WO2017073854A1 - Analogue glycosidique phénolique simple, son procédé de préparation et composition pour blanchiment de la peau ou atténuation des rides en contenant - Google Patents

Analogue glycosidique phénolique simple, son procédé de préparation et composition pour blanchiment de la peau ou atténuation des rides en contenant Download PDF

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WO2017073854A1
WO2017073854A1 PCT/KR2016/002888 KR2016002888W WO2017073854A1 WO 2017073854 A1 WO2017073854 A1 WO 2017073854A1 KR 2016002888 W KR2016002888 W KR 2016002888W WO 2017073854 A1 WO2017073854 A1 WO 2017073854A1
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hydroxyphenyl
propanoyl
glucoside
glucose
simple phenolic
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PCT/KR2016/002888
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Korean (ko)
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박제원
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고려대학교산학협력단
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Publication of WO2017073854A1 publication Critical patent/WO2017073854A1/fr

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    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
    • B01D15/16—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to the conditioning of the fluid carrier
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/52—Genes encoding for enzymes or proenzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • 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
    • 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 present invention relates to a simple phenolic glycoside derivative, a method for preparing the same, and a composition for improving skin whitening or wrinkles containing the same, and more specifically, glycosyltransferase (Glycosyltransferase) derived from Micromonospora rhodorangea
  • a method for preparing simple phenolic glycosidic analogs using MrSPGT and a composition for improving skin whitening or wrinkles containing these derivatives as an active ingredient.
  • Simple Phenolic Compounds belong to a variety of phytochemicals that exist in nature, particularly in the plant world, and are small-molecule biomaterials that show various physiological activities. For example, hydroxytyrosol or 3,4-dihydroxyphenyl ethanol, which is a major component in olive leaves or olive oil after processing, and oleuropein, one of its glycosides, can oxidize fats and nucleic acids. Antioxidant activity, antimicrobial activity against some microorganisms, platelet aggregation inhibitory activity and endothelial dysfunction prevention activity have been reported at the in vitro level (Tripoli, E. et. al., Nutr. Res. Rev. (2005) 18 (1): p. 98; de la Torre, R., (2008) 16 (5): p. 245; Barbaro, B. et al., Int. J. Mol. Sci. (2014) 15 (10): p. 18508).
  • Rhodiola rosea L or tyrosol (4-hydroxyphenyl ethanol) of SP series and salidroside (glucose) containing sugar chains are contained therein.
  • tibetan ginseng it has antioxidant activity, cardiovascular disease prevention activity, anticancer activity and anti-fatigue activity, anoxia inhibitory activity, and tonic effect such as anti-aging activity. Nakamura, S. et al., Chem. Pharm. Bull. (Tokyo) (2008) 56 (4): p. 536; Panossian, A. et al., (2008) 15 (1-2): p. 84).
  • SP-based hydroquinone or 4-hydroxyphenol extracted from bearberry and its glucose glycoside arbutin and pinus In the sylvestris or Scotch pine leaf extract, SP-based hydroxyphenyl propanol and the like have been known for their antioxidant and skin lightening activity (Sugimoto, K. et al., Chem. Pharm. Bull. (Tokyo) ( 2003) 51 (7): p. 798; Sugimoto, K. et al., Biol. Pharm. Bull. (2004) 27 (4): p. 510; O'Donoghue, JL, J. Cosmet.Dermatol. 2006) 5 (3): p. 196).
  • the simple phenolic compound (SP) and various glycosides that have been added with sugars as aglycones have recently been attracting attention as functional cosmetic raw materials according to skin whitening activity. have.
  • human skin color is mainly determined by the amount and distribution of melanin present in the epidermis.
  • Melanin is a polymer-bound polymer that has a function of absorbing a wide range of light, including UV rays, and protects the body from UV irradiation.However, when abnormal biosynthesis is inhibited, skin such as vitiligo In the case of lesions and overproduction of melanin, pigmentation such as blemishes and freckles is not only formed, but also promotes skin aging and is closely related to skin cancer.
  • Melanin is biosynthesized through a series of redox reactions involving several enzymes including tyrosinase, in particular L-DOPA (L-3,4-dihydroxyphenylalanine) using L-tyrosine as a substrate.
  • Tyrosinase which converts to L-DOPAquinone, is an important melanin biosynthesis kinetics step as an initial melanin biosynthesis reaction (Pillaiyar, T. et al., Inhibitors of melanogenesis: a patent review (2009 2014). Expert Opin. Ther. Pat. (2015) 25 (7): p. 775).
  • one of the functional enhancement techniques through structural modification of the SP-based compound is an enzymatic production method using a glycosyltransferase that can transfer sugar molecules to a hydroxy function in the chemical structure of the SP-based compound.
  • the glycosylation of such a specific compound can improve the solubility and absorption of the glycosylated compound in comparison with the original substance, thereby improving the formulation of cosmetics and pharmaceuticals, developing new formulations, and prodrugs.
  • MrSPGT novel glycotransferase
  • Another object of the present invention is to provide a method for producing a recombinant glycotransferase comprising culturing the recombinant microorganism to induce the expression of glycotransferase (MrSPGT) and then recovering it.
  • MrSPGT glycotransferase
  • Another object of the present invention to provide a method for preparing a simple phenolic glycoside derivative using the sugar transferase (MrSPGT).
  • the present invention provides a glycotransferase (MrSPGT) represented by the amino acid sequence of SEQ ID NO: 4.
  • the present invention also provides a nucleic acid encoding the enzyme; A vector containing said nucleic acid; And it provides a recombinant microorganism comprising the nucleic acid or the vector.
