WO2024251002A1 - Dérivé de salidroside, son procédé de préparation et son utilisation - Google Patents

Dérivé de salidroside, son procédé de préparation et son utilisation Download PDF

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WO2024251002A1
WO2024251002A1 PCT/CN2024/095989 CN2024095989W WO2024251002A1 WO 2024251002 A1 WO2024251002 A1 WO 2024251002A1 CN 2024095989 W CN2024095989 W CN 2024095989W WO 2024251002 A1 WO2024251002 A1 WO 2024251002A1
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salidroside
hydroxy
preparation
reaction
solution
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Chinese (zh)
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方诩
刘大明
殷文成
张爽
广濑芳彦
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Henrui Qingdao Biotech Co Ltd
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Henrui Qingdao Biotech Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • 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
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • 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
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to a salidroside derivative, in particular to a hydroxy-alpha-salidroside compound.
  • Rhodiola rosea is a precious Chinese medicine.
  • the 2020 edition of the Chinese Pharmacopoeia includes the dried roots and rhizomes of Rhodiola rosea of the Crassulaceae family. It is produced in China and other places in China and grows in areas with an altitude of about 4050 to 5400 meters.
  • Drugs such as Rhodiola rosea tablets and Xinnaoxin capsules prepared from Rhodiola rosea have the effects of promoting blood circulation and removing blood stasis, dredge meridians and relieve pain.
  • the functions of health foods such as Rhodiola rosea capsules are to enhance immunity and relieve physical fatigue.
  • Salidroside is the effective active ingredient of the traditional Chinese medicine Rhodiola rosea.
  • Salidroside has physiological activities such as protecting cardiovascular and cerebrovascular vessels, anti-fatigue, anti-depression, anti-aging, anti-hypoxia, anti-radiation, anti-tumor, immune regulation, whitening and freckle removal.
  • Salidroside in its natural state plant-derived Salidroside
  • ⁇ -Salidroside glycosidic bond
  • ⁇ -type glycosidic bond
  • Chinese patent 202211359878.5 discloses an ⁇ -salidroside and its preparation method and application.
  • the ⁇ -salidroside has a chemical name: 2-(4-hydroxyphenyl)ethyl- ⁇ -D-glucoside, a molecular weight of 300.23, and a chemical formula as follows. It has excellent free radical scavenging activity and can be used as the main raw material for cosmetics, anti-fatigue health products and other products.
  • the applicant studied salidroside and its derivatives and obtained hydroxy- ⁇ -salidroside.
  • the present invention also provides a preparation method and application of hydroxy- ⁇ -salidroside.
  • the present invention provides a hydroxy- ⁇ -salidroside compound, chemical name: 2-(3,4-dihydroxyphenyl)ethyl- ⁇ -D-glucoside, chemical formula shown in Formula I, which has an ⁇ -glucoside bond on the alcoholic hydroxyl group of hydroxytyrosol.
  • the molecular weight of the hydroxy- ⁇ -salidroside of the present invention is 316.108 after LC-MS analysis.
  • the present invention provides a method for preparing the hydroxy- ⁇ -salidroside compound.
  • the preparation method comprises dissolving ⁇ -salidroside in a buffer solution, adding hydroxylase, and performing a hydroxylation reaction in a reaction system to prepare the salidroside.
  • the hydroxylase can be selected from commercially available hydroxylase preparations.
  • the commercially available hydroxylase enzyme preparations are derived from Merck & Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd. and Shanghai Yuanye Biotechnology Co., Ltd., including but not limited to monophenol monooxygenase (Monophenol monooxygenase), polyphenol oxidase (Polyphenol Oxidase), tyrosinase (Tyrosinase) and the like.
  • the reaction system contains ammonium salt.
  • the ammonium salt preferably includes but is not limited to ammonium chloride, ammonium acetate, or ammonium sulfate.
  • the present invention provides the use of the hydroxy- ⁇ -salidroside compound in the preparation of a product having a free radical scavenging function; or the use of the hydroxy- ⁇ -salidroside compound in cosmetics having a whitening function.
  • the free radical is a 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) free radical.
  • DPPH 1,1-diphenyl-2-trinitrophenylhydrazine
  • the product is a cosmetic having the function of scavenging free radicals.
  • the product with free radical scavenging function is a functional food.
  • the present invention further provides a composition containing hydroxy- ⁇ -salidroside.
  • the composition has the function of scavenging free radicals or whitening skin.
  • the free radical is a DPPH free radical.
  • the cosmetic composition containing hydroxy- ⁇ -salidroside is selected from aqueous solutions, oils, emulsions, gel products, paste products, or others, and can be produced according to existing cosmetic technical specifications.
  • the functional food composition containing hydroxy- ⁇ -salidroside has a dosage form selected from capsules, tablets, pastes, aqueous solutions, or others, and can be produced according to existing functional food technical specifications.
  • the drugs for improving learning and memory disorders include but are not limited to drugs for treating Alzheimer's disease.
  • the drugs for improving learning and memory disorders include but are not limited to drugs for treating Parkinson's disease.
  • a method for whitening skin comprising applying an effective amount of hydroxy- ⁇ -salidroside or a composition comprising an effective amount of hydroxy- ⁇ -salidroside to the skin.
