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WO2003070960A1 - Processus de fabrication de chondroitine ou de derive de chondroitine - Google Patents

Processus de fabrication de chondroitine ou de derive de chondroitine Download PDF

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Publication number
WO2003070960A1
WO2003070960A1 PCT/JP2002/011576 JP0211576W WO03070960A1 WO 2003070960 A1 WO2003070960 A1 WO 2003070960A1 JP 0211576 W JP0211576 W JP 0211576W WO 03070960 A1 WO03070960 A1 WO 03070960A1
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Prior art keywords
chondroitin
acetyl
reaction
methyl
derivative
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Ceased
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PCT/JP2002/011576
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English (en)
Japanese (ja)
Inventor
Shiro Kobayashi
Masashi Ohmae
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Denka Co Ltd
Original Assignee
Denki Kagaku Kogyo KK
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Priority to AU2002344469A priority Critical patent/AU2002344469A1/en
Priority to JP2003569852A priority patent/JP4993844B2/ja
Publication of WO2003070960A1 publication Critical patent/WO2003070960A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates

Definitions

  • the present invention relates to a method for producing chondroitin or a chondroitin derivative using a hyaluronic acid-degrading enzyme. More specifically, the present invention relates to a method for producing chondroitin or a chondroitin derivative by enzymatically polymerizing a chondrosin oxazoline derivative as a monomer substrate using a mammalian hyaluronidase as a hyaluronic acid degrading enzyme as a catalyst.
  • Chondroitin is an unbranched high-molecular polysaccharide in which disaccharides of D-glucuronic acid and N-acetylgalactosamine are alternately linked in a linear chain. Chondroitin or chondroitin derivatives can be widely used as cosmetics, pharmaceuticals or medical materials.
  • chondroitin is contained in the corneal skin of bovine eyes and the like, and is also obtained by desulfation of chondroitin sulfate A or C which is present in large amounts in cartilage tissue.
  • a method for producing chondroitin an extraction method from skin with a relatively high content of slime is generally used, but it is economically disadvantageous because many steps are required to increase the purity.
  • it can be produced by desulfurization of chondroitin sulfate A or C, but it is difficult to say that chondroitin sulfate is an advantageous method because it needs to be extracted and purified from cartilage tissue and the like.
  • the present inventors have conducted intensive studies on the development of a novel method for producing chondroitin or a chondroitin derivative which is highly useful even at a practical level, and as a result, the enzymatic method using hyaluronidase has been used. Chondroitin or chondroitin For the first time, a new process for the production of benzoquinone derivatives.
  • hyaluronidase which is originally known as an enzyme that degrades hyaluronic acid
  • a chondroxin oxazoline derivative is used as a monomer
  • a monomer substrate was enzymatically polymerized to produce high-molecular-weight chondroitin or a chondroitin derivative at a high yield, and the present invention was completed. Disclosure of the invention
  • the present invention has the following configuration.
  • a process for producing chondroitin or a chondroitin derivative which comprises reacting a hyaluronic acid-decomposing enzyme with an oxazoline derivative represented by the following general formula (I).
  • R represents hydrogen, an alkyl group, an optionally substituted alkyl group, a phenyl group, or an optionally placed phenyl group.
  • the above oxazoline derivative is 2-methyl- [1,2-dideoxy-3-0- (sodium-D-darcopyranosyl oxalate)] — a—D—galactobranano [2,1–1d ]
  • a hyaluronic acid-degrading enzyme was produced on the oxazoline derivative at a pH of 5 to 10.
  • the production method according to any one of claims 1 to 4, wherein the method is used.
  • 1 shows a scheme of synthesis of a substrate monomer and an enzymatic polymerization reaction.
