WO2003048373A1 - Nouvelle substance fki-0550 et son procede de production - Google Patents

Nouvelle substance fki-0550 et son procede de production Download PDF

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Publication number
WO2003048373A1
WO2003048373A1 PCT/JP2001/010578 JP0110578W WO03048373A1 WO 2003048373 A1 WO2003048373 A1 WO 2003048373A1 JP 0110578 W JP0110578 W JP 0110578W WO 03048373 A1 WO03048373 A1 WO 03048373A1
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WO
WIPO (PCT)
Prior art keywords
substance
novel
fki
growth
producing
Prior art date
Application number
PCT/JP2001/010578
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English (en)
Japanese (ja)
Inventor
Satoshi Omura
Kazuro Shiomi
Rokuro Masuma
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The 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 The Kitasato Institute filed Critical The Kitasato Institute
Priority to AU2002222576A priority Critical patent/AU2002222576A1/en
Priority to PCT/JP2001/010578 priority patent/WO2003048373A1/fr
Publication of WO2003048373A1 publication Critical patent/WO2003048373A1/fr

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    • 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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines
    • 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
    • A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
    • A01N33/02—Amines; Quaternary ammonium compounds
    • A01N33/08—Amines; Quaternary ammonium compounds containing oxygen or sulfur
    • 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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton

Definitions

  • the present invention relates to a substance having NADH-fumarate reductase inhibitory activity, which is effective for pharmaceuticals, veterinary drugs, and agricultural chemicals.
  • Parasitic diseases have been decreasing due to improvements in the sanitary environment and advances in anthelmintic drugs.In recent years, imported parasitic diseases, zoonotic parasitic diseases, opportunistic parasitic diseases, and parasites derived from fresh foods Diseases have become more prominent, and a wide variety of parasitic diseases have become a problem. Parasitic diseases also pose a significant economic burden in livestock and agriculture. Among helminth infections among parasites, many compounds are currently used, such as ivermectin, mebendazole and praziquantel.
  • anti-helminthic agents such as ivermectin, mebendazole and braziquantel are not satisfactory in terms of their efficacy and toxicity, and new drugs are required.
  • the present inventors have identified NAs in the electron transport chain, one of the promising targets for antihelminthic agents. Focusing on DH-fumarate reductase, we continued to search for inhibitors of this enzyme in microbial cultures. As a result, we found FT-0554 substance (nafresin) and filed an international application (international publication). The number WO 9 9 244 3 9). This international application was transferred to the United States and was assigned No. 09/5099770 as the application number.
  • the microorganism capable of producing the FT-104 substance (naphrezin) is Aspergillus niger FT-0554 belonging to a filamentous fungus, and this strain is disclosed by the Ministry of International Trade and Industry.
  • the outline of the mycological properties of this strain is as follows. Regarding the culture characteristics on various agar media, the growth on the Gapec® yeast extract agar medium, the wort agar medium, the Gapec® yeast extract agar medium containing 20% sucrose, the bailesho's glucose agar medium, and the Miura agar medium Good, velvety and smooth peripheral.
  • the colony diameter is between 40 mm and 85 mm.
  • the color tone of the colony surface is black-brown, and the color tone of the back of the colony is light yellow and white.
  • Morphological characteristics are as follows: Wapec containing 50% seawater (salinity: 3.4%) • Yeast extract agar medium, wort agar medium, and Wapek bisect extract agar containing 20% sucrose It grew well on media such as potato and glucose agar, and conidia abundantly formed.
  • optimal growth conditions are pH 5-7, temperature 16-36 ° C, seawater concentration 50-100%.
  • the growth range is pH 3 ⁇ 10, temperature is 12 ⁇ 45 ° C, seawater concentration is 0 ⁇ 100%. Disclosure of the invention
  • the present inventors have continued to search from the culture of microorganisms, and found that the FK 1-550 substance of the novel compound produced by the filamentous fungus strain FK 1-550 was NAD H-Fuma.
  • the present inventors have found that they have an activity of inhibiting lactate reductase, and have completed the present invention based on this finding.
  • the present invention provides a substance having NADH-fumarate reductase inhibitory activity and which is satisfactory as a pharmaceutical, animal drug, or agricultural chemical having satisfactory efficacy, toxicity, etc. It is intended to do so.
  • the present invention provides a novel FK 1-550 compound which is a compound represented by the formula: and the novel FK I-550 compound has a growth inhibitory activity against microorganisms, nematodes, and arthropods, respectively. It has.
  • a further object of the present invention is to provide a method for producing a novel FK1-0550 substance having NADH-reductase fumarate inhibitory activity.
  • a microorganism having the ability to produce the FK 1-550 substance represented by the following formula is cultured in a medium, the FK 1-550 substance is accumulated in the culture, and the FK 1-55 is obtained from the culture. It provides a manufacturing method for collecting 50 substances.
  • the present invention relates to a method wherein the microorganism having the ability to produce FK 1-055 substance is a Paeci 1 omy cess p.
  • FKI-0555 (FERM BP-777) belonging to a filamentous fungus. 5)
  • FKI is a substance made from 0550 It provides a manufacturing method.
  • the present invention provides a microorganism itself which belongs to a filamentous fungus and has an ability to produce an FKI-550 substance. Further, the present invention provides Paecci mouth essp. FKI-050 (FERM BP-7785) as a microorganism.
  • An object of the present invention is to provide a NAD H-fumarate reductase inhibitor comprising an FK 1-550 substance represented by OH.
  • the microorganism having the ability to produce the novel FK 1-550 substance represented by the above formula (hereinafter referred to as "FKI-550 substance-producing bacterium") is a filamentous fungus.
  • the invention is not particularly limited as long as it has the ability to produce FKI-550 substance.
  • Preferred examples of the strain used for producing the FK 1-550 substance of the present invention include, for example, the filamentous fungus FK 1 newly isolated by the present inventors from the soil of Okigami prefecture. -0550 shares.
  • the bacteriological properties of this strain are as follows.
  • This strain grew relatively well on yeast extract ⁇ solvable starch agar, wort agar, corn'meal agar, potato glucose agar, Miura agar, and the like. Conidia formation was good on yeast extract / sol brustarch agar, wort agar, cornmeal agar, potato • glucose agar, and slightly inhibited on Miura agar. Microscopic observation of colonies grown on corn-meal agar medium reveals that the hyphae are transparent and have septum, and the conidiophores stand upright from the basal hyphae and may branch irregularly. Its length is 30-400 x 4.5-5.5 m, sometimes reaching 800 m. The tip branches into three to six rings.
  • the surface is smooth, but may be rough. Two to four fiaraids grow from the tip of the conidiophore.
  • the phialid (6.5-11.0 X 1.8-3.5 / m) has a bulging base and a sharply tapered neck at the tip.
  • Conidia are elliptical to spindle-to-lemon in size, 2.5-4.0 X 2.0-3.0 m, and are divergently linked.
  • Table 1 shows the results of macroscopic observations when this strain was cultured at 25 ° C for 14 days on various agar media.
  • Optimal growth conditions for this strain are pH 4-7, temperature 16-31 ° C.
  • the growth range of this strain is pH 3 ⁇ 10, temperature 9 ⁇ 35 ° C.
  • an FKI 0550 substance-producing bacterium belonging to a filamentous fungus may be cultured in a medium, and then separated and purified from the culture.
  • the strains that can be used in the present invention all the FK1-0550 substance-producing bacteria belonging to the filamentous fungi, including the above-mentioned strains and mutants thereof, can be used.
  • any nutrient source that can be used as a nutrient source for filamentous fungi may be used.
  • peptone commercially available peptone, meat extract, corn-steep. Spain, cottonseed flour, peanut flour, soybean flour, yeast extract, NZ-amine, casein hydrate, sodium nitrate, ammonium nitrate, sulfuric acid
  • nitrogen sources such as ammonium
  • carbohydrates such as glycerin, starch, glucose, galactose and mannose
  • carbon sources such as fat
