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WO2006048947A1 - Inhibiteur d'expansion de macrophage fki-1840 et procede de production dudit inhibiteur - Google Patents

Inhibiteur d'expansion de macrophage fki-1840 et procede de production dudit inhibiteur Download PDF

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Publication number
WO2006048947A1
WO2006048947A1 PCT/JP2004/016615 JP2004016615W WO2006048947A1 WO 2006048947 A1 WO2006048947 A1 WO 2006048947A1 JP 2004016615 W JP2004016615 W JP 2004016615W WO 2006048947 A1 WO2006048947 A1 WO 2006048947A1
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WO
WIPO (PCT)
Prior art keywords
substance
fki
culture
houma
producing
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.)
Ceased
Application number
PCT/JP2004/016615
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English (en)
Japanese (ja)
Inventor
Satoshi Omura
Hiroshi Tomoda
Rokuro Masuma
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.)
Kitasato Institute
Original Assignee
Kitasato Institute
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kitasato Institute filed Critical Kitasato Institute
Priority to PCT/JP2004/016615 priority Critical patent/WO2006048947A1/fr
Publication of WO2006048947A1 publication Critical patent/WO2006048947A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • 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
    • C12P17/10—Nitrogen as only ring hetero atom
    • 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
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the present invention provides a macrophage foam inhibitory substance FK I-1 840 (or FK 1-1840 substance which is useful for the prevention and treatment of arteriosclerosis and various diseases caused by it by specifically inhibiting macrophage foaming. And its manufacturing method.
  • FK I-1 840 or FK 1-1840 substance which is useful for the prevention and treatment of arteriosclerosis and various diseases caused by it by specifically inhibiting macrophage foaming. And its manufacturing method.
  • sutintin drugs such as Prabus Yuchin (Sankyo Co., Japan), Symbus Yuchin (Manyu Pharmaceutical Co., Japan) and Atguchi Bus Yuchin (Yamanouchi Pharmaceutical Co., Ltd.) , Japan, etc., but these drugs all inhibit cholesterol in the blood by inhibiting HMG—COA reductase, which is one of the rate-limiting enzymes of cholesterol biosynthesis in the body. This is due to the effect of lowering the value.
  • HMG—COA reductase which is one of the rate-limiting enzymes of cholesterol biosynthesis in the body. This is due to the effect of lowering the value.
  • arteriosclerosis is a complex and complex cause, and development of drugs with different mechanisms of action is strongly desired.
  • LDL low-density lipoprotein
  • the object of the present invention is to provide a novel macrophage foam inhibitory substance FK 1-1840 that can satisfy such expectations and a method for producing the same.
  • Another object of the present invention is a macrophage foam inhibitory substance FK 1 which is useful as a prophylactic or therapeutic agent for arteriosclerosis, myocardial infarction, cerebral overflow and stroke, which contains the macrophage foam inhibitor FK 1-1840 as an active ingredient.
  • FK 1 macrophage foam inhibitory substance
  • Still another object of the present invention is a microorganism belonging to the genus Houma, which has the ability to produce FK I-1 840 substance, such as Houma SP FK I-1 840 (Phoma s p. FK I-1 840, FERM ABP- 1 0 1 50) or a mutant thereof, which provides a method for producing macrophage foaming inhibitor FK 1-1840
  • FK I-1 840 substance such as Houma SP FK I-1 840 (Phoma s p. FK I-1 840, FERM ABP- 1 0 1 50) or a mutant thereof, which provides a method for producing macrophage foaming inhibitor FK 1-1840
  • Still another object of the present invention is to produce a macrophage foaming inhibitor FK I-1 840, Houma SP FK 1-1 840 (Phoma s p. FK I-1 840, FERM ABP— 1 0 1 50) Is to provide.
  • the present inventors conducted a search for a macrophage foaming inhibitor for a metabolite produced by a microorganism, and as a result, newly obtained FKI-1 840 strain isolated from soil It was found that a substance having an activity of inhibiting macrophage foaming was produced in the culture.