  • the present invention also provides a method for producing a recombinant glycotransferase comprising culturing the recombinant microorganism to induce the expression of glycotransferase (MrSPGT) and then recovering it.
  • MrSPGT glycotransferase
  • the present invention also provides a simple phenolic glycoside derivative represented by the formula (I), an isomer thereof or a solvate, hydrate or prodrug thereof acceptable as a medicament.
  • R 1 is glucose or 2-deoxy-glucose and R 2 is hydrogen, on the contrary, R 1 is hydrogen and R 2 is glucose or 2-deoxy-glucose.
  • the present invention also (a) a simple phenolic glycosidic analogs represented by the following formula (I) by reacting a simple phenolic compound (Simple Phenolics, SP) and a sugar donor in the presence of the sugar transfer enzyme MrSPGT Synthesizing); And (b) provides a method for producing a simple phenolic glycoside derivative represented by the following formula (I) comprising the step of recovering the synthesized simple phenolic glycoside derivative.
  • R 1 is glucose or 2-deoxy-glucose and R 2 is hydrogen, on the contrary, R 1 is hydrogen and R 2 is glucose or 2-deoxy-glucose.
  • the present invention also provides for the treatment of pigmentation related skin diseases, which contains a simple phenolic glycoside derivative represented by the formula (I), an isomer thereof or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient, and / Or it provides a preventive pharmaceutical composition and a cosmetic composition for skin whitening or wrinkle improvement.
  • pigmentation related skin diseases which contains a simple phenolic glycoside derivative represented by the formula (I), an isomer thereof or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient, and / Or it provides a preventive pharmaceutical composition and a cosmetic composition for skin whitening or wrinkle improvement.
  • sugar donor is a type of nucleic acid-sugar (uracil-diphosphate-glucose) or TDP-2-deoxy-glucose (thymidine-2-deoxy-glucose) and a sugar acceptor (glycosyl acceptor) 4-hydroxyphenyl-2-propanol (4-hydroxyphenyl-2-propanol, HP2P) or 4-hydroxyphenyl-3-propanol (4-hydroxyphenyl-3-propanol (HP3P)) was used as the sugar transferase, MrSPGT, It shows a schematic diagram of the reaction.
  • Figure 2 is a graphical representation comparing the antioxidant activity of the novel simple phenolic glycoside derivatives, simple phenolic aglycones before sugar addition and ascorbic acid as a positive control.
  • FIG. 3 shows the in vitro tyrosinase inhibitory activity of the novel simple phenolic glycoside derivatives, simple phenolic aglycones before sugar addition, and arbutin, a positive control, melanin biosynthesis inhibitory activity in human melanoma cell lines, and The graph shows a comparison of cytotoxicity against fibroblasts.
  • Figure 4 compares the cytotoxicity results of the high concentration (5%) of the simple phenolic glycoside derivatives and the simple phenolic aglycones and the fibroblast of arbutin as a positive control according to the present invention It is a graph.
  • Figure 5 is a graph comparing the degree of inhibition of the elastase enzyme activity of simple phenolic glycoside derivatives and sugar-added simple phenolic aglycones and positive control of asolinic acid and ascorbic acid according to the present invention.
  • the present invention provides a simple phenolic glycoside derivative compound represented by the following formula (I), which can be usefully used for skin whitening, an enzymatic preparation method of these compounds, and an active ingredient thereof, including antioxidant and skin lightening -whitening) relates to the activity and therapeutic and / or prophylactic pharmaceutical composition for the wrinkle-related skin pigmentation disorder that indicates improvement and a cosmetic composition for skin whitening, and more particularly also the micro mono spokes La expressed in E.
  • formula (I) a simple phenolic glycoside derivative compound represented by the following formula (I), which can be usefully used for skin whitening, an enzymatic preparation method of these compounds, and an active ingredient thereof, including antioxidant and skin lightening -whitening
  • R 1 is glucose or 2-deoxy-glucose and R 2 is hydrogen, on the contrary, R 1 is hydrogen and R 2 is glucose or 2-deoxy-glucose.
  • the present invention relates to a sugar transfer enzyme (MrSPGT) represented by the amino acid sequence of SEQ ID NO: 4.
  • the present invention relates to a nucleic acid encoding the enzyme.
  • the nucleic acid may be characterized by represented by the nucleotide sequence of SEQ ID NO: 3, said nucleic acid may be characterized in that the ditch Jia (Micromonospora rhodorangea) strain derived from mono to as micro-Spokane (d)
  • the nucleic acid encoding the enzyme may be a polynucleotide, but is not limited thereto.
  • a partial or complete portion of the base sequence encoding the enzyme may be used (see SEQ ID NO: 3).
  • the present invention relates to a vector comprising the nucleic acid.
  • the present invention relates to a recombinant microorganism comprising the nucleic acid or the vector.
  • the recombinant microorganism is preferably Escherichia coli, but is not limited thereto.
  • the present invention relates to a method for preparing a recombinant glycotransferase (MrSPGT) comprising culturing the recombinant microorganism to induce the expression of the glycotransferase MrSPGT, and then recovering it.
  • MrSPGT recombinant glycotransferase
  • vector refers to a DNA preparation containing a DNA sequence operably linked to a suitable regulatory sequence capable of expressing DNA in a suitable host.
  • Vectors can be plasmids, phage particles or simply potential genomic inserts. Once transformed into the appropriate host, the vector can replicate and function independently of the host genome, or in some cases can be integrated into the genome itself. Since plasmids are the most commonly used form of current vectors, "plasmid” and “vector” are sometimes used interchangeably in the context of the present invention. For the purposes of the present invention, it is preferred to use plasmid vectors.
