US20090047305A1 - Method of producing proanthocyanidin oligomer - Google Patents

Method of producing proanthocyanidin oligomer Download PDF

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Publication number
US20090047305A1
US20090047305A1 US11/814,922 US81492206A US2009047305A1 US 20090047305 A1 US20090047305 A1 US 20090047305A1 US 81492206 A US81492206 A US 81492206A US 2009047305 A1 US2009047305 A1 US 2009047305A1
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Prior art keywords
ring structure
substance
phloroglucinol
proanthocyanidin
acid
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US11/814,922
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Inventor
Takashi Tanaka
Gen-ichiro Nonaka
Isao Kohno
Hajime Fujii
Takashi Nakagawa
Hiroshi Nishioka
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Usaien Pharmaceutical Co Ltd
Amino UP Chemical Co Ltd
Nagasaki University NUC
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Usaien Pharmaceutical Co Ltd
Amino UP Chemical Co Ltd
Nagasaki University NUC
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Assigned to AMINO UP CHEMICAL CO., LTD., NAGASAKI UNIVERSITY, USAIEN PHARMACEUTICAL CO., LTD. reassignment AMINO UP CHEMICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NONAKA, GEN-ICHIRO, KOHNO, ISAO, TANAKA, TAKASHI, FUJII, HAJIME, NAKAGAWA, TAKASHI, NISHIOKA, HIROSHI
Publication of US20090047305A1 publication Critical patent/US20090047305A1/en
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Definitions

  • the invention relates to a method of producing a proanthocyanidin oligomer, which can reduce a molecular weight of proanthocyanidin polymer in plant to a level that it can be absorbed (easily by the gastrointestinal tract) into a living body.
  • the invention relates to a composition containing proanthocyanidin oligomer having a polymerization degree of 2 to 4 and having a phloroglucinol ring structure or resorcinol ring structure bonded at its terminal, which is obtained by heating a material containing proanthocyanidin polymer together with a substance having a phloroglucinol ring structure or resorcinol ring structure in an acidic solution, a production method thereof, uses of the composition and a novel proanthocyanidin oligomer having a phloroglucinol ring structure or resorcinol ring structure bonded thereto.
  • composition containing proanthocyanidin oligomer obtained according to the invention can be used in food products, health food products, foods for specified health use, cosmetic products and medical products.
  • the composition is useful as composition for health food products and medical products for prevention of lifestyle-related diseases caused by generation of reactive oxygen species, prevention and treatment of brain diseases or prevention of aging.
  • Polyphenols which are generally contained, in teas, vegetables, fruits, herbs and the like, can be expected to be ingested as food and beverages for a long period of time and serve as treatment/prevention agent free of side effects.
  • tea polyphenols especially catechins are known to have a wide range of physiological activities such as antibiotic properties, antiviral action, antimutagenic property, antioxidation effect, blood-pressure increase suppression, property of reducing cholesterol in the blood, antidecay property, antiallergic activity, improvement of enteric flora, odor eliminating activity and the like.
  • proanthocyanidins are contained in a wider range of plants.
  • proanthocyanidin compound needs to be absorbed into the living body by the gastrointestinal tract.
  • molecular weights of proanthocyanidins are generally said to be on the order of several thousands to several tens of thousands. Substance having such a large molecular weight is difficult to be absorbed by the gastrointestinal tract and in many cases, even if it is ingested, it is not absorbed in the living body and not used as nutrition.
  • proanthocyanidins is a generic name for procyanidin, prodelphinidin, propelargonidin and the like of polymers of dimer, trimer, tetramer, decamer or higher oligomers having as constituent unit flavan-3-ol (also referred to as catechins) and those with gallic acid, esterified thereto, and stereoisomers thereof, which are polyphenol compounds generating anthocyanidins through acid treatment.
  • the constituent units are bonded to each other through carbon-carbon bond between the 4-position and 8-position of the carbon skeleton or between the 4-position and 6-position, or sometimes through ether bond between the 2-position and 7-position in addition to the carbon-carbon bond.
