WO2019054822A1 - 활성물질-헥사펩타이드 복합체 및 이를 포함하는 화장료 조성물 - Google Patents
활성물질-헥사펩타이드 복합체 및 이를 포함하는 화장료 조성물 Download PDFInfo
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- WO2019054822A1 WO2019054822A1 PCT/KR2018/010914 KR2018010914W WO2019054822A1 WO 2019054822 A1 WO2019054822 A1 WO 2019054822A1 KR 2018010914 W KR2018010914 W KR 2018010914W WO 2019054822 A1 WO2019054822 A1 WO 2019054822A1
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- eemqrr
- hexapeptide
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- 0 CC[C@](C)CCCCC1=C[C@]1(CC)C[C@@]([C@]1[C@@](C)C*CC1)[C@]1CC(C2)[C@@]2CCCCC1 Chemical compound CC[C@](C)CCCCC1=C[C@]1(CC)C[C@@]([C@]1[C@@](C)C*CC1)[C@]1CC(C2)[C@@]2CCCCC1 0.000 description 4
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Images
Classifications
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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
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- 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
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K8/36—Carboxylic acids; Salts or anhydrides thereof
- A61K8/362—Polycarboxylic acids
-
- 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
- A61K8/63—Steroids; Derivatives thereof
-
- 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
-
- 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
- A61Q19/08—Anti-ageing preparations
Definitions
- the present invention relates to an active substance-hexapeptide complex and a cosmetic composition containing the same.
- Skin aging can be divided into endogenous aging and extrinsic aging.
- Endogenous aging means natural aging in which the amount of synthesis of extracellular matrix proteins such as collagen fibers and elastic fibers decreases over time and elasticity is decreased and the structure of the stratum corneum changes and the water content in skin cells decreases.
- Exogenous aging is aging caused by external stimuli such as ultraviolet rays, air pollution, tobacco smoke, stress, etc., and photoaging is a typical exogenous aging.
- Photoactivation is induced by reactive oxygen species when the skin is exposed to ultraviolet light, resulting in the inflammatory reaction induced by the activation of AP-1 (activatorprotetin-1) and NF-kB (nuclear factor-kB) , Nucleic acid, enzymes, etc. are damaged and aging occurs.
- AP-1 activatorprotetin-1
- NF-kB nuclear factor-kB
- the inventors of the present invention have developed an organic acid-hexapeptide complex comprising an organic acid and a hexapeptide, which is a functional peptide in nature, in order to develop a cosmetic composition using an active substance.
- the present inventors developed a mutant hexapeptide complex by binding a steroid effective against dermatitis or atopic patients to a hexapeptide as a functional peptide.
- the present inventors completed the present invention by confirming that the organic acid-hexapeptide complex and the mutated hexapeptide complex exhibit antioxidative and skin regenerating effects.
- One aspect of the present invention provides a hexapeptide having an amino acid sequence of EEMQRR (SEQ ID NO: 1) and an active substance-hexapeptide complex to which an active substance is bound.
- Another aspect of the present invention provides a cosmetic composition comprising the active substance-hexapeptide complex as an active ingredient.
- Another aspect of the present invention provides a pharmaceutical composition for treating skin wounds comprising the active substance-hexapeptide complex as an active ingredient.
- Another aspect of the present invention provides the use of the active substance-hexapeptide complex of the present invention for skin condition improvement.
- Another aspect of the present invention provides the use of the active substance-hexapeptide complex of the present invention for preparing a cosmetic composition for skin condition improvement.
- Another aspect of the present invention provides the use of the active substance-hexapeptide complex of the present invention for treating skin wounds.
- Another aspect of the present invention provides the use of the active substance-hexapeptide complex of the present invention for the manufacture of a medicament for treating skin wounds.
- Another aspect of the present invention provides a method for improving skin condition comprising treating the skin of an individual with the active substance-hexapeptide complex of the present invention.
- Another aspect of the present invention provides a method of treating skin wounds comprising treating the skin of an individual with an active substance-hexapeptide complex of the present invention.
- the active substance-hexapeptide complex of the present invention exhibits superior antioxidative and skin regenerating effects than conventional organic acids, steroids or hexapeptides by binding an organic acid or a steroid to a hexapeptide. Therefore, the active substance-hexapeptide complex of the present invention and the cosmetic composition containing the same can be effectively used for antioxidation and prevention of skin aging.
- Figure 1 shows the analytical results of a purified formic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- Figure 2 shows the results of the analysis of the purified glucuronic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- Figure 3 shows the results of the analysis of the purified lactic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- Figure 4 shows the results of the analysis of purified mevalonate-EEMQRR-NH 2 complexes through high performance liquid chromatography.
- FIG. 5 is a graph showing the results of analysis of the purified propionic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- Figure 6 shows the results of the analysis of the purified pyruvic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- Figure 7 shows the results of the analysis of the purified quinic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- FIG. 8 is a diagram showing the results of analysis of the shikisan-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 9 is a graph showing the results of an analysis of purified abietic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- FIG. 10 is a diagram showing the results of analysis of the asialic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- Figure 11 shows the results of the analysis of the purified cholic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- Figure 12 shows the results of the analysis of the ursodeoxycholic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 13 is a diagram showing an analysis result of a uric acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 14 is a diagram showing the results of analysis of the azelaic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 15 is a diagram showing the results of analysis of the purified dipicolinic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 16 is a diagram showing the analysis result of the purified fumaric acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 17 is a diagram showing the results of analysis of the itaconic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 18 is a diagram showing the results of analysis of a purified malic-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 19 is a diagram showing the results of analysis of the oxalic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- 20 is a diagram showing the results of analysis of a succinic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- 21 is a diagram showing the analysis result of the purified tartaric acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 22 is a diagram showing the analysis result of alpha-keto glutaric acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 23 is a diagram showing an analysis result of a purified citrate-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 24 is a diagram showing the results of analysis of the purified lipoic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 25 is a diagram showing the analysis results of the purified formic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 26 is a diagram showing an analysis result of a sorbic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 27 is a diagram showing the results of analysis of biotin-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 28 is a view showing an analysis result of a purified trethionin-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 29 is a diagram showing the results of analysis of the purified caffeic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- FIG. 30 is a diagram showing the results of analysis of cinnamic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 31 is a diagram showing the analysis result of the ferulic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 32 is a diagram showing the results of analysis of the purified rosmarinic acid-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 33 is a diagram showing the results of analysis of the nicotinic acid-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- 34 is a diagram showing the results of analysis of a purified Silesin-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 35 is a view showing a synthesis process of binding an organic acid to the C-terminal of hexapeptide.