  • Typical plasmid vectors that can be used for this purpose include (a) a replication initiation point that allows for efficient replication, including several to hundreds of plasmid vectors per recombinant microorganism, and (b) a recombinant microorganism transformed with the plasmid vector. It has a structure that includes an antibiotic resistance gene that allows it to be used and a restriction enzyme cleavage site (c) into which foreign DNA fragments can be inserted. Although no suitable restriction enzyme cleavage site is present, synthetic oligonucleotide adapters or linkers according to conventional methods can be used to facilitate ligation of the vector and foreign DNA.
  • the vector After ligation, the vector must be transformed with the appropriate recombinant microorganism. Transformation can be readily accomplished using calcium chloride methods or electroporation (Neumann, et al., EMBO J., 1: 841, 1982) and the like.
  • an expression vector known in the art may be used as the vector used for overexpression of the gene according to the present invention. Skeletal vectors that can be used in the method of the present invention are not particularly limited, but various vectors capable of transforming E. coli selected from the group consisting of pT7, pET / Rb, pGEX, pET28a, pET-22b (+) and pGEX Can be used.
  • Sequences are "operably linked” when placed in a functional relationship with other nucleic acid sequences.
  • This may be genes and regulatory sequence (s) linked in such a way as to enable gene expression when appropriate molecules (eg, transcriptional activating proteins) bind to regulatory sequence (s).
  • the DNA for a pre-sequence or secretion leader is operably linked to the DNA for the polypeptide when expressed as a shear protein that participates in the secretion of the polypeptide and the promoter or enhancer is sequenced. Coding when operably linked to the coding sequence when affecting the transcription of the ribosome binding site or when the ribosome binding site is operably linked to the coding sequence when affecting the transcription of the sequence Operably linked to the sequence.
  • operably linked means that the linked DNA sequence is in contact, and in the case of a secretory leader, is in contact and present within the reading frame.
  • enhancers do not need to touch. Linking of these sequences is performed by ligation (linking) at convenient restriction enzyme sites. If such sites do not exist, synthetic oligonucleotide adapters or linkers according to conventional methods are used.
  • the gene must be operably linked to transcriptional and translational expression control sequences that function in the chosen expression host.
  • the expression control sequence and the corresponding gene will be included in one recombinant vector containing the bacterial selection marker and the replication origin. If the recombinant microorganism is a eukaryotic cell, the recombinant vector must further comprise an expression marker useful in the eukaryotic expression host.
  • transformation means introducing DNA into a host so that the DNA is replicable as an extrachromosomal factor or by chromosomal integration.
  • the gene has the same effect as when the recombinant vector is introduced into the recombinant microorganism as described above even when the gene is inserted into the genomic chromosome of the recombinant microorganism.
  • a conventionally known genetic engineering method may be used.
  • a retroviral vector an adenovirus vector, an adeno-associated virus vector, and a herpes simplex virus vector.
  • Poxvirus vectors lentiviral vectors or non-viral vectors.
  • a simple phenolic glycoside derivative (Simple phenolic glycosidic analogs) was biosynthesized by reacting a recombinant phenol transferase with a simple phenolic compound as a substrate.
  • the structure was confirmed by mass spectrometry and nuclear magnetic resornance spectrometry.
  • the present invention relates to simple phenolic glycoside derivatives represented by the formula (I), isomers thereof or solvates, hydrates or prodrugs thereof which are acceptable as medicaments.
  • R 1 is glucose or 2-deoxy-glucose and R 2 is hydrogen, on the contrary, R 1 is hydrogen and R 2 is glucose or 2-deoxy-glucose.
  • the present invention (a) a simple phenolic glycoside derivative represented by the following formula (I) by reacting a simple phenolic compound (Simple Phenolics, SP) and a sugar donor in the presence of the sugar transfer enzyme MrSPGT phenolic glycosidic analogs); And (b) relates to a method for producing a simple phenolic glycoside derivative represented by the following formula (I) comprising the step of recovering the synthesized simple phenolic glycoside derivative.
  • R 1 is glucose or 2-deoxy-glucose and R 2 is hydrogen, on the contrary, R 1 is hydrogen and R 2 is glucose or 2-deoxy-glucose.
  • the simple phenolic compound is 4-hydroxyphenyl-2-propanol (4-hydroxyphenyl-2-propanol, HP2P) or 4-hydroxyphenyl-3-propanol (4-hydroxyphenyl-3-propanol, HP3P), but is not limited thereto.
  • the sugar donor is preferably UDP-glucose (Glc), UDP-galactose (Gal) or TDP-2'-deoxyglucose (deoxy-Glc), but is not limited thereto.
  • added sugars include glucose, mannose, galactose, allose, altrose, idose, and talos.
  • Fructose, arabinose or xylose, and the amino sugars are N-acetyl-galactosamine, N-acetyl-glucosamine (N -acetyl-glucosamine, N-acetyl-neuraminic acid, glucosamine or galactosamine, and sucrose in the case of di-saccharides. ), Cellobiose, maltose, lactose, lactose, trehalose, gentiobiose or melibiose, and raffinose in the case of tri-saccharide. (raffinose) or gentianose, but is not limited thereto.
  • the simple phenolic glycoside derivative represented by Formula (I) is 4-hydroxyphenyl-2-propanoyl- O -glucoside (4-hydroxyphenyl-2-propanoyl- O- glucoside, HPP2G), 4-hydroxyphenyl-2-propanoyl - O -2'- deoxy-glucoside (4-hydroxyphenyl-2-propanoyl- O -2'-deoxyglucoside, HPP2DG), 4- hydroxy-3-propanoyl - O - glucoside (4-hydroxyphenyl-3-propanoyl- O -glucoside, HPP3G) and 4-hydroxy-3-propanoyl - O -2'- deoxy-glucoside (4-hydroxyphenyl-3-propanoyl- O -2'-deoxyglucoside, HPP3DG) is preferably selected from the group consisting of, but is not limited thereto.