  • Proanthocyanidin has an excellent antioxidative effect (Arch. Biochem. Biophys., Vol. 374, p.p. 347-355, 2000: Non-Patent Document 2), and moreover, since it has other effects such as improvement of blood flow, antistress action, antihypertensive efficacy, antibiotic effect, antitumor effect, anticataract activity and antidiarrheic effect, it has been used as a naturally-derived substance having a health-maintaining effect.
  • Proanthocyanidins are isolated as mixture from pine bark, immature apple fruit, grape seeds and the like and now, are blended in beverages, confectioneries, health foods, cosmetic products, hair-growth drugs and the like which are commercially available.
  • proanthocyanidins In many plants containing proanthocyanidin, various proanthocyanidins from those having a low polymerization degree to those having a high molecular weight are contained as mixture, and many of them are plants mainly containing proanthocyanidins of high polymerization degree such as persimmon, banana and Chinese quince.
  • proanthocyanidins a proanthocyanidin polymer having a high polymerisation degree is said to be inferior in pharmacological activities to proanthocyanidin oligomers having polymerization degree of 2 to 4 due to its poor absorbability from the intestine.
  • proanthocyanidin polymer having strong astringency and poor solubility in water, be eliminated when the plant is used in food products (Free Radical Res., Vol. 29, p.p. 351-358, 1998: Non-Patent Document 3).
  • proanthocyanidin oligomer having a polymerization degree of 2 to 4 have been attracting attention as having excellent health-maintaining effect, and those derived from pine bark are used in beverages and health foods.
  • proanthocyanidin oligomer having the cysteine bonded thereto to thereby reduce the molecular weight and be excellent in systemic absorption can be obtained. It has been confirmed that the proanthocyanidin oligomer has no toxicity and can be used safely.
  • some countries including Japan
  • Patent Document 1 Japanese Patent Application Laid-Open Ho. H06-49053
  • Patent Document 2 PCT Publication No. WO00/64883
  • Patent Document 3 PCT Publication No. WO03/091237
  • Patent Document 4 PCT Publication No. WO2004/103988
  • Non-Patent Document 1 Bioorganic & Medicinal Chemistry, Vol. 10 (2002), p.p. 2497-2509
  • Non-Patent Document 2 Arch. Biochem. Biophys., Vol. 374, p.p. 347-355, 2000
  • Non-Patent Document 3 Free Radical Res., Vol. 29, p.p. 351-358, 1998
  • the object of the invention is to provide a convenient and efficient method for reducing molecular weight of proanthocyanidin oligomer, being widely distributed in nature as proanthocyanidin polymer but limited in naturally-derived materials as oligomer, by using as starting material proanthocyanidin polymer, plant containing proanthocyanidin polymer or extract thereof and bonding the material to a substance having a phloroglucinol ring structure or resorcinol ring structure.
  • proanthocyanidin can be fractionated and reduced in its molecular weight and at the same time can be converted into proanthocyanidin oligomer having catechin bonded thereto at terminal by gently boiling fruit, fruit skin, bark, leaves or extract thereof containing proanthocyanidin polymer such as date plum, banana, grape, pine, Chamaecyparis obtuse, camphor tree, wax myrtle, Chinese quince, litchee, Myrica rubra and Cinnamomi Cortex together with green tea or fresh tea leaves containing a large amount of low-molecular weight catechins in an acidic solution for 2 to 3 hours.
  • proanthocyanidin polymer such as date plum, banana, grape, pine, Chamaecyparis obtuse, camphor tree, wax myrtle, Chinese quince, litchee, Myrica rubra and Cinnamomi Cortex together with green tea or fresh tea leaves containing a large amount of low-molecular weight catechins in
  • proanthocyanidin can be fractionated, reduced in its molecular weight and converted into proanthocyanidin oligomer having a substance having a phloroglucinol ring structure or resorcinol ring structure bonded thereto by using the substance having a phloroglucinol ring structure or resorcinol ring structure and other plant materials (such as grape seed and grape skin) containing such a substance instead of green tea or fresh tea leaves, and have completed the invention based on the findings.