- 36 is a view showing a synthesis process of binding an organic acid to the N-terminal of a hexapeptide.
- FIG. 37 is a view showing a synthesis process of binding an organic acid to a side chain of a hexapeptide.
- Figure 38a is rojeumarinsan -EEMQRR-NH 2, Cafe acid -EEMQRR-NH 2, ferulic acid -EEMQRR-NH 2, tartaric -EEMQRR-NH 2, malic -EEMQRR-NH 2, azelaic acid -EEMQRR-NH 2, abietic
- the skin regeneration effect of the acid-EEMQRR-NH 2 , pyruvic acid-EEMQRR-NH 2 and succinic acid-EEMQRR-NH 2 complexes was confirmed by a wound recovery experiment.
- Figure 38b is a lactic acid Asia -EEMQRR-NH 2, biotin -EEMQRR-NH 2, cholic acid -EEMQRR-NH 2, cinnamic acid -EEMQRR-NH 2, citric acid -EEMQRR-NH 2, Diffie choline acid -EEMQRR-NH 2, formic acid - EEMQRR-NH 2, fumaric -EEMQRR-NH 2, jeran acid -EEMQRR-NH 2, glucuronic acid -EEMQRR-NH 2, itaconic acid -EEMQRR-NH 2, lipoic -EEMQRR-NH 2, lactic acid -EEMQRR-NH 2 , mevalonic acid -EEMQRR-NH 2, nicotinic acid -EEMQRR-NH 2, oxalate -EEMQRR-NH 2, acid -EEMQRR-NH 2, kwinsan -EEMQRR-NH 2, to Mishan -EEMQRR
- Figure 38c is a EEMQRR-NH 2, Acetyl-EEMQRR -NH 2 (Acetyl hexapeptide-8), rojeumarinsan, ferulic acid, rojeumarinsan -EEMQRR-NH 2 and the skin regeneration of ferulic acid -EEMQRR-NH 2 complex hexapeptide of the present invention The effect is shown by the wound recovery experiment.
- FIG. 39 is a graph showing the skin regeneration effect of zeolanic acid-EEMQRR-NH 2, COOH-EEMQRR-geranic acid, and COOH-EE (geranic acid) MQRR-NH 2 complex through wound recovery experiments.
- 40 is a graph showing a result of WST-1 analyzes performed to determine the cytotoxicity of jeran acid -EEMQRR-NH 2, COOH-EEMQRR- jeran acids and COOH-EE (jeran acid) MQRR-NH 2 complex.
- 41 is a view showing a process for synthesizing a Betamethasone-EEMQRR-NH 2 complex using glutaric anhydride as a linker.
- Betamethasone-EEMQRR-NH 2 complex using malonic acid as a linker.
- Figure 43 shows the results of the analysis of the Betamethasone-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- Figure 44 shows the results of the analysis of the dexamethasone-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- 45 is a diagram showing the results of analysis of the hydrocortisone-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- FIG. 46 shows the results of analysis of the purified Friedrich-EEMQRR-NH 2 complex through high performance liquid chromatography.
- 47 is a diagram showing the results of analysis of the methylprednisone-EEMQRR-NH 2 complex purified through high performance liquid chromatography.
- Figure 48 is a diagram showing the analysis results of the purified estriol-EEMQRR-NH 2 complex by high performance liquid chromatography.
- Figure 50 is betamethasone valerate -EEMQRR-NH 2, betamethasone propionate as deep -EEMQRR-NH 2, di-fluorenyl cor discussion valerate -Glutaroyl-EEMQRR-NH 2, hydrocortisone 17-butyrate -EEMQRR-NH 2, Mo
- the skin regeneration effect of the metaphosphate-EEMQRR-NH 2 and methylprednisolone sulfonate-EEMQRR-NH 2 complexes was confirmed by a wound recovery experiment.
- betamethasone valerate -Glutaric-EEMQRR-NH 2 betamethasone valerate -Succinic-EEMQRR-NH 2
- betamethasone valerate -Maleic-EEMQRR-NH 2 betamethasone valerate -Malonic-EEMQRR-NH 2
- betamethasone valerate EemQRR-NH 2 betamethasone valerate-Fumaric-EEMQRR-NH 2
- Betamethasone valerate-Isophthalic-EEMQRR-NH 2 Betamethasone valerate-Terephthalic-EEMQRR- NH 2
- Betamethasone valerate-2,6-Naphthalenedicarboxylic - EEMQRR-NH 2 complex of the present invention was confirmed through wound recovery experiments.
- Figure 52 is betamethasone valerate -EEMQRR-NH 2, betamethasone propionate as deep -EEMQRR-NH 2, di-fluorenyl cor discussion valerate -Glutaroyl-EEMQRR-NH 2, hydrocortisone 17-butyrate -EEMQRR-NH 2, Mo 2 is a graph showing the results of WST-1 analysis performed to examine the cytotoxicity of methasone furoate-EEMQRR-NH 2 and methylprednisolone acetonate-EEMQRR-NH 2 complexes.
- betamethasone valerate -Glutaric-EEMQRR-NH 2 betamethasone valerate -Succinic-EEMQRR-NH 2
- betamethasone valerate -Maleic-EEMQRR-NH 2 betamethasone valerate -Malonic-EEMQRR-NH 2
- betamethasone valerate EemQRR-NH 2 Betamethasone valerate-Fumaric-EEMQRR-NH 2
- Betamethasone valerate-Isophthalic-EEMQRR-NH 2 Betamethasone valerate-Terephthalic-EEMQRR- NH 2
- One aspect of the present invention provides a hexapeptide having an amino acid sequence of EEMQRR (SEQ ID NO: 1) and an active substance-hexapeptide complex to which an active substance is bound.
- the active material may be an organic acid.
- the organic acid may be any one selected from the group consisting of mono-acid, di-oxide, tri-acid, fatty acid, cinnamic acid, and aromatic acid.
- the organic acid may have at least one carboxyl group.
- the mono-acid may be selected from the group consisting of formic acid, glucuronic acid, lactic acid, mevalonic acid, propionic acid, pyruvic acid, quinic acid, And any one selected from the group consisting of Shikimic acid, Abietic acid, Asiatic acid, Cholic acid, Ursodeoxycholic acid and Ursolic acid. Lt; / RTI >
- formic acid used in the present invention means organic acids contained in plants such as nettle, in addition to ants, also called formic acid or methaconic acid.
- the structure of the formic acid is shown in the following formula (1).
