the form of powder, granule, tablet, capsule or beverage.
  • the health food means a food having an active health maintenance or promotion effect compared to general food
  • the health supplement food means a food for the purpose of health supplementation.
  • the terms health functional food, health food, and dietary supplement are used interchangeably.
  • the food composition may further include a physiologically acceptable carrier, the type of carrier is not particularly limited and any carrier commonly used in the art may be used.
  • the composition may include additional ingredients that are commonly used in food to improve odor, taste, vision, and the like.
  • vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, and the like may be included.
  • it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chromium (Cr).
  • it may include amino acids such as lysine, tryptophan, cysteine, and valine.
  • the composition includes a preservative (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), a disinfectant (bleaching powder and high bleaching powder, sodium hypochlorite, etc.), an antioxidant (butylhydroxyanisole (BHA), butylhydroxy Toluene (BHT), etc.), coloring agents (tar pigments, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleach (sodium sulfite), seasonings (MSG, etc.), sweeteners (dulcin, cyclimate, saccharin, sodium, etc.) ), flavorings (vanillin, lactones, etc.), expanding agents (alum, D-potassium hydrogen tartrate, etc.), strengthening agents, emulsifiers, thickeners (flavors), film agents, gum base agents, foam inhibitors, solvents, food additives such as improving agents ) may be included.
  • the additive may be selected according to the type of
  • It may further include a food pharmaceutically acceptable food supplement additive together with the Penicillium glabrum extract of the present invention, and may be used with other foods or food ingredients, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient may be suitably determined according to the purpose of its use (prevention, health or therapeutic treatment).
  • the terms “improvement”, “prevention” and “treatment” should be interpreted in the broadest sense, and “improvement” means any action that temporarily/continuously relieves a disease or one or more clinical symptoms.
  • "Prevention” means preventing the progression of one or more of the clinical symptoms of a disease in a patient who may be exposed to or susceptible to the disease but has not yet experienced or exhibited symptoms of the disease.
  • Treatment means any action that arrests or reduces the development of a disease or one or more clinical symptoms thereof.
  • the fungal strain of SF-7123 was cultured on an agar Petri plate in a medium containing 3% NaCl at 25°C for 21 days. After extracting the culture medium with EtOAc, the filtered extract was concentrated in vacuo to obtain a crude extract, and compounds 1 to 4 were obtained from the crude extract using a chromatography method (Example) 3).
  • the present invention in another aspect, (a) Penicillium glabrum ( Penicillium glabrum ) culturing SF-7123; (b) extracting the strain culture obtained in step (a) with ethyl acetate (EtOAc); and (c) separating the ethyl acetate (EtOAc) extract obtained in step (b) by column chromatography.
  • EtOAc ethyl acetate
  • R 1 to R 9 are each independently H, linear or branched C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 aryl, preferably H, CH 3 or CH 2 CH 3 .
  • step (a) is a step of culturing Penicillium glabrum SF-7123, and the strain culture is preferably cultured in a medium containing nutrients that can be used by ordinary microorganisms.
  • a known nutrient source conventionally used for culturing mold can be used.
  • a carbon source glucose, starch syrup, dextrin, starch, molasses, animal oil, vegetable oil, etc.
  • a nitrogen source wheat bran, soybean meal, wheat, malt, cottonseed meal, fish meal, cornstarch, broth, yeast Extracts, ammonium sulfate, sodium nitrate, urea, etc.
  • shaking culture or stationary culture is preferable under aerobic conditions, but is not limited thereto.
  • the culture temperature is slightly different depending on the conditions when culturing under each of the above conditions, but it is usually preferred to culture at 20 to 37° C., more preferably at 25° C., but is not limited thereto.
  • the present invention relates to an anti-inflammatory or anti-diabetic pharmaceutical composition
  • an anti-inflammatory or anti-diabetic pharmaceutical composition comprising one or more metabolites selected from the group consisting of the following Chemical Formulas 1 to 4:
  • R 1 to R 9 are each independently H, linear or branched C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 is aryl.
  • R 1 to R 9 may be each independently H, CH 3 or CH 2 CH 3 , but is not limited thereto.