  • the invention relates to the following 1 to 14 items, a composition containing as its main component proanthocyanidin oligomer to terminal of which a substance having a phloroglucinol ring structure or resorcinol ring structure is bonded by heating a plant containing proanthocyanidin polymer or extract thereof with green tea or fresh tea leaves in an acidic aqueous solution (1 to 5),
  • the composition containing proanthocyanidin oligomer described in 10 used in cosmetic products for prevention of aging caused by generation of reactive oxygen species.
  • n is 0 or an integer of 1 to 2.
  • n is 0 or an integer of 1 to 2.
  • the invention provides a method for producing a composition containing as its main component proanthocyanidin oligomer to which a substance having phloroglucinol ring structure or resorcinol ring structure has been bonded at the terminals and which thereby has been reduced in the molecular weight, which composition is obtained by concentrating and drying a reaction solution obtained by heating plant materials containing proanthocyanidin polymer or extract thereof with a substance or plants having a phloroglucinol ring structure or resorcinol ring structure or extract thereof in an acidic aqueous solution.
  • proanthocyanidin oligomer to which a substance having phloroglucinol ring structure or resorcinol ring structure has been bonded at the terminals and which thereby has been reduced in the molecular weight, and which is useful as composition for health food products and pharmaceutical products for treatment/prevention of lifestyle-related diseases caused by generation of reactive oxygen species and brain diseases or for prevention of aging, can be efficiently produced from proanthocyanidin polymer-containing materials.
  • Raw materials used for producing proanthocyanidin oligomer according to the method of the invention are proanthocyanidin polymer-containing plants (such as fruit, fruit skin, bark and leaves) or extracts thereof.
  • proanthocyanidin polymer-containing plants include fruit vegetables such as astringent persimmon, banana, apple, pear, grape, strawberry, persea americana, blueberry, hawthorn, lotus root, buckwheat, litchee and Myrica rubra, herbs, spices, wood, Cinnamomi Cortex and pine balk.
  • fruit vegetables such as astringent persimmon, banana, apple, pear, grape, strawberry, persea americana, blueberry, hawthorn, lotus root, buckwheat, litchee and Myrica rubra
  • herbs spices, wood, Cinnamomi Cortex and pine balk.
  • astringent persimmon, banana, grape, pine, Chamaecyparis obtusa, camphor tree, wax myrtle, Chinese quince, litchee and Myrica rubra are preferably used.
  • these plants containing proanthocyanidin polymer are chopped (cut) or crushed and then used and extracts obtained by heating and concentrating/drying these materials in aqueous solvent are used.
  • the substance having phloroglucinol ring structure or resorcinol ring structure used in the reaction of the present invention is a plant containing resveratrol, phloroglucinol, flavonoid and flavonoid (galloylester of catechin) or extracts thereof.
  • the substance is a plant containing resveratrol, phloroglucinol, flavonoid and flavonoid (galloylester of catechin) or extracts thereof.
  • examples thereof include green tea, fresh tea leaves, grape seed, grape seed coat, cube gambir, red algae and extracts thereof.
  • the main uses of the proanthocyanidin oligomer produced in the present invention is health food products, ingredient for food for specified health use, cosmetic products and pharmaceutical products, especially food for specified health use and pharmaceutical products, grape seed, grape seed coat, green tea, fresh tea leaves and extracts thereof, which have been conventionally applied to drinking and safety of which has been confirmed, are prefer red.
  • the proportion of proanthocyanidin polymer-containing plant materials and substance having phloroglucinol ring structure or resorcinol ring structure used in the reaction is arbitrarily selected. It is preferred, that the amount of the latter be large enough to bond to the fragments of the proanthocyanidin polymer having reduced in the molecular weight. If the amount of the substance having phloroglucinol ring structure or resorcinol ring structure is too small, proanthocyanidin having a high molecular weight may remain unreacted, and in that case, the remaining proanthocyanidin having a high molecular weight can be easily removed by column chromatography.
  • Reaction between plant containing proanthocyanidins or proanthocyanidins contained in extract thereof and the substance having phloroglucinol ring structure or resorcinol ring structure (herein after, sometimes simply referred to as “phloro/resorcinol ring-containing substance”) is conducted in solvent by heating.