  • FIG. 1 shows the synthesis scheme. That is, methyl (2,3,4-tri-0-acetyl-] 3-D-darcopyranosyl trichloroacetimidate) peronate is converted to a sugar donor, benzyl 2-azido-4,6-0-benzylidene-2. -Doxy-0-D-galactopyranoside as a sugar acceptor JP02 / 11576
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • acetic anhydride is added dropwise at 0 ° C in dehydrated pyridine and reacted at room temperature for 3 hours to obtain benzyl 2-acetoamide-4,6-di-0-acetyl-2-deoxy-3-0- (Methyl 2,3,4-tri-0-acetyl-) 3-D-Darcopyranosyl-N-)-) 3-D-galactopyranoside (3) was obtained.
  • TMSOTi is allowed to act on (4) at room temperature under an argon atmosphere in dehydrated dichloromethane for 2 hours, and then triethylamine is caused to act at 0 ° C, whereby 2-methyl- [4,6-di- -0-Acetyl-1, 2-dideoxy-3-0- (methyl 2,3,4-tri- 0-acetyl -j3 -D -Darcopyranosyl ester)-CK-D-Galactopyrano]- [2, l, d] -2-oxazoline (5) was obtained.
  • the chondrosin oxazoline derivative thus obtained is suitably used as a substrate monomer of a hyaluronan degrading enzyme as a polymerization catalyst.
  • Substrate model during enzyme reaction The nomer concentration is 0.1% by weight or more, preferably 1% by weight or more, from a practical viewpoint.
  • the reaction pH is preferably 5 to 10 and preferably 6.5 to 9.5 in consideration of the reactivity of the enzyme and the stability of the substrate monomer.
  • the reaction temperature is from 5 ° C to 60 ° C, preferably from 20 ° C to 40 ° C.
  • mammalian-derived hyaluronidase is preferable, and specifically, a testis-derived or sheep that is classified as end-i3-acetylhexosamidase (EC 3.2.1.35).
  • Testicular hyaluronidase and the like are suitable, and the enzyme can be used in the form of an immobilized enzyme in which the enzyme is immobilized on a suitable carrier. Either batch reaction or continuous reaction is employed.
  • the reaction is an aqueous solvent or an aqueous solvent such as methanol, ethanol, alcohols such as n-propanol, polyols such as glycerin and polyethylene glycol, dimethyl sulfoxide, dimethylformamide, ethyl acetate, dioxane, and adversely affect the reaction. It proceeds even under the condition that various inorganic salts or PH buffer etc. which do not affect the environment are appropriately added.
  • the substrate monomer is not limited to the 2-methyl-chondrosinoxazoline derivative (6), but is a compound of the general formula (I) having a chondrosinoxazoline basic structure in which a polymerization reaction by hyaluronidase proceeds. Mouth synoxazoline derivatives are included in the present invention.
  • an alkyl group such as ethyl, propyl, and butyl, a phenyl group, a halogen-substituted alkyl group, a halogen-substituted phenyl group, and the like can be used in place of hydrogen or methyl for R in the general formula (I).
  • the substrate monomer is not particularly limited as long as it is in the form of a free acid, a metal salt such as sodium or potassium, an ammonium salt, a triethylamine salt, or the like.
  • the resulting chondroitin or chondroitin derivative depends on the form of the glucuronic acid salt of the substrate monomer, and includes free acids or forms such as metal salts such as sodium and potassium, ammonium salts, and triethylamine salts.
  • chondroitin or chondroitin derivatives can be isolated and purified by combining known purification means such as dense filtration, various adsorption columns, solvent precipitation, and chromatographic separation.
  • the chondroitin or chondroitin derivative thus obtained can be widely used as cosmetics, pharmaceuticals, medical materials and the like.
  • TMSOTf trimethylsilyl trifluoromethanesulfonate
  • dehydrated dichloromethane 1.00 ml
  • MS4A was removed by celite filtration
  • the filtrate was diluted with chloroform, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and the organic layer was dried over magnesium sulfate. I let it. After drying, magnesium sulfate was removed by cerite filtration, and the filtrate was distilled off under reduced pressure.
