KR20220017695A - Ascorbic acid derivative and composition including thereof - Google Patents

Abstract

The present invention relates to an ascorbic acid derivative in which ascorbic acid is conjugated with at least one peptide consisting of at least one neutral or hydrophobic amino acid or an analog thereof and at least one positively charged amino acid or a derivative thereof, and a functional cosmetic composition and antibacterial composition comprising the ascorbic acid derivative as an active ingredient. The ascorbic acid derivative has excellent stability and permeability to skin tissues and cells, and has physiological activities such as antibacterial properties, collagen synthesis induction, and melamine production inhibition.

Description

Ascorbic acid derivatives and compositions comprising the same

This application relates to the results of the project "Development of bio-preservative material with excellent antibacterial properties and safety" as part of the "Startup Growth Technology Development Project" of the Ministry of Small and Medium Business of the Republic of Korea (Organization: Remibio Co., Ltd., task number: S2696111).

The present invention relates to an ascorbic acid derivative, and more particularly, to an ascorbic acid derivative having improved bioavailability and a composition comprising the same.

One of the water-soluble vitamins, vitamin C, that is, ascorbic acid, has an endol group connected to one double bond carbon with two hydroxyl groups. Ascorbic acid was discovered as a substance having a specific effect on scurvy, and now, 2-keto- is a hydrolyzed diisopropylidene derivative produced by condensing sorbose, a monosaccharide, with acetone in the presence of sulfuric acid and oxidizing it with potassium permanganate. It is industrially synthesized via L-gulonic acid. Most mammals can synthesize ascorbic acid from glucose, but since humans do not have ascorbic acid synthase in the body of ascorbic acid, ascorbic acid is one of the essential vitamins that must be ingested through food.

Ascorbic acid and its derivatives are representative antioxidants with very strong reducing properties and improve the immune function of the human body. In addition, when applied to the skin, ascorbic acid and its derivatives promote the production of collagen, which is a component of human cartilage, capillaries, muscles, etc. Not only does it prevent damage, it prevents wrinkles on the skin, keeps the skin healthy, is involved in the healing of damaged skin tissue, prevents the formation of histamine, which is known to cause allergic reactions, and prevents the skin from aging during the aging process. It is known to play an anti-aging role by preventing the formation of melamine, which fades the skin. Accordingly, ascorbic acid and its derivatives are expected to be utilized not only as active ingredients in cosmetics, but also in pharmaceutical compositions or health functional foods.

However, since ascorbic acid and its derivatives have a structure similar to gamma-lactone and are very unstable, they are sensitive substances that are easily decomposed and oxidized by external environments such as heat, light, water, and oxygen. The oxidation reaction of ascorbic acid and its derivatives occurs by two successive electron transfer processes. First, as one electron is lost from ascorbic acid, an intermediate, semi-hydroascorbate radical, is formed. Subsequently, as the second electron is lost from two molecules of semi-dihydroascorbate radicals, it is known that one molecule of ascorbic acid and dehydroascorbic acid are generated.

Due to this rapid oxidation, a significant amount of ascorbic acid and its derivatives cannot be stabilized, particularly in aqueous solution. Therefore, it has been reported that only a trace amount of ascorbic acid can be used as an active ingredient when ascorbic acid and its derivatives are applied to cosmetics, pharmaceuticals, foods, etc. As a method to supplement the inherent problems of ascorbic acid and to improve stability, a method of adding antioxidants or formulating stabilization has been proposed. However, ascorbic acid, whose oxidation is inhibited by this method, has a problem in that activity or efficiency is lowered than that of pure ascorbic acid.

In addition, recently, many studies have been conducted to improve the oxidation resistance to water, light, and air by changing the structure of ascorbic acid. For example, in the structure of ascorbic acid, a phosphate salt is chemically linked to a site where oxidation occurs, and then a metal is added, or an ascorbic acid derivative linking fatty acids or glucose to ascorbic acid through an ether bond or an ester bond. has been proposed Although these ascorbic acid derivatives have a stabilized chemical structure, these ascorbic acid derivatives have lower efficacy than pure ascorbic acid, and harmful solvents may remain in the process of synthesizing the derivative, which may cause skin irritation. In addition, it has been reported that the stability of these ascorbic acid derivatives is destroyed when exposed to water, light, or air for a long time.