  • the step (b) is a reversed phase C18 stationary phase, acetonitrile: methanol: water: formic acid 10: 40 ⁇ 60: 30 ⁇ 50: 0.05 ⁇ 0.2 (v / v / v / v), preferably 10: 45-55: 35-45: 0.07-0.12 (v / v / v / v), most preferably 10: 50: 39.9: 0.1 (v / v / v / / v) mixed liquid mobile phase and 6-9 minutes
  • MPLC Medium Pressure Liquid Chromatography
  • the present invention provides antioxidant activity, inhibitory activity against human tyrosinase, inhibitory activity against melanin biosynthesis in human melanoma cell line and fibroblasts.
  • the present invention provides a pigment-related skin containing a simple phenolic glycoside derivative represented by Formula (I), an isomer thereof, or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient.
  • a pharmaceutical composition for treating and / or preventing a disease containing a simple phenolic glycoside derivative represented by Formula (I), an isomer thereof, or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient.
  • R 1 is glucose or 2-deoxy-glucose and R 2 is hydrogen, on the contrary, R 1 is hydrogen and R 2 is glucose or 2-deoxy-glucose.
  • the simple phenolic glycoside derivative represented by Formula (I) is 4-hydroxyphenyl-2-propanoyl- O -glucoside (4-hydroxyphenyl-2-propanoyl- O- glucoside, HPP2G), 4-hydroxyphenyl-2-propanoyl - O -2'- deoxy-glucoside (4-hydroxyphenyl-2-propanoyl- O -2'-deoxyglucoside, HPP2DG), 4- hydroxy-3-propanoyl - O - glucoside (4-hydroxyphenyl-3-propanoyl- O -glucoside, HPP3G) and 4-hydroxy-3-propanoyl - O -2'- deoxy-glucoside (4-hydroxyphenyl-3-propanoyl- O -2'-deoxyglucoside, HPP3DG) is preferably selected from the group consisting of, but is not limited thereto.
  • the present invention provides a pigmentation for administering a pharmaceutical composition containing a simple phenolic glycoside derivative represented by Formula (I), an isomer thereof, or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient.
  • a method for treating and / or preventing related skin diseases is also known in the art.
  • the present invention provides a pigment-related skin containing a simple phenolic glycoside derivative represented by Formula (I), an isomer thereof or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient. It relates to the use in the manufacture of a pharmaceutical composition for treating and / or preventing diseases.
  • a simple phenolic glycoside derivative represented by Formula (I) an isomer thereof or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient. It relates to the use in the manufacture of a pharmaceutical composition for treating and / or preventing diseases.
  • composition means a mixture of a compound represented by the formula (I), which is a simple phenolic glycoside derivative of the present invention, with other chemical components such as diluents or carriers.
  • physiologically acceptable is defined as a carrier or diluent that does not impair the biological activity and the properties of the compound.
  • carrier is defined as a compound that facilitates the addition of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the incorporation of many organic compounds into cells or tissues of an organism.
  • diot is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.
  • Compounds containing simple phenolic glycoside derivatives as used herein may be administered to a human patient as such or as a pharmaceutical composition in combination with other active ingredients as in combination therapy or with a suitable carrier or excipient. .
  • compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.
  • prevention used in the present invention indicates the antioxidant activity by administration (or application) of the pharmaceutical composition comprising a simple phenolic glycoside derivative represented by the above formula (I), or a pharmaceutically acceptable salt thereof, and the skin
  • tyrosinase involved in the pigment melanin biosynthesis means any action that inhibits or delays excessive melanin pigmentation due to blemishes, freckles, skin pigmentation abnormal symptoms and UV exposure.
  • treatment used in the present invention, skin pigment abnormal deposition by administration (or application) of the pharmaceutical composition comprising a simple phenolic glycoside derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof It means any activity that improves or cures the condition.
  • the simple phenolic glycoside derivative represented by Formula (I) may be used in the form of a pharmaceutically acceptable salt, and the salt may be an acid addition salt formed by free acid which is pharmaceutically acceptable.
  • Inorganic and organic acids can be used as the free acid, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. can be used as the inorganic acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfuric acid.
  • Phonic acid, glyconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galluxuronic acid, embonic acid, glutamic acid, aspartic acid and the like can be used.
  • sulfuric acid can be used.
  • the simple phenolic glycoside derivatives represented by the above formula (I) according to the present invention include all salts, hydrates and solvates that can be prepared by conventional methods, as well as salts that are pharmaceutically acceptable.
  • the simple phenolic glycoside derivative represented by the formula (I) according to the present invention can be prepared in crystalline form or amorphous form, when the simple phenolic glycoside derivative represented by the formula (I) is prepared in the crystalline form Optionally hydrated or solvated.
  • compositions of the present invention may be formulated in oral or parenteral administration (coating) form according to standard pharmaceutical practice. These formulations may contain, in addition to the active ingredient, additives such as pharmaceutically acceptable carriers, excipients, adjuvants or diluents.
  • Carriers, excipients and diluents that may be included in the pharmaceutical composition and the composition for skin whitening described below include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose ( It is prepared by mixing sucrose or lactose and gelatin.
  • excipients such as starch, calcium carbonate, sucrose ( It is prepared by mixing sucrose or lactose and gelatin.