  • reaction solvent water, methanol, ethanol and a mixture of two or more of them is used.
  • water and ethanol are preferred.
  • reaction be carried out under an acidic condition.
  • An acid appropriately selected from inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid and organic acids such as acetic acid, citric acid, ascorbic acid and malic acid is used in a concentration of 0.1 to 1.0 N, preferably about 0.5 N.
  • Reaction between plant or plant extract containing proanthocyanidins and phloro/resorcinol ring-containing substance is carried out at a temperature of room temperature to 100° C. for 0.5 hours to 1 week, preferably at 90 to 100° C. for 1 to 4 hours.
  • the reaction solution after the reaction is subject to filtration or the like treatment to thereby remove solid content and isolate the liquid.
  • the resultant extract (liquid) containing proanthocyanidin oligomer can be used in various forms such as liquid, powder, gel, solid molded product or the like after condensed and dried.
  • the reaction solution after the reaction may be concentrated, and dried or concentrated and fractionated.
  • the target substance is separated from the reaction solution, concentrated and purified by conventional method.
  • the concentrated liquid can be purified by subjecting the extract to film treatment (such as ultrafiltration and reverse osmosis treatment) or to treatment with adsorbent or the like treatment to thereby concentrate and isolate the target substance.
  • adsorbents examples include styrene-divinylbenzene adsorbent, methacrylic acid adsorbent, hydrophilic vinyl polymer, modified, dextran gel, polyacrylamide gel, reverse-phase silica gel and ion-exchange resin.
  • proanthocyanidin oligomers which have been reduced in the molecular weigh through reaction with the phloro/resorcinol ring-containing substance, are contained in fraction adsorbed to the adsorbent (herein after, referred to as “adsorbed fraction(s)”).
  • aromatic compound-based synthetic adsorbent include cross-linked styrene-based porous polymer such as SEPABEADS.
  • proanthocyanidin oligomer contains dimers to tetramers of proanthocyanidin whose typical chemical structure is represented by formulae (1) and (2).
  • R 1 represents a hydrogen atom or a hydroxyl group
  • R 2 represents a hydrogen atom or a hydroxyl group
  • R 2 represents a hydrogen atom or a galloyl group
  • n 0 or an integer of 1 to 2.
  • proanthocyanidin polymer having a high molecular weight (5 in terms of polymerization degree) and not absorbable into living body can be easily fragmented to thereby render the polymer a low molecular weight substance absorbable and at the same time, a composition mainly containing proanthocyanidin oligomers of dimer to tetramer can be obtained.
  • products containing the proanthocyanidin oligomer of the invention as active ingredient have not only an action to suppress generation of lipid peroxide in vivo but also effects on diseases caused by oxidative induced due to active oxygen. Therefore, the products, which have effects of preventing various organ failures caused by generation of lipid peroxide or active oxygen and also preventing aging, are effective in preventing and treating various diseases caused by such organ failures and aging. Moreover, the products can be considered to be effective in suppressing/preventing/treating cerebral dysfunctions such as dementia presumably caused by brain aging. At the same time, along with improvement in brain functions, enhancement in learning function, easing irritation, relieving insomnia, easing disconcertedness and the like effects can be expected. Thus, products containing proanthocyanidin oligomer of the invention as active ingredient can be used in health food products, pharmaceutical products, cosmetics and the like.
  • proanthocyanidin oligomer of the invention No toxicity is observed with products containing proanthocyanidin oligomer of the invention as active ingredient and the products can be used safely. These products are used orally or parenterally.
  • the dosage amount in a case of oral use differs depending on the age, weight, symptoms, target therapeutic effect, administration method and the like. Generally, it is in a range of 50 to 1000 mg per dose for adults.
  • products of the invention are used in form of tablet, ball, capsule, powder, granulated powder, syrup and the like.
  • parenteral administration they are used in form of injectable solution, coating agent and the like.
