WO2010076879A1 - 硫酸化c-配糖体及びその単離方法並びに合成方法 - Google Patents
硫酸化c-配糖体及びその単離方法並びに合成方法 Download PDFInfo
- Publication number
- WO2010076879A1 WO2010076879A1 PCT/JP2009/071700 JP2009071700W WO2010076879A1 WO 2010076879 A1 WO2010076879 A1 WO 2010076879A1 JP 2009071700 W JP2009071700 W JP 2009071700W WO 2010076879 A1 WO2010076879 A1 WO 2010076879A1
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- WO
- WIPO (PCT)
- Prior art keywords
- glycoside
- sulfated
- chafuroside
- tea
- represented
- Prior art date
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- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/82—Theaceae (Tea family), e.g. camellia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/14—Ortho-condensed systems
Definitions
- the present invention relates to a sulfated C-glycoside which is a novel compound. Specifically, the present invention relates to a sulfated C-glycoside which is a precursor of chafuroside and its analogs that are expected to have physiological activities such as an anti-inflammatory effect equivalent to or better than that of a steroid agent, and its tea leaves.
- the present invention relates to an isolation method, a novel synthesis method thereof, and a method for producing chafuroside and its analogs from the sulfated C-glycoside.
- Chafuroside is a flavone C-glycoside which is a kind of flavone derivative, and is known to exhibit an antioxidant action, an antiallergic action, an anti-inflammatory action, a carcinogenesis-inhibiting action, and the like. Chafloside is known to be a compound isolated from oolong tea, and its structural formula has been determined.
- chafloside A and B can be represented as A2-2 and B2-2, respectively, in the following structural formulas.
- chafuroside A exerts an effective inhibitory effect on azoxymethane (AOM) -induced intestinal polyp formation in the rat large intestine of Min mice at the same dose of 2.5 mg / kg as indomethacin. It was. This effect was presumed to be because chafloside A acts on COX-2 in an inhibitory manner. From these and its structure, chafloside A is highly likely to be a new type of anti-inflammatory agent (see Patent Document 2 and Non-Patent Document 3).
- Chafloside A and B exhibit a physiological activity superior to that of one of the most useful drugs at present, which is superior to steroidal anti-inflammatory agents, their usefulness is expected.
- Various methods have been studied. For example, attempts have been made to synthesize from the known flavone C glycosides isovitexin and vitexin, respectively. Among them, Mitsunobu reaction from isovitexin and vitexin has the following chemical reaction formula. It has been proposed to synthesize chafuroside A and B by using (Patent Document 2). However, since this method uses an azo reagent with a high risk of explosion, its industrialization is extremely difficult.
- Non-patent document 2 described above discloses a novel chemical synthesis method of chafuroside A, but has a drawback of low safety (see Patent Document 3, Patent Document 4, and Non-Patent Document 2). Due to the structure, production method and physiological activity of chafloside A and B as described above, the production mechanism of chafuroside A and B in oolong tea leaves is very interesting, but it is simple, high yield and safe. In view of the high availability of these compounds, the development of an efficient production method is strongly desired.
- the present invention relates to a sulfated C-glycoside which is a novel compound as a precursor of chafuroside and its analogs, a method for efficiently producing the sulfated C-glycoside, and chafroside and its analogs using the same. It is an object of the present invention to provide a method for producing a body efficiently.
- the inventor has examined the generation factors of chaflosides A and B and succeeded in identifying the generation factors. And based on this result, each precursor of chafuroside A and B was isolated, the structure of both these precursors which are novel compounds was estimated from various physicochemical data, and the structure was determined by synthesis. Furthermore, it has been found that these precursors can be converted into chaflosides A and B easily and with high yield, respectively, that is, chaflosides A and B can be obtained more efficiently than these precursors.
- the compound having the partial structure (a) of each of the precursors of chafuroside A and B (left in the following formula) has the same partial structure (b) (following formula It is considered that the compound group having the same partial structure as chafuroside A and B can be obtained in the same manner from the other compound group having the partial structure (a). Is estimated.
- chafuroside and its related compounds are derived from 2-sulfate, a sugar derivative that can be produced in nature or synthetically, and has completed the present invention.
- the present invention provides the following sulfated C-glycoside, a method for isolation and synthesis thereof, and a method for producing chafuroside and its analogs from the sulfated C-glycoside. .
- R 1 , R 2 and R 3 each independently represents a hydrogen atom or an OH group.
- the sulfated C-glycoside is a sulfated form of isovitexin represented by the following formula (A1-2) or a sulfated form of vitexin represented by the following general formula (B1-2):
- A1-2 isovitexin represented by the following formula (A1-2)
- B1-2 a sulfated form of vitexin represented by the following general formula (B1-2):
- Concentration / drying step (c) The dried solid material containing the sulfated C-glycoside obtained in the concentration / drying step (b) is liquid-liquid distributed using water and an n-butanol solvent. Purification process to purify the aqueous layer by chemical separation and purification
- a method for synthesizing a sulfated C-glycoside according to (1) or (2), wherein the flavone C-glycoside represented by the following general formula (A0) or (B0) and a sulfate group A method for synthesizing a sulfated C-glycoside, comprising a step of reacting with an introduction agent and sulfating the flavone C-glycoside.