  • the present invention relates to a food for improving inflammation or diabetes comprising one or more metabolites selected from the group consisting of the following Chemical Formulas 1 to 4:
  • R 1 to R 9 are each independently H, linear or branched C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 is aryl.
  • R 1 to R 9 may be each independently H, CH 3 or CH 2 CH 3 , but is not limited thereto.
  • the present invention relates to a method for preventing or treating an inflammatory disease or diabetes comprising administering the extract, the metabolite, or the pharmaceutical composition of the Penicillium glabrum SF-7123. .
  • the present invention relates to the use of the extract of Penicillium glabrum SF-7123 or the metabolite for anti-inflammatory or anti-diabetes.
  • the present invention relates to the use of the extract or the metabolite of Penicillium glabrum SF-7123 for the prevention or treatment of inflammatory diseases or diabetes.
  • the present invention relates to the use of the extract or the metabolite of Penicillium glabrum SF-7123 in the manufacture of a medicament for the treatment of inflammatory diseases or diabetes.
  • the present invention relates to the use of the extract or the metabolite of the Penicillium glabrum SF-7123 in the manufacture of a functional food for the prevention or improvement of inflammatory diseases or diabetes.
  • Optical rotation was recorded using a Jasco P-2000 digital polarimeter.
  • UV spectra were recorded on a Beckman DU 800 UV-Visible Spectrophotometer.
  • IR spectra were obtained on an Agilent Cary 630 FT-IR spectrometer.
  • NMR spectra (1D and 2D) were recorded in CD 3 OD or CDCl 3 using a JEOL JNM ECP-400 spectrometer (400 MHz for 1 H and 100 MHz for 13 C) and the corresponding residual solvent signal (CD 3 OD: d H 3.30/ d C 49.0 and CDCl 3 : d H 7.26/ d C 77.0) referenced chemical shifts.
  • HRESIMS data were obtained using an ESI Q-TOF MS/MS system (AB SCIEX Triple). TLC was performed on Kieselgel 60 F 254 (1.05715; Merck) or RP-18 F 254s (Merck) plates. The spots were visualized by spraying 10% H 2 SO 4 aqueous solution followed by heating. Column chromatography was performed on YMC octadecyl-functionalized silica gel (C 18 ).
  • Example 2 Strain Materials and Fermentation.
  • Penicillium glabrum SF-7123 (Accession No.: KCTC 14169BP) was isolated from sediments collected on January 10, 2015 using a dredge in the Ross Sea (N 77 ⁇ 34.397′ W 166 ⁇ 10.8653′). 1 g of sample was mixed with sterile seawater (10 mL). A portion (0.1 mL) of the sample was treated using the spread plate method in potato dextrose agar (PDA) medium containing sterile seawater. Plates were incubated at 25° C. for 14 days. After subculture of the isolates several times, the final pure culture was selected and stored at -70°C.
  • PDA potato dextrose agar
  • Fungal strain SF-7123 was identified based on analysis of the 28S ribosomal RNA (rRNA) gene sequence. GenBank search using the 28S rRNA gene of SF-7123 (GenBank accession number KY563089) revealed 100%, 99.64% and 97.13% sequence identity to Penicillium glabrum (JN938946), P. spinulosum (HM469405) and P. multicolor (HM469407), respectively. shown as the closest match representing . Therefore, the marine-derived fungal strain SF-7123 was identified as Penicillium glabrum.
  • rRNA ribosomal RNA
  • Example 3 Extraction and isolation of compounds 1-4.
  • Fungal strain SF-7123 was cultured in 10 Fernbach flasks (300 mL) each containing 300 mL of PDA medium containing 3% NaCl (w/v). Flasks were individually inoculated with 2 mL of seed cultures of fungal strains and incubated at 25° C. for 14 days. The combined culture medium was extracted with EtOAc (4 L). The combined extraction solution was filtered through filter paper and then evaporated to dryness to obtain a crude extract SF7123 (1.0 g).
  • the SF7123-4 fraction was first separated with compound 3 (2.5 mg), followed by two SF7123-4-1 and SF7123 using Sephadex LH-20 as stationary phase and a 3/1 (v/v) mixture of MeOH in water as mobile phase.
  • the -4-2 sub-fraction was subjected to column chromatography (3 x 35 cm).