  • the present invention has been completed based on this finding, and has the following formula:
  • the present invention further provides macrophage foaming useful as a prophylactic or therapeutic drug for atherosclerosis, myocardial infarction, cerebral overflow and stroke, etc., comprising the macrophage foaming inhibitor FK 1-1840 as represented by the above formula as an active ingredient Inhibitor FKI — 1 8 4 0
  • a microorganism belonging to the genus Houma and having the ability to produce the FK1-1840 substance represented by the above formula is cultured in a medium, and the FKI-1840 substance is accumulated in the culture.
  • the present invention also relates to a method for producing a macrophage foaming inhibitor FK 1-1840 which collects FK 1-1840 from the culture.
  • the present invention further relates to a microorganism belonging to the genus Houma and having the ability to produce the FK 1-1 840 substance represented by the above formula, such as Houma SP FK I-1 840 (Phomas sp. FK I-1 840, FERM ABP— 1 0 1 50) or a variant thereof Macrophage foaming inhibitor FK I-1840
  • the present invention also provides that the microorganism belonging to the genus Houma is Houma SP FKI.
  • FK 1-1 840 (Phoma s p. FK I— 1 840, FERM AB P-1 0 1 50).
  • the Phoma s p. FK I-1840 strain newly isolated by the present inventors from the fallen leaves of Okinawa Prefecture is an example of the strain most effectively used in the present invention.
  • the bacteriological properties of the strain are as follows.
  • Conidia and fruit consist of dark brown, thin reticulated mycelial tissue, spherical to subspherical, size 150-300 ⁇ m, formed from semi-buried in the medium.
  • the conidia and fruit had 1 to 4 holes.
  • Conidia are formed in the Faro form from the innermost cell of the conidia.
  • the conidia are viscous, elliptical to oblong or oval, with a size of 4.0 to 6.5 X 2.3 to 3.0 m.
  • the conidia With conidia fruit maturation, the conidia are secreted from the ostium, and the conidia mass is light pink.
  • the optimum growth conditions for this strain are pH 3.0 to 10 and temperature 6.0 to 34.0 ° C.
  • the growth range of this strain is pH 5.0 to 6.0, temperature 14.0 to 32.0 ° C.
  • this strain belongs to the genus Phoma. It was identified as a strain belonging to it and named Houma SP FK I-1840. This strain is Homa FSP I-1 840 (Phoma s p. FK I-1840), based on the Budapest Treaty on the International Approval of Deposit of Microorganisms in Patent Procedures.
  • Preferred examples of the FK 1-1840 substance-producing bacterium used in the present invention include the aforementioned Phoma sp. FK I-1 840 strain.
  • the nature of the is very variable and is not constant, but naturally or commonly used UV radiation or mutant derivatives such as N-methyl-N'-nitro-N-nitrosguanidine, ethylmethanesulfone. It is a well-known fact that it can be mutated by means of artificial mutagenesis, and such artificial mutant strains as well as natural mutant strains belong to the genus Houma and are represented by the above formula. Any strain capable of producing I-1840 substance can be used in the present invention.
  • FK I-1840 substance-producing bacteria belonging to the genus Houma are cultured in a medium.
  • Nutrient sources suitable for producing the FK 1-1840 substance of the present invention include a carbon source that can be assimilated by microorganisms, a nitrogen source that can be digested, and a nutrient medium containing inorganic salts, vitamins, etc. as necessary. used.
  • Carbon sources include glucose, fructose and maltose Saccharides such as lactose, galactose, dextrin, starch, and vegetable oils such as soybean oil are used alone or in combination.
  • Nitrogen sources include peptone, yeast extract, meat extract, soy flour, cottonseed flour, corn steep liquor, malt extract, casein, amino acid, urea, ammonium salts, nitrates, etc. It is done. Others As required Phosphate, magnesium salt, calcium salt, sodium salt, potassium salt, etc. Heavy iron salt such as iron salt, manganese salt, copper salt, cobalt salt, zinc salt, vitamins, etc.FK 1 -1 8 4 0 Add suitable for production of substances.
  • the medium may be liquid or solid as long as it contains the above-mentioned nutrient sources. Usually, it is better to use a liquid medium for culture. In the case of small-scale production, culture using a flask is preferable. .
  • the composition of the medium used for the preculture and the medium used for the production culture may be the same, or may be changed if necessary.
