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WO2002027010A1 - Compose a base de xanthone - Google Patents

Compose a base de xanthone Download PDF

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Publication number
WO2002027010A1
WO2002027010A1 PCT/JP2001/008566 JP0108566W WO0227010A1 WO 2002027010 A1 WO2002027010 A1 WO 2002027010A1 JP 0108566 W JP0108566 W JP 0108566W WO 0227010 A1 WO0227010 A1 WO 0227010A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
cells
wss2138
culture
chloroform
Prior art date
Application number
PCT/JP2001/008566
Other languages
English (en)
Japanese (ja)
Inventor
Yuichi Terui
Zeng Xiang Chen
Tsutomu Ando
Yi Wen Chu
Akira Kawashima
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Sichuan Industrial Institute Of Antibiotics Of China National Pharmaceutical Groupe
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 Taisho Pharmaceutical Co., Ltd., Sichuan Industrial Institute Of Antibiotics Of China National Pharmaceutical Groupe filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU2001292303A priority Critical patent/AU2001292303A1/en
Priority to JP2002530773A priority patent/JPWO2002027010A1/ja
Publication of WO2002027010A1 publication Critical patent/WO2002027010A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin

Definitions

  • the present invention relates to a novel xanthone compound having an antitumor effect.
  • An object of the present invention is to provide a novel xanthone compound having an antitumor effect. Disclosure of the invention
  • the present inventors have isolated a large number of strains from soil and plants, and conducted various studies on metabolites of the strains.As a result, the present inventors have found that certain strains produce novel xanthones having strong antitumor activity. I found it. Furthermore, the present inventors have chemically modified this novel substance, found a derivative thereof that has maintained a strong antitumor effect, and have completed the present invention.
  • the present invention provides a compound represented by the formula (I):
  • R 1 and R 2 are each a hydrogen or a methyl group, and ⁇ is a compound represented by the following formula ( ⁇ ) or formula (IV)
  • the strain producing the compound of the formula (I) (hereinafter referred to as WSS2138) is a strain newly isolated from the natural world by the present inventors, and the name of the microorganism is rstreptomyces sp. National Institute of Advanced Industrial Science and Technology Patent Organism Depositary Center (IP0D)
  • the underlying hyphae are well-developed and irregularly branched, but no division is observed.
  • Sporulation The aerial hyphae are poorly formed, and the spore chain is usually a loop with a tip of 1-3 turns or a dense spiral (10-20 spores).
  • the spores are 0.6 to 0.7 urn in width, Si 0 to 0.5 m in length, cylindrical in shape, and smooth in surface. No sporulation is observed in the agar medium. Neither the formation of sporangia sclerotium nor the spore motility is observed.
  • B. Cultural properties
  • Table 1 shows the results of macroscopic observations when the cells were cultured at 28 ° C for 14 days on various media.
  • the c-color display refers to the system color name of the Japan Standards Association, JIS Color Name Book (1985).
  • Production of WSS2138 is carried out by culturing TA-0410 in a medium containing various nutrients under aerobic conditions in accordance with the production of general fermentation products.
  • the medium is mainly a liquid medium and consists of a carbon source, a nitrogen source, and inorganic salts. If necessary, vitamins, precursors and antifoaming agents can be added, and the pH is adjusted to around 7.
  • a carbon source for example, glucose, sucrose, dextrin, glycerin, starch or the like is used alone or in combination.
  • the nitrogen source for example, meat excise, oatmeal, yeast extract, soy flour, polypeptone, corn steve liquor, urea, ammonium salt, etc. are used alone or in combination.
  • an inorganic salt For example, monopotassium phosphate, magnesium sulfate, sodium chloride, calcium carbonate, or the like is used alone or in combination.
  • Adekinol or a silicon compound can be used.
  • Aerobic culture such as shaking culture and aeration and stirring culture is suitable for the culture method, and the pH is 4 to 10 and 25 to 35. Incubate at C for 2-5 days, preferably at pH 6-8, 25-28 for 4 days.
  • the WSS2138 produced by this culture can be isolated according to a general method for collecting fermentation products.
  • the following method is effective. That is, after completion of the culture, a culture filtrate is obtained by centrifugation or filtration, adsorbed on a polystyrene resin such as Diaion HP-20 (trade name, manufactured by Mitsubishi Chemical Corporation), and then an organic solvent such as a lower alcohol or acetone. To elute. The cells are extracted with an organic solvent such as lower alcohol or acetone.
  • the bacterial cell extract and the eluate from the adsorption resin are combined and concentrated under reduced pressure to remove the organic solvent, and then transferred to a non-water-soluble organic solvent such as ethyl acetate, black form, and n-butanol. This is concentrated to a syrup.
  • This sample is dissolved again in an organic solvent such as benzene, ethyl acetate, acetone, methanol, or chloroform, and then silica gel column chromatography, gel filtration column chromatography, and column chromatography packed with ODS for reverse layer partitioning.
  • the compound of the present invention can be purified and isolated by subjecting it to high performance liquid chromatography.
