WO1995004154A1 - Procede de production de taxol et de ses analogues a l'aide de micro-organismes - Google Patents

Procede de production de taxol et de ses analogues a l'aide de micro-organismes Download PDF

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Publication number
WO1995004154A1
WO1995004154A1 PCT/JP1994/001239 JP9401239W WO9504154A1 WO 1995004154 A1 WO1995004154 A1 WO 1995004154A1 JP 9401239 W JP9401239 W JP 9401239W WO 9504154 A1 WO9504154 A1 WO 9504154A1
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WIPO (PCT)
Prior art keywords
taxol
diterpene
group
compound
taxane skeleton
Prior art date
Application number
PCT/JP1994/001239
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English (en)
Inventor
Makoto Tahara
Tetsuo Sakamoto
Masamichi TAKAMI
Kenji Takigawa
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Nippon Steel Corporation
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.)
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Publication date
Application filed by Nippon Steel Corporation filed Critical Nippon Steel Corporation
Publication of WO1995004154A1 publication Critical patent/WO1995004154A1/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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero 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
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial 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
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/13—Brevibacterium

Definitions

  • the present invention relates to novel microorganisms capable of producing diterpene-like compounds having a taxane skeleton and to processes for producing diterpene-like compounds having a taxane skeleton using microorganisms.
  • Taxol is a diterpene contained in plants of the genus Taxus and is sanctioned as an agent for treating ovarian and breast cancers in the United States, Canada, Sweden and other countries. In addition to taxol, its analogues having a taxane skeleton have been developed as new anti-tumor agents.
  • taxol as an anti-tumor agent
  • Taxol is currently extracted from the bark of Taxus brevifolia NUTT. However, this plant is not suitable for cultivation because of its slow growth and the like, and there is a limitation on gathering this plant which grows naturally mainly on the North American Pacific coast.
  • the chemical synthesis of taxol has been studied at many research institutes in the world and full synthesis was first achieved in 1994. Among various aspects of its chemical structure, the taxane skeleton is particularly difficult to synthesize and its commercial production by synthesis is considered to be unfeasible.
  • An object of the present invention is to provide novel processes for producing taxol and its analogues having a taxane skeleton such as baccatin III, 10-deacetylbaccatin III and the like which are essential to the synthesis of taxol and taxotere.
  • the inventors discovered a novel bacterium capable of producing taxol and other compounds having a taxane skeleton, and succeeded in efficiently producing taxol and its analogues having a taxane skeleton from the bacterial culture, thereby accomplishing the present invention.
  • the present invention provides Brevibacterium sp. which is capable of producing a diterpene-like compound having a taxane skeleton.
  • Brevibacterium sp. capable of producing a diterpene-like compound having a taxane skeleton includes Brevibacterium sp. TA519 strain.
  • the present invention provides processes for producing diterpene-like compounds having a taxane skeleton, which comprise the steps of culturing in a medium a microorganism of the genus Brevibacterium capable of producing the diterpene-like compounds having a taxane skeleton and obtaining the diterpene-like compounds having a taxane skeleton from the culture.
  • the diterpene-like compounds having a taxane skeleton include compounds represented by the following formula (I):
  • R 1 is a hydrogen atom or an acyl group
  • R 2 is a hydrogen atom or an acyl group
  • R 3 is an oxygen atom or the combination of an acetoxyl group and a hydrogen atom
  • R 4 is a hydrogen atom or a hydroxyl group
  • R 5 is a hydrogen atom, an acetyl group or a xylosyl group
  • Ph is a phenyl group