- glucuronic acid as used in the present invention is a constituent component of structural polysaccharides such as straw and wood, and is an essential component of mucopolysaccharides of higher animals in animal species and contained in hyaluronic acid, heparin, chondroitin sulfate and the like ≪ / RTI >
- the structure of the glucuronic acid is represented by the following general formula (2).
- lactic acid used in the present invention is also referred to as lactic acid, and means an organic acid generated from a sugar by lactic acid bacteria.
- the lactic acid is widely distributed in the natural world, and most of the lactic acid exists in the free state in the plant, and is produced in the fermentation of the fruit of the plant.
- the structure of the lactic acid is represented by the following general formula (3).
- mevalonic acid used in the present invention is also referred to as hiochic acid and means an organic acid contained in sake or beer.
- the mevalonic acid is necessary for the growth of Lactobacillus heterohiochii , which is a genuine osteoblus that reproduces and decays in Cheongju.
- the structure of mevalonic acid is shown in the following chemical formula 4.
- propionic acid used in the present invention means a product of fermentation of alcohol or propionic acid, and means an organic acid contained in chyle and sweat.
- the structure of the propionic acid is represented by the following general formula (5).
- pyruvic acid used in the present invention means an organic acid produced by the Emden-Meyerhof pathway or the Entner-Doudor off pathway in bacteria and yeast fermentation .
- the structure of the pyruvic acid is represented by the following general formula (6).
- quinic acid used in the present invention means an organic acid having a ring structure peculiar to higher plants, which is contained in fruit such as quince tree bark, coffee seed, apple, peach and the like.
- the structure of the above quinic acid is represented by the following general formula (7).
- shikisimo acid used in the present invention means an unsaturated derivative of quinic acid, which is an organic acid of tetrahydrotrihydroxybenzoic acid, which is contained in the fruit of the pteridophyte.
- the structure of the above shikisan is represented by the following general formula (8).
- abietic acid used in the present invention means an organic acid of ditertepen, which is the main component of the pine root.
- the structure of the abietic acid is shown in the following formula (9).
- asialic acid used in the present invention means an organic acid of dermal acid contained in centella asiatica.
- the structure of the above-mentioned asialic acid is shown in the following chemical formula (10).
- cholic acid refers to an organic acid present in the bile of an animal that secretes bile, such as mammals, birds, reptiles, amphibians and the like.
- the structure of the cholic acid is represented by the following general formula (11).
- ursodeoxycholic acid as used in the present invention means bile acid known as the main component of urethane.
- the structure of the above-mentioned ursodeoxycholic acid is shown in the following general formula (12).
- uric acid used in the present invention means a coating material in a waxy state such as apple, cherry, or the like, and is an organic acid of? -Amyrin type triterpene.
- the structure of the above uronic acid is shown in the following chemical formula (13).
- the die acid may be selected from the group consisting of azelaic acid, dipicolinic acid, fumaric acid, itaconic acid, malic acid, oxalic acid, succinic acid, Tartaric acid, and alpha -Ketoglutaric acid.
- azelaic acid used in the present invention means an organic acid of saturated dicarboxylic acid contained in grains such as wheat, rye and barley.
- Azelaic acid is an antimicrobial agent that reduces bacteria in hair follicles and pores, and is known to have antioxidant and anti-inflammatory properties.
- skin cells or hair follicles when abnormally proliferated or transformed into acne, they regenerate to normal, and cystic acne, acne pigmentation and redness are alleviated.
- the structure of the azelaic acid is shown in Formula 14 below.
- dipicolinic acid as used in the present invention means an organic acid of pyridine-dicarboxylic acid contained in the spores of many Bacillus species including Bacillus subtilis.
- the dipicolinic acid acts as an antioxidant of ascorbic acid in food.
- the structure of the dipicolinic acid is shown in the following formula (15).
- fumaric acid used in the present invention means an organic acid of unsaturated dicarboxylic acid contained in mosses, fungi and the like of Icelandic acid.
- the structure of the fumaric acid is shown in the following chemical formula (16).
- itaconic acid used in the present invention is also referred to as methylenesuccinic acid, and refers to an organic acid of dicarboxylic acid produced by a fungus of plum on the basis of saccharides. In addition, itaconic acid also accumulates in a small amount of medium.
- the structure of itaconic acid is shown in the following chemical formula (17).
- malic acid used in the present invention means an organic acid corresponding to hydroxysuccinic acid, which is also called malic acid or malic acid and is contained in fruits such as apple and grape.
- the structure of the malic acid is represented by the following general formula (18).
- oxalic acid used in the present invention means an organic acid which is widely distributed in plants in the form of a potassium salt or a calcium salt.
- the oxalic acid is the simplest dicarboxylic acid with two carboxy groups attached.
- the structure of the oxalic acid is shown in the following chemical formula 19.
- succinic acid used in the present invention refers to organic acids such as amber, turpentine, tribe, lichen, fungi and the like, also called succinic acid.
- the succinic acid is dicarboxylic acid.
- the structure of the succinic acid is shown in Chemical Formula 20 below.
- tartaric acid as used in the present invention means also an organic acid of dioxysuccinic acid, which is also called tartaric acid and present in grapes and wines. Tartaric acid can be obtained by adding calcium carbonate to tin and treating the resulting precipitate with sulfuric acid.
- the structure of the above tartaric acid is represented by the following general formula (21).
- alpha-ketoglutaric acid used in the present invention means an organic acid synthesized from glucose through ketogluconic acid by microbial fermentation of Pseudomonas sp.
- the structure of the alpha-keto glutaric acid is shown in the following formula (22).
- the triaxide may be citric acid.
- citric acid as used in the present invention means citric acid, and refers to an organic acid mainly present in citrus fruit such as lemon and lime.
- the citric acid is a polybasic carboxylic acid having a hydroxy group and is contained in the seed or juice of many plants as a free acid.
- the structure of the citric acid is shown in the following chemical formula (23).
- the fatty acid may be any one selected from the group consisting of lipoic acid, geranic acid, sorbic acid, biotin, and tretinoin.
- lipoic acid used in the present invention is also referred to as thioxane and means an organic acid having a disulfide bond with a fatty acid.
- the structure of the lipoic acid is shown in the following chemical formula (24).
- geranic acid used in the present invention means an organic acid which is a perfume component contained in roses, herbs and the like.
- the structure of the above-mentioned geranic acid is shown in the following chemical formula (25).
- sorbic acid refers to an organic acid, also called 2,4-hexadienoic acid, contained in the immature fruit of Sorbus commixta Hedlund .
- the sorbic acid suppresses the growth of microorganisms and is used as a preservative for processed foods.
- the structure of the sorbic acid is shown in the following Chemical Formula 26.
