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WO1993014111A1 - Nouveau compose appele ustiloxine a ou b, ou son derive - Google Patents

Nouveau compose appele ustiloxine a ou b, ou son derive Download PDF

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Publication number
WO1993014111A1
WO1993014111A1 PCT/JP1993/000018 JP9300018W WO9314111A1 WO 1993014111 A1 WO1993014111 A1 WO 1993014111A1 JP 9300018 W JP9300018 W JP 9300018W WO 9314111 A1 WO9314111 A1 WO 9314111A1
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WO
WIPO (PCT)
Prior art keywords
ustyroxine
compound
salt
rice
hydrogen atom
Prior art date
Application number
PCT/JP1993/000018
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English (en)
Japanese (ja)
Inventor
Shigeo Iwasaki
Kuniko Koiso
Tomowo Kobayashi
Original Assignee
Sankyo Company, Limited
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 Sankyo Company, Limited filed Critical Sankyo Company, Limited
Publication of WO1993014111A1 publication Critical patent/WO1993014111A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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 compound having an antitumor effect, ustyroxin A or ustyroxin B, a derivative thereof, or a salt thereof (hereinafter, referred to as “us thyroxines”), and a method for producing them.
  • the rice koji disease fungus (Ustyraginoidea 'Virens Cooke') belongs to imperfect fungi, but a complete generation formed on the sclerotium has been observed, and Claviceps virens Sakurai and (Yadao Harada, Nissho Disease Report, Volume 3, p. 387 (1984)).
  • Ustilagino idinn A, B and C (Tadaharu Yabuta, Yusuke Sumiki, Journal of the Japanese Society of Agricultural Chemistry, Vol. 9, p. 47S (1933)) and Ustilaginoidin D, E, F, G, I1, I and J (K. Koama and S. Natori, Chem. Pharm. Bull., Vol. 36, p. 146, (1988)) are known.
  • these compounds and the ustyroxins of the present invention are clearly different in physicochemical properties and structure.
  • Examples of the 13-membered ring compound having one ether bond and two peptide bonds in ⁇ include Phomopsisin A (Phomopsin A) produced from Phomopsis leptostromiformis (CLAUDE CJ CULVENOR et al., Tetrahedron, Vol. 45, No. 8, p. 2351 (1989)) is known. However, the structure of the side chain is completely different from usthyroxines.
  • the present inventors have found that the novel compounds ustiloxin A and ⁇ styroxine B, which are novel compounds isolated from rice koji, which naturally occurred in rice ears or artificially generated in rice ears, caused a strong antitumor effect.
  • the present inventors have found that the inducer has a strong antitumor effect, and have completed the present invention.
  • the present invention General formula
  • R 1 is In addition hydrogen atom an alkyl group having 1 to 5 carbon atoms
  • R 2 is an aliphatic Ashiru group having 2 to 6 water ⁇ resonator or carbon atoms
  • R 3 is methyl group or propyl group
  • R 1 is a water atom or a alkyl group having 1 to 5 carbon atoms
  • R 2 is water, an atom or an aliphatic acyl group having 2 to 6 carbon atoms,
  • n R 3 is a methyl group or a pulp ⁇
  • R 1 is an alkyl group having 1 to 5 carbon atoms
  • examples thereof include straight-chain or branched-chain alkyl groups such as methyl, ethyl, propyl, butyl, t-butyl, and pentyl. It is preferably a linear or branched alkyl group having 1 to 3 carbon atoms, and most preferably a methyl group.
  • R 2 is an aliphatic acetyl group having 2 to 6 carbon atoms
  • examples thereof include a linear or branched aliphatic acetyl group such as acetyl, propionyl, butyryl, valeryl, and hexanoyl.
  • it is an aliphatic acetyl group having 2 to 4 carbon atoms in a direct sale form or a branched sale form, and most preferably an acetyl group.
  • the compound represented by the above general formula (I) of the present invention can be converted into a salt according to a conventional method.