  • the reaction solution was distilled off under reduced pressure, the residue was diluted with chloroform, and washed sequentially with 4% (w / v) aqueous potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate, and saturated saline.
  • the organic layer was dried with magnesium sulfate. After drying, magnesium sulfate was removed by celite filtration, and the filtrate was distilled off under reduced pressure.
  • the analysis data is as follows.
  • the obtained white amorphous substance was dissolved in pyridine (10.0 ml), and acetic anhydride (0.315 ml, 3.23 mmol) was added dropwise at 0 ° C and dried.
  • the reaction was performed for 3 hours at room temperature under an atmosphere. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and the residue was diluted with chloroform.Then, washed sequentially with 4% (w / v) aqueous sodium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate, and saturated saline.
  • the organic layer was dried with magnesium sulfate. After drying, magnesium sulfate was removed by celite filtration, and the filtrate was distilled off under reduced pressure.
  • the analysis data is as follows.
  • Substrate monomer 2-methyl- [], 2-dideoxy-3-0- (sodium-D-glucopyranosylone) -a-D-galactovirano]-[2, trid] -2 -oxazoline (5.OOmg, 12.5 mol) was dissolved in phosphate buffer (50 mM, H7.5, 1251), and hyaluronidase from sheep testis (ICN Biochemicals, Lot No. 6830B, 0.500 mg of 2160 units / mg, hereinafter referred to as H-0TH) was added, and the reaction was carried out at 30 for 24 hours.
  • phosphate buffer 50 mM, H7.5, 1251
  • hyaluronidase from sheep testis
  • the reaction solution was heated in a hot water bath at 90 ° C for 3 minutes to inactivate the enzyme, then an excess amount of THF was added, and the resulting precipitate was collected by centrifugation. .
  • the obtained precipitate was dissolved again in pure water to obtain an aqueous solution of a polymerization product.
  • the GPC measurement conditions are shown below.
  • FIG. 2 shows the 1 H NMR spectrum of the obtained chondroitin
  • FIGS. 3 and 4 (enlarged views of the sugar skeleton in FIG. 3) show the 13 C R spectrum. These spectra were consistent with those of naturally occurring chondroitin.
  • the peak assignments of the Awakening R vector are as follows.
  • Sheep testis-derived hyaluronidase (ICN Biochemicals, Lot No. 9303B, 560 units / mg, hereinafter referred to as 0TH) as a catalytic enzyme in the polymerization reaction, bovine testis-derived hyaluronidase (SIGMA, Lot No. .30K7049, 330units / mg, hereinafter referred to as BTH), H-0TH, or bovine testis-derived hyaluronidase (SIGMA, Lot No.38H7026, IOIOUnits / mg, hereinafter referred to as H-BTH) Table 1 shows the results of the same reaction and analysis as in Example 7 except that the reaction time was changed to 23 hours or 40 hours. Chondroitin synthesis was possible using any of the hyaluronidases.
  • Table 5 shows the results of the same reaction and analysis as in Example 7, except that the amount of the catalytic enzyme H-0TH and the reaction time were changed to the conditions described in Table 5 in the polymerization reaction.
  • Table 6 shows the results of the same reaction and analysis as in Example 7, except that the reaction temperature and the reaction time in the polymerization reaction were changed to the conditions described in Table 6.
  • the obtained compound (453 mg, 0.741 mmol) was dissolved in pyridine (10 ml), and acetic anhydride (0.431 ml, 4.44 bandol) was added dropwise at 0 ° C under a dry atmosphere, and the reaction was carried out at room temperature for 4 hours. I let it. After completion of the reaction, the reaction solution was distilled off under reduced pressure, the residue was diluted with chloroform, washed successively with 4% (w / v) aqueous sodium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate, and saturated saline, and then washed with an organic solvent. The layer was dried with magnesium sulfate.
  • the obtained residue was dissolved in methanol (10 ml), and triethylamine (1 ml) and then propionic anhydride (0.180 ml, 1.44 mmol) were added under a dry atmosphere at 01 :, and the mixture was reacted at room temperature for 2 hours. .