  • lubricants such as magnesium stearate and talc are also used.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • the non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
  • As the base of the suppository witepsol, macrogol, tween 60, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • composition of the present invention When the composition of the present invention is used as a medicine, a pharmaceutical composition containing at least one active phenolic glycoside derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient may be used during clinical administration (application). It may be formulated and administered (coated) in various oral or parenteral administration (coating) forms as follows, but is not limited thereto.
  • Formulations for oral administration may be, for example, tablets, pills, hard capsules, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like.
  • Tods dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine
  • lubricants such as silica, talc, magnesium salts of stearic acid, calcium salts of stearic acid and / or polyethylene glycol have.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally with starch, agar, alginic acid or its sodium salt.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally with starch, agar, alginic acid or its sodium salt.
  • binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally with starch, agar, alginic acid or its sodium salt.
  • Formulations for parenteral administration may be by a method of injecting subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.
  • a formulation for parenteral administration it comprises at least one simple phenolic glycoside derivative represented by Formula (I), or a pharmaceutically acceptable salt thereof, and mixed with water with a stabilizer or a buffer in solution or It can be prepared in suspension, which can be prepared in ampule or vial unit dosage forms.
  • the composition may contain sterile and / or preservatives, stabilizers, emulsifiers or emulsifiers, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, which are conventional methods of mixing, granulating Or according to a coating method.
  • the present invention provides a method for treating and inhibiting (or alleviating) pigmentation related skin diseases by administering (or applying) to a subject a simple phenolic glycoside derivative, or a composition comprising a simple phenolic glycoside derivative.
  • a composition comprising a simple phenolic glycoside derivative according to the present invention is administered (or applied) in an amount effective as a medicament for the treatment of pigmentation related skin diseases or to inhibit (or alleviate) symptoms of pigmentation related skin diseases.
  • compositions of the present invention may be administered (coated) or sequentially administered (coated) together with the pharmacological or physiological components described above, and may also be administered (coated) in combination with additional conventional therapeutic agents and with conventional therapeutic agents. May be administered (coated) sequentially or simultaneously.
  • administration application
  • Such administration may be single or multiple administration (application).
  • “individual” means a mammal suffering from or at risk of a condition or disease that can be reduced, inhibited or treated by administering (coating) a simple phenolic glycoside derivative according to the present invention, preferably human Means.
  • the dosage (coating amount) of the compound of the present invention to the human body may vary depending on the age, weight, sex, type of administration (coating), health condition and degree of disease of the patient, and is based on an adult patient having a weight of 70 kg. In general, it is generally 0.001 to 1,000 mg / day, preferably 0.01 to 500 mg / day, and may be dividedly administered once a day to several times at regular intervals according to the judgment of a doctor or a pharmacist (coating). have.
  • a therapeutically effective amount for any of the simple phenolic glycoside derivatives, or mixtures comprising them, used in the methods of the present invention can be measured initially from cell culture assays.
  • the dose can be calculated in an animal model to obtain a range of circulating concentrations that includes a half maximal inhibitory concentration (IC50) or a half maximal effective concentration (EC50) determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • IC50 half maximal inhibitory concentration
  • EC50 half maximal effective concentration
  • Toxicity and therapeutic efficiencies of the simple phenolic glycoside derivatives described herein, or mixtures comprising the same are, for example, LD50 (fatal to 50% of the population), ED50 (50% of the population) to have a therapeutic effect.
  • Dose), to determine IC50 (a dose with a therapeutic inhibitory effect on 50% of the population), can be estimated by surface pharmaceutical procedures in cell culture or laboratory animals.
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50 (or IC50).
  • Compounds showing high therapeutic indices are preferred.
  • the data obtained from these cell culture assays can be used to estimate the range of doses used in humans.
  • the dosage or dosage of such compounds is preferably in the range of circulating concentrations comprising ED 50 (or IC 50) in the absence or little toxicity.
  • Example 2-1 shows the antioxidant activity of the simple phenolic glycoside derivative represented by the formula (I) of the present invention (Example 2-1), inhibits melanin synthesis against human melanoma cell line, and inhibits the intracellular tyrosinase. Inhibiting activity while exhibiting relatively low cytotoxicity (Example 2-2) and having inhibitory activity against elastase enzyme reactions associated with skin aging (Example 2-3), skin whitening or wrinkles It can be usefully used as a functional cosmetic for improvement.
  • the present invention comprises a simple phenolic glycoside derivative represented by the formula (I) prepared by the above method, an isomer thereof or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient. It relates to a cosmetic composition for skin whitening or wrinkle improvement.
  • R 1 is glucose or 2-deoxy-glucose and R 2 is hydrogen, on the contrary, R 1 is hydrogen and R 2 is glucose or 2-deoxy-glucose.
  • the simple phenolic glycoside derivative represented by Formula (I) is 4-hydroxyphenyl-2-propanoyl- O -glucoside (4-hydroxyphenyl-2-propanoyl- O- glucoside, HPP2G), 4-hydroxyphenyl-2-propanoyl - O -2'- deoxy-glucoside (4-hydroxyphenyl-2-propanoyl- O -2'-deoxyglucoside, HPP2DG), 4- hydroxy-3-propanoyl - O - glucoside (4-hydroxyphenyl-3-propanoyl- O -glucoside, HPP3G) and 4-hydroxy-3-propanoyl - O -2'- deoxy-glucoside (4-hydroxyphenyl-3-propanoyl- O -2'-deoxyglucoside, HPP3DG) is preferably selected from the group consisting of, but is not limited thereto.