- biotin used in the present invention means a vitamin B complex, and refers to an organic acid containing a sulfur and having a valeric acid group and a tetrahydrothiophene ring bonded to a ureido ring.
- the structure of the biotin is shown in the following chemical formula (27).
- tretinoin refers to the all-trans isomer of retinoic acid, a derivative of vitamin A.
- the structure of the tretinoin is shown in the following formula (28).
- the cinnamic acid may be any one selected from the group consisting of caffeic acid, cinnamic acid, ferulic acid and rosmarinic acid.
- caffeic acid used in the present invention is a kind of phenolic acid compound present in various crops such as coffee beans, potatoes, grains and vegetables, and includes 3- (3,4-dihydroxyphenyl) -2- Means an organic acid represented by 3- (3,4-dihydroxyphenyl) -2-propenoic acid.
- the structure of the caffeic acid is shown in the following formula (29).
- cinnamic acid used in the present invention means an organic acid of unsaturated carboxylic acid contained in oil of cinnamon or balsam tree such as quercus variabilis.
- the structure of cinnamic acid is shown in the following chemical formula (30).
- ferulic acid used in the present invention means a precursor substance of lignin forming the cell wall of a plant.
- the structure of the ferric acid is shown in the following formula (31).
- rosmarinic acid as used in the present invention means an organic acid mainly contained in herbal plants such as peppermint, spearmint, and rosemary.
- the structure of the above rosmarinic acid is shown in Formula 32 below.
- the aromatic acid may be any one selected from the group consisting of nicotinic acid and syringic acid.
- nicotinic acid used in the present invention is also referred to as vitamin B3 or niacin, and refers to an organic acid of pyridine-3 carboxylic acid widely present in vivo such as liver, yeast, legumes and cereals of animals.
- the structure of the nicotinic acid is shown in the following chemical formula (33).
- sicric acid used in the present invention means an organic acid of trihydroxybenzoic acid contained in plants such as Robinia pseudacacia L and Cascara sagrada .
- the structure of the above Sic acid is shown in the following chemical formula (34).
- the active substance in the active substance-hexapeptide complex of the present invention is an organic acid
- the hexa-peptide bonded to the organic acid is referred to as an " organic acid-hexapeptide complex"
- the present invention provides an organic acid-hexapeptide complex wherein an organic acid is bonded to a hexapeptide having an amino acid sequence of EEMQRR (SEQ ID NO: 1).
- the organic acid may be bonded to the N-terminal, C-terminal or side chain of the hexapeptide.
- the carboxyl group of the organic acid may be peptide-linked to the N-terminal of the hexapeptide.
- the organic acid can be C-terminally bound to the hexapeptide through a linker.
- the organic acid may be bonded to the C-terminal of the hexapeptide through a substituted or unsubstituted C 1-6 linker.
- ethylene glycol was used as the linker.
- the organic acid may be peptide-bonded to a hexapeptide in which the C-terminal of the hexapeptide is substituted with a carboxyamide amide group.
- the organic acid may bind to the side chain of the hexapeptide.
- the organic acid may be bonded to the carboxy group or the amide group position of the side chain of the hexapeptide.
- the organic acid when it is bonded to the carboxy group, it can be bonded through a linker such as ethylene glycol or the like, and when the organic acid is bonded to the amide group, the peptide bond can be achieved.
- organic acid-hexapeptide complex may be represented by the following chemical formula (35).
- X is an organic acid and R 'and R " are each independently hydrogen or C 1-3 alkyl.
- An embodiment of the complex in which the organic acid is bound to the N-terminus of the hexapeptide through a linker may be represented by the following chemical formula [35-1].
- X is an organic acid
- L is a linker
- hexapeptide used in the present invention means a hexapeptide having the amino acid sequence of Glu-Glu-Met-Gln-Arg-Arg. Further, the hexapeptide may be one in which the carboxy group is substituted with an amide group at the C-terminal of the hexapeptide.
- the hexapeptide may be an amino acid sequence represented by SEQ ID NO: 1.
- the amide group may be any one of an amide group selected from the group consisting of primary, secondary and tertiary amide groups.
- the amide group may be a primary amide group.
- An embodiment of the hexapeptide structure is represented by the following chemical formula (36).
- the present inventors prepared an organic acid-hexapeptide complex in which an organic acid and a hexapeptide existing in nature are combined (Fig. 1 to Fig. 34).
- the present inventors confirmed that the above organic acid-hexapeptide complex exhibits an antioxidative activity equivalent to that of vitamin C (Table 7). Furthermore, the present inventors confirmed that the above organic acid-hexapeptide complex exhibited excellent effects on skin regeneration and wound healing (Figs. 38A to 38C). Therefore, it can be usefully used as a composition for skin regeneration and wound healing, which comprises the organic acid-hexapeptide complex of the present invention as an active ingredient.
- the active substance may be steroid.
- betamethasone refers to a glucocorticoid hormone that exhibits a glucocorticoid action.
- the betamethasone exhibits excellent anti-inflammatory effect.
- the structure of the betamethasone is shown in the following chemical formula (37).
- dexamethasone as used in the present invention means a derivative of prednisolone which is a glucocorticoid hormone agent exhibiting glucocorticoid action.
- the structure of dexamethasone is shown in Formula 38 below.
- hydrocortisone used in the present invention means a corticosteroid hormone which is also called cortisone and exhibits a glucocorticoid action.
- the structure of hydrocortisone is shown in the following formula (39).
- prednisone means a cortisone derivative, which is a glucocorticoid hormone that exhibits a glucocorticoid action.
- the structure of prednisone is shown in the following chemical formula (40).
- methylprednisone used in the present invention means an adrenocorticotropic agent in which hydrogen bonded at the 6th carbon position of prednisone is substituted with an alpha methyl group.
- the structure of the methyl prednisone is shown in the following chemical formula (41).
- estriol used in the present invention means a kind of estrogen hormone belonging to follicular hormone.
- the structure of the estriol is represented by the following general formula (42).
- the structure of the betamethasone valerate is represented by the following general formula (43).
- betamethasone dipropionate is shown in the following chemical formula (44).
- hydrocortisone 17-butylate is shown in the following chemical formula 46.
- the active substance in the active substance-hexapeptide complex of the present invention is a steroid
- the hexapeptide bound to the steroid is referred to as " mutated hexapeptide complex".
- the present invention provides mutated hexapeptide complexes in which a steroid is conjugated to a hexapeptide having the amino acid sequence of EEMQRR (SEQ ID NO: 1).