  • Ac is an acetyl group.
  • the acyl group as R 1 in formula (I) includes an acetyl group or a group represented by the following formula (II):
  • R 6 is a 1-methyl-1-propenyl, phenyl or n-pentyl group, and Ph is a phenyl group.
  • the acyl group as R 2 in formula (I) includes an acetyl or ⁇ -hydrolybutyryl group.
  • diterpene-like compounds having a taxane skeleton represented by formula (I) include taxol, cephalomannine, 10-deacetyltaxol, 10-deacetylcephalomannine, 7-xylosyl-10-deacetyltaxol, 7-xylosyl-10-deacetylcephalomannine, 7-xylosyl-10-deacetyltaxol C, 7-xylosyltaxol, 7-xylosylcephalomannine, 7-xylosyltaxol C, 10-( ⁇ -hydroxybutyryl)-10-deacetyltaxol, 10-( ⁇ -hydroxybutyryl)-10-deacetylcephalomannine, baccatin III, 19-hydroxybaccatin III, 10-deacetylbaccatin III and baccatin VI.
  • R 5 H
  • R 2 CH 3 CH ( OH ) CH 2 CO
  • the bacteria capable of producing the diterpene-like compounds having a taxane skeleton were isolated from natural sources by the inventors and include the TA519 strain.
  • the TA519 strain has, been depositted with National Institute of Bioscience and Human-Technology, the Agency of Industrial Science and Technology, Japan, with accession number FERM BP-4721.
  • TA519 strain is capable of producing the diterpene-like compounds having a taxane skeleton such as taxol and the like and has the following mycological properties.
  • This strain exhibits the following morphological properties when being cultured in a broth agar medium and a broth liquid medium.
  • Acid and gas production from saccharides No detectable acid or gas production from the following saccharides.
  • this strain was identified as a microorganism of the genus Brevibacterium according to the description in Bergey's Manual of Systematic Bacteriology (Noel R. Kreig et al edited, Williams & Wilkins). However, the mycological properties of this strain are not completely consistent with those of any known species of the genus Brevibacterium and therefore the strain is designated as Brevibacterium sp. TA519.
  • Taxol and its analogues having a taxane skeleton can be obtained by culturing the bacteria of the present invention in a conventional manner for culture of microorganisms.
  • the medium to be used any natural or synthetic media containing carbon sources, nitrogen sources, inorganic compounds and trace amounts of other nutrients required by the bacteria to be cultured can be used.
  • the carbon sources carbohydrates such as glucose, fructose, galactose, molasses, wort, starch hydrolyzates, cellulose hydrolyzates and the like, and organic acids such as pyruvic acid, acetic acid, fumaric acid, malic acid, citric acid and the like can be used.
  • inorganic salts such as ammonium sulfate, ammonium chloride, ammonium nitrate, ammonium phosphate and the like, ammonium salts of organic acids, amines, peptone, meat extract, casein hydrolyzates, soybean-cake hydrolyzates, various kinds of fermented cells or their digests and the like can be used.
  • inorganic compounds potassium dihydrogenphosphate, dipotassium hydrogenphosphate, magnesium phosphate, magnesium sulfate, sodium chloride, ferrous sulfate, manganese sulfate, copper sulfate, calcium carbonate and the like can be used.
  • corn starch, yeast extract, meat extract and the products of decomposition of defatted soybean cake with acids can be used as growth promoters and vitamins may be added as appropriate.
  • Cultivation may preferably be carried out under aerobic conditions in shake culture or aeration culture at pH's of 5-9 and at temperatures of 20°C -40 °C.
  • Taxol and its analogues having a taxane skeleton can be isolated from the culture of the microorganism. Briefly, these compounds can be isolated from the culture of the microorganism, the microorganism cells or medium separated from the culture solution, the cells or solid medium in the solid culture, and the like.
  • Any known method for extracting compounds from cultured microorganisms or medium can be used for extracting taxol and its analogues having a taxane skeleton. They include, for example, a method comprising the steps of separating the microorganism cells from the culture solution in the liquid culture by centrifugation, for example, and then immersing the recovered cells in an organic solvent such as methylene chloride (dichloromethane), methanol, acetone or the like, and a method comprising the steps of subjecting the culture solution in the liquid culture to an ultrasonic treatment and conducting extraction with a water-immiscible organic solvent such as methylene chloride or the like.