  • the present invention provides a skin whitening using a cosmetic composition containing a simple phenolic glycoside derivative represented by the formula (I), an isomer thereof, or a solvate, hydrate or prodrug thereof acceptable as a medicament, or It relates to a wrinkle improvement method.
  • a cosmetic composition containing a simple phenolic glycoside derivative represented by the formula (I), an isomer thereof, or a solvate, hydrate or prodrug thereof acceptable as a medicament, or It relates to a wrinkle improvement method.
  • the present invention provides a skin whitening or wrinkle containing a simple phenolic glycoside derivative represented by the formula (I), an isomer thereof, or a solvate, hydrate or prodrug thereof acceptable as a medicament as an active ingredient. It relates to the use in the preparation of the cosmetic composition for improvement.
  • the content of the simple phenolic glycoside derivatives added to the cosmetic is preferably 0.001% to 10% by weight of the various cosmetics, more preferably 0.01% to 5% by weight.
  • the content of the glycoside derivative is less than 0.001% by weight, the whitening effect cannot be expected.
  • the content of the glycoside derivative is more than 10% by weight, the amount of the glycoside derivative may not be as effective as the amount used, and there may be difficulties in safety and formulation.
  • composition for skin whitening that is acceptable as a cosmetic of the present invention preferably contains other whitening ingredients that can give a synergistic effect to the whitening effect within the range of not inhibiting the whitening effect of the present invention in addition to the glycoside derivative. It may also contain.
  • this whitening component an ascorbic acid derivative, alpha-bisabolol, etc. are mentioned.
  • the skin whitening cosmetics containing the simple phenolic glycoside derivatives of the present invention are not particularly limited in the formulation, for example, supple cosmetics (skin), astringent cosmetics, nourishing cosmetics, nutrition cream, massage cream, essence It can be formulated into cosmetics such as eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, powder, body lotion, body cream, body oil, body essence, pack, skin patch and skin adhesive gel. .
  • the formulation of the skin whitening composition of the present invention may contain additives such as carriers, excipients, adjuvants or diluents that are acceptable as cosmetics in addition to the active ingredient.
  • Micromonospora In order to isolate the glycotransferase MrSPGT using a simple phenolic compound derived from the rhodorangea strain as a substrate, first, a genome isolated from the micromonospora rodoranga strain was used as a template and produced based on the nucleotide sequence of the genome. Polymerase chain reaction (PCR) was performed with primers of SEQ ID NO: 1 and SEQ ID NO: 2 as follows. The N-terminal primer is the sequence of SEQ ID NO: 1 below, and the C-terminal primer is the sequence of SEQ ID NO: 2 below.
  • PCR Polymerase chain reaction
  • the total nucleotide sequence was 1176bp, and it was confirmed that the post-translational protein consists of 391 amino acids (41.78 kDa in total).
  • MrGT1 DNA fragment E. coli BL21 (DE3) (Stratagene, La Jolla, CA, USA) was transformed. At this time, 50 ppm of kanamycin antibiotics were used for selection of the transformants.
  • the recombinant E. coli was inoculated at 1% by volume in LB medium (Luria Bertani) to which the above-described antibiotic and sorbitol and 2.5 mM betaine were added at a final concentration of 1 M, and then cultured at 37 ° C. (optical density) When the growth is confirmed between 0.6 and 0.8, to induce protein expression, isopropyl-D-thiogalactopyranoside (IPTG; Sigma, St. Louis, MO, USA). Recombinant E. coli strains were further incubated at 20 ° C. for 24 hours.
  • the culture medium was centrifuged at 2000 rpm for 10 minutes to recover the strain, and the cells were dissolved in 50 mM sodium phosphate lysis buffer (300 nM NaCl, 10 mM imidazole, 10% glycerol, 1% Triton X-100), Sonication was performed. Then, refrigerated centrifugation at 12000rpm for 20 minutes, the supernatant was collected separately and some samples were analyzed by 12% SDS-PAGE to confirm the expression level of the recombinant glycotransferase MrGT1.
  • 50 mM sodium phosphate lysis buffer 300 nM NaCl, 10 mM imidazole, 10% glycerol, 1% Triton X-100
  • the supernatant described above was equilibrated in 50mM phosphate buffer (0.3M NaCl, 20mM imidazole), Talon-metal affinity resin, Clontech, Mountain View, CA, USA) and incubated for 1 hour at 4 °C. After refrigeration and centrifugation at 2000 rpm for 5 minutes, the resin was introduced into a disposable column and washed with a phosphate buffer solution containing 20 mM imidazole of 10 times the resin volume. Finally, the recombinant glycotransferase MrSPGT bound to the resin was purified with 3 ml of phosphate buffer containing 180 mM imidazole.
  • Tyrosol (4-hydroxyphenyl ethanol; Sigma, St. Louis, MO, USA), hydroxyphenyl-propanol (4-hydroxyphenyl propanol; Sigma, St. Louis, MO, USA), hydroxyphenyl-2-propanol (4 -hydroxyphenyl-2-propanol; UROSY, Lithuania) and hydroxyphenyl-3-propanol (4-hydroxyphenyl-3-propanol; USOSY, Lativia) were dissolved in methanol at a level of 100 mM, followed by reaction buffer (50 mM phosphate buffer, Diluted to 10 mM magnesium chloride, 1 mg / ml bovine serum albumin) to a final concentration of 2 mM, followed by UDP-glucose and TDP-2-deoxy-glucose with 50 ⁇ M of MrSPGT glycotransferase and nucleic acid-sugars.