- R 1 , R 2 and R 3 each independently represents a hydrogen atom or an OH group.
- R 1 , R 2 and R 3 each independently represents a hydrogen atom or an OH group.
- a novel sulfated C-glycoside (a sulfated form of isovitexin and vitexin) could be isolated as a precursor of chafuroside A and B. Since both compounds were novel compounds, their structures were estimated from various physicochemical data and determined by synthesis.
- chafuroside A and B are produced from sulfated forms of isovitexin and vitexin, respectively, in tea leaves.
- flavone glycosides and sulfated flavone C-glycosides have not been found so far, and have been found for the first time in the present invention.
- chafloside A and chafloside B are generated by heat treatment.
- Chafloside A and chafloside B exhibit an anti-inflammatory effect, and in particular, the former action is reported to be superior to commercially available steroids.
- chafuroside A and B are produced from a precursor of chafuroside A (isovitexin 2-sulfate) and a precursor of chafuroside B (vitexin 2-sulfate), respectively. It is presumed that a compound having the same partial structure as both precursors of B is converted into a compound having the same partial structure as chafuroside A and B.
- excellent steroid-like anti-inflammatory physiological activity is also expected for these compound groups having the same partial structure as chafuroside A and B.
- the sulfated C-glycoside of the present invention easily undergoes a cyclization reaction accompanied by steric inversion by heating in the solid state. Therefore, according to the present invention, there is provided an inexpensive method for synthesizing chafuroside and its analog, which can synthesize chafuroside and its analog via sulfated C-glycoside from flavone C-glycoside such as isovitexin and vitexin. be able to. According to the method of the present invention, it is possible to produce chafuroside and its analogs in a high yield in spite of the use of inexpensive and safe starting materials and reagents and relatively mild reaction conditions. Industrial production is possible by scaling up, which is extremely useful in industry.
- a chafuroside precursor a sulfated body, in tea leaves is significant.
- the chafuroside precursor which is a novel compound of the present invention, is sulfated and easily dissolved in water.
- isovitexin and vitexin which are extremely insoluble in water, it has a high ability to migrate to the human body, and its pharmacokinetics and physiological activity. Is expected to have the same pharmacological action as isovitexin and vitexin, and is likely to be used as a new naturally-occurring anti-inflammatory agent with higher efficiency and superior safety.
- chafuroside precursor is low in many commercial black teas, it is of interest to how the chafuroside precursor is metabolically converted by the oxidative enzyme reaction in the fermentation of tea production.
- the sulfated C-glycoside of the present invention is a novel compound and has a flavone skeleton represented by the following general formula (A1) or (B1). It is a sulfated product of
- R ⁇ 1 >, R ⁇ 2 > and R ⁇ 3 > respectively independently represent a hydrogen atom or OH group.
- R 1 is an OH group
- R 1 and R 2 are each a hydrogen atom.
- Specific examples of the compound represented by the general formula (A1) or (B1) include A1-1, A1-2, A1-3, A1-4, B1-1, B1-2, And B1-3 and B1-4. (In the formula, R, R 1 and R 2 have the same meanings as in the general formulas (A1) and (B1), respectively).
- chafuroside precursor A prechafuroside A
- compound (A1-2) which is a sulfated form of isovitexin
- chafuroside precursor B previfuroside B
- vitexin 2 "-sulfate a particularly preferred compound
- the sulfated C-glycoside represented by the general formula (A1) or (B1) of the present invention is the sulfated C-glycoside. It can be isolated from tea leaves or tea astringents containing the body by extraction with water, a lower alcohol solvent or a mixture thereof. That is, in the method for isolating a sulfated C-glycoside of the present invention, water, a lower alcohol solvent having 1 to 3 carbon atoms or a mixture thereof is obtained from tea leaves or tea astringents containing the sulfated C-glycoside. And a step of extracting the sulfated C-glycoside.
- the specific procedure for isolation is not particularly limited, but it is preferably carried out by a method including the following steps (a) to (c).
- (b) The extract obtained in the extraction step (a) is heated and concentrated to dryness under reduced pressure to obtain a dry solution containing the sulfated C-glycoside Concentration / drying step for obtaining substances
- examples of the tea leaves include fresh tea leaves, green tea tea leaves, roast tea tea leaves, tea tea leaves, oolong tea and the like. Particularly preferred are fresh tea leaves, green tea leaves that are not heated strongly, or oolong tea leaves.