- the steroid may bind to the N-terminal, C-terminal or side chain of the hexapeptide. Specifically, the steroid may be linked to the N-terminal, C-terminal, or side chain of the hexapeptide via a linker.
- the steroid may be linked to the carboxyl or amide group at the N-terminus, C-terminus, or side chain of the hexapeptide through a linker.
- the carboxyl group located in the side chain may be located on the side chain of glutamic acid.
- the amide group on the side chain may be located on the side chain of glutamine.
- One embodiment of the mutated hexapeptide complex may be represented by the following formula (49).
- Y is a steroid and R 'and R " are each independently hydrogen or C 1-3 alkyl.
- An embodiment of the complex in which the steroid is bound to the N-terminus of the hexapeptide through a linker may be represented by the following formula (49-1).
- Y is a steroid
- L ' is a linker.
- the linker may be represented by the following chemical formula (50).
- Z is C 1-10 alkylene, C 2-12 alkenylene or C 6-14 arylene.
- alkylene refers to a branched or straight or cyclic, branched or cyclic, saturated or unsaturated, monovalent radical having two monovalent radical centers derived by removal of two hydrogen atoms from the same or different two carbon atoms of the parent alkane Quot; refers to a saturated hydrocarbon radical.
- an alkylene group may have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms.
- Typical alkylene radicals are methylene (-CH 2 -), 1,1- ethyl (-CH (CH 3) -) , 1,2- ethyl (-CH 2 CH 2 -), 1,1- propyl (- (CH 2 CH 3 ) -), 1,2-propyl (-CH 2 CH (CH 3 ) -), 1,3-propyl (-CH 2 CH 2 CH 2 - CH 2 CH 2 CH 2 CH 2 -), and the like.
- alkenylene refers to an unsaturated hydrocarbon radical having two monovalent radical centers derived from two identical or different two carbon atoms of the parent alkane, Quot;
- the alkenylene group may have from 1 to 20 carbon atoms, from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms.
- aryl refers to an aromatic hydrocarbon radical derived from six carbon atoms of a parent aromatic ring system by removal of one hydrogen atom.
- the aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
- Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, substituted or unsubstituted naphthalene, substituted or unsubstituted anthracene, substituted or unsubstituted biphenyl, .
- X represents , , , , , , , And ≪ / RTI >
- the linker is selected from the group consisting of glutaric acid, succinic acid, maleic acid, malonic acid, adipic acid, fumaric acid, isophthalic acid, Isophthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid.
- hexapeptide used in the present invention means a hexapeptide having the amino acid sequence of Glu-Glu-Met-Gln-Arg-Arg. Further, the hexapeptide may be one in which the carboxy group is substituted with an amide group at the C-terminal of the hexapeptide.
- the hexapeptide may be an amino acid sequence represented by SEQ ID NO: 1.
- the amide group may be any one of an amide group selected from the group consisting of primary, secondary and tertiary amide groups.
- the amide group may be a primary amide group.
- One embodiment of the hexapeptide structure is the same as described above in the organic acid-hexapeptide complex.
- Table 3 shows the structure of the hexapeptide complex to which betamethasone is linked through the above 8 linkers.
- Table 4 shows the hexapeptide complex to which betamethasone valerate was bound through the above 9 kinds of linkers.
- Betamethasone valerate-glutaroyl-EEMQRR-NH 2 Betamethasone valerate-malonoyl-EEMQRR-NH 2 3
- Betamethasone valerate-terephthaloyl-EEMQRR-NH 2 Betamethasone valerate-succinoyl-EEMQRR-NH 2 5
- Betamethasone valerate-adipoyl-EEMQRR-NH 2 6
- Betamethasone valerate-2,6-naphthalenedicarboxyloyl-EEMQRR-NH 2 Betamethasone valerate-maleoyl-EEMQRR-NH 2 8
- Betamethasone valerate-isophthaloyl-EEMQRR-NH 2 Betamethasone valerate-fumaryl-EEMQRR-NH 2
- the present inventors produced hexapeptide complexes mutated by binding steroids effective for dermatitis or atopic skin diseases and hexapeptides having physiological activity to cosmetics (Figs. 43 to 48).
- the present inventors confirmed that the complex using the above steroid showed antioxidative activity (Table 11). Furthermore, the present inventors confirmed that the mutated hexapeptide complex exhibited excellent effects on skin regeneration and wound healing (FIGS. 50 and 51). Therefore, it can be usefully used as a composition for skin regeneration and wound healing which comprises the mutated hexapeptide complex of the present invention as an active ingredient.
- Another aspect of the present invention provides a cosmetic composition comprising an active substance-hexapeptide complex as an active ingredient.
- the active substance-hexapeptide complex may be an organic acid-hexapeptide complex or a mutated hexapeptide complex.
- the cosmetic composition can exhibit skin aging prevention and skin regeneration effect.
- the cosmetic composition may be any one selected from the group consisting of lotion, cream, lotion, serum, essence, and sunscreen.
- the components contained in the cosmetic composition include components commonly used in cosmetic compositions in addition to an organic acid-peptide complex or a mutated hexapeptide complex as an active ingredient. Examples thereof include antioxidants, stabilizers, solubilizers, vitamins, Such as conventional adjuvants or carriers.
- the cosmetic composition may be prepared in any form conventionally produced in the art, and examples thereof include solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant- , Oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured into a formulation of lotion (convergent lotion, soft lotion, etc.), cream, lotion, serum, essence, nutritional gel or massage cream.
- the formulation of the cosmetic composition is a paste, a cream or a gel, an animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide .
- the carrier component may be a fatty acid ester of water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan have.
- a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
- the carrier component is selected from aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid Amide ether sulfate, alkylamidobetaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester.
- Another aspect of the present invention provides a pharmaceutical composition for treating skin wounds comprising an active substance-hexapeptide complex as an active ingredient.
- the active substance-hexapeptide complex may be an organic acid-hexapeptide complex or a mutated hexapeptide complex.
- the pharmaceutical composition may comprise a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carriers are those conventionally used in the formulation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, But are not limited to, cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
- the pharmaceutical composition may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.
- the pharmaceutical composition may be prepared in a unit dosage form by formulating it with a pharmaceutically acceptable carrier and / or an excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs.
- a pharmaceutically acceptable carrier and / or an excipient Into a capacity container.
- the formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
- the pharmaceutical composition may be diluted in an ointment base to prepare an ointment for topical application.
- the ointment base may be applied to lesions 1 to 5 times a day.
- a packaged preparation for topical application diluted in a gel preparation is prepared, It can be applied to the lesion site five times.
- Another aspect of the present invention provides the use of the active substance-hexapeptide complex of the present invention for skin condition improvement.