  • reaction buffer 50 mM phosphate buffer, Diluted to 10 mM
  • TDP-2-deoxy-glucose was added at a concentration of 4 mM to carry out a sugar transferase reaction at 37 ° C for 1 hour. After the reaction, the same amount of ethyl acetate was added to stop the reaction, and only the upper organic solvent layer was collected and vacuum dried. High pressure liquid chromatography (HPLC) analysis was performed to confirm the biosynthesis of the target compound in the extract.
  • acetonitrile: methanol: water: formic acid 10: 50: 39.9: 0.1 (v / v / v / v) mixed liquid is used as a mobile phase at a speed of 130 ⁇ l / min and Acquity CSH C18 (Waters, 50 ⁇ 1.0 mm) , 1.7 ⁇ m; Milford, MA, USA) was used to perform instrumental analysis (see FIG. 1).
  • the simple phenolic compounds used as the substrate were aliquoted with a holding time of 12 to 15 minutes on the MPLC system, and the desired simple phenolic glycoside derivatives were detected between 6 to 9 minutes, which is faster than the substrate.
  • NMR samples were prepared by dissolving the respective glycoside derivatives in 200 ⁇ l of CD 3 OD and then leaving the solvent in a 5 mm Shigemi Advanced NMR microtube (Sigemi advanced NMR microtube, Sigma, St. Louis, Mo.). 13 C NMR spectra were acquired at 298K using a Varian INOVA 500 spectrophotometer and chemical shifts were recorded in ppm using TMS as internal reference. All NMR data calculation was performed using a Mnova Suite 5.3.2 software, it was compared with 13 C-NMR spectrum of the dividend derivative before reaction with the simple phenolic compounds (see Table 1).
  • Table 1 shows the 13 C-NMR results according to the nuclear magnetic resonance spectrometry instrument analysis of four simple phenolic glycoside derivatives purified by MPLC column chromatography.
  • the antioxidant capacity was measured using DPPH (2,2-diphenyl-1-picrylhydrazyl).
  • the purified glycosides were diluted in 0.1 to 2mM sections with 5 sections (0.1, 0.2, 0.5, 1.0 and 2.0mM) in methanol, and 1.9ml of 100 ⁇ M DPPH reagent (DMSO dissolved) was added to each 0.1ml sample. Then, it was left to stand at 37 degreeC for 15 minutes. The absorbance was then measured at 515 nm UV-VIS spectrophotometer.
  • ascorbic acid L-ascorboic acid; Sigma, St.
  • the IC 50 was found to be about 0.16mM
  • two comparative phenolic compounds of the comparative group showed an IC 50 of about 0.19mM
  • a simple phenolic dividend Derivatives appeared between about 0.20 and 0.22 mM.
  • the results showed that the simple phenolic derivatives, which were sugar-transferred, had lower antioxidant activity than the positive control ascorbic acid, which had strong antioxidant activity, but maintained similar antioxidant activity within the statistical significance level than the simple phenolic compounds before sugar transfer. .
  • the arbutin positive control group showed tyrosinase inhibitory activity of about 46%, and the two simple phenolic compounds of the comparative group were about 76% and about 73%, respectively.
  • Simple phenolic glycoside derivatives appeared in between, showing inhibitory activity ranging from about 55% to 64%.
  • B16 / F10 melanoma cell line was used. That is, DMEM medium containing 10% FBS was dispensed at a level of 2000 cells / well in a 96 well plate, and then incubated at 37 ° C. with a 5% carbon dioxide concentration for 24 hours.
  • the recovered cells were dried at 55 ° C., and 100 ⁇ l of 1N sodium hydroxide solution was added to dissolve the melanin in the cells and diluted with phosphate buffer to measure absorbance with a final 475 nm Microplate reader (Molecular Devices).
  • DMSO was used as a negative control, and arbutin at a concentration of 0.3 mM (DMSO lysis) was used as a positive control, and the melanin biosynthesis inhibitory activity was shown as a bar graph in FIG.
  • the positive control group arbutin showed melanin biosynthesis inhibitory activity against melanoma cell line was about 41%, two comparative phenolic compounds of about 64% and about 66%, respectively %, With simple phenolic glycoside derivatives showing intervening activity in the range of about 49% to about 57%.
  • the results showed that the sugar-transferred simple phenolic derivatives showed a weaker melanin biosynthesis inhibitory activity than the simple phenolic compounds before sugar transfer, and improved melanin biosynthesis inhibitory activity within a significant level range than arbutin, one of the existing positive controls. It was confirmed that it has.
  • Example 1 in order to test the degree of cytotoxicity of the biosynthesis simple phenolic derivatives from the dividend, and using the MTT assay using fibroblast cells (fibroblast) (Mosmann, Tim, Journal of Immunological Methods, 65 (1-2 ): 55-63, 1983).
  • Fibroblasts in log phase were dispensed at 8000 cells / well in 96 well plates and incubated for 24 hours at 37 ° C. with 5% carbon dioxide concentration in 200 ⁇ l DMEM medium. The medium was reacted for about 20 hours after adding four simple phenolic glycosides and two simple phenolic compounds before the reaction, which were immobilized at a final 0.3 mM level (DMSO dissolution).
  • the two simple phenolic compounds of the comparison group showed cell survival rates of about 72% and about 77%, respectively, compared to the control group at the final 0.3 mM level, and the simple phenolic glycoside derivatives were Cell viability was shown to range from 98% to 107% higher. This suggests that the simple phenolic glycoside derivatives having a concentration of 0.3 mM showing inhibitory activity on tyrosinase and melanoma cells are significantly lower in cytotoxicity than the simple phenolic compounds as the original compounds.
  • the high concentration standards were based on the maximum whitening content of 5%, which is currently known by the Korea Food and Drug Administration.