- tea astringents that contain sulfated C-glycosides as the astringent tea, use must be made of powdered tea from the relatively brittle parts of tea leaves, such as the buds in the green tea production process, or those that have hardened. Can do.
- the method for pulverizing these tea leaves or tea astringents is not particularly limited.
- the lower alcohol solvent having 1 to 3 carbon atoms used in the extraction step (a) includes methanol, ethanol, propanol, etc., preferably methanol.
- tea leaves or tea astringents containing sulfated C-glycoside are pulverized and dispersed in water, and the tea leaves or tea astringent powders are mixed with the water 5 Sulphation is carried out using an extraction operation at 5 to 70 ° C. for 5 to 30 minutes using an aqueous solution of 40 to 60 wt% (preferably 45 to 55 wt%) of methanol of 20 to 20 times (preferably 5 to 15 times).
- An extract containing C-glycoside is obtained.
- the extract obtained in the extraction step (a) is subjected to a sufficient temperature (preferably 20 boiling points of the extract) under reduced pressure (preferably 10 to 500 mmHg).
- the solvent of the extract is evaporated to concentrate, and further heating is continued at the concentration temperature to substantially remove the solvent, and the substance dissolved in the extract is dried. It is particularly preferable to obtain a dried solid material containing sulfated C-glycoside.
- the dried solid material containing the sulfated C-glycoside obtained in the concentration / drying step (b) is liquid-liquid distributed using water and an n-butanol solvent.
- the aqueous layer is purified by the method used for chemical separation and purification. Examples of the chemical separation and purification method include thin layer chromatography, adsorption chromatography, partition chromatography, gel filtration chromatography, ion exchange chromatography, high performance liquid chromatography (HPCL), electrophoresis and the like.
- the sulfated C-glycoside is a highly polar substance with high water solubility due to the presence of sulfate groups. Therefore, in the liquid-liquid partition between water and n-butanol solvent, isovitexin, vitexin, and chafuroside migrate to the n-butanol solvent layer, whereas the sulfated C-glycoside is contained in the aqueous layer portion.
- the aqueous layer portion after the liquid-liquid distribution is passed through a synthetic adsorbent and the like, and after sufficiently washing with water, the adsorbing portion is 10 to 60% methanol (preferably 30% methanol) and then fractionated by gel filtration, silica gel column chromatography, etc., and each eluted fraction is heated at 140-190 ° C. for 5-180 minutes (more preferably at 160 ° C. for 40 minutes).
- the amount of chafuroside produced after treatment is determined by LC-MS / MS analysis, and only the fraction with the highest production amount is subjected to purification by HPLC.
- LC-MS / MS analysis method an HPLC-MS / MS analysis method using a methanol aqueous solution or an acetonitrile aqueous solution can be used.
- HPLC-MS / MS analysis method for example, “Cadenza CD C18 HPLC-MS / MS analysis method” using a specific solvent using a C18 column manufactured by Intact Corporation can be used.
- the methanol aqueous solution or acetonitrile aqueous solution is 20 to 80 wt% methanol aqueous solution or 10 to 60 wt% acetonitrile aqueous solution, which can be obtained with high accuracy in the separation process of tea leaves or more particularly in HPLC-MS / MS analysis. More preferably, the chafuroside or its analog contained therein can be quantified after the heat treatment of the fractions.
- the sulfated C-glycoside of the present invention is a flavone C— represented by the following general formula (A0) or (B0): It can also be obtained by synthesis from glycosides.
- R 1 , R 2 and R 3 each independently represent a hydrogen atom or an OH group.
- Examples of the flavone C-glycoside represented by the above general formula (A0) or (B0) include A0-1, A0-2, A0-3, A0-4, B0-1, B0- 2, B0-3, and B0-4. (In the formula, R, R 1 and R 2 have the same meanings as in the general formulas (A1) and (B1), respectively).
- isovitexin the above compound (A0-2)
- vitexin the above compound (B0-2)
- the method for synthesizing a sulfated C-glycoside of the present invention comprises reacting the flavone C-glycoside represented by the above general formula (A0) or (B0) with a sulfate group introducing agent, and then reacting the flavone C-glycoside. It includes a step of sulfating a saccharide.
- the sulfate group introducing agent used here is not particularly limited, but is selected from the group consisting of pyridine-SO 3 complex (Pyridine-SO 3 (1: 1) complex), sulfuric acid-DCC, and triethylamine-SO 3 complex. Things.
- the method for synthesizing chafuroside precursors A and B from isovitexin and vitexin among the above synthesis methods will be described more specifically.
- the hydroxyl groups at positions 4 and 5 of isovitexin or vitexin are protected in advance.
- the protecting group for example, benzaldehyde dimethyl acetal-PPTS, benzaldehyde-zinc chloride or the like can be used.
- a sulfate group introducing agent is reacted with the compound having a protecting group introduced at the 4th and 5th positions to introduce a sulfate group at the desired 2nd position.