- Another aspect of the present invention provides the use of the active substance-hexapeptide complex of the present invention for preparing a cosmetic composition for skin condition improvement.
- Another aspect of the present invention provides the use of the active substance-hexapeptide complex of the present invention for treating skin wounds.
- Another aspect of the present invention provides the use of the active substance-hexapeptide complex of the present invention for the manufacture of a medicament for treating skin wounds.
- Another aspect of the present invention provides a method for improving skin condition comprising treating the skin of an individual with the active substance-hexapeptide complex of the present invention. Improving the skin condition may be to prevent aging of the skin or promote regeneration of the skin.
- Another aspect of the present invention provides a method of treating skin wounds comprising treating the skin of an individual with an active substance-hexapeptide complex of the present invention.
- Fmoc-Glu tbu
- Fmoc-Met OH
- Fmoc-Gln OH
- Fmoc-Arg Pbf
- the source of Fmoc-Glu (tbu) -OH, Fmoc-Met-OH, Fmoc-Gln (Trt) -OH and Fmoc-Arg (Pbf) -OH were purchased from GLS (GL Biochem, Shanghai).
- the organic acids were also purchased from TCI (TCI chemicals, India) and Sigma (Sigma Aldrich, US) (Table 5).
- DMF dimethylformamide
- DIEA N, N-diisopropylethylamine
- DCM dichloromethane
- the synthesis process of the organic acid-hexapeptide complex is represented by the following process steps 1) to 6).
- the synthetic process conditions are shown in Table 6 below.
- Chlorotritylchloride resin (Bead Tech) was used to synthesize a peptide having a carboxy group (-COOH) at the synthetic end in a solid-phase synthesis reactor equipped with a filtration membrane.
- a peptide synthesis terminated with a peptide bond (-CONH 2 ) at the synthetic end was carried out using Rink amide resin (GLS).
- DCM and DMF were used to swell the resin for 30 minutes.
- Synthesis using chlorotrityl chloride resin involves loading the first amino acid into the resin. The swollen resin was removed under reduced pressure through a filtration membrane. Two equivalents of Fmoc-Arg (Pbf) -OH in the resin were completely dissolved in DMF, added to chlorotrityl chloride resin, and DIEA in consideration of density was added in an amount corresponding to 4 equivalents of chlorotrityl chloride resin. Thereafter, the reaction was carried out at 25 ° C to 32 ° C for 5 hours or more using a reactor.
- the synthesis procedure using the chlorotrityl chloride resin or linkamid resin involved the deprotection of Fmoc.
- the resin Fmoc deprotection was performed by removing the solvent through a filtration membrane under reduced pressure and then washing with DMF containing 20% (v / v) piperidine for 5 minutes. Then, it was washed with DMF supplemented with 20% (v / v) piperidine for 10 minutes. The reaction solution was removed by filtration under reduced pressure, and washed with DCM or DMF six times for 2 minutes each.
- the dried ferulic acid-EEMQRR-NH 2 composite resin was separated using a 70% (v / v) TFA / 29% (v / v) DCM / 1% (v / v) H 2 O solution for 4 h Respectively.
- the separated solvent was extracted by recrystallizing the crude product with ethyl ether.
- the ferulic acid-EEMQRR-NH 2 complex preparation prepared in Example 1.1 was dissolved in distilled water containing 10% (v / v) acetonitrile. Thereafter, it was purified by HPLC under gradient conditions as described below and then lyophilized to obtain a ferulic acid-EEMQRR-NH 2 complex (FIGS. 1 to 34). The above gradients are shown in Table 7 below.
- EEMQRR-NH2 EEMQRR-NH2 , COOH-EEMQRR-geranic acid and COOH-EE (geranic acid) MQRR-NH2 in order to confirm that organic acids at N-, C- or side chain positions of the hexapeptide can bind. 2 complex was synthesized.
- FIGS. 35 Methods for synthesizing the above-mentioned geranic acid-EEMQRR-NH 2, COOH-EEMQRR-generator acid and COOH-EE (geranic acid) MQRR-NH 2 complexes are shown in FIGS.
- the generator acid-EEMQRR-NH 2 complex was synthesized in the same manner as in Example 1 (FIG. 35).
- the COOH-EEMQRR-generator complex was synthesized through the following procedure. First, trityl resin was added to the reactor, washed twice with DCM / DMF, and the resin was swelled in the reactor for 30 minutes using DCM. Then, 2 eq of arginine (Arg, R) amino acid and 1 eq of DIEA were added to the resin and loaded for 4 hours. After loading, it was washed 5 times with DMF. The remaining 5 amino acids were loaded in the order of arginine, glutamine (Gln, Q), methionine (Met, M), glutamic acid (Glu, E) and glutamic acid in the same manner as the method of loading the arginine.
- the COOH-EEMQRR-generator acid which had been reacted was washed 3 to 4 times with DMF, 3 to 4 times with DCM, and dried using a pump. After the drying process, separation was carried out using 70% TFA in the same manner as in Example 1.1 (5) for 4 hours.
- Example 1.1 (6) In the same manner as in the recrystallization of Example 1.1 (6), a cleavage solution was taken from the reactor, transferred to a tube, air-dried, and COOH-EEMQRR- And recovered in a solid state. The recovered COOH-EEMQRR-fumaric acid was subjected to HPLC analysis and purified.
- the COOH-EE (genetic acid) MQRR-NH 2 was synthesized with EEMQRR-NH 2 peptide in the same manner as in Experimental Example 1, followed by removing the protecting group of glutamine, adding EDC and HoAt, After the glycol linker was bound and washed three times with DMF, the geranic acid was bound using HOBt, DIC (FIG. 37). Thereafter, separation and recrystallization processes were carried out in the same manner as in (1.1) separation of Example 1.1 and (6) recrystallization. The recovered COOH-EE (geranic acid) MQRR-NH 2 was subjected to HPLC analysis and then purified.
- the antioxidant activity of the sample was measured indirectly by measuring the degree of decrease of the radicals by a spectrophotometer using a stable free radical, DPPH (1,1-Diphenyl-2-picryhydrazyl, Sigma D9132-1G). Specifically, 0.5 ml of 0.1 mM DPPH solution and 0.4 ml of various organic acid-hexapeptide complexes (samples) prepared in Example 1 were added to 0.4 ml of ethanol, vortexed vigorously for 10 seconds, The reaction was carried out in cattle for 30 minutes.
- DPPH 1,1-Diphenyl-2-picryhydrazyl
- the absorbance was then measured at a wavelength of 517 nm using a spectrophotometer ELISA.