  • the multiproliferative fibroblasts were dispensed in 96 well plates at a level of 8000 cells / well and incubated for 24 hours at 37 ° C. with 5% carbon dioxide concentration in 200 ⁇ l of DMEM medium.
  • the two simple phenolic compounds of the comparison group showed cell survival rates of about 33% and 36%, respectively, compared to the control group at the maximum content of whitening components known from the Korea Food and Drug Administration, 5%. Rick's dividend derivatives showed statistically significant cell viability in the range of 84% to 98%. On the other hand, 5% high concentration of arbutin, a positive control, about 94% cell survival rate compared to the control group.
  • novel simple phenolic glycoside derivatives of the present invention showed no difference in arbutin, which is a positive control, and its cytotoxicity, based on the concentration of 5%, which is the maximum content of the whitening compound of the regulatory agency.
  • novel simple phenolic glycoside derivatives of the present invention can be added to the preparation of cosmetic compositions at high concentration levels of 5%.
  • Elastase uses elastase (Sigma) derived from porcine pancreas, and N-succinyl- [L-alanine-alanine-alanine [ p -nitroanilide (N-succinyl- [L-alanine-alanine-] as a substrate. After 20 minutes of reaction at 25 ° C. using alanine] -p- nitroanilide (Sigma), the absorbance was measured using a 405 nm Microplate reader (Molecular Devices).
  • the positive control group of asolic acid showed an IC 50 of about 0.08 mM, while ascorbic acid was about 5.12 mM.
  • the two simple phenolic compounds of the comparative group showed an IC 50 of more than 1.2 mM and the simple phenolic glycoside derivatives were between 0.30 and 0.70 mM.
  • the sugar-transferred simple phenolic derivatives showed lower elastase inhibitory activity than that of ascorbic acid, which was lower than the positive control asolic acid with strong elastase inhibitory activity.
  • simple phenolic glycoside derivatives have been found to have improved elastase inhibitory activity after sugar addition, simple phenolic glycoside derivatives show some anti-wrinkle effect.
  • Micromonospora Rhodonangia Simple phenolic glycoside derivatives biosynthesized using glycotransferase are applicable to human skin as they have no antioxidant activity, tyrosinase inhibitory activity and melanin biosynthesis inhibitory activity and cytotoxicity in human melanoma cell lines.

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Abstract

La présente invention concerne un analogue glycosidique phénolique simple ; son procédé de préparation ; et une composition cosmétique pour le blanchiment de la peau ou l'atténuation des rides en contenant et, plus particulièrement, un procédé de préparation d'un analogue glycosidique phénolique simple utilisant de la glycosyltransférase de Micromonospora rhodorangea (MrSPGT) ; et une composition cosmétique pour le blanchiment de la peau ou l'atténuation des rides contenant cet analogue en tant qu'ingrédient actif. Selon la présente invention, un analogue glycosidique phénolique simple biosynthétisé à l'aide de MrSPGT présente une activité antioxydante, une activité d'inhibition de la tyrosinase et une activité d'inhibition de la biosynthèse de la mélanine dans des lignées cellulaires de mélanome humain et ne présente pas de cytotoxicité, ce qui rend possible son application sur la peau humaine, et présente des effets remarquables en matière de blanchiment de la peau et d'atténuation des rides, ce qui explique son utilité sous la forme d'une composition pharmaceutique visant à prévenir ou traiter les maladies de la peau associées à la pigmentation, ainsi que sous la forme d'une composition cosmétique pour le blanchiment de la peau ou l'atténuation des rides.
PCT/KR2016/002888 2015-10-30 2016-03-23 Analogue glycosidique phénolique simple, son procédé de préparation et composition pour blanchiment de la peau ou atténuation des rides en contenant WO2017073854A1 (fr)

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KR1020160033921A KR101884382B1 (ko) 2015-10-30 2016-03-22 단순 페놀릭 배당 유도체, 이의 제조방법 및 이를 함유하는 피부미백 또는 주름개선용 조성물

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100683236B1 (ko) * 2000-03-28 2007-02-15 에자끼구리고가부시키가이샤 당 전이물의 제조방법
JP2007330112A (ja) * 2006-06-12 2007-12-27 Sanei Gen Ffi Inc フェノール性化合物のグルコース配糖体の製造方法
JP2008187927A (ja) * 2007-02-02 2008-08-21 Chiba Univ 新規なフェノール配糖化酵素
KR20090020697A (ko) * 2006-06-14 2009-02-26 리브라겐 기능성 미용제품 및 치료용 약품에 적용되는 수용성 및 활성 페놀화합물 유도체 및 그 유도체의 제조방법
WO2013073659A1 (fr) * 2011-11-17 2013-05-23 国立大学法人長崎大学 Procédé de production d'un glycoside comprenant un phénol à titre d'aglycone

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100683236B1 (ko) * 2000-03-28 2007-02-15 에자끼구리고가부시키가이샤 당 전이물의 제조방법
JP2007330112A (ja) * 2006-06-12 2007-12-27 Sanei Gen Ffi Inc フェノール性化合物のグルコース配糖体の製造方法
KR20090020697A (ko) * 2006-06-14 2009-02-26 리브라겐 기능성 미용제품 및 치료용 약품에 적용되는 수용성 및 활성 페놀화합물 유도체 및 그 유도체의 제조방법
JP2008187927A (ja) * 2007-02-02 2008-08-21 Chiba Univ 新規なフェノール配糖化酵素
WO2013073659A1 (fr) * 2011-11-17 2013-05-23 国立大学法人長崎大学 Procédé de production d'un glycoside comprenant un phénol à titre d'aglycone

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