- the reaction temperature at this time is preferably 20 to 80 ° C., more preferably 30 to 40 ° C., and the reaction time is 0.5 to 8 hours, more preferably 2 to 4 hours.
- the isovitexin or vitexin derivative obtained by protecting the hydroxyl groups at the 4th and 5th positions of isovitexin or vitexin and sulphated at the 2 "or 3" position was converted into a cation exchange resin (IR-120), 40 After removing the 4- and 5-hydroxyl protecting groups by hydrolysis with% acetic acid, etc., the desired chafuroside precursor is distributed column chromatography using Sep-Pack C18, HPLC using ODS-C18 column, gel filtration Etc., and can be isolated and purified.
- the method for producing chafloside and its analog of the present invention includes a step of heating the sulfated C-glycoside at 140 to 190 ° C, preferably 150 to 180 ° C. It is characterized by that. By heating the sulfated C-glycoside, it is considered that an intramolecular cyclization reaction proceeds through a transition state to generate chafuroside and its analogs.
- the chafuroside represented by the following general formula (A2) and its analogs are obtained from the sulfated C-glycosides represented by the general formula (A1).
- chafuroside represented by the following general formula (B2) and its analogs can be obtained.
- R, R 1 and R 2 have the same meanings as in the general formulas (A1) and (B1), respectively.
- the sulfated C-glycosides represented by the following general formulas (A1-1) and (B1-1) are each represented by the following general formula ( The analogues of chafuroside represented by A2-1) and (B2-1) are obtained. From the chafuroside precursors A and B represented by the general formulas (A1-2) and (B1-2), chafuroside A and B represented by the following general formulas (A2-2) and (B2-2), respectively, can get.
- Example 1 the contents of chafloside A and chafloside B contained in various tea leaves were analyzed by the following method. Firstly, using Puriri (Vitex lucens) from New Zealand as a raw material, chafloside A and B were synthesized from isovitexin and vitexin prepared from them by Mitsunobu reaction, and using them, a calibration curve for chafloside analysis was prepared. And quantitative analysis of chafloside A and B in various tea leaves.
- Puriri Vitex lucens
- Reagents All reagents and solvents used for the synthesis were Wako Pure Chemicals special grades. “ODS C18” packed in the trade name “Sep-Pack C18 Cartridge” of Waters was used as the distribution type separating agent. The product name “Sephadex LH 20” (Pharmacia) was used for gel filtration, and the product name “Diaion SP825” (Mitsubishi Chemical Corporation) was used as the adsorptive separation agent. The trade name “Cadenza CD-C18” (manufactured by Intact Corporation) was used for the HPLC column for separation.
- NMR measurement is performed under the trade name “JNM-ECA 500” (manufactured by JEOL Ltd.), and LC-MS / MS analysis is performed under the trade names “Agilent 1100” and “API 2000” (Applied Bio).
- Product name "QSTAR” (Applied Bio) for QTOF-MS measurement product name "U3900” (manufactured by Hitachi, Ltd.) for UV measurement, and heating chamber for microdistillation for heating (Buchi) was used.
- a calibration curve was prepared from the peak area of each compound in the chromatogram obtained using 10 ⁇ l of the standard solution of each concentration, and quantitative analysis was performed by the PLC-MS / MS method using the ESI method. MS / MS conditions are shown below.
- Table 2 shows the results of analyzing the amounts of chafloside A, chafuroside B, isovitexin, and vitexin contained in the tea leaves of each brand by the HPLC-MS / MS method.
- the unit of content shown in the table is “ng / g”.
- chafloside A and chafloside B were detected together with isovitexin and vitexin.
- the content of isovitexin and vitexin was several tens to 100 ⁇ g per gram of tea leaves, and when viewed in average values, the amounts were in the order of green tea, roasted tea, oolong tea, and black tea, and there was no significant difference between each tea and brand.
- Green tea is steamed from fresh young leaves and then immediately cooled, dried at a temperature of about 80 ° C, with water blown by hand and dried.
- Black tea is bent over about 8 hours, drained, drained, and then oxidatively fermented by hand for several hours, and then tea is made with hot air of about 90 ° C. while drying in a short time.
- Oolong tea deflects mature leaves by sunbathing for 2-3 hours, moderately fermented with shaking on the bamboo basket in the room, then kills the enzyme in a short time with hot air of 160-260 ° C, and finally Make tea at 90 ° C while drying.
- Roasted green tea is made by roasting green tea at 160-200 ° C for a short time.
- the oolong tea made from Shizu 7132 had no evidence of roasting marks that were strongly burned when the content of oolong tea was high at room temperature.
- the content of green tea made from the same tea leaves of the same family increased significantly when roasted. From the above, it was speculated that one of the generation factors of chafloside A and chafloside B was heating at a high temperature of 160 ° C. or higher.
- Oolong tea made from Sei 7132 was heated at 120, 140, 160, 180 and 200 ° C. for 40 minutes, and then the contents of chafuroside A and B in each tea leaf were determined. The results shown are obtained.