  • a method comprising the steps of separating the microorganism cells from the culture solution in the liquid culture by centrifugation, for example, and then immersing the recovered cells in an organic solvent such as methylene chloride (dichloromethane), methanol, acetone or the like
  • an organic solvent such as methylene chloride (
  • Pure taxol and its analogues having a taxane skeleton can be obtained from the extract by any known method including partition between a water-immiscible organic solvent and water, adsorption chromatography, gel filtration chromatography, high performance liquid chromatography, droplet counter current chromatography and the like, as well as methods in which these techniques are combined as appropriate with affinity chromatography using antibodies against taxol and taxane skeletons.
  • Taxol and its analogues having a taxane skeleton in the extract from the culture or enriched solution can be determined quantitatively by any known method including high performance chromatography, enzyme immunoassays and the like.
  • Example 1 Microorganism culture and Taxol production in a Flask
  • Microorganism culture Brevibacterium sp. TA519 strain (FERM BP-4721) was inoculated in a 300 ml flask containing 100 ml of a liquid medium (Tryptic Soy Broth) containing 1.7% pancreatic digest of casein, 0.3% papaic digest of soybean-cake, 0.25% glucose, 0.5% sodium chloride and 0.25% dipotassium hydrogenphosphate, and incubated at 25 °C for 4 days on a rotary shaker at 100rpm. The cultured medium was centrifuged at 10,000 rpm for 30 min, and approximately one gram (fresh weight) of the microorganism cells was obtained as a pellet .
  • the amounts of the taxane skeleton-containing compounds and taxol contained in the cell extract were determined using two kinds of enzyme immunoassay kits (manufactured by Hawaii Biotechnology Group Inc.) employing a polyclonal antibody against a taxane skeleton-containing compound and a monoclonal antibody against taxol, respectively.
  • enzyme immunoassay kits manufactured by Hawaii Biotechnology Group Inc.
  • the value represents the concentration of each compound required to lower the binding of each antibody to taxol in a solid phase by 50% when each antibody is reacted in the presence of a certain amount of taxol (in a solid phase).
  • the reactivity greatly differs between the two antibodies, in particular the reactivity against cephalomannine (the polyclonal antibody is more reactive).
  • cephalomannine the polyclonal antibody is more reactive.
  • Example 2 Microorganism Culture and Taxol Production in a 30 1 Fermenter 1. Microorganism culture
  • Brevibacterium sp. TA519 strain (FERM BP-4721) was inoculated in three 500 ml flasks with baffles each containing 200 ml of a liquid medium.
  • the medium was Tryptic Soy Broth, which contained 1.7% pancreatic digest of casein, 0.3% papaic digest of soybean-cake, 0.25% glucose, 0.5% sodium chloride and 0.25% dipotassium hydrogenphosphate.
  • the bacterium was incubated at 25 °C for 7 days. In this way, a seed culture solution to be inoculated in a fermenter was obtained.
  • the thus obtained seed culture solution (450ml) was inoculated in a 30 1 fermenter (Mitsuwa Rikagaku model KMJ-301MGU-2U) containing 18 1 of a liquid medium (Tryptic Soy Broth) containing 1.7% pancreatic digest of casein, 0.3% papaic digest of soybean-cake, 0.25% glucose, 0.5% sodium chloride and 0.25% dipotassium hydrogenphosphate, and incubated at 25°C for 2 days.
  • the medium pH was adjusted at 7.4 with 2N HCl; the number of revolutions of the agitator blade was set at 300 rpm; and aeration was provided at a rate of 18 l/min.
  • the medium was centrifuged at 13,000 rpm with a continuous-flow centrifuge rotor to thereby obtain a supernatant.
  • HPLC high performance liquid chromatography
  • the extract sample revealed an elution peak at 22.18 min which was nearly the same as the elution time of the authentic taxol standard (approximately 23.0 min).