  • a method for improving learning and memory disorders comprising administering to a subject an effective amount of hydroxy- ⁇ -salidroside or a composition comprising an effective amount of hydroxy- ⁇ -salidroside.
  • the "subject" of the present invention refers to any organism that needs treatment, prevention or diagnosis, preferably a mammal, and more preferably a human.
  • Figure 1 TLC spectrum of the enzyme-catalyzed reaction solution of Example 1; in the figure, from left to right are lane 1 and lane 2; lane 1 is ⁇ -salidroside, and lane 2 is hydroxy- ⁇ -salidroside.
  • reagents or raw materials used in the present invention can be purchased through conventional channels. Unless otherwise specified, the reagents or raw materials used in the present invention are used in a conventional manner in the art or in accordance with the product instructions. In addition, any method and material similar to or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.
  • the hydroxy- ⁇ -salidroside of the present invention has a chemical name: 2-(3,4-dihydroxyphenyl)ethyl- ⁇ -D-glucoside, and its structural formula is shown in Formula I.
  • the preparation method of hydroxy- ⁇ -salidroside of the present invention uses ⁇ -salidroside as a substrate and realizes hydroxylation under the action of hydroxylase.
  • the hydroxylase may be a commercially available hydroxylase preparation from Merck & Co., Ltd., Shanghai MacLean Biochemical Technology Co., Ltd. and Shanghai Yuanye Biotechnology Co., Ltd., including catechol oxidase but not limited to monophenol monooxygenase, polyphenol oxidase, tyrosinase and the like.
  • the method of using the hydroxylase enzyme preparation includes adding it to the reaction system in the form of powder or liquid, or fixing the enzyme preparation on a resin to make an immobilized enzyme preparation and adding it to the reaction system.
  • the immobilized enzyme preparation can be reused.
  • the amount of hydroxylase and the reaction conditions have a great influence on the production efficiency, so it is crucial to select appropriate reaction conditions such as the amount of enzyme and reaction time.
  • the reaction can be carried out in the presence of a solvent, and the solvent used in the reaction can be any solvent as long as it does not affect the type and concentration range of the reaction, and specifically can include common reagents such as DMSO, 2-propanol, ethanol, etc. These solvents can be used alone or in combination of two or more.
  • the enzyme used in the present invention can be inactivated by heating or changing the pH value, thereby stopping the enzyme catalyzed reaction.
  • the mixture containing the hydroxy- ⁇ -salidroside compound, the hydrolyzate of the mixture, the enzyme-inactivated product of the mixture, the purified product of the mixture, and the dry powder product thereof can be used in foods, beverages and cosmetics containing the hydroxy- ⁇ -salidroside compound, and can also be used as an ingredient of food, special medical food, health products or medicines, and used in the production of food and beverages, cosmetics, special medical food, health products or medicines.
  • HPLC analysis conditions High performance liquid chromatograph: Hitachi HPLC 5440 chromatograph, chromatographic column: Kromasil 100-5C18 (250*4.6mm), detector: photodiode array (DAD 280nm), detection wavelength: UV 280nm, injection volume: 10 ⁇ L, flow rate: 1mL/min, column temperature: 30°C, mobile phase: acetonitrile: 0.1% formic acid aqueous solution (v/v) isocratic elution.
  • DAD 280nm photodiode array
  • LC-MS analysis conditions chromatographic column: Kromasil 100-5C18 (250*4.6mm), detector: photodiode array (DAD 280nm), detection wavelength: 280nm, injection volume: 10 ⁇ L, flow rate: 1mL/min, column temperature: 30°C, mobile phase with detection time of 5-15min; H-ESI mode, molecular weight scanning range 50 ⁇ 800.
  • the inventors of the present invention carried out acetylation treatment on the hydroxy- ⁇ -salidroside compound of the present invention according to the method described in the document, and then carried out carbon spectrum and hydrogen spectrum analysis, but could not obtain the carbon spectrum and hydrogen spectrum data of the acetylated product and its supplementary document. Therefore, the hydroxy- ⁇ -salidroside compound obtained by the present invention is different from the compound obtained in the document.
  • the feed amount was simultaneously increased by 10 times, the reaction was stirred at 35° C., and the reaction was carried out for 24 hours to obtain an enzyme catalytic reaction solution.
  • FIG. 1 The TLC analysis spectrum of the reaction solution of Example 1 is shown in Figure 1, which shows that new substances are produced in the enzyme-catalyzed reaction solution.
  • Figure 1 shows that new substances are produced in the enzyme-catalyzed reaction solution.
  • lane 1 is ⁇ -salidroside
  • lane 2 is the new substance produced by the enzyme-catalyzed reaction.
  • Example 1 According to the above chromatographic conditions, the purified reaction solution of Example 1 was subjected to HPLC analysis. The HPLC spectrum is shown in FIG2 .
  • the LC-MS spectrum is shown in FIG3 .
  • a semi-preparative HPLC was used (BRIX 2850, Beijing Chengda Instrument Co., Ltd.).
  • the chromatographic column was COSMOSIL 5C18-MS-II (250*20mm).
  • the mobile phase was acetonitrile: 0.1% formic acid aqueous solution (v/v) with an isocratic elution ratio of 1:9.
  • a photodiode array detector was used with a detection wavelength of UV 280nm.
  • the injection volume was 100 ⁇ L and the flow rate was 18mL/min.
  • the H-NMR spectrum of the product in Example 1 has two single peaks (s, 1H: OH) at 8.64ppm and 8.69ppm, which is the "characteristic of bisphenol hydroxyl".