In addition, since ascorbic acid is easily decomposed and has hydrophilicity, the permeability to cells is very low. Therefore, in order for ascorbic acid to maintain its biological activity, a large amount of ascorbic acid must be used.

An object of the present invention is to provide an ascorbic acid derivative having excellent stability and tissue and cell permeability.

Another object of the present invention is to provide an antibacterial composition and a cosmetic composition comprising the ascorbic acid derivative.

According to one aspect, a compound having a structure of Formula 1 is disclosed.

[Formula 1]

In Formula 1, R ₁ and R ₂ are each independently hydrogen or a structure of Formula 2 below, and at least one of R ₁ and R ₂ has a structure of Formula 2 below.

[Formula 2]

In Formula 2, R ₃ is a C ₁ ~ C ₂₀ alkyl group, C ₂ ~ C ₂₀ alkenyl group, C ₂ ~ C ₂₀ alkynyl group, C ₁ ~ C ₂₀ alkyl disulfide group, C ₄ ~ C ₃₀ alicyclic group ), as a first group selected from the group consisting of C ₆ ~ C ₃₀ aryl group and C ₃ ~ C ₃₀ heteroaryl group, the alicyclic, aryl group and hetero aryl group are each independently unsubstituted or at least one C ₁ -C ₂₀ alkyl group, C ₆ -C ₂₀ aryl group and C ₃ -C ₃₀ first group substituted with a functional group selected from the group consisting of heteroaryl group, or C ₁ -C ₂₀ alkyl amino group, C ₁ -C ₂₀ alkyl As a second group selected from the group consisting of a guanidyl group, a C ₁ -C ₂₀ alkyl polyamine, and a C ₀ -C ₃₀ heteroaryl group connected directly or through a C ₁ -C ₂₀ alkylene group and having at least one nitrogen atom, , The C ₁ -C ₂₀ heteroaryl group having at least one nitrogen atom is a second group unsubstituted or substituted with at least one C ₁ -C ₂₀ alkylamino group, and among the entire molecules having the structure of Formula 2, the first the proportion of unit units having groups is 30 to 70%; R ₄ is a hydroxyl group or an amino group; L is a direct bond, C ₁ ~ C ₂₀ alkylene group, C ₆ ~ C ₃₀ arylene group or C ₃ ~ C ₃₀ hetero arylene group; p is an integer from 6 to 20;

According to another aspect, a functional cosmetic composition comprising, as an active ingredient, a compound having the structures of Formulas 1 and 2 or a cosmetically acceptable salt thereof, for example, at least one of whitening, wrinkle improvement and skin aging prevention. Disclosed is a cosmetic composition having a function.

According to another aspect, an antibacterial composition comprising as an active ingredient a compound having the above-described structures of Formulas 1 and 2, and a pharmaceutically, food engineering and/or cosmetically acceptable salt thereof is disclosed.

According to another aspect, an anti-inflammatory composition comprising as an active ingredient a compound having the structures of the aforementioned Chemical Formulas 1 and 2, and a pharmaceutically, food engineering and/or cosmetically acceptable salt thereof is disclosed.

At least one neutral amino acid and a derivative thereof and at least one positively charged amino acid and at least one peptide having a positively charged amino acid and a derivative thereof are conjugated to ascorbic acid, and the stability and tissue and cell permeability are improved compared to ascorbic acid. In addition, the ascorbic acid derivative not only promotes collagen production and prevents the formation of melamine, but also promotes an immune response and has excellent antibacterial activity.

Conventional ascorbic acid has almost no skin permeability, so the clinical bioefficiency is low. Since the ascorbic acid derivative according to the present invention has good skin permeability and cell permeability, it exhibits physiological effects even at low concentrations, thereby improving bioefficiency.

Therefore, the ascorbic acid derivative can be applied as an active ingredient such as a cosmetic for skin wrinkle improvement, whitening and/or skin aging prevention and/or a drug for antibacterial or immune promotion, or a health functional food.