  • pyridine (1 ml) was added, the reaction solution was distilled off under reduced pressure, and the obtained residue was dried overnight under reduced pressure.
  • the obtained white amorphous substance was dissolved in pyridine (10 ml), acetic anhydride (0.084 ml, 0.863 mmol) was added dropwise at 0 ° C under a dry atmosphere, and the mixture was reacted at room temperature for 3 hours.
  • reaction solution was distilled off under reduced pressure, and the residue was diluted with chloroform.Then, washed sequentially with 4% (w / V) aqueous potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate, and saturated saline, and then organically. The layer was dried with magnesium sulfate. After drying, magnesium sulfate was removed by cerite filtration, and the filtrate was distilled off under reduced pressure.
  • Glucopyranosyl ⁇ mouth)-3-D-galactopyranoside (7) (315 mg, 0.453 mmol) is dissolved in methanol (30 ml), and 10% palladium hydroxide carbon (150 mg) is added.
  • the azide group was converted to an amino group, and at the same time, the benzyl group was deprotected.
  • the analysis data is as follows.
  • the reaction was carried out for 3.5 hours to convert the azide group to an amino group, and at the same time, deprotection of the benzyl group was performed.
  • 10% palladium hydroxide and carbon were removed by filtering the reaction solution through celite, and the filtrate was distilled off under reduced pressure.
  • the obtained residue was dissolved in methanol (30 ml), and triethylamine (1 ml) and benzoyl chloride (0.1 ml, 0.863 related) were added at 0 ° C under a dry atmosphere, and the mixture was reacted for 1 hour.
  • pyridine (3 ml) was added, the reaction solution was distilled off under reduced pressure, and the obtained residue was dried overnight under reduced pressure.
  • a methanol solution of sodium methoxide (3.04 mg, 0.0158 ol) was added at 0 ° C, and the mixture was stirred at 0 ° C for 0.5 hour and at room temperature for 1 hour.Then, a methanol solution of sodium methoxide (3.04 mg, 0.0158 mmol) was added. Was added and the mixture was stirred at room temperature for 0.5 hour to deprotect all 0-acetyl groups. After completion of the reaction, the reaction solution was dried under reduced pressure. After drying, the compound was dissolved in carbonate buffer (50 mM, H 10.6, 1.58 ml), and the methyl ester was deprotected by stirring at room temperature for 1 hour.
  • carbonate buffer 50 mM, H 10.6, 1.58 ml
  • the enzyme was inactivated by heating the reaction solution in a water bath at 90 ° C. for 3 minutes, then an excess amount of THF was added, and the resulting precipitate was collected by centrifugation. The obtained precipitate was dissolved again in pure water to obtain an aqueous solution of a polymerization product.
  • Table 11 shows the yield and molecular weight of the polymerization product, based on the substrate monomer, determined by GPC measurement of the obtained aqueous solution. GPC measurement and calibration curve preparation were performed under the same conditions as in Example 7. From the aqueous solution of the polymerization product obtained from the reaction solution using the substrate monomers (14) and (15), the polymerization product was purified using Sephadex G-10 size exclusion chromatography.
  • Residual rate of substrate monomer (16) Residual rate (%) Reaction Residual rate (%) Time Time
  • Substrate monomer 2-ethyl- [1,2-di-doxy-3-0- (sodium ⁇ -D-Darcopyranosyl lipate)- ⁇ -D-galactovirano] [2, 1-d] -2- Oxazoline (14) (15.Omg, 36.mol) was dissolved in 3601 phosphate buffer (50 mM, H7.5), and sheep testis-derived hyaluronidase (H-0TH; 2502 units / mg, Lot No. 8838E) was added and reacted at 30 ° C.
  • the method for producing chondroitin or a chondroitin derivative according to the present invention is a simpler synthesis method than an extraction method from a biomaterial which has been conventionally used industrially, and a product from a reaction solution. And a method for producing chondroitin or a chondroitin derivative which can be easily isolated and purified.
  • the collected chondroitin or chondroitin derivative is industrially useful as a material for cosmetics, pharmaceuticals and medical materials.