  • the structure of the WSS2138 obtained by the above purification method was determined by the analysis of the molecular weight, ultraviolet absorption spectrum, —NMR spectrum, 13 C—NMR spectrum, and the like, as in the formula (I).
  • Figure 1 shows the results measured by the KBr method.
  • Figure 2 shows the measurement results in deuterated dimethyl sulfoxide at 500 MHz.
  • Figure 3 shows the results of measurement at 125 MHz in deuterated dimethyl sulfoxide.
  • the methylated WSS2138 can be produced by reacting WSS2138 with a methylating agent in the presence of a base.
  • a methylating agent methyl iodide, dimethyl sulfate, methyl methanesulfonate, and the like are used as the methylating agent, and lithium hydroxide, sodium hydrogen carbonate, potassium carbonate, silver oxide, triethylamine, and the like are used as the base.
  • a reaction solvent an organic solvent which does not adversely influence the reaction, for example, N, N-dimethylformamide, dimethyl sulfoxide, getyl ether, tetrahydrofuran, chloroform, and acetonitrile is used.
  • the reaction temperature is usually from about 170 ° C. to 150 ° C., preferably from 130 to 80 ° C.
  • the reaction time is Incubate for 10 minutes to 10 hours.
  • a liquid culture medium containing 2.5% soluble starch, 1% glucose, 0.5% fishmeal, 0.5% pharma media, 0.3% NZ case, 0.2% yeast extract and 0.2% calcium carbonate is placed in a 300m1 Erlenmeyer flask and placed at 120 ° C, sterilized at 2 atmospheres for 20 minutes.
  • the TA-0410 strain was inoculated into this sterile medium, and the cells were subjected to rotary shaking culture at 200 rpm for 3 days at 28 to obtain seed culture.
  • a sterile liquid medium consisting of 2% oatmeal, 1% glucose, 2.5% dextrin, 1% pharma media, 0.5% fishmeal, 0.5% molasses, 0.2% ebios, and 0.3% calcium carbonate was added to a 500ml triangle.
  • the flask was placed in a flask, and 100 ml of the above-mentioned seed culture solution (4 ml) was added thereto, and the mixture was subjected to rotary shaking culture at 28 ° C and 20 Orpm for 6 days.
  • WSS8028 13 C-NMR (CDCls) 6c; 193.6 (s), 192.6 (s), 174.7 (s), 159.5 (s), 154.0 (s), 148.9 (s), 147.0 (s), 146. (s), 144.9 (s), 142.8 (s), 138.3 (s), 133.5 (s), 128.5 (s), 125.5 (d), 125.5 (s), 122. (s), 121.2 (d), 119.4 (s), 115.1 (s), 100.5 (d), 91.6 (t), 75.7 (s), 68.9 (d), 64.3 (d), 61.6 (q), 54.9 (d), 32.2 (q), 22.4 (t), 22.2 (d).
  • WSS8003 13 C-NMR (CDCh) 5c; 197.3 (s), 192. (s), 174.6 (s), 159.3 (s), 153.8 (s), 148.9 (s), 147.5 (s), 146.1 (s ), 144.9 (s), 142.8 (s), 138.l (s), 133.5 (s), 128.5 (s), 126.l (s), 125.5 (d), 122. (s), 121.2 (d ), 119.3 (s), 115.2 (s), 101.1 (d), 91.7 (t), 77.3 (s), 69.2 (d), 64.2 (d), 61.6 (d), 56.1 (s), 32.1 (q ), 31.7 (t), 22.2 (q), 21.3 (q) 0
  • WSS8028 and WSS8003 are represented by the formula ( ⁇ ) in which R 1 is hydrogen, R 2 is a methyl group, 1 A— is a structure of the formula ( ⁇ ), R 1 is a methyl group, R 2 Is a methyl group, and — A— has the structure of formula ( ⁇ ).
  • Example 3
  • WSS8029 13C -NMR (CDC ") 6c; 194.7 (s), 193.l (s), 181.3 (s), 163.8 (s), 162.4 (s), 149.9 (s), 149.0 (s), 145.2 (s), 143.8 (s), 143.l (s), 135.0 (s), 133. (s), 131.5 (s), 125.9 (d), 120.5 (d), 120.2 (s), 115.5 (s ), 112.9 (d), 111.3 (s), 107.5 (d), 91.6 (t), 76.l (s), 69.4 (d), 61.7 (d), 55.l (q), 54.7 (d) , 24.9 (q), 23.4 (t).
  • WSS8030 13 C-NMR (CDCls) 6c; 193.5 (s), 193.0 (s), 174.6 (s), 163.3 (s), 162.5 (s), 148.9 (s), 147.0 (s), 144.9 (s) , 143.2 (s), 142.8 (s), 138.4 (s), 133.5 (s), 128.3 (s), 125.5 (d), 125.l (s), 122. (s), 121.2 (d), 115.0 (s), 113.3 (s), 111.1 (d), 91.7 (t), 75.9 (s), 68.8 (d), 64.0 (q), 61.6 (q), 54.7 (d), 24.9 (q), 22.6 (t).
  • WSS8029 and WSS8030 show that, in the formula (R), R 1 is hydrogen, R 2 is a hydrogen group, 1 A— is a structure of the formula (IV), R 1 is hydrogen, R 2 Has been determined to be a methyl group, and —A— has the structure of formula (IV).
  • Test example 1 shows that, in the formula (R), R 1 is hydrogen, R 2 is a hydrogen group, 1 A— is a structure of the formula (IV), R 1 is hydrogen, R 2 Has been determined to be a methyl group, and —A— has the structure of formula (IV). Test example 1.
  • WSS2138 was dissolved in DMSO to a concentration of 1 Omg / ml and diluted with sterile water to the desired concentration. (Test cell)
  • WSS2138, WSS8003, WSS8028, WSS8029 and WSS8030 were dissolved in DMSO to a concentration of 1 Omg / m 1 and diluted with sterile water to the desired concentration.
  • Inhibition rate (%) 100— [ ⁇ (value of group without drug-value of group with drug added) value of group without drug ⁇ X 100]
  • the compound of the present invention has a growth inhibitory effect on KB cells and HL-60 cells, it is useful as an antitumor agent.
  • FIG. 1 shows the infrared absorption spectrum of WSS2138 measured by the KBr method.
  • FIG. 2 shows the 1 H-NMR spectrum of WSS2138 measured at 500 MHz in deuterated dimethyl sulfoxide.
  • FIG. 3 shows the 13 C-NMR spectrum of WSS2138 measured in deuterated dimethyl sulfoxide at 125 MHz.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé à base de xanthone présentant une activité antitumorale. Ce composé à base de xanthone est représenté par la formule générale (I).
PCT/JP2001/008566 2000-09-29 2001-09-28 Compose a base de xanthone WO2002027010A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2001292303A AU2001292303A1 (en) 2000-09-29 2001-09-28 Xanthone compound
JP2002530773A JPWO2002027010A1 (ja) 2000-09-29 2001-09-28 キサントン系化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000298572 2000-09-29
JP2000-298572 2000-09-29