  • ⁇ -Salidroside is a single peak at 9.10ppm, which is the "characteristic of monophenol hydroxyl”
  • the C-NMR spectrum of the product in Example 1 has 14 characteristic peaks, while ⁇ -Salidroside has only 12 characteristic peaks, which are obviously different.
  • the HPLC spectrum, LC-MS spectrum, H-NMR spectrum, and C-NMR spectrum of the product of the enzyme-catalyzed reaction of Example 2-4 are the same as those of the reaction solution of Example 1. Therefore, the substance obtained by the enzyme-catalyzed reaction of Example 2-4 is also hydroxy- ⁇ -salidroside.
  • Example 6-8 Based on Example 3, an ammonium salt, such as ammonium chloride, ammonium acetate, or ammonium sulfate, is added to the reaction system to carry out an enzymatic reaction.
  • an ammonium salt such as ammonium chloride, ammonium acetate, or ammonium sulfate.
  • DPPH free radical scavenging experiment Free radicals directly or indirectly play a strong oxidative role and are widely involved in the physiological and pathological processes of the body. When there are excessive free radicals in the body, they can damage the body through oxidation. Salvianolic acid compounds are donors of phenolic hydroxyl groups and have a structural basis for antioxidant activity. This experiment uses the DPPH free radical scavenging reaction to study the scavenging efficiency of hydroxy- ⁇ -salidroside, ⁇ -salidroside, and ⁇ -salidroside on DPPH free radicals.
  • the DPPH free radical scavenging rate was calculated according to the following formula. The results are shown in Table 4.
  • Enzyme reaction tube C Take 1 mL of sodium hydrogen phosphate-citrate buffer, add 0.5 mL of tyrosinase, mix well, incubate in a 37°C water bath for 10 min, then add 2 mL of L-DOPA, control the reaction time to 5 min, and immediately measure the absorbance at 475 nm.
  • Solvent background C 0 Take 1.5 mL of sodium hydrogen phosphate-citrate buffer, incubate in a 37°C water bath for 10 min, add 2 mL of L-DOPA, control the reaction time to 5 min, and immediately measure the absorbance at 475 nm.
  • Hydroxy- ⁇ -salidroside sample solution The target substance of Example 4 was prepared according to the method described in Example 5, and prepared into a 10 mg/mL solution.
  • ⁇ -Salidroside sample solution The ⁇ -Salidroside is the raw material for preparing hydroxy- ⁇ -Salidroside in the examples, and is prepared into a 10 mg/mL solution.
  • the drugs were administered according to the following schedule starting from the second day after the 7th week of modeling and continued for 30 days.
  • AD model group 1 Each rat was intragastrically administered with hydroxy- ⁇ -salidroside sample solution once a day, with a dose of 5 mg per kg body weight.
  • AD model group 3 Each rat was intragastrically administered with ⁇ -salidroside sample solution once a day, with a dose of 5 mg per kg body weight.
  • AD model group 2 and blank control group each rat was intragastrically administered with the sample solution once a day, with the same volume of distilled water as that of the AD model group 1.
  • the constant temperature swimming pool used in the experiment was 120 cm in diameter and 50 cm in height, with a water depth of 30 cm and a water temperature maintained at (22 ⁇ 1)°C.
  • Two objects were randomly hung on the wall of the pool as close visual cues.
  • the built-in platform was 7 cm in diameter and was submerged 2 cm under water. There were several small holes on it to provide a surface for rats to stand easily.
  • the environment information was kept fixed throughout the experiment. Milk was added to the pool to make the platform invisible. The maze was divided into 4 quadrants, and the platform was placed in the center of one of the quadrants as the only way for the animals to escape the water environment in the experiment.
  • the platform was placed in a quadrant, and the positioning navigation test was performed, and the escape latency was recorded.
  • the test was repeated for 3 consecutive days, 3 times a day, and the entry point was changed each time.
  • the order of the entry points for all rats was kept consistent every day (clockwise).
  • the rats were gently placed in the water toward the pool wall. 120s was set as the longest escape latency, and the recording stopped automatically after 120s. If the rat found the platform within 120s, its actual escape latency was recorded; if the platform was not found within 120s, the experimenter led it to the platform and stayed for 10s, and the escape latency was recorded as 120s.
  • the Morris water maze test is an experiment that forces experimental animals (rats and mice) to swim and learn to find a platform hidden in the water. It is mainly used to test the learning and memory ability of experimental animals for spatial position and direction (spatial positioning).
  • Escape latency refers to the time it takes for an animal to swim from the starting position in the water maze to find the hidden platform. As the number of experiments increases, the time it takes for the animal to find the platform should gradually decrease, indicating that they have made progress in learning and remembering the location of the platform. A longer escape latency may indicate that the animal's spatial learning and memory abilities are impaired.
  • the AD model group 1 was the hydroxy- ⁇ -salidroside treatment group, and its escape latency was shorter than that of the AD model group 3 ( ⁇ -salidroside treatment group) and the AD model group 2 (blank model group), indicating that the AD model rats in the AD3 group needed a shorter time to find the underwater hidden platform, and that hydroxy- ⁇ -salidroside had a certain effect on improving the spatial learning and memory ability of the AD model rats.