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Abstract

Un processus de fabrication de chondroitine ou de dérivé de chondroitine qui est un procédé de synthèse plus facile que les processus industriels traditionnels destinés à la production par extraction à partir de matériaux biologiques et dans lequel le produit de réaction peut être facilement isolé à partir d'un mélange de réaction puis purifié. La chondroitine ou le dérivé de chondroitine collecté peut avoir un usage médical en tant que matériau pour produits cosmétiques, médicaments, matières médicales, etc. Le procédé, destiné à la fabrication de chondroitine ou d'un dérivé de chondroitine, est caractérisé en ce qu'il fait agir l'enzyme de décomposition d'acide hyaluronique sur un dérivé d'oxazoline.
PCT/JP2002/011576 2002-02-20 2002-11-06 Processus de fabrication de chondroitine ou de derive de chondroitine Ceased WO2003070960A1 (fr)

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AU2002344469A AU2002344469A1 (en) 2002-02-20 2002-11-06 Processes for producing chondroitin or chondroitin derivative
JP2003569852A JP4993844B2 (ja) 2002-02-20 2002-11-06 コンドロイチン又はコンドロイチン誘導体の製造法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1642570A1 (fr) 2004-10-04 2006-04-05 L'oreal Composition cosmétique et/ou dermatologique pour peaux sensibles
JP2006129796A (ja) * 2004-11-08 2006-05-25 Denki Kagaku Kogyo Kk 構造明確なコンドロイチン４−硫酸及びその製造法
WO2007069693A1 (fr) * 2005-12-15 2007-06-21 Seikagaku Corporation Longue chaine de sucre de chondroitine et son procede de production et procede favorisant la synthese de la chondroitine
JP5301427B2 (ja) * 2007-03-09 2013-09-25 生化学工業株式会社 糖オキサゾリン誘導体の製造方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH093088A (ja) * 1995-06-19 1997-01-07 Shin Etsu Chem Co Ltd アミノ二糖及びキチン又はその類似多糖類の製造方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH093088A (ja) * 1995-06-19 1997-01-07 Shin Etsu Chem Co Ltd アミノ二糖及びキチン又はその類似多糖類の製造方法

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
KABAYASHI S. ET AL.: "Enzymatic polymerization to artificial hyaluronan: a novel method to synthesize a glycosaminoglycan using a transition state analogue monomer", J. AM. CHEM. SOC., vol. 123, no. 47, 28 November 2001 (2001-11-28), pages 11825 - 11826, XP002952442 *
KOBAYASHI S. ET AL.: "Enzymatic ring-opening polyaddition for chitin synthesis: a cationic machanism in basic solution?", MACROMOL. SYMP., vol. 132, 1998, pages 415 - 420, XP000790753 *
KOBAYASHI S. ET AL.: "Synthesis of artificial chitin: irreversible catalytic behavior of a glycosyl hydrolase through a transition state analogue substrate", J. AM. CHEM. SOC., vol. 118, 1996, pages 13113 - 13114, XP002952443 *
SHIRO KOBAYASHI ET AL.: "Koso shokubai jugo ni yoru chondroitin no gosei", POLYMER PREPRINTS, JAPAN, vol. 51, 10 May 2002 (2002-05-10), pages 901, XP002967733 *
SHIRO KOBAYASHI ET AL.: "Sen'i jotai analogue monomer o mochiita koso shokubai jugo ni yoru jinko chondroitin no gosei", THE CHEMICAL SOCIETY OF JAPAN DAI 81 SHUNKI NENKAI KOEN YOKOSHU II, 11 March 2002 (2002-03-11), pages 817, XP002967734 *
TAKAGAKI K. ET AL.: "Synthesis of chondroitin sulfate oligosaccharides using enzymatic reconstruction", TRENDS IN GLYCOSCIENCE AND GLYCOTECHNOLOGY, vol. 12, no. 67, 2000, pages 295 - 306, XP002967735 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1642570A1 (fr) 2004-10-04 2006-04-05 L'oreal Composition cosmétique et/ou dermatologique pour peaux sensibles
JP2006129796A (ja) * 2004-11-08 2006-05-25 Denki Kagaku Kogyo Kk 構造明確なコンドロイチン４−硫酸及びその製造法
WO2007069693A1 (fr) * 2005-12-15 2007-06-21 Seikagaku Corporation Longue chaine de sucre de chondroitine et son procede de production et procede favorisant la synthese de la chondroitine
US8067204B2 (en) 2005-12-15 2011-11-29 Seikagaku Corporation Long-chain chondroitin sugar chain and method for producing the same and method for promoting synthesis of chondroitin
JP5301427B2 (ja) * 2007-03-09 2013-09-25 生化学工業株式会社 糖オキサゾリン誘導体の製造方法

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