  • the SF7123-4-2 sub-fraction was then chromatographed on a RP C 18 column (1.2 x 30 cm) eluting with MeOH in water [2/3 (v/v)] to give 3 sub-fractions.
  • the SF7123-5 fraction was subjected to column chromatography packed with Sephadex LH-20 (2.0 x 30 cm). The column was then eluted with a mixture of MeOH in H 2 O [3/1 (v/v)] to separate into three subfractions SF7123-5-1 to SF7123-5-3.
  • Example 4 Determination of structures of compounds 1 to 4.
  • R 1 is CH 3
  • Table 1 Precise analysis of the COZY and HMBC spectra of Compound 1 in which R 1 is CH 3 (Table 1) is actually a derivative of nuchromenin in which a hydroxyl group is substituted with a methoxy group attached to C-9, in which R 1 is CH 3
  • R 1 is CH 3
  • Table 1 The planar structure of This assignment was confirmed by observation of the HMBC correlation from 9-OCH 3 to C-9.
  • R 1 is CH 3 structure of the compound 1 was determined as shown in formula 1 R 1 is CH 3, 9- O based on the above-described proof-methyl New chroman menin (9- O -methylneuchromenin) with Named.
  • the NMR data of Compound 1 in which R 1 is H was almost identical to the NMR data of Compound 1 in which R 1 is CH 3 and having a pyranchromene skeleton belonging to a citromycetin analog.
  • a scrutiny of 1 H and 13 C NMR data for compound 1 in which R 1 is H in the literature eventually led to the assignment of its structure as neuchromenin, which was found in Eupenicillium javanicum var. It was isolated from the culture medium of meloforme PF1181. It has been reported that neuchromenin can induce neurite outgrowth in PC12 rat pheochromocytoma cells (Tanada, Y.; Mori, K. European J. Org. Chem . 2001 , 2001 , 1963.).
  • the absolute configuration of naturally occurring neuchromenin was determined to be S by synthetic studies of the enantiomer of neuchromenin (Hayakawa, Y., et al., Tetrahedron Lett . 1996 , 37). , 6363-6364.). NMR data and specific rotation values of compound 1 in which R 1 is H and the literature (Tanada, Y.; Mori, K. European J. Org. Chem . 2001 , 2001 , 1963.) and the close similarity of specific rotation values suggested that the absolute configuration of compound 1 in which R 1 is H should be the same as that of (-)-neuchromenin. Therefore, it was suggested that the absolute configuration of compound 1 where R 1 is CH 3 is similar to the absolute configuration of compound 1 where R 1 is H, since they were isolated from chemical investigations on the same fungal strain.
  • diphenyl ether was isolated, which was identified as asteric acid ( compound 2 in which R 2 to R 4 is each independently CH 3 ) known as an endothelin binding inhibitor (Liao, WY, et al., J. Nat. Prod . 2012 , 75 , 630-635.; Ohashi, H., et al., Antibiot (Tokyo) . 1992 , 45 , 1684-1685.).
  • Example 5 Effect of secondary metabolites isolated from SF-7123 on the production of pro-inflammatory mediators.
  • LPS lipopolysaccharide
  • neurochromenin is formed by a methoxyl group (Compound 1 in which R 1 is CH 3) It was found that replacement of the hydroxyl group at the C-9 position of (neuchromenin, compound 1 in which R 1 is H) significantly reduced this effect.
  • the most active compound in this assay was identified as Compound 1 in which R 1 is H, and further studies were conducted to determine the additional anti-inflammatory effect of this compound and its underlying mechanism. As shown in FIG.
  • Example 6 PTP1B inhibitory effect of isolated compounds 1 to 4.
  • p-nitrophenyl phosphate was used as an enzyme substrate to evaluate the effect of the compound on PTP1B activity.
  • ursolic acid a known phosphatase inhibitor
  • ursolic acid a known phosphatase inhibitor
  • Example 7 Cell culture and viability assay.