  • R 1 is a hydrogen atom, for example, salts of alkali metals such as lithium, sodium, and potassium; salts of alkaline earth metals such as magnesium, calcium, and barium; methylamine, ethylamine, dimethylamine, and dipyramine And salts of aliphatic primary to tertiary amines such as trimethylamine; salts of amino acids such as lysine and arginine; and ammonium salts.
  • it is a salt of an alkaline metal such as sodium or potassium.
  • R 2 is a hydrogen atom
  • salts of hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid; nitrates; perchlorates; sulfates; Or an alkanesulfonic acid salt of a lower alkanesulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; a salt of an arylarylsulfonic acid such as benzenesulfonic acid or di-toluenesulfonic acid; glutamic acid or asparagine Organic acid salts such as salts of amino acids such as acids; salts of carboxylic acids such as fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, and maleic acid; Preferably, it is a hydrochloride.
  • the optimal one is a pharmacologically acceptable i. '
  • the compound having the above general formula (I) has ⁇ isomerism.
  • all of these isomers are represented by the formula 5- . Therefore, the present invention includes all of these isomers and mixtures of these isomers.
  • a so-called “prodrug compound” which is derived into a compound having the general formula (I) in vivo
  • R 1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms
  • R 2 represents a hydrogen atom or an aliphatic acyl group having 2 to 4 carbon atoms
  • R represents a methyl group or a propyl group
  • a compound or a salt thereof A compound or a salt thereof.
  • R 1 represents a hydrogen atom or a methyl group
  • R 2 represents a hydrogen atom or an acetyl group
  • R 3 represents a methyl group or a propyl group
  • a compound or a salt thereof A compound or a salt thereof.
  • the compound No. 1-2.6.7.10, 16 or a salt thereof the thyroxine belonging to the genus Ustyraginoidea or the thyroxine B 'production ability
  • rice cypress A which has the ability to produce ustyroxin A or usty sigma xin ⁇ belonging to the genus Styraginoidea, is available from Ustilaginoidea virens (Cooke) Takahashi SAN 15391 strain.
  • R 1 represents a hydrogen atom
  • R 2 represents a hydrogen atom
  • R 3 represents a methyl group
  • a compound ie, ustyroxin A
  • R 1 represents a hydrogen atom
  • R 2 represents a hydrogen atom
  • R 3 represents a propyl group
  • the rice koji (koji grain) generated in the rice spike due to the infection of the rice koji disease fungus (Ustilaginoidea virens Cooke) in the rice field is collected.
  • the koji grains can be picked up by hand from the 'spreading ears' in the piloerection, air-dried indoors for about one week, and pulverized with a mill.
  • those stored in a refrigerator at around 5 ° C can also be used.
  • an extract containing thyroxine A or usthyroxine B can be obtained. This can be achieved by isolating and purifying Usuloxin A or Ustiloxin B from the product: 2. Utilizing its physicochemical properties. For example, it can be removed using an adsorbent. Examples of the adsorbent used include activated carbon or adsorbent resin Amberlite XAI3-2, XAD-4, XAD-7, etc.
  • cellulose such as Avicel (Asahi Kasei Kogyo Co., Ltd.) or Sephadex LH-20 (manufactured by Pharmacia) is used.
  • Effective methods include column chromatography, extraction using the difference in the partition ratio of solvents mixed with usthyroxine A or b, and the counter-current partitioning method.
  • Ustiloxin A or usthyroxin B can be separated and purified by repeatedly using the above separation and purification means alone or in an appropriate combination.
  • the rice two to six weeks before heading can be inoculated from above with conidia or chlamydospores of SANK 15391 to generate rice koji.
  • the conidiospore suspension can be obtained by transplanting the mycelium pieces into an Erlenmeyer flask containing a potato decoction medium for adding sucrose, and performing liquid culture under dark conditions at 26 ° C. for 12 to 20 days.
  • a surfactant 20, such as Tween This suspension was added 0.05% equivalent amount, field of rice, a method of approximately IL / ra 2 sprayed and inoculated from the top of the body is preferred.
