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WO1999031127A1 - Cyclopeptolides - Google Patents

Cyclopeptolides Download PDF

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Publication number
WO1999031127A1
WO1999031127A1 PCT/JP1998/005716 JP9805716W WO9931127A1 WO 1999031127 A1 WO1999031127 A1 WO 1999031127A1 JP 9805716 W JP9805716 W JP 9805716W WO 9931127 A1 WO9931127 A1 WO 9931127A1
Authority
WO
WIPO (PCT)
Prior art keywords
substance
group
val
antifungal
chc
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/JP1998/005716
Other languages
English (en)
Japanese (ja)
Inventor
Kenichi Kaida
Toshiyuki Kameyama
Ryosuke Fudou
Toshihiko Andou
Makoto Ojika
Youji Sakagami
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.)
Ajinomoto Co Inc
Original Assignee
Ajinomoto Co Inc
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 Ajinomoto Co Inc filed Critical Ajinomoto Co Inc
Priority to AU16835/99A priority Critical patent/AU1683599A/en
Publication of WO1999031127A1 publication Critical patent/WO1999031127A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • 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
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • 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
    • A01N63/50—Isolated enzymes; Isolated proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel cyclic peptide and an antifungal containing the peptide as an active ingredient.
  • bacteriosis has been easily and effectively treated with the use of a number of chemotherapeutic agents, mainly antibiotics.
  • chemotherapeutic agents mainly antibiotics.
  • due to the use of these chemotherapeutic agents deep mycosis due to infection with soybeans, yeasts, and other fungi has been taken up as a problem.
  • the present inventors have improved the fungi and improved the piles j J) to ') -filtrate, and selected antibiotics having antifungal activity to obtain antifungal agents.
  • Microorganisms were searched extensively from the field and succeeded in obtaining microorganisms suitable for this purpose. These microorganisms were filamentous fungi belonging to Clavaryopsis. The antibiotic produced by this microorganism was separated and its structure was determined. As a result, it was found to be a cyclic deb-peptide.
  • the present invention has been made based on these findings, and the cyclic depsibeptide of the present invention has the following amino acid sequence.
  • Cyclic depsipeptide FA-l cyclo (-2-hydroxy isovaleryl- Hpr-MeVa Val-MeAsp-Me 11 e-Me 11 eG 1 y-MeVal ⁇ Tyr (OMe)-), or cyclic depsipeptide FA15- 2: cyclo (-2-hydroxvisovaleryl-Hpr-Val-Val-MeAsp-MeI le- eI le-Gly- eVal- Tyr (OMe) -) c is be shown as follows the annular Depushi peptide by structure
  • FIG. 1 is UV absorption scan Bae spectrum diagram of the cyclic depsipeptide FA15-1
  • FIG. 2 IR absorption scan Bae-vector diagram
  • FIG. 3 is 1 H- NMR spectrum view
  • Fig. 4 13 FIG. 3 is a C-NMR spectrum diagram.
  • Fig. 5 shows the UV absorption spectrum of cyclic depsipeptide FA15-2
  • Fig. 6 shows I.
  • FIG. 7 is a 1 H-NMR spectrum diagram
  • FIG. 8 is a 13 C-NMR spectrum diagram.
  • Microorganisms producing the cyclic debpeptides FA15-1 and FA15-2 of the present invention include Clavariopsis aquatica AJ 117363. Strain (FERM BP-6594). AJ 117363 strain was isolated as follows. The fallen leaves in a mountain stream collected at Takaoyama, Hachioji, Tokyo were soaked in water.
  • the colony surface is light gray fluff, and the back surface is greenish black. No leaching of dye or formation of oil droplets in the medium is observed.
  • the growth on the malt extract agar medium is slow, and the diameter of the colony is 19 mm in 25 :, 14 days.
  • the colony surface is gray fluffy, and the back surface is greenish black. No leaching of dye or formation of oil droplets in the medium was observed.
  • the conidia obtained by immersing the cultured cells in water are It is a tetrapot type consisting of two cells, a main shaft and three accessory branches.
  • the main axis is in the center with one septum, club-shaped, and the size is (30-40) X (10-) ⁇ m.
  • the three appendages are radial near the tip of the main shaft, are thin thread-like, and lack a septum-the size is (50-70) X (1.5-2.5) ⁇ .
  • H is 3-10.
  • this fungus was used in accordance with the Mycobacterium Illustrative Guidebook (1978, Kodansha (Japan), Shunichi Udagawa, Keisuke Tsubaki, et al., 6 authors), incomplete mycoplasma, incomplete filamentous fungi, and Clavaryopsis.
  • the strain was identified as belonging to Aquatica (Clavariopsis aquatica), and this strain was named Clavariopsis aquatica AJ 117363 strain.
  • Bacteria producing such novel antibiotics F A15-1 and F A15-2 can be cultivated using a general method for culturing filamentous fungi.
  • a medium obtained by solidifying a food material such as oatmeal or the like, adding an additive solution to the solid layer, and sterilizing by high pressure steam can be used.
  • Substance FA - 1 and substance FA 15-2-producing bacteria it is most desirable to culture at 10 e C ⁇ 30 as possible out culturing ° C shall force particularly 20 ⁇ 25 C.
  • Culture period is usually 14 days ⁇ 21 days; can be appropriately changed depending on the culture conditions.
  • the substance FA15_1 and the substance FA12 produced by the culture accumulate in the culture.
  • a solvent extraction method using an organic solvent such as acetone or methanol an adsorption column chromatography using a silica gel or the like, a reverse phase partitioning force chromatography using an octadodecylated ( () US) silica gel as a carrier, and a column chromatography. Then, it is isolated and purified by a combination of means for purifying C.
  • the C ⁇ H group of MeAsp of FA15-1 and FA15-2 can be easily modified, and alkyl ester group, aryl ester group, aralkyl ester group, alkyl amide group, aryl It can lead to mono- and aralkyl amide groups.
  • alkyl group include an alkyl group having 1 to 12 carbon atoms, which may be linear or branched or cyclic. Further, it may contain 1 to 3 hetero atoms in the chain or the ring.
  • Examples of the alkyl group include a methyl group, an ethyl group, an isopropyl group, a tertiary butyl group, a cyclohexyl group, a methoxymethyl group, and an ethoxycarbonyloxy-2-ethyl group.
  • Examples of the aryl group include an aryl group having 1 to 12 carbon atoms, which may have a substituent. Further, it may contain 1 to 3 hetero atoms in the chain or the ring.
  • Examples of the aryl group include a phenyl group, a methoxyphenyl group, a nitrophenyl group, a naphthyl group, a 'pyridyl group and a quinolyl group.
  • the aralkyl group includes an aralkyl group having 1 to 12 carbon atoms, and the ring may have a substituent. Also, the chain or the substituent may contain 1-3 heteroatoms. Examples of the aralkyl group include a benzyl group, a methoxybenzyl group, a naphthylmethyl group, and a pyridylmethyl group.