  • RAW264.7 and BV2 cells were treated with Dulbecco's Fertilized Eagle supplemented with 10% fetal bovine serum (FBS), penicillin G (100 U/mL), streptomycin (100 mg/L) and L-glutamine (2 mM). It was maintained at 5 ⁇ 10 5 cells/mL in a medium (Dulbecco's modified eagle's medium, DMEM), and incubated at 37° C. in a humidified atmosphere containing 5% CO 2 . DMEM, FBS and other tissue culture reagents were purchased from Gibco BRL Co. Cell viability was determined using the previously described MTT assay (Cho, KH, et al., Neurochem. Int . 2016. 95. 55-62.).
  • Example 8 nitrite crystals.
  • Example 9 Preparation of cytoplasmic and nuclear fractions.
  • Cytoplasmic and nuclear fractions were extracted using an Affymetrix Nuclear Extraction kit (Affymetrix, Inc. Santa Clara, CA). Dissolution of each fraction was performed according to the manufacturer's instructions. Details of the assay are described in a previous report (Cho, KH, et al., Neurochem. Int . 2016. 95. 55-62.).
  • Example 10 Western blot analysis.
  • Example 11 DNA binding activity of NF- ⁇ B.
  • DNA-binding activity of NF- ⁇ B in nuclear extracts was measured using the TransAM® kit (Active Motif, Carlsbad, CA) according to the manufacturer's instructions. Analyzes were performed independently in triplicate.
  • the level of PGE 2 present in each sample was measured using a commercially available kit from R&D Systems (Minneapolis, Minn.). Three independent analyzes were performed according to the manufacturer's instructions.
  • Example 13 Quantitative real-time reverse transcriptase PCR (qRT-PCR).
  • PTP1B human, recombinant
  • Enzyme activity was measured in a reaction mixture containing 2 mM p-nitrophenyl phosphate (pNPP) in 50 mM citrate, pH 6.0 (composition: 0.1 M NaCl, 1 mM EDTA and 1 mM dithiothreitol [DTT]).
  • the reaction mixture was placed in an incubator maintained at 30° C. for 30 minutes, and 1N NaOH was added to terminate the reaction.
  • the amount of p-nitrophenol produced was estimated by measuring the increase in absorbance at 405 nm.
  • Non-enzymatic hydrolysis of 2 mM pNPP was corrected by measuring the increase in absorbance at 405 nm in the absence of PTP1B enzyme (Hamaguchi, T., et al., FEBS Lett . 1995 , 372 , 54-58.).
  • reaction mixtures consisted of different concentrations of pNPP as PTP1B substrate in the presence or absence of compounds 3 and 5, and the analysis was performed as described above.
  • Michaelis-Menten constant (Km) and maximum velocity (Vmax) of PTP1B were determined by Lineweaver-Burk plot using GraphPad Prism® 4 program (GraphPad Software Inc., USA).
  • a composition comprising a metabolite of the marine-derived fungus Penicillium glabrum SF-7123 is produced in LPS-stimulated RAW264.7 macrophages and BV2 microglia cells with NO, prostaglandin E 2 (PGE 2 ), the production of pro-inflammatory mediators such as inducible nitric oxide enzyme (iNOS) and cyclooxygenase-2 (COX-2) and inhibits the expression of PTP1B, thus preventing inflammatory diseases or diabetes or It can be usefully used for therapeutic purposes.
  • PGE 2 prostaglandin E 2
  • iNOS inducible nitric oxide enzyme
  • COX-2 cyclooxygenase-2

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Abstract

La présente invention concerne : une composition anti-inflammatoire ou antidiabétique comprenant un métabolite du champignon d'origine marine Penicillium glabrum SF-7123 ; un aliment destiné à atténuer l'inflammation ou le diabète ; ainsi qu'un procédé de séparation de ce métabolite. La composition selon l'invention comprend un métabolite du champignon d'origine marine Penicillium glabrum SF-7123 destiné, selon la présente invention, à inhiber la production d'un médiateur pro-inflammatoire, tel que NO, la prostaglandine E2(PGE2), l'oxyde nitrique synthase inductible (iNOS) et la cyclooxygénase-2 (COX-2), et l'expression de PTP1B, et pouvant donc être utile dans la prévention ou le traitement des maladies inflammatoires ou du diabète.
PCT/KR2021/005622 2020-05-07 2021-05-04 Composition anti-inflammatoire ou antidiabétique comprenant un métabolite du champignon d'origine marine penicillium glabrum sf-7123 WO2021225363A1 (fr)

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