1 is a graph showing the results of high-performance liquid chromatography (HPLC) analysis of ascorbic acid derivatives synthesized according to an exemplary embodiment of the present invention.
2 is a graph showing the results of MS (mass spectrometry) analysis of the ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention.
3 is a graph showing the results of the ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention to promote collagen synthesis.
4 is a graph showing the results of the ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention inhibiting melamine production.
5 is a graph showing the anti-inflammatory effect of an ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention.
6 is a graph showing the antibacterial effect of an ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention.
7 is a graph showing the results of measuring the temperature stability of the ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention.
8 is a graph showing the results of measuring the in vitro skin tissue permeability of an ascorbic acid derivative synthesized according to an exemplary embodiment of the present invention using pig skin.

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings, if necessary.

[Ascorbic acid derivatives]

The ascorbic acid derivative of the present invention eliminates the disadvantages of pure ascorbic acid having low tissue and cell permeability as well as being unstable because it is easily oxidized by conjugation of a peptide consisting of 6 or more amino acids to ascorbic acid. The peptide bound to ascorbic acid may consist of an amino acid having a neutral or hydrophobic side branch and an amino acid having a positively charged side branch in an in vivo environment. The ascorbic acid derivative according to the present invention has the structure of Formula 1 below.

[Formula 1]

In Formula 1, R ₁ and R ₂ are each independently hydrogen or a structure of Formula 2 below, and at least one of R ₁ and R ₂ has a structure of Formula 2 below.

[Formula 2]

In Formula 2, R ₃ is a C ₁ ~ C ₂₀ alkyl group, C ₂ ~ C ₂₀ alkenyl group, C ₂ ~ C ₂₀ alkynyl group, C ₁ ~ C ₂₀ alkyl disulfide group, C ₄ ~ C ₃₀ alicyclic group ), as a first group selected from the group consisting of C ₆ ~ C ₃₀ aryl group and C ₃ ~ C ₃₀ heteroaryl group, the alicyclic, aryl group and hetero aryl group are each independently unsubstituted or at least one C ₁ -C ₂₀ alkyl group, C ₆ -C ₂₀ aryl group and C ₃ -C ₃₀ first group substituted with a functional group selected from the group consisting of heteroaryl group, or C ₁ -C ₂₀ alkyl amino group, C ₁ -C ₂₀ alkyl As a second group selected from the group consisting of a guanidyl group, a C ₁ -C ₂₀ alkyl polyamine, and a C ₀ -C ₃₀ heteroaryl group connected directly or through a C ₁ -C ₂₀ alkylene group and having at least one nitrogen atom, , The C ₁ -C ₂₀ heteroaryl group having at least one nitrogen atom is a second group unsubstituted or substituted with at least one C ₁ -C ₂₀ alkylamino group, and among the entire molecules having the structure of Formula 2, the first the proportion of unit units having groups is 30 to 70%; R ₄ is a hydroxyl group or an amino group; L is a direct bond, C ₁ ~ C ₂₀ alkylene group, C ₆ ~ C ₃₀ arylene group or C ₃ ~ C ₃₀ hetero arylene group; p is an integer from 6 to 20;

In the present specification, 'unsubstituted' refers to a hydrogen atom bonded thereto, and in this case, the hydrogen atom includes light hydrogen, deuterium and tritium. In the term 'substituted' as used herein, 'substituent' is unsubstituted or substituted with halogen C ₁ ~C ₂₀ alkyl (eg, -CF ₃ ), unsubstituted or substituted with halogen C ₁ ~ C ₂₀ Alkoxy group, halogen, cyano group, hydroxy group, carboxy group, carbonyl group, amino group, C ₁ ~ C ₁₀ alkyl amino group, C ₆ ~ C ₃₀ aryl amino group, C ₃ ~ C ₃₀ hetero aryl amino group, nitro group, hydra hydrazyl group, sulfonic acid group, C ₁ ~ C ₂₀ alkyl silyl group, C ₁ ~ C ₂₀ alkoxy silyl group, C ₃ ~ C ₃₀ cycloalkyl silyl group, C ₆ ~ C ₃₀ aryl silyl group, C ₃ ~ C ₃₀ heteroaryl silyl group, C ₆ ~ C ₃₀ aryl group, C ₃ ~ C ₃₀ heteroaryl group and the like may be mentioned, but the present invention is not limited thereto.