- the unit of content shown in the table is “ng / g”.
- chafuroside A and B are produced by Mitsunobu reaction in which triphenylphosphine and diethylazodicarboxylate are allowed to act on isovitexin and vitexin. Therefore, we first examined the extraction of precursors and their properties as follows.
- the precursors were separated by drying the fractions obtained in each separation step, followed by heat treatment at 160 ° C. for 40 minutes, and then LC-MS / MS analysis of chafuroside A and B. Then, only the fraction with the highest production amount of chafuroside A and B was used for the next separation.
- FIG. 1 chart diagram
- Oolong tea leaves (1 Kg) made from Shizu 7132 were pulverized and extracted with MeOH (10 L) under reflux. The obtained extract was concentrated to dryness under reduced pressure, and the extract (348 g) was suspended in water (4 L) and extracted with n-BuOH (4 and 1 L). The aqueous layer (142 g) was dissolved in water (3 L), applied to “Diaion SP825” (2.4 L), washed with water (3 L), and eluted with 30% methanol (8 L). The 30% methanol eluate (248 g) was fractionated by gel filtration using “Sephadex LH-20” (12 L) developed with methanol.
- the aqueous layer is attached to a strongly basic ion exchange resin, and the adsorption part is developed by gel filtration using “Sephadex LH-20” (12 L) and developed with a 20% acetonitrile solution.
- ODS-C18 "(400 mL) column chromatography can be purified by HPLC or the like to use the" Cadenza CD-C18 “column and 0,05% HCO 2 H-CH 3 CN (82:18).
- Chafloside precursor A has maximum absorption in its UV spectrum at the same wavelengths as isovitexin, 330 nm ( ⁇ 40200) and 284 nm ( ⁇ 64200), and chafuroside precursor B has maximum absorption wavelengths of vitexin, 325 nm ( ⁇ 44100) and 285 nm ( Maximum absorption was observed at ⁇ 62200). Further, isovitexin was produced from chafuroside precursor A and vitexin was produced almost quantitatively from chafuroside precursor B by hydrolysis with pyridine-dioxane (1: 1).
- chafloside precursor A and chafuroside precursor B are isovitexin and vitexin, respectively. It was strongly suggested that the OH group at the C-2 ′′ position was sulfated.
- chafuroside precursors A and B were “isovitexin 2” -O-sulfate ”and“ vitexin 2 ”-O-sulfate” shown in the following chemical formulas, respectively.
- the left is “isovitexin 2” -O-sulfate ”and the right is“ vitexin 2 ”-O-sulfate”.
- chafloside precursor A is a fragment ion (m / z 431.1040 (calcd for C 21 H 19 O 10 , 431.0978)) that can be assigned to C 21 H 19 O 10 corresponding to [isovitexin-H].
- the compound hydroxyl group in the side chain of the sulfated saccharide or bile alcohol is sulfated, OH close by strong alkali treatment O - and becomes nucleophile, resulting SN 2 type displacement reaction is induced, intramolecular ring It is known that the process proceeds.
- chafuroside precursor A was synthesized from isovitexin.
- Isovitexin 2 "-sulfate was directly compared in structure with that extracted from tea leaves in Example 2 above, and confirmed to be the chafroside precursor A. Also, this Isovitexin 2" -sulfate When sulfate was heated at about 160-170 ° C., chafloside A was produced in a yield of about 85%.
- chafuroside precursor B was synthesized from vitexin.
- Vitexin 2 "-sulfate Vitexin 2" -sulfate
- Compound D dissolved in 20% MeOH and acidic type cation exchange resin (trade name "Amberlite IR-120 (H +)" (Rohm & Haas)
- acidic type cation exchange resin trade name "Amberlite IR-120 (H +)” (Rohm & Haas)
- the product was adjusted to pH 3 and heated with stirring at 50 ° C. for about 1 hour to obtain Vitexin 2 ′′ -sulfate (yield: 100%).
- Vitexin-2 "-sulfate was directly compared with that extracted from tea leaves in Example 2 above, and confirmed to be the chafuroside precursor B. Also, this Vitexin 2" -sulfate was confirmed. When sulfate was heated at about 160-170 ° C., chafloside B was produced in a yield of about 85%.
- the chafuroside precursors (chafuroside precursors A and B), which are novel compounds found in the present invention, have excellent pharmacological actions such as antioxidant action, antiallergic action, anti-inflammatory action, and carcinogenesis-suppressing action by themselves.
- a sulfate group is introduced, it has high water solubility and excellent compatibility with the human body.
- this chafuroside precursor is used, it becomes possible to produce chafuroside A and B, which are already known to have such medicinal components, in an extremely high yield.
- the scale-up can be used for industrial production. Production is possible and is extremely useful in industry.
