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WO2007148412A1 - Nouvelle substance fki-3389 et son procédé de fabrication - Google Patents

Nouvelle substance fki-3389 et son procédé de fabrication Download PDF

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Publication number
WO2007148412A1
WO2007148412A1 PCT/JP2006/312946 JP2006312946W WO2007148412A1 WO 2007148412 A1 WO2007148412 A1 WO 2007148412A1 JP 2006312946 W JP2006312946 W JP 2006312946W WO 2007148412 A1 WO2007148412 A1 WO 2007148412A1
Authority
WO
WIPO (PCT)
Prior art keywords
substance
culture
fki
producing
medium
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/JP2006/312946
Other languages
English (en)
Japanese (ja)
Inventor
Satoshi Omura
Kazuro Shiomi
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/JP2006/312946 priority Critical patent/WO2007148412A1/fr
Publication of WO2007148412A1 publication Critical patent/WO2007148412A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
    • C12P17/162—Heterorings having oxygen atoms as the only ring heteroatoms, e.g. Lasalocid
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/30—Microbial fungi; Substances produced thereby or obtained therefrom
    • A01N63/36—Penicillium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/80—Penicillium

Definitions

  • the present invention relates to a novel FK 1-3 3 8 9 substance effective as a pharmaceutical, an animal drug, and an agrochemical and a method for producing the same because it has NADH-reductase inhibitory activity.
  • Parasitic diseases have decreased due to improvements in the hygienic environment and advances in anthelmintic drugs.
  • imported parasitic diseases, zoonotic parasitic diseases, opportunistic parasitic diseases, parasitic diseases derived from ginger foods This has become a problem again.
  • parasitic diseases also bring great economic burden.
  • many compounds are currently used for worm infections, such as ivermectin, mebendazol, and praziquantel.
  • the present inventors focused on NADH-fumarate reductase in the electron transport system, which is one of the promising targets of anti-helminths, and searched for inhibitors of this enzyme from microbial cultures.
  • FT— 0 5 5 4 Nafredin was found (W 09 9/24 4 3 9.
  • the novel compound FK 1-3 3 8 9 produced by the filamentous fungus FK 1-3 3 8 9 has NAD H -fumarate reductase inhibitory activity.
  • the present invention has been completed based on this finding. That is, the present invention has the following formula:
  • the present invention further belongs to a filamentous fungus, and has the following formula:
  • the microorganism having the ability to produce the FK 1-3389 substance represented by the medium is cultured in the medium, and the FK 1-3389 substance is accumulated in the culture, and the FK 1-3338 substance is collected from the culture. It provides a process for the production of the novel FK 1-3389 features.
  • the present invention further relates to a microorganism belonging to a filamentous fungus and capable of producing FK I-3389 substance, Penicillium sp. (Penici 1 1 i um sp,) FKI-3389 (NI TE ABP— 244) is provided according to claim 2.
  • the present invention also provides Penicillium SP (Penici 11 ium sp.) FK I-3389 (N I TE ABP-244).
  • the FK I-3389 substance-producing bacterium is not particularly limited as long as it is a filamentous fungus and has the ability to produce the FK I-3389 substance.
  • the filamentous fungus FK 1-3389 newly isolated from the soil by the present inventors can be mentioned.
  • the bacteriological properties of this strain are as follows:
  • This strain grows well on lapec yeast extract agar, 25% glycerin 'nitrate agar, wort agar, potato, carrot agar, Miura agar, etc. Was good.
  • Table 1 shows the results of macroscopic observation when this strain was cultured on various agar media at 25 ° C for 7 days.
  • Raised state slightly raised centrally pale yellowish green
  • Raised protuberance Central raised yellow
  • Raised state Slightly raised centrally Green Grayish green None Peripheral part: All edges Surrounding
  • the optimal growth conditions for this strain are pH 4-7, temperature 26-35 ° C.
  • the growth range of this strain is pH 2-8, temperature 13-38 ° C
  • Penicillium 'SP FK I-3389 Penici 1 1 i urn s p. FK I-3389
  • Kisarazu Kazusa
  • Kamasa Chima
  • a microorganism having the ability to produce the FK I-3389 substance that kills filamentous fungi is cultured in a medium, and the culture is performed. Separation and purification from products.
  • the strains that can be used in the present invention include the above-mentioned strains and mutants thereof, and all of the FK1-3389 substance-producing bacteria belonging to the filamentous fungi.
  • Nutrient sources suitable for the production of the above FK 1-3389 substance may be those that can be used as nutrient sources for filamentous fungi.
  • nutrient sources for filamentous fungi for example, commercially available peptone, meat extract, corn steep liquor, cottonseed powder, peanut powder, soy flour, yeast extract, NZ-amine, casein hydrate, sodium nitrate, ammonium nitrate, ammonium sulfate, etc.
  • trace amounts of metal salts, vegetation, planting, mineral oil, etc. can be added as antifoaming agents. These can be used as long as they are used by the producing bacteria and are useful for the production of the FK 1-3389 substance, and all known filamentous fungal culture materials can be used.
  • Mass culture of FK I-3389 substance can be carried out in solid culture or liquid culture, and the culture temperature can be applied within the range where FK I-3389 substance can be produced. Culturing can be carried out by selecting as appropriate according to the properties of the FK 1-3389 substance-producing bacteria using the conditions described above.
  • the FK I-3389 substance can be extracted from the culture medium with a water-immiscible organic solvent such as chloroform or ethyl acetate.
  • a water-immiscible organic solvent such as chloroform or ethyl acetate.
  • known methods used for collecting fat-soluble substances such as adsorption chromatography, gel filtration chromatography, scraping from thin layer chromatography, centrifugal countercurrent distribution chromatography, high performance liquid chromatography It can be collected purely by combining or repeating the first class as appropriate.
  • the physicochemical properties of the FK 1-3389 substance of the present invention are as follows.
  • FK I-3 3 8 9 substance is expressed by the following formula.
  • the chemical structure was determined. .
  • FK I _ 3 3 8 9 As described above, the various physicochemical properties of FK I _ 3 3 8 9 were described in detail. No compound matching this property has been reported so far, and it was determined that this FK I-3 389 substance is a novel substance.
  • the NAD H-reductase inhibitory activity of the substance FK 1-3389 of the present invention is as follows.
  • Hog roundworm muscle was homogenized in 1 2 OmM sodium phosphate solution (pH 7.0) and centrifuged at 3000 xg for 10 minutes, and the supernatant was collected. collected. The precipitate was suspended in 1 2 OmM sodium phosphate solution (pH 7.0) to obtain 0 T of mitcon. 9
  • Add 20% 50% dimethyl sulfoxide solution of this substance to 6-well mic plate and add 0.35 mM NADH, 7.2 mM disodium fumarate 1 20 mM sodium phosphate solution (PH 7.0) 80/1 was added, and pre-incubation was performed at 37 ° C for 3 minutes using a microplate reader ELX808 (Bio-Tek Industries).
  • FKI-3389 substance inhibited NADH-fumarate reductase activity by 50% at a concentration of 2.4 nM. Therefore, it is expected that FK I-3389 substance can be used as a composition for treating or preventing helminth infections.
  • FIG. 1 is an ultraviolet absorption spectrum of a methanol solution (10 gZml) of the FK 1-3389 substance of the present invention.
  • Fig. 2 shows the best mode for carrying out the invention in the infrared absorption spectrum (KBr tablet) of the substance FK 1-3389 of the present invention.
  • Benicillium sp. FK I-3389 strain (NITE ABP-244) cultured on an agar slant medium, glucose 2.0%, polypeptone (Nippon Pharmaceutical Co., Ltd., Japan) 0.5%, yeast extract (Oriental Yeast Co., Ltd.) Japan) 0.2%, agar 0.1%, potassium dihydrogen phosphate 0.1%, magnesium sulfate heptahydrate 0.05% liquid medium (p FT6.0.0) is 1 0 Om 1 A 500-ml triangular flask was inoculated with 1 platinum loop and incubated at 2'7 ° C for 2 days.
  • microorganisms belonging to filamentous fungi and capable of producing FK I-3389 substance are cultured in a medium, and FK 1-3389 substance is accumulated in the culture, and FK 1-3389 is accumulated from the culture.
  • the FK1-3389 substance of the present invention obtained and obtained by isolating the substance inhibits NAD H-reductase activity of NAD H-fumarate and is used as a composition for treating or preventing helminth infections. From getting medicine ⁇ P, expected to be an effective substance for animal medicine and pesticides ⁇