In the present specification, the term 'hetero' used in 'heteroaromatic ring', 'heteroalicyclic ring', 'heterocycloalkylene group', 'hetero arylene group', 'heterocycloalkyl group', 'heteroaryl group', etc. At least one of the carbon atoms constituting the (aromatic) or alicyclic ring, for example, 1 to 5 carbon atoms, is one or more heteroatoms selected from the group consisting of N, O, S, P and combinations thereof means replaced.

As defined in Formula 2, the peptide moiety is an amino acid or a derivative thereof having a first group of hydrophobic or neutral substituents (hereinafter, hydrophobic amino acid or derivative thereof) and an amino acid having a side branch of a second group that is a positively charged substituent or derivatives thereof (hereinafter, positively charged amino acids or derivatives thereof) are included.

As the first group in Formula 2, an aliphatic substituent C ₁ ~ C ₂₀ alkyl group, C ₂ ~ C ₂₀ alkenyl group, C ₂ ~ C ₂₀ alkynyl group, C ₁ ~ C ₂₀ alkyl group constituting an alkyl disulfide group, respectively; an alkyl group substituted with an alicyclic group, an aryl group, and a heteroaryl group; As a second group, a C ₁ -C ₂₀ alkyl amino group, a C ₁ -C ₂₀ alkyl guanidyl group, and an alkyl group each constituting a C ₁ -C ₂₀ alkylamino group that may be substituted with a heteroaryl group having at least one nitrogen atom; A C ₁ ~ C ₂₀ alkylene group connecting a side branch that is a C ₁ ~ C ₃₀ heteroaryl group having at least one nitrogen atom and a peptide backbone; and C ₁ to C ₂₀ alkylene groups constituting L may each independently be an alkyl group or an alkylene group having 1 to 10 carbon atoms.

On the other hand, an aliphatic chain constituting a side branch or a linker, that is, an alkyl group, an alkenyl group, an alkynyl group, an alkyl disulfide group, an alkyl amino group, an alkyl guanidyl group, an alkylene group constituting R ₃ or L in Formula 2, respectively In the aliphatic chain, each may have a linear structure or a branched structure.

In Formula 2, the C ₄ -C ₃₀ alicyclic ring constituting R ₃ as the first group is a C ₄ -C ₃₀ cycloalkyl group, preferably a C ₄ -C ₂₀ cycloalkyl group or a C ₄ -C ₃₀ cycloalkenyl group, preferably Examples include, but are not limited to, a C ₄ -C ₃₀ cycloalkenyl group.

C ₆ ~ C ₃₀ aryl group and C ₃ ~ C ₃₀ hetero aryl group constituting R ₃ as the first group in Formula 2 are each a C ₆ ~ C ₂₀ aryl group (eg, C ₆ ~ C ₁₅ aryl group) and C ₃ -C ₂₀ heteroaryl group (eg, C ₆ -C ₁₅ heteroaryl group), but is not limited thereto. In addition, the C ₀ ~ C ₃₀ heteroaryl group having at least one nitrogen atom as the second group in Formula 2 includes a C ₀ ~ C ₂₀ heteroaryl group (eg, C ₀ ~ C ₁₅ heteroaryl group), However, the present invention is not limited thereto.

For example, in Formula 2, the C ₆ -C ₃₀ aryl groups constituting R ₃ as the first group are each independently unsubstituted or at least one C ₁ -C ₁₀ alkyl group, C ₆ -C ₂₀ aryl group, and C ₃ -C ₃₀ phenyl, biphenyl, terphenyl, naphthyl, anthracenyl, pentalenyl, indenyl, indenoindenyl, heptalenyl, biphenylenyl, indacenyl, phenalenyl substituted with a functional group selected from the group consisting of 30 heteroaryl groups , phenanthrenyl, benzophenanthrenyl, dibenzophenanthrenyl, azulenyl, pyrenyl, fluoranthenyl, triphenylenyl, chrysenyl, tetraphenyl, tetracenyl, pleidaenyl, pycenyl, pentaphenyl , pentacenyl, fluorenyl, indenofluorenyl or spiro fluorenyl may be an unfused or fused aryl group, but is not limited thereto.