  • the absorption spectrum over the range of 190-400 nm of the extract sample at that elution peak was identical to the spectrum of taxol, having a peak absorption value at 227 nm.
  • the agreement of elution times was confirmed by mixing the extract sample and the standard taxol solution, subjecting the resultant mixture to HPLC analysis, and finding that the taxol elution peaks comigrate.
  • Brevibacterium sp. TA519 strain (FERM BP-4721) was inoculated in a 500 ml flask with baffles containing 200 ml of a liquid medium (Tryptic Soy Broth) containing 1.7% pancreatic digest of casein, 0.3% papaic digest of soybean-cake, 0.25% glucose, 0.5% sodium chloride and 0.25% dipotassium hydrogenphosphate, and incubated at 25 °C for 5 days on a rotary shaker at 100 rpm. The cultured medium was centrifuged at 10,000 rpm for 30 min, and approximately 1.3 g (fresh weight) of the microorganism cells was obtained as a pellet.
  • the diluted extract was analyzed with two kinds of enzyme immunoassay kits (manufactured by Hawaii Biotechnology Group Inc.) using a polyclonal antibody against a taxane skeleton-containing compound and a monoclonal antibody against taxol, respectively. As a result, it was confirmed that substances reactive to the antibodies were contained in the extract sample.
  • HPLC high performance liquid chromatography
  • the extract sample revealed an elution peak at 14.7 min which was nearly the same as the elution time of the authentic taxol standard (approximately 14.5 min).
  • the absorption spectrum over the range of 190-400 nm of the extract sample at that elution peak was identical to the spectrum of taxol, having a peak absorption value at 227 nm.
  • the agreement of elution times was confirmed by mixing the extract sample and the standard taxol solution, subjecting the resultant mixture to HPLC analysis, and finding that the taxol elution peaks co-migrate.
  • the authentic taxol standard was analyzed, and it was found that the elution time of taxol was approximately 9.5 min. With respect to the mass spectrum, a large number of ion counts was observed at 525, 792 and 852 m/z (mass/electric charge). Therefore, these three ions (m/z) were selected for SIM (selected ion monitoring) analyses, and the extract sample was subjected to the analyses. As a result, the peaks of the ion counts were observed for all three ions (m/z) at the same elution time (approximately 9.5 min) as that of the standard taxol.
  • Brevibacterium sp. TA519 strain (FERM BP-4721) was inoculated in a 500 ml flask with baffles containing 200 ml of a liquid medium (Tryptic Soy Broth) containing 1.7% pancreatic digest of casein, 0.3% papaic digest of soybean-cake, 0.25% glucose, 0.5% sodium chloride and 0.25% dipotassium hydrogenphosphate, and incubated at 25 °C for 5 days on a rotary shaker at 100 rpm. The cultured medium was centrifuged at 10,000 rpm for 30 min, and approximately 1.3 g (fresh weight) of the microorganism cells was obtained as a pellet.
  • the resultant dilution was analyzed with an enzyme immunoassay kit (TAO3 manufactured by Hawaii Biotechnology Group Inc.) using a monoclonal antibody against baccatins to thereby examine if baccatins were contained in the extract. As a result, it was found that 90 ng* of baccatins was contained per liter of the medium (* a value estimated in terms of an amount in which the monoclonal antibody reacts against baccatin III).
  • a diterpene-like compound having a taxane skeleton can be produced highly efficiently.
  • the taxol content of a culture of the microorganisms of the present invention belonging to the genus Brevibacterium is by far greater than that of the fungus described in Science as mentioned earlier in this specification.
  • the taxol content per gram of dry matter of the microorganisms of the present invention is similar to that of the known plant producing taxol.
  • the culture period of the microorganisms of the present invention required for the production of taxol and the like is several days at most, which is far shorter than that required for the tissue culture of plants of the genus Taxus, i.e. several weeks, and also far shorter than that required for growing and harvesting plants of the genus Taxus, i.e. several years at least.