  • Alkyl ester groups and aryl ester groups can be introduced by dissolving FA-1 and FA15-2 in solvents such as acetonitrile, chloroform, dimethylformamide, dimethylsulfoxide, and dioxane, and then dissolving them in thionyl chloride and oxychloride. It can be carried out by deriving an acid halide with phosphorus or the like and then subjecting it to dehydration condensation with an alcohol in the presence of an alcohol catalyst or an acid catalyst.Also, it can be reacted with an alkyl halide or aryl halide in the presence of a base. Often, in the case of the methyl ester, it is easily obtained by reacting with diazomethane or its equivalent.
  • Alkyl amides and aryl amides can be introduced by dissolving FA 15-1 and DO 15-2 in solvents such as acetonitrile, chlorophonolem, dimethinoleformamide, dimethylsulfoxide, and dioxane, and then adding thionyl chloride and phosphorus oxychloride.
  • the reaction can be carried out by leading to an acid halide by the method described above, and then reacting with the amine using a condensing agent such as dicyclohexyl carbamide or the like, a reaction force with the corresponding amine.
  • a condensing agent such as dicyclohexyl carbamide or the like
  • N-hydroxysuccinimide ⁇ N-hydroxybenzotriazole or the like may coexist and the active ester form may be used.
  • an excess amine may be used to condense by heating, and once an appropriate ester form is formed, it may be reacted with an amine to perform an ester-amide
  • the modified product thus obtained can be purified by ordinary purification means such as column chromatography, thin-layer chromatography, crystallization and the like.
  • An example of a method for purifying the substance FA-11 is as follows. (4) An equal amount of acetone was added to the iWiW and 'H materials and extracted. After extraction, the extract obtained by centrifugation was concentrated using a rotary evaporator to obtain an aqueous extract solution. The aqueous extract solution was extracted with ethyl acetate. This ethyl acetate layer was concentrated to dryness with a rotary-evaporator. This concentrated and dried product was dissolved in a small amount of a solution containing 5% of mouth mouth 95 ° / ⁇ methanol 5%, and subjected to silylation gel chromatography equilibrated with the same solvent to elute.
  • the antibacterial activity against Aspergillus niger was concentrated, and the solution was concentrated on reversed phase partition force column chromatography (C18), washed with a 60% aqueous solution of acetonitrile, and eluted with an 80% aqueous solution of acetonitrile.
  • the eluate was concentrated and subjected to high performance liquid chromatography (condition column, Shiseido's CAPSELL PAK C18 UG 120 10 X 250 mm developing solvent 85% acetonitrile, 0.1 /. TFA aqueous solution, flow rate 2.5 ml / min, 18- (Elution for 20 minutes) to obtain substance FA15-1.
  • An example of a purification method for the substance FA15-2 is as follows.
  • This fraction was dissolved in methanol and passed through a cartridge for ODS pretreatment (T0Y0PAK ODS M), and the adsorbed substance was eluted with chloroform-formanol. Separation of methanol-eluted fraction by high-performance liquid chromatography (Condition column, Shiseido's CAPSELL PAK C18 UG80 10 X 250 ⁇ Selution solvent ⁇ 0% methanol, 0.1% TFA- 100% methanol 0.1% TF ⁇ , 3 () min gradient, flow rate 2. ⁇ / ⁇ ⁇ ).
  • Substance F A15-1 has the following physicochemical properties.
  • the structure of this substance was analyzed.
  • the substance has the molecular formula C 59 H 95 N 9 from high-resolution mass spectrometry.
  • 1 4 has the (integer molecular weight 1153), the absorption of your Keru Ami de the IR spectrum (1681, 1648 cm-l), Ami de NH hydrogen and NCH3 hydrogen signals in 1 H NMR, 11 pieces in @ 13 C NMR Amide (or ester, carboxylic acid) was estimated to be a peptide compound from the carbonyl signal.
  • the plane structure is
  • the 2D NMR was determined by a detailed examination. That is, 10 amino acid residues (Tyr (or Tyr (OMe)) from COSY and H0HAHA, MeVal x 2, Gly, Melle x 2, MeAsp
  • Substance F A15-2 has the following physicochemical properties.
  • Solubility Soluble in chloroform, methanol, acetone, ethyl acetate, dimethyl sulfoxide, poorly soluble in water
  • the antifungal activity of substance FA15-1 was determined by the agar dilution method, and a small number of three substances F ⁇ ⁇ -1 were prepared. 25 ⁇ l of the mixture was mixed with 10 ml of the heated and dissolved sub-agar-agar medium and dispensed into a plate.c. The culture suspension of the test bacterium was spread on an agar plate containing this new antibiotic FA15-1. The cells were cultured at 25 nC for 2 to 4 days, and the growth inhibitory concentration was measured. (Rib: 25 ° C, 4 days, Yeast and bacteria: 25 ° C, 2 days) The results are shown in Table 1.
  • the antifungal activity of the substance FA15-2 was determined by the microdilution method. After dissolving the substance FA15-2 with a small amount of dimethylsulfoxide, an equal dilution series was prepared with dimethyls / rephoxide. 0.5% of RPMI was added to RPM I medium (manufactured by Nissui Pharmaceutical Co., Ltd. fh). In the RPMI medium, the suspension spore solution was added to a final spore concentration of 2 ⁇ 105 C FU / ml was added. The medium containing the diluted material and the spore solution was added to a 96-well microtiter plate in a 1-well volume. After culturing at 37 ° C for 24 hours, the minimum growth inhibitory concentration was visually determined after culturing. Table 2 shows the results.
  • the cyclic debpeptide of the present invention is excellent in antifungal activity and can provide an antifungal agent having a strong new antibacterial activity.
  • this cyclic depsipeptide can be produced by a usual microbial culture method, and since no special method is used for extraction and purification, industrial mass production is possible.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Environmental Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Dentistry (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Virology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne des cyclopeptolides, cyclo(-2-hydroxyisovaléryl-Hpr-MeVal-Val-MeAsp-MeIle-MeIle-Gly-MeVal-Tyr(OMe)-) et cyclo(-2-hydroxyisovaléryl-Hpr-Val-Val-6eAsp-MeIle-MeIle-Gly-MeVal-Tyr(OMe)-) obtenus à l'aide d'un moule du type Clavariopsis et présentant une puissante activité antifongique.
PCT/JP1998/005716 1997-12-18 1998-12-17 Cyclopeptolides Ceased WO1999031127A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16835/99A AU1683599A (en) 1997-12-18 1998-12-17 Cyclopeptolides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/348402 1997-12-18
JP34840297 1997-12-18