  • appropriate auxiliary agents such as starches, dextrin, sweetening agents, colorants and flavoring agents
  • Procyanidin B4(100 mg) and epigallocatechin 3-O-gallate (100 mg) were dissolved in 40 mL of 2% citric acid solution and heated at 100° C. for 2 hours. After cooled down, the reaction solution was subjected to MCI-gel CHP20P (aqueous methanol) column chromatography and then to Sephadex LH-20(60% methanol) column chromatography, to thereby recover as raw material procyanidin B4(10 mg) and epigallocatechin 3-O-gallate (59.2 mg) and also obtain newly generated ( ⁇ )-epicatechin (25.4 mg) and (+)-catechin (4 ⁇ 8) ( ⁇ )-epigallocatechin 3-O-gallate (17.3 mg).
  • MCI-gel CHP20P aqueous methanol
  • Sephadex LH-20(60% methanol) column chromatography Sephadex LH-20(60% methanol) column chromatography
  • procyanidin polymer extracted from beetle nut and ( ⁇ )-epigallocatechin 3-O-gallate were dissolved in 200 mL of 2% citric acid solution and heated at 95° C. for 3 hours.
  • the reaction solution was subjected to column chromatography in the same manner as Example 1, epigallocatechin 3-O-gallate (403 mg), newly generated (+)-catechin (48.6 mg) and ( ⁇ )-epicatechin (4 ⁇ 8)-( ⁇ )-epigallocatechin 3-O-gallate (148.3 mg) which is proanthocyanidin were obtained (see the above structural formulae).
  • the extract liquid obtained in Example 3 by heating Japanese cypress hark and green tea in the citric acid solution was concentrated and then subjected to solvent partition with 50 mL of water and 50 mL of ethyl acetate 5 times.
  • the obtained ethyl acetate layer was gathered together and also concentrated to thereby obtain 0.67 g of ethyl acetate extracted product.
  • the extracts obtained from the separately treated Japanese cypress bark and green tea respectively were subjected to solvent partition in the same manner, to thereby obtained 0.30 g of ethyl acetate extracted product from the Japanese cypress bark and 0.37 g of ethyl acetate extracted product from the green tea.
  • the thus obtained three extracts of ethyl acetate were analyzed by TLC.
  • the conditions of TLC are as follows.
  • Coloring reagent vanillin hydrochloric acid reagent (see TLC in FIG. 2 .)
  • Vanillin hydrochloric acid reagent which is a detection reagent for catechins and proanthocyanidins, takes on a color of characteristic red when these substances are present. With respect to the extract obtained through treatment of Japanese cypress bark and green tea in the citric acid solution, spots derived from proanthocyanidin dimmer and trimer were acknowledged.
  • proanthocyanidin having a higher molecular weight than the molecular weight of those transferred to the ethyl acetate layer, remains. Then, molecular weights of acetylated compounds of proanthocyanidins contained in the water layer were compared by gel permeation chromatography analysis.
  • the water layer after Japanese cypress bark and green tea was treated with citric acid solution and the water layer of Japanese cypress bark were concentrated and dried to be solid. After dissolved in acetic anhydride-pyridine, the solution was left standing at room temperature for 8 hours.
  • the reaction solutions were respectively poured into ice water, and insoluble matter deposited was taken out though filtration and vacuum-dried.
  • the obtained acetylated body was analysed under conditions of TSK-GEL G4000H6 column, solvent of tetrahydrofuran, and detection with 254 nm UV absorption.
  • molecular weight of the obtained products estimated based on calibration curves prepared by using benzene and polystyrenes having molecular weights of 4000, 25000 and 50000, the peak top of proanthocyanidin contained in the water layer after treating Japanese cypress bark and green tea with citric acid was about 1300 while the peak top of proanthocyanidin contained in the water layer of Japanese cypress bark was about 2000. It was found out that by adding green tea in the citric acid treatment, the molecular weight was reduced.
  • 100 g of fresh banana skin was pulverized together with 300 mL of acetone-water mixture solution (4:1, v/v) by using a whirling blender and subjected to suction filtration.
  • Acetone was distilled off the filtrate by using an evaporator to thereby prepare an aqueous solution, insoluble matter was filtered out and water is added to the solution to make the total amount 200 ml.
  • 3 g of green tea leaves was boiling extraction in 300 mL of water and after the resultant was subjected to suction filtration, water was added to make the total amount 300 ml.