  • the time of spray inoculation is preferably around 19:00.
  • Chlamydospores can be obtained by the following method. If ⁇ ⁇ if] Using a potato decoction medium at step 26 26: ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ !!! ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ .
  • the chaos of the chlamydospores directly above the rice plant in the field can produce the koji.
  • the inoculation is preferably used a small dusting device, also, as the intake of 30 to 40 sheets per m 2 petri dish chlamydospores are preferred. ⁇
  • the inoculation time is preferably performed during the day.
  • test varieties There are no particular restrictions on the test varieties, but late-growing varieties such as No. 1 and Norin 21 are preferred.
  • Rice koji strain Ustilaginoidea virens (Cooke) Takahashi SAN K 15391 which makes rice koji can be isolated, stored and used as needed as follows. Immediately, spores (chlamydospores) are collected from rice panicles that show diseased and dark green symptoms, and are placed in a culture medium such as a potato-glu-use medium and cultured at 23 to 28 ° C for 1 to 2 days. . A part of this culture solution is taken, observed under a microscope, and spores that have begun to germinate are subjected to monospore separation using a manipulator.
  • a culture medium such as a potato-glu-use medium and cultured at 23 to 28 ° C for 1 to 2 days.
  • a suitable agar medium for example, potato dextrose agar medium, and cultured at 23 to 28 ° C, and the well-grown one is stored.
  • Growth on potato dextrose agar is slow, with initially white fluffy hyphae growing, but then dark greenish brown. It also produces a dark green soluble pigment in the medium.
  • the mycelium is colored and has partition walls. Its diameter is 2-0 to 5.0 ⁇ , the wall is very thick, dark green-brown, and often forms hyphal mass. Conidia occur in the symposiform type, and are 1 cell, colorless, 5.0-8.0 ⁇ 3.0-4.5 m. Chlamydospores found in rice koji are not observed.
  • R 1 represents an alkyl group
  • the compound is obtained as follows.
  • an esterification reaction with ustiloxin ⁇ or ustiloxin ⁇ and an alcohol such as methanol or ethanol with an acid.
  • the acid used in the reaction is not particularly limited.
  • mineral acids such as sulfuric acid, hydrochloric acid, chloric acid, and perchloric acid; and organic acids such as formic acid and trifluoroacetic acid are preferred.
  • the reaction temperature and reaction time vary depending on the reagents and solvents used, but are usually 0-100. C can be converted to another alkyl group by transesterification in 1 to 24 hours.
  • the target compound After completion of the reaction, the target compound is obtained by distilling off the solvent from the reaction mixture and drying the residue. If an acid is used in excess of usthyroxine A or usthyroxine B as the starting compound, the target compound is obtained as a salt of the acid.
  • the target compound thus obtained can be further purified by recrystallization or ordinary column chromatography.
  • the reaction can also be achieved by reacting with diazoal compounds such as diazome.
  • the reaction is performed in the presence of a solvent.
  • the solvent to be used is not particularly limited as long as it does not affect the reaction. Ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane; esters such as ethyl acetate; dimethylform Amides such as amides; sulfoxides such as dimethyl sulfoxide; are preferred.
  • the reaction temperature and the reaction time vary depending on the reagents, solvents and the like to be used.
  • reaction temperature and reaction time are ffl. Although different, usually 0 to 0 ° C ⁇ L to time is suitable.
  • the solvent of the target compound is distilled off from the reaction mixture, and water and an organic solvent such as nitrile acetate are added to the residue to carry out liquid separation. It is obtained by concentrating the organic layer and purifying the residue by recrystallization or ordinary column chromatography.
  • R 2 represents an aliphatic acyl group
  • the compound is obtained as follows.
  • acylating agent used in the reaction for example, acid anhydrides such as acetic anhydride and propionic anhydride; and acid halides such as acetyl chloride and acetyl bromide are preferable.