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Abstract
Description
また、Minマウスのラット大腸におけるアゾキシメタン(AOM)誘発腸管ポリープ形成に対してチャフロサイドAは、インドメタシン(indomethacin)と同用量の2.5mg/kgで効果的に抑制する作用を発揮することが確認された。そして、この効果はチャフロサイドAがCOX-2に阻害的に作用するためと推察された。これらのこととその構造から、チャフロサイドAは新しいタイプの抗炎症剤となる可能性が高い(特許文献2,非特許文献3参照)。
上述したようなチャフロサイドA及びBの構造、製法及び生理活性などから、チャフロサイドA及びBのウーロン茶葉中における生成メカニズムには非常に興味が持たれているが、簡便かつ高収率で、しかも安全で安価な工業的生産方法は未だ確立されておらず、これらの化合物の高い有用性からすると、その効率よい生産方法の開発が強く望まれている。
さらに、これら前駆体を加熱処理することにより、容易かつ高収率にてそれぞれチャフロサイドAとBへ変換可能、すなわちこれら前駆体より極めて効率的にチャフロサイドAとBが得られることを見いだした。
(1)下記一般式(A1)又は(B1)で表される硫酸化C-配糖体。
(イ)前記硫酸化C-配糖体を含有する茶葉又は茶渋の粉砕物を、水、炭素数1~3の低級アルコール溶剤又はそれらの混合液を用いて抽出し、該硫酸化C-配糖体を含む抽出液を得る抽出工程
(ロ)前記抽出工程(イ)で得られた抽出液を減圧下で加熱濃縮乾固させ、前記硫酸化C-配糖体を含む乾固物質を得る濃縮・乾固工程
(ハ)前記濃縮・乾固工程(ロ)で得られた硫酸化C-配糖体を含む乾固物質を、水及びn-ブタノール溶剤を用いて液液分配し、その水層部を化学分離精製法により精製する精製工程
(7)下記一般式(A2)又は(B2)で表されるチャフロサイド及びその類縁体を製造する方法であって、(1)又は(2)記載の硫酸化C-配糖体を130~190℃で加熱する工程を含むことを特徴とする、チャフロサイド及びその類縁体の製造方法。
本発明で確認されているのはチャフロサイドAの前駆体(イソビテキシン2-sulfate)とチャフロサイドBの前駆体(ビテキシン2-sulfate)からそれぞれチャフロサイドAとBが生成することのみであるが、チャフロサイドA及びBの両前駆体と同じ部分構造を有する化合物は、チャフロサイドAとBと同じ部分構造を有する化合物に変換されることが推定される。また、チャフロサイドA及びBと同じ部分構造を有するこれらの化合物群にも優れたステロイド様の抗炎症の生理活性が期待される。
(1)硫酸化C-配糖体
本発明の硫酸化C-配糖体は新規化合物であり、下記一般式(A1)又は(B1)で表されるフラボン骨格を有するフラボンC-配糖体の硫酸化体である。
本発明の上記一般式(A1)又は(B1)で表される硫酸化C-配糖体は、該硫酸化C-配糖体を含有する茶葉又は茶渋から水、低級アルコール溶剤又はそれらの混合物を用いて抽出することにより単離することができる。すなわち、本発明の硫酸化C-配糖体の単離方法は、前記硫酸化C-配糖体を含有する茶葉又は茶渋から水、炭素数1~3の低級アルコール溶剤又はそれらの混合液を用いて該硫酸化C-配糖体を抽出する工程を含むことを特徴とする。
(イ)前記硫酸化C-配糖体を含有する生茶葉、茶葉又は茶渋の粉砕物を、水、炭素数1~3の低級アルコール溶剤又はそれらの混合液を用いて抽出し、該硫酸化C-配糖体を含む抽出液を得る抽出工程
(ロ)前記抽出工程(イ)で得られた抽出液を減圧下で加熱濃縮乾固させ、前記硫酸化C-配糖体を含む乾固物質を得る濃縮・乾固工程
(ハ)前記濃縮・乾固工程(ロ)で得られた硫酸化C-配糖体を含む乾固物質を、水及びn-ブタノール溶剤を用いて液液分配し、その水層部を化学分離精製法により精製する精製工程
ゲル濾過は、商品名「Sephadex LH-20」(ファルマシア社製)、Bio Gel P-2等のゲル濾過クロマトグラフィーを用いることができる。
本発明の硫酸化C-配糖体は、下記一般式(A0)又は(B0)で表されるフラボンC-配糖体から合成することによっても得ることができる。ここで、下記一般式(A0)及び(B0)中、R1、R2及びR3は各々独立して水素原子又はOH基を表す。
次いで、4位と5位に保護基を導入された前記化合物に硫酸基導入剤を反応させ、所望する2位に硫酸基を導入する。このときの反応温度は、好ましくは20~80℃、より好ましくは30~40℃であり、反応時間は0.5~8時間、より好ましくは2~4時間である。
本発明のチャフロサイド及びその類縁体の製造方法は、前記硫酸化C-配糖体を140~190℃、好ましくは150~180℃で加熱する工程を含むことを特徴とする。硫酸化C-配糖体を加熱することによって、遷移状態を経て分子内環化反応が進行しチャフロサイド及びその類縁体が生成すると考えられる。その化学反応式について、チャフロサイド前駆体A(イソビテキシン2"-sulfate)からチャフロサイドAの製造、及びチャフロサイド前駆体B(ビテキシン2"-sulfate)からチャフロサイドBの製造における化学反応の例を以下に示す。