  • the obtained extracts of ethyl acetate were analysed by TLC (see TLC in FIG. 3 ). Due to the high molecular weight of proanthocyanidin in the banana skin extract, the extract is positive for vanillin hydrochloric acid, reagent only at the origin point on the TLC analysis while in the product obtained by treating banana skin extract and green tea extract with citric acid, spots derived from new proanthocyanidin dimmer and trimer, which had not existed in the original extracts before the treatment, were observed.
  • Astringent component contained in a large amount in astringent persimmon is proanthocyanidin having a very high molecular weight and constituted by four kinds of tea catechins (Tanaka et al., J. Chem. Soc. Perkin Trans 1, 1013-1022, 1994).
  • 100 g of fresh immature persimmon fruit was pulverized, together with 500 mL of 1% citric acid solution by using a whirling blender and further, 500 mL of 1% citric acid solution and 20 g of green tea were blended therein and the mixture was gently boiled for 3 hours.
  • the reaction solution was subjected to suction filtration while it was hot, to thereby obtain 950 mL of filtrate.
  • the eluate was concentrated to thereby obtain 3.26 g of fraction containing catechin and proanthocyanidin.
  • the molecular weight of proanthocyanidin in persimmon is assumed to be approximately 1.38 ⁇ 10 4 (Mastuo, T. et al., Agric. Biol. Chem., 42, 1637-1643, 1978), too large to come into pores of Sepabeads.
  • persimmon proanthocyanidin treated with green tea, fractionated and reduced in the molecular weight can come into pores of Sepabeads to be adsorbed.
  • Fr. 1 which mainly contained epicatechin and epigallocatechin
  • Fr. 2 which mainly contained epicatechin 3-O-gallate
  • Fr. 3 which mainly contained epigallocatechin 3-O-gallate
  • Fr. 4 which was a mixture of epigallocatechin 3-O-gallate and proanthocyanidin dimmer, was 0.2 g.
  • Fr. 7 which mainly contained proanthocyanidin trimer
  • Fr. 8 which contains the same trimer as Fr. 7 or proanthocyanidins having molecular weight higher than that, was 1.63 g.
  • Invention Substance A a powder (herein after, abbreviate as Invention Substance A) was obtained.
  • This dry powder was dissolved in 1 mL of 70% methanol and with this solution, a column of MCI-gel CHP-20 (inner diameter 2 cm, length 15 cm about 50 mL) was charged. 50 mL of the same solvent was allowed to pass through the column to thereby concentrate the fraction of the target substance. After freeze-drying treatment, 2.4 mg of a powder was obtained. The obtained powder was subjected to HR-FAB-MS (High Resolution Fast Atom Bombardment Mass Spectrum) and 1 H-NMR (hydrogen nuclear magnetic resonance spectrum, see Table 1).
  • Invention Substance B was dissolved in 5 mL of 70% methanol and a column of Sephadex LB-20 (inner diameter 3 cm, length 25 cm, about 180 ml) was charged with the solution. 500 mL of the same solvent was allowed to pass through the column, and the target fraction was concentrated and freeze-dried to thereby obtain 62.2 mg of a powder. The obtained powder was subjected to HR-FAB-MS and 1 H-NMR analyses. With respect to the compound the obtained fraction mainly contained, [M] + was observed at m/z:414.0941, in HR-FAB-MS, which coincided with the calculation value 414.0950 corresponding to the molecular formula C 21 H 18 O 9 , with an error margin of 2.2 ppm.
  • the compound was assumed to have a molecular formula of C 21 H 18 O 9 , which suggested, a chemical structure where phloroglucinol was bonded to catechin or epicatechin through carbon-carbon bond.
  • 1 H-NMR of the compound in addition to five proton, signals on the aromatic ring common to catechin and epicatechin, a group of signals having oxygen atoms at the foot was observed at 5.01 (1H, br.s, 2-H) and 3.96 (1H, br.s, 3-H), suggesting that the compound had an epicatechin steric configuration. It was assumed that the proton signal of ⁇ 4.53 (1H.