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Mycology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Environmental Sciences (AREA)
  • Dentistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Plant Pathology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Botany (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne une substance FKI-3389 qui est produite en cultivant un micro-organisme (NITE ABP-244), qui est une bactérie filamenteuse et qui possède une aptitude à produire la substance FKI-3389, dans un milieu, en accumulant la substance FKI-3389 dans la culture et en isolant la substance FKI-3389 à partir de la culture. Comme la substance FKI-3389 de l'invention ainsi obtenue inhibe une activité du système NADH/fumarate réductase, elle peut être utilisée en tant que composition pour traiter et prévenir une infection helminthique, par conséquent, on s'attend à ce qu'elle soit une substance efficace en tant que produit pharmaceutique, médicament pour animaux ou produit chimique agricole.
PCT/JP2006/312946 2006-06-22 2006-06-22 Nouvelle substance fki-3389 et son procédé de fabrication Ceased WO2007148412A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2006/312946 WO2007148412A1 (fr) 2006-06-22 2006-06-22 Nouvelle substance fki-3389 et son procédé de fabrication

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2006/312946 WO2007148412A1 (fr) 2006-06-22 2006-06-22 Nouvelle substance fki-3389 et son procédé de fabrication

Publications (1)

Publication Number Publication Date
WO2007148412A1 true WO2007148412A1 (fr) 2007-12-27

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ID=38833164

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PCT/JP2006/312946 Ceased WO2007148412A1 (fr) 2006-06-22 2006-06-22 Nouvelle substance fki-3389 et son procédé de fabrication

Country Status (1)

Country Link
WO (1) WO2007148412A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3490095B2 (ja) * 1996-11-08 2004-01-26 タカラバイオ株式会社 抗生物質ｔｋｒ２６４８及びその製造方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3490095B2 (ja) * 1996-11-08 2004-01-26 タカラバイオ株式会社 抗生物質ｔｋｒ２６４８及びその製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TORRES M. ET AL.: "Bactericidal and fungicidal activity of Aspergillus ochraceus metabolites and some derivatives", PESTICIDE SCIENCE, vol. 53, no. 1, 1998, pages 9 - 14, XP003019912 *

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