- vitamin C ascorbic acid
- DPPH free radical scavenging ability (%) ⁇ 1-absorbance of sample / absorbance of blank ⁇ x 100 ⁇
- DPPH is inherently purple in ethanol. When it is reduced by antioxidants, it will lose its original purple color and turn yellow. DPPH is capable of measuring radicals through spectral analysis at a wavelength of 517 nm.
- SC 50 of Table 8 means the sample concentration at the time of scavenging free radicals and 50% other organic acid-hexapeptide to show the DPPH free-radical scavenging activity in the complex of the 34 species of the above organic acid-hexa-peptide complexes are antioxidant cosmetic composition It can be used as a composition.
- Wound healing assay was used to assess skin regeneration effects by stimulating cell proliferation and migration by organic acid - hexapeptide complexes.
- DMEM Dulbecco's Modified Eagle's Medium
- FBS fat bovine serum
- HaCaT cells were cultured in DMEM with 10% FBS and 1% Antibiotic-Antimycotic in a 100 mm / 60.1 cm 2 culture dish in an incubator at 37 ° C, 5% CO 2 , 100% wet condition.
- the degree of cell saturation of HaCaT cells reaches about 90%, the cells are plated at 1.5 x 10 cells / 12-well plate in a 100 mm / 60.1 cm 2 culture dish and incubated for 48 hours at 37 ° C, 5% CO 2 , 100% Lt; / RTI >
- the cells were replaced with DMEM without FBS, and the wells were scratched with a 200 ⁇ l tip.
- the organic acid-hexapeptide complex prepared in Example 1 was used and treated at a concentration of 100 ng / ml.
- HEGF Sigma-Aldrich, USA
- 1xPBS was used as a negative control.
- Wound healing area (%) ⁇ (A-B) / A ⁇ x 100
- Fmoc-Glu (tbu) -OH, Fmoc-Met-OH, Fmoc-Gln (Trt) -OH and Fmoc-Arg (Pbf) -OH were purchased from GLS (GL Biochem, Shanghai).
- betamethasone valerate, betamethasone dipropionate, Mometasone furoate, dexamethasone, hydrocortisone, hydrocortisone 17-butyrate, betamethasone valerate, Prednisone, methylprednisone and estriol were purchased from Sigma (Sigma Aldrich, US).
- glutaric anhydride was purchased from TCI chemicals.
- Diflucortolone valerate and Methylprednisolone aceponate were purchased from Henan Tianfu Chemical.
- DMF dimethylformamide
- DIEA N, N-diisopropylethylamine
- DCM diichloromethane
- piperidine was purchased from purified gold.
- the process for synthesizing mutated hexapeptide complexes is represented by the following process steps 1) to 8).
- the synthetic process conditions are shown in Table 9 below.
- Chlorotritylchloride resin (Bead Tech) was used to synthesize a peptide having a carboxy group (-COOH) at the synthetic end in a solid-phase synthesis reactor equipped with a filtration membrane.
- a peptide synthesis terminated with a peptide bond (-CONH 2 ) at the synthetic end was carried out using Rink amide resin (GLS).
- DCM and DMF were used to swell the resin for 30 minutes.
- Synthesis using chlorotrityl chloride resin involves loading the first amino acid into the resin. The swollen resin was removed under reduced pressure through a filtration membrane. Two equivalents of Fmoc-Arg (Pbf) -OH in the resin were completely dissolved in DMF, added to chlorotrityl chloride resin, and DIEA in consideration of density was added in an amount corresponding to 4 equivalents of chlorotrityl chloride resin. Thereafter, the reaction was carried out at 25 ° C to 32 ° C for 5 hours or more using a reactor.
- the synthesis procedure using the chlorotrityl chloride resin or linkamid resin involved the deprotection of Fmoc.
- the resin Fmoc deprotection was performed by removing the solvent through a filtration membrane under reduced pressure and then washing with DMF containing 20% (v / v) piperidine for 5 minutes. Then, it was washed with DMF supplemented with 20% (v / v) piperidine for 10 minutes. The reaction solution was removed by filtration under reduced pressure, and washed with DCM or DMF six times for 2 minutes each.
- Fmoc deprotection was performed on the resin in which the hexapeptide was synthesized, and 3 equivalents of glutaric anhydride as a linker, DIEA as a linker, and glutaric acid anhydride equivalent and amount of linkamid resin . Thereafter, synthesis was carried out at 25 ° C to 32 ° C using a reactor for 5 hours or more. When the reaction was completed, the solvent was evacuated and washed with clean DMF for 6 min each for 2 min.
- Succinic acid or maleic anhydride was used instead of the glutaric anhydride to bind a succinic acid linker or a maleic acid linker.
- adipic acid fumaric acid, isophthalic acid, terephthalic acid or 2,6-naphthalenedicarboxylic acid instead of malonic acid
- Adipic acid linker fumaric acid linker, isophthalic acid linker, terephthalic acid linker or 2,6-naphthalene dicarboxylic acid linker.
- the separated solvent was recrystallized by using ethyl ether to obtain Betamethasone-EEMQRR-NH 2 And extracted.
- betamethasone in the same manner as -EEMQRR-NH 2 Synthesis dexamethasone -EEMQRR-NH 2, hydrocortisone -EEMQRR-NH 2, the pre-Denis hand -EEMQRR-NH 2, methyl pre Denis hand -EEMQRR-NH 2 and estriol -EEMQRR-NH 2, betamethasone valerate -EEMQRR-NH 2, betamethasone propionate as deep -EEMQRR-NH 2, di-fluorenyl cor discussion valerate -Glutaroyl-EEMQRR-NH 2, hydrocortisone 17-butyrate -EEMQRR-NH 2, mometasone furoate -EEMQRR-NH 2, methylprednisolone fibroblasts carbonate -EEMQRR-NH 2, Betamethasone valerate -Glutaric-EEMQRR-NH 2, betamethasone valerate -Succinic-EEMQRR-NH 2,
- Betamethasone-EEMQRR-NH 2 complex preparation prepared in Example 2.1. was dissolved in distilled water containing 10% (v / v) acetonitrile. Thereafter, it was purified by HPLC under the following gradient conditions and then lyophilized to obtain a Betamethasone-EEMQRR-NH 2 complex (FIGS. 43-48). The above gradients are shown in Table 10 below.