  • grape seed polyphenol powder (Grape Seed P.E., LAYN, proanthocyanidin content 95%) was dispersed and dissolved in about 100 mL of water and then the solution was poured into a column of SEPABEADS SP850 (inner diameter 3.8 cm, length 20 cm, about 230 mL) and elated with water. The obtained fraction was concentrated and freeze-dried to thereby obtain 2.44 g of a polymer powder (48.8%).
  • the obtained liquid was concentrated and yellow crystal of myricitrin (myricetin 3-O- ⁇ -L-rhamnopyranoside) was filtered out repeatedly by using filter paper.
  • the obtained filtrate, after further concentration, was freeze-dried to thereby obtain a dark brown powder at a yield of 14% from resin piece.
  • litchee nut polyphenol powder (Litchi P.E., product of Guilin Layn Natural Ingredients Corp., proanthocyanidin content: 90% or more) was dispersed and dissolved in about 100 mL of water and a column of SEPABEADS SP850 (inner diameter 3.8 cm, length 20 cm, about 230 mL) was charged with the mixture. The fraction obtained by eluting with water was concentrated and freeze-dried to thereby obtain 3.02 g of a polymer powder (60.4%).
  • 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity was evaluated as follows. In a 96-hole microplate, 100 ⁇ L of DPPH solution (60 ⁇ M ethanol solution) was placed. Added thereto was 100 ⁇ L of ethanol solution of test sample or 100 ⁇ L of ethanol as control, and the mixture was gently mixed together and left standing at room temperature for 30 minutes. Then, absorbance at 520 nm was measured. The DPPH radical-scavenging activity was calculated by the following formula and 50% effective concentration (EC50) was calculated from The DPPH radical-scavenging activity value of test sample gradually diluted and its concentration.
  • EC50 effective concentration
  • DPPH radical-scavenging activity (%) (1-absorbance of test sample)/absorbance of control ⁇ 100
  • Invention Substances C (41.3%) and D (35.1%) showed higher scavenging activities than the compared substances did (26.9%).
  • TEAC Topical Equivalent Antioxidant Capacity
  • Test method NIH3T3 cells were seeded on a 96-hole plate and cultivated overnight at 37° C. On the next day, the medium was changed to a serum-free culture medium and the substance to be tested was added thereto and further cultivation is conducted for an hour. Then, UV was irradiated for 20 minutes. The medium was changed to a serum-containing medium and cultivation was conducted overnight at 37° C. Cell viability was evaluated by MTT method. The cell in the medium without addition of the substance to be tested was used as control group (C).
  • Test method To Slc:ddY male mice of 9 weeks old. Invention Substance F, LP and TE were forcibly orally administered respectively each in an amount of 50 mg/kg body weight every day for 3 weeks. To a control group of mice (C), the same amount of water was administered. Two hours after administration of the test substance on the final day, the TEAC antioxidative activity and the amount of lipid peroxide in the serum were measured by collecting blood from the heart under ether anesthesia. The TEAC measurement was conducted in the above-described manner.
  • the lipid peroxide amount was measured by using a commercially available kit (lipid peroxide-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.) and measuring fluorescence at excitation wavelength 515 nm and fluorescent wavelength 553 nm in reaction between precipitation of lipid peroxide and 2-thiobarbituric acid reagent in phosphotungstic acid solution under the acidic condition of sulfuric acid.
  • lipid peroxide-Test Wako manufactured by Wako Pure Chemical Industries, Ltd.
  • Invention Substance F showed significantly high antioxidative activity as compared with the compared substance and the control group. Also, the amount of lipid peroxide in the serum was significantly low as compared with the case using the compared substance.
  • Test method To Slc:ddY male mice of 6 weeks old, Invention Substance F, LP and TE were forcibly orally administered respectively each in an amount of 50 mg/kg body weight every day for 3 weeks. To a control group of mice (C), the same amount of water was administered.
  • FIG. 1(A) is an HPLC chromatogram on Example 3 treating Japanese cypress bark and green tea with heat under an acidic condition.