Optionally, the C ₃ -C ₃₀ aryl groups constituting R ₃ as the first group in Formula 2 are each independently unsubstituted or at least one C ₁ -C ₁₀ alkyl group, C ₆ -C ₂₀ aryl group and C ₃ -C ₃₀ pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, imidazolyl, pyrazolyl, indolyl, isoindolyl substituted with a functional group selected from the group consisting of 30 heteroaryl groups , indazolyl, indolizinyl, pyrrolizinyl, carbazolyl, benzocarbazolyl, dibenzocarbazolyl, indolocarbazolyl, indenocarbazolyl, benzofurocarbazolyl, benzothienocarbazolyl, quinolinyl, Isoquinolinyl, phthalazinyl, quinoxalinyl, cinolinyl, quinazolinyl, quinozolinyl, quinolinyl, purinyl, benzoquinolinyl, benzoisoquinolinyl, benzoquinazolinyl, benzoquinoc Salinyl, acridinyl, phenanthrolinyl, perimidinyl, phenanthridinyl, pteridinyl, naphtharidinyl, furanyl, pyranyl, oxazinyl, oxazolyl, oxadiazolyl, triazolyl, dioxynyl , benzofuranyl, dibenzofuranyl, thiopyranyl, xanthenyl, chromenyl, isochromenyl, thioazinyl, thiophenyl, benzothiophenyl, dibenzothiophenyl, difuropyrazinyl, benzofurodibenzo uncondensed or fused heteroaryl groups such as furanyl, benzothienobenzothiophenyl, benzothienodibenzothiophenyl, benzothienobenzofuranyl, benzothienodibenzofuranyl or N-substituted spirofluorenyl; However, the present invention is not limited thereto.

For example, when the side branch of the first group is a ring-type consisting of a C ₄ -C ₃₀ alicyclic group, a C ₆ -C ₃₀ aryl group, and a C ₃ -C ₃₀ heteroaryl group, represented by Formula 2 At least one of the ring-type side branches constituting the amino acid or derivative thereof included in the peptide is selected from the group consisting of at least one C ₁ -C ₁₀ alkyl group, C ₆ -C ₂₀ aryl group and C ₃ -C ₃₀ heteroaryl group It may be substituted with a functional group.

In addition, the C ₀ ~ C ₃₀ heteroaryl group having at least one nitrogen atom constituting R ₃ as the second group in Formula 2 may be an azole group. For example, the azole group is an imidazole group, a pyrazole group, a 1,2,3-triazole group, a 1,2,4-triazole group, a tetrazole group, an azole group consisting of only nitrogen atoms as a hetero atom such as a pentazole group, as well as an oxa group Zol group, isoxazole group, 1,2,3-oxadiazole group, 1,2,4-oxadiazole group, 1,2,5-oxadiazole group, 1,3,4-oxadiazole group, thiazole group, iso Others such as oxygen or sulfur, such as thiazole group, 1,2,3-thiidazole group, 1,2,4-thiadiazole group, 1,2,5-thiadiazole group, 1,3,4-thiadiazole group It may include an azole group including a hetero atom, but is not limited thereto.

In addition, the arylene group and the hetero arylene group constituting L in Formula 2 may be an aromatic or heteroaromatic linking group corresponding to the aforementioned aryl group and heteroaryl group, respectively.

On the other hand, in the present specification, the term 'nucleic acid' is meant to include DNA (eg, cDNA) and RNA, and includes nucleotides in addition to natural nucleotides (adenine, thymine, guanine, cytosine, uracil). It is meant to include an analog in which the constituting sugar or base region is modified.

As used herein, the term 'peptide' refers to proteins, fragments of proteins, peptides isolated from naturally occurring or synthesized by recombinant techniques or chemically, as well as 'peptide analogs (analogs)'. )', ie, an analog in which one or more of the side branches of L-amino acids and/or the backbone of alpha-amino acids are substituted. For example, amino acid side chains and/or backbones are modified peptide analogs (peptidomimetics), hydroxyproline in which a pyrrolidine ring is substituted with a hydroxyl group, or N- A 'peptoid' in which a substituent such as an alkyl group is attached to an amino group, such as methyl glycine, may be included, but is not limited thereto. On the other hand, the terms 'neutral' or 'positive charge' in relation to the side branches included in amino acids or analogs thereof are based on physiological conditions in vivo.

In general, the peptides and nucleotides referred to herein are isolated. An 'isolated' nucleotide or peptide has been removed from its original environment. For example, a peptide in its natural state is isolated by removing all or some of the substances present together in that state.