- betamethasone propionate as deep -EEMQRR-NH 2
- di-fluorenyl cor discussion valerate -Glutaroyl-EEMQRR-NH 2
- hydrocortisone 17-butyrate -EEMQRR-NH 2 mometasone furoate -EEMQRR- NH 2, methylprednisolone fibroblasts carbonate -EEMQRR-NH 2 complex
- the antioxidant activity of the sample was measured indirectly by measuring the degree of decrease of the radicals by a spectrophotometer using a stable free radical, DPPH (1,1-Diphenyl-2-picryhydrazyl, Sigma D9132-1G). Specifically, 0.5 ml of a 0.1 mM DPPH solution and 0.4 ml of mutated hexapeptide complexes (samples) prepared at various concentrations prepared in Example 2 were added to 0.4 ml of ethanol, vortexed vigorously for 10 seconds, The reaction was carried out in cattle for 30 minutes.
- the absorbance was then measured at a wavelength of 517 nm using a spectrophotometer ELISA.
- vitamin C ascorbic acid
- DPPH free radical scavenging ability (%) ⁇ 1-absorbance of sample / absorbance of blank ⁇ x 100 ⁇
- DPPH is inherently purple in ethanol. When it is reduced by antioxidants, it will lose its original purple color and turn yellow. DPPH is capable of measuring radicals through spectral analysis at a wavelength of 517 nm.
- SC 50 refers to the concentration of the sample at the time of scavenging free radicals 50% that in the hexa-peptide complexes variation outside to show the DPPH free-radical scavenging 6 species hexa-peptide complexes variations of the above may be used as an antioxidant cosmetic composition Respectively.
- Wound healing assay was used to assess skin regeneration effects by stimulating cell proliferation and migration by mutated hexapeptide complexes.
- DMEM Dulbecco's Modified Eagle's Medium
- FBS fat bovine serum
- HaCaT cells were cultured in DMEM with 10% FBS and 1% Antibiotic-Antimycotic in a 100 mm / 60.1 cm 2 culture dish in an incubator at 37 ° C, 5% CO 2 , 100% wet condition.
- the degree of cell saturation of HaCaT cells reaches about 90%, the cells are plated at 1.5 x 10 cells / 12-well plate in a 100 mm / 60.1 cm 2 culture dish and incubated for 48 hours at 37 ° C, 5% CO 2 , 100% Lt; / RTI >
- the cells were replaced with DMEM without FBS, and the wells were scratched with a 200 ⁇ l tip.
- the mutated hexapeptide complexes synthesized in Example 2 were used and treated at a concentration of 100 ng / ml.
- HEGF Sigma-Aldrich, USA
- 1xPBS was used as a negative control.
- Wound healing area (%) ⁇ (A-B) / A ⁇ x 100
- betamethasone valerate -EEMQRR-NH 2 betamethasone propionate as deep -EEMQRR-NH 2
- di-fluorenyl cor discussion valerate -Glutaroyl-EEMQRR-NH 2, prepared in hydrocortisone 17-butyrate -
- the skin regeneration effect was assessed by cell proliferation and migration promotion by EEMQRR-NH 2 , mometasone furoate-EEMQRR-NH 2 and methylprednisolone acetonate-EEMQRR-NH 2 complex. The experiment was carried out in the same manner as described above.
- betamethasone valerate -EEMQRR-NH 2 betamethasone propionate as deep -EEMQRR-NH 2
- di-fluorenyl cor discussion valerate -Glutaroyl-EEMQRR-NH 2
- Mo meta hand furoate -EEMQRR-NH 2 and methylprednisolone fibroblasts carbonate -EEMQRR-NH 2 conjugate were both about 2 times or more and recovery area (healing area), respectively as compared to the negative control group increased (Fig. 50).
- Example 2 was betamethasone valerate -Glutaric-EEMQRR-NH 2, betamethasone valerate -Succinic-EEMQRR-NH 2, betamethasone valerate -Maleic EEMQRR--binding steroid using a linker of the nine kinds of manufactured NH 2, betamethasone valerate -Malonic-EEMQRR-NH 2, betamethasone valerate -Adipic-EEMQRR-NH 2, betamethasone valerate -Fumaric-EEMQRR-NH 2, betamethasone valerate -Isophthalic-EEMQRR-NH 2, betamethasone valerate -Terephthalic-EEMQRR-NH 2 and Betamethasone valerate-2,6-Naphthalenedicarboxylic-EEMQRR-NH 2 complexes to stimulate cell proliferation and migration.
- the experiment was carried out in the same manner as described above.
- betamethasone valerate -Glutaric-EEMQRR-NH 2 betamethasone valerate -Succinic-EEMQRR-NH 2
- betamethasone valerate -Maleic-EEMQRR-NH 2 betamethasone valerate -Malonic-EEMQRR-NH 2
- betamethasone valerate EemQRR-NH 2 Betamethasone valerate-Fumaric-EEMQRR-NH 2
- Betamethasone valerate-Isophthalic-EEMQRR-NH 2 Betamethasone valerate-Terephthalic-EEMQRR- NH 2
- Betamethasone valerate-2,6-Naphthalenedicarboxylic all -EEMQRR-NH 2 complex were increased about 2-fold recovery area (healing area), respectively as compared to the negative control.
- the mutated hexapeptide complexes are effective in promoting proliferation and migration of cells to
- betamethasone valerate -EEMQRR-NH 2 betamethasone dipropionate -EEMQRR-NH 2, di-fluorenyl cor discussion valerate -Glutaroyl-EEMQRR-NH 2, hydrocortisone 17-butyrate -EEMQRR-NH 2, mometasone Eight -EEMQRR-NH 2, methylprednisolone fibroblasts carbonate -EEMQRR-NH 2, betamethasone valerate -Glutaric-EEMQRR-NH 2, betamethasone valerate -Succinic-EEMQRR-NH 2, betamethasone valerate -Maleic-EEMQRR-NH 2, Betamethasone valerate-Malonic-EEMQRR-NH 2 , Betamethasone valerate-Adipic-EEMQRR-NH 2 , Betamethasone valerate-Fumaric-EEMQRR-NH 2 , Betamethasone valerate- Is
- betamethasone valerate -EEMQRR-NH 2 betamethasone propionate as deep -EEMQRR-NH 2
- di-fluorenyl cor discussion valerate -Glutaroyl-EEMQRR-NH 2
- hydrocortisone 17- butyrate -EEMQRR-NH 2 mometasone furoate -EEMQRR-NH 2, methylprednisolone fibroblasts carbonate -EEMQRR-NH 2
- betamethasone valerate -Glutaric-EEMQRR-NH 2 betamethasone valerate -Succinic-EEMQRR-NH 2
- betamethasone valerate -Malonic-EEMQRR-NH 2 betamethasone valerate -Adipic-EEMQRR-NH 2
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