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Abstract

La présente invention concerne un dérivé de salidroside, et concerne en particulier un composé hydroxy-α-salidroside. Le composé hydroxy-α-salidroside est supérieur à l'α-salidroside dans les aspects de piégeage de radicaux libres de DPPH, de blanchiment et d'amélioration de troubles de l'apprentissage et de la mémoire, et peut être ajouté en tant que nouveau composant fonctionnel à des produits cosmétiques, des aliments fonctionnels ou des compositions pharmaceutiques. Selon le procédé de préparation d'hydroxy-α-salidroside de la présente invention, l'α-salidroside est utilisé en tant que substrat, et l'hydroxy-α-salidroside est synthétisé sous l'action de l'hydroxylase.
PCT/CN2024/095989 2023-06-08 2024-05-29 Dérivé de salidroside, son procédé de préparation et son utilisation Ceased WO2024251002A1 (fr)

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CN202310670529.3 2023-06-08
CN202310670529.3A CN116396342A (zh) 2023-06-08 2023-06-08 一种红景天苷的衍生物及制备方法和应用
CN202410159803.5A CN118027118B (zh) 2023-06-08 2024-02-04 红景天苷的衍生物及制备方法和应用
CN202410159803.5 2024-02-04

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CN119770504B (zh) * 2024-12-30 2025-09-19 黑龙江中医药大学 一种用于防治ad的药物组合物及其应用

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