As will be described later, it is well known that amino acids constituting a peptide may have the same function even if they are mutated into other amino acids. For example, it is well known that even if the amino acids constituting the peptide are modified, the biological function of the corresponding peptide is not at all affected or the function of the original peptide is enhanced. Accordingly, one or more amino acids may be substituted and/or added to the amino acid sequence constituting the peptide.

Such so-called 'conservative substitution' can be determined according to relative similarity, such as hydrophobicity/hydrophilicity, size, and charge, of substituents forming a side chain of amino acids, in particular. For example, conservative substitution may be considered in consideration of a hydrophobic index or a hydrophilic value according to each amino acid side branch.

For example, hydrophobic amino acids alanine (A), valine (V), isoleucine (I), leucine (L), methionine (M), phenylalanine (F), tyrosine (W), tryptophan (W), proline (P) variation between; The hydrophilic amino acids lysine (K), arginine (R), histidine (H), aspartic acid (D), asparagine (N), cysteine (C), glutamic acid (E), glutamine (Q), serine (S), variation between threonine (T); mutations between amino acids glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I) and proline (P) having aliphatic side branches; a mutation between serine (S), threonine (T) and tyrosine (Y), which are amino acids having a side branch containing a hydroxyl group; mutations between arginine (R), lysine (K) and histidine (H), which are amino acids having a side branch containing a basic group such as an amino group, aspartic acid (D), an amino acid having a side branch containing a carboxylic acid and an amide; variation between asparagine (N), glutamic acid (E), and glutamine (Q); mutations between cysteine (C) and methionine (M), amino acids having a side branch containing a sulfur atom; It has mutations among amino acids with aromatic side branches: histidine (H), phenylalanine (F), tyrosine (Y), and tryptophan (W). In addition, in that alanine (A), glycine (G) and serine (S) have similar sizes, it is possible to form a mutant without significant change in protein activity. Representatively, (1) alanine (A) / glycine (G), (2) aspartic acid (D) / glutamic acid (E), (3) asparagine (N) / glutamine (Q), (4) lysine (K) /arginine (R), (5) leucine (L) / isoleucine (I) / valine (V) / methionine (M), (6) phenylalanine (F) / tyrosine (Y) / tryptophan (W), (7) mutations between serine (S)/threonine (T), (8) cysteine (C)/methionine (M).

A 'substitutional variant' refers to a molecule in which one or more amino acids are replaced or deleted in an amino acid sequence, but retains characteristics specifically recognized by cells. The amino acid sequence of the replaceable variant preferably has at least 80% identity with the original amino acid sequence, more preferably at least 90% or more. In conclusion, when considering the variation having an equivalent biological activity between the aforementioned amino acids, the peptide or analog thereof related to the present invention should be construed as including a peptide or analog having substantially equivalent activity to that having a specific amino acid sequence. .

The peptide or its analog can be isolated after preparation by recombinant means or chemical synthesis. For example, the nucleotide encoding the amino acid constituting the peptide having the structure of Formula 2 is cloned into an appropriate recombinant expression vector by using PCR technique to prepare a recombinant vector, and then an appropriate host After mass expression in the form of a peptide in cells, it can be produced by pure purification. Suitable host cells include prokaryotes, yeast, and eukaryotes, for example, E. coli, yeast or mammalian cell lines (such as Cos or CHO) may be used as host cells, but are limited thereto. doesn't happen In order to purify the recombinant peptide, the supernatant containing the recombinant protein secreted into the culture medium obtained from the aqueous host/vector system is concentrated using a commercially available filter. Next, the obtained concentrate is purified using an appropriate purification matrix such as an affinity matrix or an ion exchange resin. Finally, pure recombinant peptide can be obtained by performing reverse phase HPLC in one or several steps.

Optionally, peptide fragments or peptide variants consisting of less than 100 amino acids, generally less than 50 amino acids, can be prepared by chemical synthesis. For example, peptides may be synthesized using commercially available solid-phase techniques, that is, a Merrifield solid-phase synthesis method in which amino acids are sequentially added to a growing amino acid chain.