  • the culture temperature can be appropriately changed within the range in which this FKI-1 8 40 substance-producing bacterium produces this FK 1-1840 substance, but is usually 20 to 30 ° C, preferably 2 Incubate at around 7 ° C.
  • the culture pH is usually 5 to 5 and preferably about 6.
  • the culture time varies depending on the culture conditions, but is usually about 4-6 days.
  • the FK 1-1840 substances accumulated in the culture thus obtained are usually present in the cultured cells.
  • Collect target FK 1-1 8 4 0 substances from cultured cells Extract the whole culture with a water-miscible organic solvent such as acetone, distill the extract with an organic solvent under reduced pressure, and then extract the residue with a water-immiscible organic solvent such as ethyl acetate. Is done by.
  • Infrared absorption scan Bae spectrum measured by Nioikaryoku Riumu tablet method has ma X 1 767, 1 71 8 , 1 685, 1 460, 1 3 92, characteristic absorption maximum at 1 240 cm- 1,
  • Proton and carbon nuclear magnetic resonance spectra The chemical shift of hydrogen (ppm) and the chemical shift of carbon (P Pm) measured with a Varian 400 MHz nuclear magnetic resonance spectrometer in heavy-duty form are as shown below. . ⁇ : 0.73 (3 ⁇ ) 0, • 77 (1H), 0.86 (3H) 0.88 9 (3
  • ⁇ c 1 1. 1, 1 2. 3, 1 4. 2, 2 1 • 8, 22. 2, 2 3. 2, 25.
  • FIG. 1 shows the ultraviolet absorption spectrum (in methanol solution) of the FK 1-1840 substance according to the present invention.
  • Fig. 2 shows the infrared absorption spectrum (potassium bromide method) of the FK 1-1840 substance according to the present invention.
  • FIG. 3 shows the proton nuclear magnetic resonance spectrum (in heavy-cloned form) of the FK 1-1840 substance according to the present invention.
  • Fig. 4 shows the carbon nuclear magnetic resonance spectrum of FK 1-1840 (according to the present invention) (in heavy chloroform).
  • Agar slope culture medium (glycerol 0.1% (Kanto Chemical Co., Japan)), KH 2 P 0 4 0. 0 8% (Kanto Chemical Co., Japan), K 2 HP 0 4 0. 0 2% (Kanto Chemical) , Japan), MgS0 4 '7H 2 0 0. 0 2% (Wako Pure Chemical Industries, Japan), KC 1 0.0 2% (Kanto Chemical Co., Japan), NaN0 3 0.2% ( Wako Pure Chemicals, Japan), Houma SP FK cultured in yeast extract 0.02% (Oriental Yeast Co., Japan), Agar 1.5 (Shimizu Foods Co., Japan), adjusted to pH 6.0) 1 — 1840 strain (Phoma s p.
  • FK I— 1 8 4 0, FERM ABP-1 0 1 5 0 was added to seed medium (glucose 2% (Wako Pure Chemicals, Japan), polypeptone 0. ( Wako pure Chemical Industries, Japan), MgS0 4 ⁇ 7H 2 00. 0% ( Wako pure Chemical Co., Japan), yeast extract 0.2% (Oriental yeast Co., Japan), KH 2 P 0 4 0 .
  • production medium glycerol 3.0% (Kanto Chemical Co., Japan), oatmeal 2.0% (Nippon Food Manufacturing Co., Japan), dry yeast 1.0% (Asahi Kasei Co., Japan) , KH 2 PO4 1.% (Kanto Chemical Co., Japan), Na 2 HPO4 1.0% (Kanto Chemical Co., Japan), MgCl 2 6H 2 ⁇ 0.5% (Kanto Chemical Co., Japan)
  • Macrophages isolated from mouse abdominal cavity were suspended in Dulbecco's modified Eagle's medium (6.8% LPDS—DMEM medium) containing 6.8% lipoprotein-deficient serum at 2.0 x 1 0 5 eel 1 s / m 1 0.25ml in a 48-well microplate (Cornig, USA).