Publications (1)

Publication Number Publication Date
WO1999031127A1 true WO1999031127A1 (fr) 1999-06-24

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Application Number Title Priority Date Filing Date
PCT/JP1998/005716 Ceased WO1999031127A1 (fr) 1997-12-18 1998-12-17 Cyclopeptolides

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AU (1) AU1683599A (fr)
WO (1) WO1999031127A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02134399A (ja) * 1988-09-23 1990-05-23 Sandoz Ag ピペコリン酸含有ペプトリド類、それらの製法および医薬組成物
JPH08504165A (ja) * 1991-12-20 1996-05-07 ノボ ノルディスク アクティーゼルスカブ 特定の化合物の農業的使用、該化合物を含有する組成物および該化合物の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02134399A (ja) * 1988-09-23 1990-05-23 Sandoz Ag ピペコリン酸含有ペプトリド類、それらの製法および医薬組成物
JPH08504165A (ja) * 1991-12-20 1996-05-07 ノボ ノルディスク アクティーゼルスカブ 特定の化合物の農業的使用、該化合物を含有する組成物および該化合物の製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EMMER G. et al., "Derivatives of a Novel Cyclopeptolide. 1. Synthesis, Antifungal Activity and Structure-Activity Relationships", J. MED. CHEM., 1994, Vol. 37, No. 13, pp. 1908-1917. *

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AU1683599A (en) 1999-07-05

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