  • the reaction is suitably performed in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not affect the reaction. For example, water, alcohols such as methanol and ethanol, or a mixed solvent thereof are preferable.
  • the reaction is performed in the presence of a base.
  • Examples of the base used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate and hydrogen carbonate Metal bicarbonates such as potassium sulfide; aromatic amines such as pyridine; heterocyclic amines such as proline; aliphatic amines such as triethylamine and getylamine.
  • the reaction temperature varies depending on the type of the acylating agent, etc. Usually, 0 to 50 ° C is preferable.
  • the reaction time varies depending on the reaction conditions, but is usually 1 to 5 hours.
  • the target compound thus obtained may be subjected, if necessary, to adsorption column chromatography using a carrier such as silica gel or florisil; reverse-phase partition chromatography using silica gel having octadecyl or octyl groups; Distribution column chromatography using frullose or SEPHADE "NOX Lii-20 [manufactured by FULL MACIA CORPORATION] or the like; Use a difference in the distribution ratio of the pure substance to the solvent to make the purification process easier.
  • a carrier such as silica gel or florisil
  • reverse-phase partition chromatography using silica gel having octadecyl or octyl groups
  • the compound of the present invention having the general formula (I) can be obtained by appropriately combining the reactions of the above 1) to 3).
  • R 1 is a hydrogen atom
  • compounds in which R 1 is an alkyl compound such as sodium hydroxide, hydroxide hydroxide, and other alkali metal hydroxides; and sodium carbonate, potassium carbonate, and other alkali metals. It can also be obtained by hydrolyzing in the presence of a metal carbonate.
  • the compound having the above general formula (I) thus obtained is further exemplified by an adsorption column chromatograph using a carrier such as silica gel or Florisil, and Fadex LH-20 (manufactured by Pharmacia). It can be purified by partition column chromatography used, high-performance liquid chromatography using normal phase or reverse phase columns, and the like.
  • Rice ears caused by the infection of rice koji fungus (Ustilaginoidea virens Cooke) :; spikelets that were spontaneously generated were collected. After drying, 100 g of the rice koji were pulverized in a mixer with 10 times the volume of water, and extracted by shaking at room temperature for i hours. 100 () ml of the extract was filtered, concentrated to one tenth, and applied to a 50 ml iDODS column (ODS-T. Senshiyu Kagaku (Sekiyu)).
  • the mixture was developed and eluted with 0.5 liter of a mixture of methanol and water at a ratio of 2:98, and 200 ml of the eluted fraction between 200 and 400 ml was collected to obtain a fraction containing ustiloxin A.
  • crude crystals of about 20 nig were obtained. When this crude crystal is recrystallized with water, the melting point
  • the ultraviolet absorption spectrum measured in water is as follows.
  • the nuclear magnetic resonance spectrum (500 MHz) measured in heavy water at 50 ° C using tetramethylsilane as an external standard is as shown below.
  • Nuclear magnetic spectrum (00 MHz) measured in heavy water using tetra-ethylsilane as an external standard is as follows.
  • Adsorbent silica gel plate Art. 5715 (Merck)
  • Koji grains were generated in rice plants by artificial inoculation, and Soxin A was isolated from O and purified.
  • the seedlings sown on April 14 were transplanted to Honda on May 20.
  • the cultivation density was: i. 75 plants per 3 m 2 , i. Fertilizer: nitrogen (N) as the basal dressing, phosphate (P 2 0,) and using the per 10a 8 Kg potassium to (K 2 0) as the component amount, the nitrogen (N) as a top dressing on July 14 2 kg was applied per llhi. Other methods followed the customary law.
  • Rice koji disease SANK 15391 strain was cultured, and chlamydospores formed after standing were obtained by the following method.
  • the mycelial suspension obtained by liquid culture at 26 ° C for 7 days using a potato decoction medium for sucrose was poured onto a potato decoction agar medium for sucrose so that it spreads thinly.
  • the cells were cultured in the dark at 25 ° C.
  • the rice spores were generated by inoculating the chlamydospores directly on the rice plant in the field.