  • inorganic salts such as salt, phosphate, calcium carbonate, magnesium sulfate and the like, alone or in combination it can.
  • trace amounts of metal salts and animal / vegetable / mineral oils can be added as antifoaming agents. Any of these can be used as long as they are useful for the production of FK 1-0550 substance by using the producing bacteria, and any known culture materials of filamentous fungi can be used.
  • liquid culture is preferable, and the culture temperature can be applied within a range in which the producing bacteria can grow and produce the FKI-0550 substance. The cultivation can be carried out by appropriately selecting according to the properties of the FK 1-0550 substance-producing bacterium using the conditions described above.
  • the FKI-550 substance can be extracted from the culture solution with a water-immiscible organic solvent such as black form and ethyl acetate.
  • a water-immiscible organic solvent such as black form and 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, and high-performance liquid chromatography
  • Infrared absorption spectrum measured by the bromide power tablet method is 3350, 3286, 2924, 2852, 1574, 164. has an absorption maximum in a 1 3 7 7, 1 0 8 0 cm 1,
  • the various physicochemical properties of the FK 1-0550 substance of the present invention have been described in detail.However, no compound matching such properties has been reported so far, and the FKI-0550 substance is considered to be a novel substance. Were determined. Next, the NADH-fumarate reductase inhibitory activity of the FK 1-0550 substance of the present invention will be described in detail.
  • the precipitate was collected by centrifugation at 0 xg for 20 minutes.
  • the precipitate was suspended in a 12 OmM sodium phosphate solution (pH 7.0) to obtain a mitochondrial fraction.
  • 96 Add 10 l of a 50% dimethylsulfoxide solution of the FK1-0550 substance to a 6-well microplate, then add 0.35 mM NADH, 7.2 mM sodium fumarate, 18 mg Zm1 bovine serum Add 1 20 mM sodium phosphate solution (pH 7.0) 801 containing albumin and add it to a microplate reader.
  • the FKI-0550 substance can be used as a composition for treating or preventing helminth infection.
  • Table 3 shows the minimum growth inhibitory concentrations (based on the agar plate dilution method) of the FK 1-550 substance of the present invention for various microorganisms on a nutrient agar medium.
  • the FK1-0550 substance of the present invention has growth inhibitory activity against several microorganisms. showed that. Next, the anti-nematode and anti-arthropod activities of the FK 1-0550 substance of the present invention will be described in detail below.
  • a methanol solution of the substance FK 1-0550 of the present invention was added to a 96-well plate (manufactured by Corning Incorporated, U.S.A.), and methanol was distilled off under a vacuum pump. Then, a medium for assay (lecithin 0.01%, Sodium bicarbonate (7.5 mM), potassium chloride (7.5 mM), calcium chloride dihydrate (7.5 mM), magnesium sulfate heptahydrate (7.5 mM), 250 z1 were added, and the mixture was shaken for 15 minutes.
  • a medium for assay lecithin 0.01%, Sodium bicarbonate (7.5 mM), potassium chloride (7.5 mM), calcium chloride dihydrate (7.5 mM), magnesium sulfate heptahydrate (7.5 mM), 250 z1 were added, and the mixture was shaken for 15 minutes.
  • agar medium for nematode growth [Pactogar (Difco, USA) 1.7 Nectopeptone (Difco, USA) 0.5%, Yeast extract (Difco, USA) 1.0%, 0.3% sodium chloride, 0.0005% cholesterol, 0.0007% calcium chloride, 0.03% magnesium sulfate, 0.34% potassium hydrogen phosphate, 0.11% dipotassium hydrogen phosphate Escherichia coli grown on a medium]
  • Arthropod A rt hatched in 50 1 of a buffer solution containing several larvae of Emiasa 1 ina was added.
  • the FK 1-0550 substance of the present invention is Best mode for carrying out the invention that is effective as an insecticide or insecticide
  • a liquid medium pH 5.7
  • cultivator No. 100 [(trade name) made by Yaizu Suisan Chemical Co., Ltd., Japan] 100 ml of liquid medium (pH 6.0) consisting of 0.2% and agar 0.1% 100 ml of 500 ml Erlenmeyer flasks dispensed at a time were inoculated in an amount of 1 ml each, and cultured at 27 ° C. for 9 days with shaking.
  • the culture was centrifuged, and the resulting cells were extracted with methanol, concentrated under reduced pressure to remove the solvent, and further extracted with ethyl acetate and concentrated under reduced pressure to obtain 46 lmg of crude substance I. .
  • This was placed on a silica gel column (Merck Art. 7734, Merck, USA) packed with black-mouthed form, washed with black-mouthed methanol (10: 1), and then washed with black-mouthed methanol (1: 1). The mixture was eluted in 1) and concentrated under reduced pressure to obtain 12 Omg of crude substance II.
  • a microorganism having the ability to produce a FK 1-550 substance belonging to a filamentous fungus is cultured in a medium, and the FK 1-550 substance is accumulated in the culture.
  • the FKI-550 substance obtained by isolating the present FK 1-550 substance from microorganisms has a growth inhibitory activity against microorganisms, nematodes and arthropods, It is expected to be an effective substance for animal and pesticides.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Engineering & Computer Science (AREA)
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  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biotechnology (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Dentistry (AREA)
  • Environmental Sciences (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne un micro-organisme capable de produire une substance FKI-0050 représentée par la formule suivante (I). On cultive ledit micro-organisme dans un milieu et, puis, on en recueille la substance FKI-0050 ainsi accumulée dans le milieu de culture. En raison de son activité d'inhibition sur la croissance de micro-organismes, les nématodes et les arthropodes, on utilise la substance FKI-0050 ainsi obtenue en tant qu'agent antihelminthique ou insecticide.
PCT/JP2001/010578 2001-12-04 2001-12-04 Nouvelle substance fki-0550 et son procede de production WO2003048373A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2002222576A AU2002222576A1 (en) 2001-12-04 2001-12-04 Novel substance fki-0550 and process for producing the same
PCT/JP2001/010578 WO2003048373A1 (fr) 2001-12-04 2001-12-04 Nouvelle substance fki-0550 et son procede de production

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2001/010578 WO2003048373A1 (fr) 2001-12-04 2001-12-04 Nouvelle substance fki-0550 et son procede de production

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999041266A1 (fr) * 1998-02-12 1999-08-19 Emory University Derives de sphingolipides et procedes d'utilisation
EP1033370A1 (fr) * 1997-11-11 2000-09-06 The Kitasato Institute Nouvelle substance ft-0554 et procede de fabrication

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1033370A1 (fr) * 1997-11-11 2000-09-06 The Kitasato Institute Nouvelle substance ft-0554 et procede de fabrication
WO1999041266A1 (fr) * 1998-02-12 1999-08-19 Emory University Derives de sphingolipides et procedes d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HORN W.S. ET AL.: "Sphingofungins E and F: novel serinepalmitoyl transferase inhibitors from paecilomyces variotii", J. ANTIBIOT., vol. 45, no. 10, 1992, pages 1692 - 1696, XP002909014 *

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