  • FIGS. 1(B) and (C) are HPLC chromatograms on Example 3 treating Japanese cypress bark ( FIG. 1(B) ) and green tea ( FIG. 1(C) ) each independently with heat under an acidic condition, respectively.
  • FIG. 2 is a TLC photograph showing that new proanthocyanidins which had not been present in raw material Japanese cypress bark and green tea were generated by heat treating the materials with heat in Example 4.
  • A is the result on ethyl acetate layer of green tea after treatment
  • B is the result on ethyl acetate layer of Japanese cypress bark after treatment
  • C is the result on ethyl acetate layer of Japanese cypress bark and green tea after treatment.
  • M is derived from Non-galloylated monomer
  • MG is derived from galloylated proanthocyanidin monomer
  • D is derived mainly from galloylated proanthocyanidin dimer
  • T is derived mainly from galloylated proanthocyanidin trimer.
  • FIG. 3 is a TLC photograph showing that new proanthocyanidins which had not been present in raw material banana skin extract and green tea were generated by heat treating the materials with heat in Example 6.
  • A is the result on ethyl acetate layer of green tea alone after treatment
  • B is the result on ethyl acetate layer of banana skin extract alone after treatment
  • C is the result on ethyl acetate layer of banana skin extract and green tea after treatment.
  • FIG. 4 is a TLC photograph showing that new proanthocyanidins which had not been present in raw material immature persimmon fruit and green tea were generated by heat treating the materials with heat in Example 5.
  • A is the result on ethyl acetate layer of green tea alone after treatment
  • B is the result on ethyl acetate layer of immature persimmon fruit alone after treatment
  • C is the result on ethyl acetate layer of immature persimmon fruit and green tea after treatment
  • D is the result of the product obtained by allowing the resultant (extract liquid) obtained by treating the immature persimmon fruit and green tea to pass through Sepabead 825 and elating the adsorbed portion with water-ethanol.
  • Spots M, MG, D and T are the same as in FIG. 2 .
  • FIG. 5(A) is the results of normal-phase HLPC analysis on the product obtained after allowing the resultant (extract liquid) obtained by treating the immature persimmon fruit and green tea to pass through Sepabead 825 and then elating the adsorbed portion with water-ethanol in Example 5.
  • FIG. 5(B) is the results of normal-phase HLPC analysis on the Japanese cypress proanthocyanidin used as comparative example.
  • FIG. 6 shows the result of TLC analysis on fractions (Fr 1 to Fr 8 ) obtained by treating immature persimmon fruit and green tea with heat under acidic condition and then allowing the obtained catechins and proanthocyanidins to pass through Sephadex LH-20column chromatography and on a mixture (E) before the separation in Example 6.
  • FIG. 7 shows the DPPH radical-scavenging activity of Invention Substance A obtained in Example 7.
  • FIG. 8 shows the DPPH radical-scavenging activity of Invention Substance B obtained in Example 8.
  • FIG. 9 shows the DPPH radical-scavenging activity of Invention Substances C to E obtained in Examples 9-11.
  • FIG. 10 shows the results of evaluation by TEAC method on antioxidative ability of Invention Substance A obtained in Example 7.
  • FIG. 11 shows the results of evaluation by TEAC method on antioxidative ability of Invention Substance B obtained in Example 8.
  • FIG. 12 shows the results of evaluation by TEAC method on antioxidative ability of Invention Substances C to S obtained in Examples 9 to 11.
  • FIG. 13 shows the results of UV-protection effect test, on Invention Substance F obtained in Example 12.
  • FIG. 14 shows the results of evaluation by TEAC method on antioxidative ability of Invention Substance F obtained in Example 12.
  • FIG. 15 shows measurement results of the LPO level in the serum in the antioxidative ability test on Invention Substance F obtained in Example 12.
  • FIG. 16 shows measurement results of the GOT and GPT levels in the serum in the antioxidative ability test on Invention Substance F obtained in Example 12.
  • FIG. 17 shows measurement results of the LPO level in the liver in the antioxidative ability test on Invention Substance F obtained in Example 12.

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KR20070110040A (ko) 2007-11-15
EP1852430A1 (en) 2007-11-07
CN101133043A (zh) 2008-02-27
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