  • rice spikelets were generated when sprayed on rice ears growing in the field and left for a certain period of time (about 2 months).
  • These rice koji were collected and uthyroxine A was isolated and purified in the same manner as described in Example 1.
  • About 1 mg of the target compound was isolated from 10 g of rice koji.
  • Example 2 5 mg of usthyroxine A obtained in Example 1 was dissolved in 0.5 ml of methanol containing 12% hydrochloric acid and released overnight at 4 ° (: overnight. The solution was concentrated under reduced E; After distilling off the agent, the desired product-m.m3 ⁇ 4 was obtained.
  • the nuclear magnetic resonance spectrum (500 MHz) measured at 50 using tetramethylsilane as an external standard in deuterated dimethyl sulfoxide is as follows.
  • Koji grains were generated in rice by artificial inoculation, and ustyroxin B was isolated and purified from this.
  • the artificial inoculation was performed using the rice koji fungus SANK 15391 strain, and the inoculation was performed according to the method described in Example 2.
  • Ustyroxine B obtained in this example exhibited the following physical properties.
  • the infrared absorption spectrum measured with calcium fluoride (CaF) ⁇ film (film) is as follows.
  • Nuclear magnetic resonance spectra (500) measured in 5 () using 2,2-dimethyl-2-shiventan-5-sulfonic acid sodium (DSS) as an external standard in heavy water. MHz) is as shown below.
  • the nuclear magnetic resonance spectrum (100 ⁇ ⁇ ) measured in heavy water using DSS as the external standard is as follows.
  • Rf cruise: D.14 Adsorbent-Shiri gel plate 5715
  • Ustyroxine ⁇ and ustyroxine ⁇ of the present invention and their induction have an antitumor effect.
  • the compound having the s-general formula (I) is a novel compound which has not been described in the literature, and has a strong growth inhibitory effect on various human cancer cells.
  • E The compound having the general formula (r) is used as a medicament as a medicament, in a funeral hall, or in accordance with a conventional method, by itself or an appropriate pharmaceutically acceptable carrier, excipient, or diluent. They can be mixed and safely administered orally or parenterally in the form of powders, condyles, tablets, capsules, injections and the like.
  • the dose varies depending on the target disease, the administration route and the number of administrations. For example, the effective daily dose for adults is 1

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Nouveau composé appelé ustiloxine A ou B, répondant à la formule générale (I) et présentant une puissante activité antitumorale, ses dérivés et ses sels. Dans ladite formule, R1 représente hydrogène ou alkyle C¿1-5; R?2 représente hydrogène ou acyle aliphatique C¿2-6?; et R?3¿ représente méthyle ou propyle.
PCT/JP1993/000018 1992-01-08 1993-01-08 Nouveau compose appele ustiloxine a ou b, ou son derive WO1993014111A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4/1139 1992-01-08
JP113992 1992-01-08

Publications (1)

Publication Number Publication Date
WO1993014111A1 true WO1993014111A1 (fr) 1993-07-22

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PCT/JP1993/000018 WO1993014111A1 (fr) 1992-01-08 1993-01-08 Nouveau compose appele ustiloxine a ou b, ou son derive

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103760353A (zh) * 2014-02-08 2014-04-30 中国农业大学 检测稻曲菌素a的方法及其专用酶联免疫试剂盒
CN106279359A (zh) * 2016-08-11 2017-01-04 中国水稻研究所 一种制备五种稻曲病菌毒素的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL AND ORGANISM, Vol. 30, No. 8, p. 491-492, 1992. *
TETRAHEDRON LETTERS, Vol. 33, No. 29, p. 4157-4160, 1992. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103760353A (zh) * 2014-02-08 2014-04-30 中国农业大学 检测稻曲菌素a的方法及其专用酶联免疫试剂盒
CN106279359A (zh) * 2016-08-11 2017-01-04 中国水稻研究所 一种制备五种稻曲病菌毒素的方法

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