Abstract

Brevibacterium sp. pouvant produire un composé de type diterpène présentant un squelette taxane, et procédés de production de composés de type diterpène présentant un squelette taxane, consistant à cultiver les micro-organismes dans un milieu et à en extraire le composé de type diterpène présentant un squelette taxane. Par conséquent, on peut produire rapidement et efficacement des composés de type diterpène présentant un squelette taxane.
PCT/JP1994/001239 1993-07-27 1994-07-27 Procede de production de taxol et de ses analogues a l'aide de micro-organismes WO1995004154A1 (fr)

Applications Claiming Priority (4)

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JP18540293 1993-07-27
JP5/185402 1993-07-27
JP28094993 1993-11-10
JP5/280949 1993-11-10

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034972A1 (fr) * 1995-05-05 1996-11-07 Bcm Developpement Inc. Production bacterienne en masse de paclitaxel
US5589502A (en) * 1994-11-17 1996-12-31 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
WO1997016200A1 (fr) * 1995-11-03 1997-05-09 Merck & Co., Inc. Transformation microbienne du taxol et de la cephalomannine
US5677470A (en) * 1994-06-28 1997-10-14 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
WO1999032651A1 (fr) * 1997-12-22 1999-07-01 Bcm Developpement Inc. Production de masse de taxanes et de paclitaxel a l'aide de bacteries
WO1999042561A1 (fr) * 1998-02-20 1999-08-26 Pharmacia & Upjohn S.P.A. Production de paclitaxel par actinomycetes
EP1285920A1 (fr) * 2001-07-31 2003-02-26 Florida State University Research Foundation, Inc. Taxanes substitués par ester en C10 utilisés comme agents anticancereux
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100466734B1 (ko) * 1997-11-25 2005-12-27 주식회사 코오롱 탁솔함유진균배양물로부터용매추출에의한탁솔의추출및정제방법

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021338A1 (fr) * 1992-04-16 1993-10-28 The Research And Development Institute, Inc. Production de taxol par un microbe

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993021338A1 (fr) * 1992-04-16 1993-10-28 The Research And Development Institute, Inc. Production de taxol par un microbe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANDREA STIERLE ET AL.: "Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of pacific yew.", SCIENCE, vol. 260, 9 April 1993 (1993-04-09), LANCASTER, PA US, pages 214 - 216 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5677470A (en) * 1994-06-28 1997-10-14 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
US5589502A (en) * 1994-11-17 1996-12-31 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
US5608073A (en) * 1994-11-17 1997-03-04 Tanabe Seiyaku Co., Ltd. Baccatin derivatives and processes for preparing the same
WO1996034972A1 (fr) * 1995-05-05 1996-11-07 Bcm Developpement Inc. Production bacterienne en masse de paclitaxel
WO1997016200A1 (fr) * 1995-11-03 1997-05-09 Merck & Co., Inc. Transformation microbienne du taxol et de la cephalomannine
US5756536A (en) * 1995-11-03 1998-05-26 Purdue Research Foundation Microbial transformation of taxol and cephalomannine
WO1999032651A1 (fr) * 1997-12-22 1999-07-01 Bcm Developpement Inc. Production de masse de taxanes et de paclitaxel a l'aide de bacteries
US6528301B1 (en) * 1998-02-20 2003-03-04 Pharmacia & Upjohn Spa Paclitaxel production by actinomycetes
WO1999042561A1 (fr) * 1998-02-20 1999-08-26 Pharmacia & Upjohn S.P.A. Production de paclitaxel par actinomycetes
US7524869B2 (en) 2000-02-02 2009-04-28 Florida State University Research Foundation, Inc. Taxanes having a C10 ester substituent
US6649632B2 (en) 2000-02-02 2003-11-18 Fsu Research Foundation, Inc. C10 ester substituted taxanes
JP2003055360A (ja) * 2001-07-31 2003-02-26 Florida State Univ Research Foundation Inc Ｃ１０エステル置換タキサン
EP1285920A1 (fr) * 2001-07-31 2003-02-26 Florida State University Research Foundation, Inc. Taxanes substitués par ester en C10 utilisés comme agents anticancereux
US7589111B2 (en) 2004-02-13 2009-09-15 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8003812B2 (en) 2004-02-13 2011-08-23 Florida State University Research Foundation, Inc. C10 cyclopentyl ester substituted taxanes
US8242166B2 (en) 2008-03-31 2012-08-14 Florida State University Research Foundation, Inc. C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes

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