本実施例1では、各種の茶葉中に含まれるチャフロサイドAとチャフロサイドBの含量を、以下の方法で分析した。まず、ニュージランド産のPuriri(Vitex lucens)を原料として、これから調製したイソビテキシン及びビテキシンから光延反応でチャフロサイドAとBをそれぞれ合成し、それらを用いてチャフロサイド分析用の検量線を作製し、それをもとに各種茶葉中のチャフロサイドAとBの定量分析を行った。
合成に使用した試薬、溶媒はすべて和光純薬社製特級品を用いた。分配型分離剤としてはWaters社の商品名「Sep-Pack C18 Cartridge」に充填されている「ODS C18」を用いた。ゲル濾過に商品名「Sephadex LH 20」(ファルマシア社製)、吸着分離剤として商品名「Diaion SP825」(三菱化学(株)製)を使用した。分離用HPLCカラムに商品名「Cadenza CD-C18」(インタクト(株)製)を使用した。
実験用茶葉には以下の品種のものを使用した。
緑茶;静7132、藪北、さやまかおり
焙じ茶;静7132、藪北
ウーロン茶;静7132、水仙、鉄観音
紅茶;静7132、アッサム、ダージリン
なお、静7132から製造した緑茶、ウーロン茶、及び紅茶は、静岡県島田市在住の茶製造の専門家が作成したものである。
NMR測定は、商品名「JNM-ECA 500」(日本電子社製)、LC-MS/MS分析には商品名「Agilent 1100」及び「API 2000」(Applied Bio社製)を併用し、QTOF-MS測定には商品名「QSTAR」(Applied Bio社製)、UV測定は商品名「U3900」((株)日立製作所製)、加熱にはミクロ蒸留用加熱恒温槽(Buchi社製)を使用した。
予め合成したチャフロサイドAとB、及びイソビテキシンとビテキシンから、それぞれ0.2ng/ml、1.0ng/ml、10ng/ml、100ng/ml及び1000ng/mlの標準溶液を調製した。これらの各標準溶液を使用し、カラムには商品名「Cadenza CD-C18」(3×150mm)を用い、溶出展開はH2O-CH3CNの混合溶媒を用いて20分かけて15~50%とするグラジエント法を使用した。
上記各銘柄の茶葉に含まれるチャフロサイドA、チャフロサイドB、イソビテキシン、及びビテキシンの量をHPLC-MS/MS法で分析した結果を、下記表2に示す。なお、表中に示される含有量の単位は「ng/g」である。
以上のことから、チャフロサイドAとチャフロサイドBの生成要因の一つは160℃以上の高温での加熱と推察された。
静7132より製したウーロン茶を120、140、160、180及び200℃で40分間加熱した後、それぞれの茶葉中のチャフロサイドAとBの含有量を求め、表3に示す結果を得た。なお、表中に示される含有量の単位は「ng/g」である。
本実施例では、チャフロサイド前駆体の分離・精製、及び構造決定を行った。
上述したように、チャフロサイドAとBはイソビテキシンとビテキシンにトリフェニルホスフィンとジエチルアゾジカルボキシレートを作用させる光延反応により生成する。そこで、最初に前駆体の抽出とその性状について以下のように検討を加えた。
静7132より製したウーロン茶葉(1g)を粉砕し、環流下、MeOH、50%-MeOH及び水(1ml)で抽出し、抽出液を減圧下濃縮乾固後、水(0.4ml)に懸濁しn-BuOH(4及び1ml)で抽出した。各抽出物、それらより液液分配で得た水層部とn-BuOH層部を160℃で40分間加熱した。
Negative modeでのQTOF-MS分析により求めたチャフロサイド前駆体AとB両化合物の精密分子量(prechafuroside A: m/z 511.05612 (M-H) _と prechafuroside B:m/z 511.05643 (M-H)-)と、13C-NMRデータ(下記表5参照)より、両化合物の分子式を「C21H20O13S」(calcd. for C21H20O13S _ H, 511.05625)と決定した。
本実施例では、チャフロサイド前駆体Aを、イソビテキシンから合成した。
(1)イソビテキシンの4位と5位の水酸基を保護した化合物の合成
ジメチルホルムアルデヒド(DMF)中で、触媒量のPPTS(Pyridine-p-Toluenesulfuric acid complex)の存在下、イソビテキシンに2当量のBenzaldehyde dimethylacetalを50℃で2時間作用させ、イソビテキシンの4位と5位の水酸基を保護した「化合物A」(Mw(分子量)=520)を合成した(収率:100%)。