  • Dulbecco's modified Eagle's medium (6.8% LPDS—DMEM medium) containing 6.8% lipoprotein-deficient serum at 2.0 x 1 0 5 eel 1 s / m 1 0.25ml in a 48-well microplate (Cornig, USA).
  • a microorganism belonging to the genus Houma having the ability to produce FK 1-1 840 substance of the present invention is cultured in a medium, FK 1-1840 substance is accumulated in the culture, and FK 1— collected from the culture is collected.
  • 1 840 substance is expected to be useful as a preventive and therapeutic agent for arteriosclerosis and diseases caused by it because it has an inhibitory activity against macrophage foaming.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Botany (AREA)
  • Mycology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Biomedical Technology (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne un inhibiteur d'expansion de macrophage FKI-1840, et un procédé de production dudit inhibiteur. Ce procédé consiste à incuber un microbe appartenant au gène Phoma qui peut produire la substance FKI-1840 (Phoma sp. FKI-1840, FERMABP-10150) dans un milieu de culture ; à accumuler la substance FKI-1840 dans la culture et à recueillir la substance FKI-1840 à partir de ladite culture. La substance FKI-1840 ainsi obtenue présente une activité inhibitrice de l'expansion de macrophage, de façon à être utilisée en tant que médicament pour la prévention ou de traitement de l'athérosclérose ou de maladies associées, de l'infarctus du myocarde, de l'apoplexie cérébrale et de l'AVC.
PCT/JP2004/016615 2004-11-02 2004-11-02 Inhibiteur d'expansion de macrophage fki-1840 et procede de production dudit inhibiteur Ceased WO2006048947A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2004/016615 WO2006048947A1 (fr) 2004-11-02 2004-11-02 Inhibiteur d'expansion de macrophage fki-1840 et procede de production dudit inhibiteur

Applications Claiming Priority (1)

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PCT/JP2004/016615 WO2006048947A1 (fr) 2004-11-02 2004-11-02 Inhibiteur d'expansion de macrophage fki-1840 et procede de production dudit inhibiteur

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104749314A (zh) * 2015-04-13 2015-07-01 山东省花生研究所 一种酵母中甘油三酯的薄层层析检测方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11279195A (ja) * 1998-03-30 1999-10-12 Kitasato Gakuen 新規ｆｏ−６９７９物質およびその製造法
JP2002275194A (ja) * 2001-03-21 2002-09-25 Kitasato Gakuen 新規ｆｏ−６９７９−ｍ０物質、ｆｏ−６９７９−ｍ１物質、ｆｏ−６９７９−ｍ２物質、ｆｏ−６９７９−ｍ３物質及びｆｏ−６９７９−ｍ４物質並びにそれらの製造法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11279195A (ja) * 1998-03-30 1999-10-12 Kitasato Gakuen 新規ｆｏ−６９７９物質およびその製造法
JP2002275194A (ja) * 2001-03-21 2002-09-25 Kitasato Gakuen 新規ｆｏ−６９７９−ｍ０物質、ｆｏ−６９７９−ｍ１物質、ｆｏ−６９７９−ｍ２物質、ｆｏ−６９７９−ｍ３物質及びｆｏ−６９７９−ｍ４物質並びにそれらの製造法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NAMATAME K. ET AL.: "Shijokin no Seisan suru Macrophage Homatsuka Sogaizai Beauveriolide-rui ni Kansuru Kenkyu", DAI 44 KAI SYMPOSIUM ON THE CHEMISTRY OF NATURAL PRODUTS, SYMPOSIUM PAPERS, HEISEI 14 NEN 9 GATSU 1 NICHI, pages 181 - 186, XP003006172 *
TONOMURA Y. ET AL.: "Kujiratake Shijittai Yurai no Macrophage Homatsuka Sogai Busshitsu", JAPAN SOCIETY FOR BIOSCIENCE, BIOTECHNOLOGY, AND AGROCHEMISTRY 2003 NENDO (HEISEI 15 NENDO) TAIKAI KOEN YOSHISHU, 2003, pages 270, 3E02P15, XP003006171 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104749314A (zh) * 2015-04-13 2015-07-01 山东省花生研究所 一种酵母中甘油三酯的薄层层析检测方法

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