Publications (1)

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WO2002027010A1 true WO2002027010A1 (fr) 2002-04-04

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AU (1) AU2001292303A1 (fr)
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1550700A (en) * 1975-05-20 1979-08-15 Ciba Geigy Ag Antibiotic and processes for its manufacture
JPS63188394A (ja) * 1987-01-30 1988-08-03 Mitsubishi Kasei Corp 多環性キサントン系化合物の製造法
JPH02167092A (ja) * 1988-12-19 1990-06-27 Kirin Brewery Co Ltd リソリピンｘを含む抗腫瘍剤およびリソリピンｘの製造法
JPH0426625A (ja) * 1990-05-22 1992-01-29 Banyu Pharmaceut Co Ltd リゾリピン類を有効成分とする抗腫瘍剤
EP0512522A1 (fr) * 1991-02-26 1992-11-11 Hoechst Aktiengesellschaft Composés antibiotiques et leur production

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1550700A (en) * 1975-05-20 1979-08-15 Ciba Geigy Ag Antibiotic and processes for its manufacture
JPS63188394A (ja) * 1987-01-30 1988-08-03 Mitsubishi Kasei Corp 多環性キサントン系化合物の製造法
JPH02167092A (ja) * 1988-12-19 1990-06-27 Kirin Brewery Co Ltd リソリピンｘを含む抗腫瘍剤およびリソリピンｘの製造法
JPH0426625A (ja) * 1990-05-22 1992-01-29 Banyu Pharmaceut Co Ltd リゾリピン類を有効成分とする抗腫瘍剤
EP0512522A1 (fr) * 1991-02-26 1992-11-11 Hoechst Aktiengesellschaft Composés antibiotiques et leur production

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BOCKHOLT H. ET AL.: "Biosynthetic studies on the xanthone antibiotics lysolipins X and I", J. ORG. CHEM., vol. 59, no. 8, 1994, pages 2064 - 2069, XP002907290 *
DOBLER M. ET AL.: "19. Metabolites of microorganisms. 162nd communication(1). The crystal and molecular structure of lysolipin I", HELV. CHIM. ACTA, vol. 60, no. 1, 1977, pages 178 - 185, XP002907291 *
DUTHALER R.O. ET AL.: "206. Experiments on the total synthesis of lysolipin I", HELV. CHIM. ACTA, vol. 67, no. 7, 1984, pages 1755 - 1766, XP002907292 *
DUTHALER R.O. ET AL.: "207. Experiments on the total synthesis of lysolipin I", HELV. CHIM. ACTA, vol. 67, no. 7, 1984, pages 1767 - 1775, XP002907293 *
KOBAYASHI K. ET AL.: "Actinoplanones C,D,E,F and G, new cytotoxic polycyclic xanthones from actinoplanes sp.", J. ANTIBIOT., vol. 41, no. 6, 1988, pages 741 - 750, XP002907289 *

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AU2001292303A1 (en) 2002-04-08

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