前記化合物Aをピリジン(Pyridine)に溶解後、1.5当量のPyridine-SO3 (1:1) complexを50℃で2時間作用させ、前記化合物Aの2"-sulfate(以下、「化合物B」とする)(Mw=600)を合成した(収率:約50%)。この方法で、化合物Bと同じ量の化合物Aの3"-sulfateが生成した。
20%MeOHに溶解した化合物Bに酸性タイプの陽イオン交換樹脂(商品名「Amberlite IR-120(H+)」(ローム&ハース社製)を加え、pH3とし、約1時間50℃で撹拌下加熱し、Isovitexin 2"-sulfateを得た(収率:100%)。これらの化学反応を以下の化学式で示す。
本実施例では、チャフロサイド前駆体Bを、ビテキシンから合成した。
(1)ビテキシンの4位と5位の水酸基を保護した化合物の合成
ジメチルホルムアルデヒド(DMF)中で、触媒量のPPTS(Pyridine-p-Toluenesulfuric acid complex)の存在下、ビテキシンに2当量のBenzaldehyde dimethylacetalを50℃で2時間作用させ、ビテキシンの4位と5位の水酸基を保護した「化合物C」(Mw(分子量)=520)を合成した(収率:100%)。
前記化合物Cをピリジン(Pyridine)に溶解後、1.5当量のPyridine-SO3 (1:1) complexを50℃で2時間作用させ、前記化合物Cの2"-sulfate(以下、「化合物D」とする)(Mw=600)を合成した(収率:約50%)。この方法で、化合物Dと同じ量の化合物Cの3"-sulfateが生成した。
20%MeOHに溶解した化合物Dに酸性タイプの陽イオン交換樹脂(商品名「Amberlite IR-120(H+)」(ローム&ハース社製)を加え、pH3とし、約1時間50℃で撹拌下加熱し、Vitexin 2"-sulfateを得た(収率:100%)。これらの化学反応を以下の化学式で示す。
したがって、本発明によれば、安価で安全な出発物質や試薬を用い、且つ比較的穏やかな反応条件であるにもかかわらず、高収率でチャフロサイドを生成することができるため、スケールアップにより工業的生産が可能であり、産業上極めて有用である。
Claims (7)
- 請求項1又は2記載の硫酸化C-配糖体を単離する方法であって、前記硫酸化C-配糖体を含有する茶葉又は茶渋から水、炭素数1~3の低級アルコール溶剤又はそれらの混合液を用いて該硫酸化C-配糖体を抽出する工程を含むことを特徴とする、硫酸化C-配糖体の単離方法。
- 以下の工程(イ)、(ロ)及び(ハ)を含むことを特徴とする、請求項3記載の硫酸化C-配糖体の単離方法。
(イ)前記硫酸化C-配糖体を含有する生茶葉、茶葉又は茶渋の粉砕物を、水、炭素数1~3の低級アルコール溶剤又はそれらの混合液を用いて抽出し、該硫酸化C-配糖体を含む抽出液を得る抽出工程
(ロ)前記抽出工程(イ)で得られた抽出液を減圧下で加熱濃縮乾固させ、前記硫酸化C-配糖体を含む乾固物質を得る濃縮・乾固工程
(ハ)前記濃縮・乾固工程(ロ)で得られた硫酸化C-配糖体を含む乾固物質を、水及びn-ブタノール溶剤を用いて液液分配し、その水層部を化学分離精製法により精製する精製工程 - 前記硫酸基導入剤が、ピリジン-SO3錯体、硫酸?DCC、及びトリエチルアミン-SO3錯体からなる群から選択されるものである、請求項5記載の硫酸化C-配糖体の合成方法。
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JP2016222581A (ja) * | 2015-05-29 | 2016-12-28 | 静岡県公立大学法人 | 硫酸化ビテキシン2”または硫酸化イソビテキシン2”の前駆体、メラニン生成抑制剤およびそれらを含む飲食品 |
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Also Published As
Publication number | Publication date |
---|---|
EP2385049A1 (en) | 2011-11-09 |
EP2385049A4 (en) | 2012-08-08 |
KR101615876B1 (ko) | 2016-04-27 |
KR20110120278A (ko) | 2011-11-03 |
CA2748729A1 (en) | 2010-07-08 |
CN102272129A (zh) | 2011-12-07 |
US8367622B2 (en) | 2013-02-05 |
JP5597142B2 (ja) | 2014-10-01 |
US20120029183A1 (en) | 2012-02-02 |
CN102272129B (zh) | 2014-10-08 |
JPWO2010076879A1 (ja) | 2012-06-21 |
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