Specifically, the chemical synthesis method of the peptide may include a method of synthesizing a solid-phase peptide using an organic synthesizer for peptide synthesis. For solid-phase synthesis, an amino acid constituting the carboxy terminus (C-terminus) of a peptide or an analog thereof is coupled to an appropriate resin for solid-phase synthesis, thereby swelling the C-terminal amino acid binding resin. The resin for solid phase synthesis may be an insoluble, porous solid support treated with an appropriate linker (linker). For example, the resin binding to the C-terminus of the peptide is a polystyrene resin, polyamide resin, PEG-hybrid polystyrene resin, hydroxymethyl resin, aminomethyl resin, chloromethylated resin or Chlorotritity resin (eg, 2-chlorotrityl chloride resin (2-chlorotritylchloride, CTC resin)) may be used, but is not limited thereto. C-terminal amino acids or analogs thereof are loaded into these resins to , C-terminal amino acids or analogs thereof are ester-linked to these resins.

Subsequently, desired amino acids or analogs thereof are sequentially coupled in the amino-terminal (N-terminal) direction of the peptide through a solid-phase synthesis reaction. Regarding the chemical synthesis of peptides, as a protecting group for protecting the alpha-amino group contained in amino acids or analogs thereof, t-BOC (t-butyloxycarbonyl), Fmoc (9-fluorenyl methoxyarbonyl), benzyloxy-carbonyl (Z) ( benzyloxy-carbonyl (Z)) and the like can be used, and in particular, Fmoc, which can be removed even in weak alkaline conditions and does not require special equipment, can be used. In addition, when synthesizing a peptide, a coupling reagent for activating the carbonyl group located at the C-terminus may be used as an activator, and an appropriate deprotecting agent may be used for the protecting group at the N-terminus after coupling.

The activator that can be used to activate the C-terminus of the peptide in the coupling of the peptide is (N-[(dimethylamino-)-1H -1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]- N-methylmethanaminium hexafluorophosphate N-oxide (HATU) and 1-hydroxy-7-azabenzotriazole (HOAt) or HBTU (N-[(1H-benzotriazol-1-yl) (dimethylamino )methylene]-N-methylmethanaminium hexafluorophosphate N-oxide) and 1-hydroxybenzotriazole (HOBt) can be used together with DIEA (N,N-diisopropylethylamine), and N,N'-diiso With bases such as propylcarbodiimide (DIC) and dicyclohexylcarbodiimide (DCC), which react with carboxylic acids to form highly reactive O-acylisoureas, and bases such as carbodiimides, racemization can be prevented. 1-hydroxy-benzotriazole (HOBt) such as 6-chloro-1-hydroxy-1H-benzotriazole or 1-hydroxy Triazoles, such as -7-aza-benzotriazole (HOAt), can be used. These triazoles react with O-acylisourea formed by the reaction of a carboxyl group and carbodiimides to form an ester with weak reactivity, thereby preventing racemization.

After peptide synthesis, the fatty acid derivative is separated from the solid resin by a cleavage solution containing trifluoroacetic acid (TFA), and a deprotection reaction is performed to remove a protecting group (eg, fmoc protecting group) using piperidine. to terminate the peptide synthesis. If necessary, a process of separating the peptide from which the protecting group has been removed from the resin using an appropriate acid is first performed, and then a binding reaction with a carboxylic acid may be performed.

On the other hand, in order to induce conjugation through an amide group between the 2nd and/or 3rd position of the ring constituting ascorbic acid and the peptide or analog thereof, the hydroxyl groups at the 5th and 6th positions of ascorbic acid Washing with acetone/hexane protects the hydroxyl groups at these positions with suitable protecting groups such as acetal/ketal groups. By refluxing carbonyl diimidazole in a suitable solvent such as tetrahydrofuran (THF), the hydroxyl group at the 2nd and/or 3rd position of ascorbic acid is substituted with an imidazole ester. Since the substituted imidazole ester group has strong reactivity with the primary amine, ascorbic acid or a derivative thereof in which a hydroxyl group at a specific position is substituted with an imidazole ester group may react with an amino group located at the end of the peptide to form an amide bond. . Then, for example, by reacting a strong acid such as hydrochloric acid, or performing a deprotection reaction using trifluoroacetic acid (TFA) and CH ₂ Cl ₂ , to remove the protecting groups at positions 5 and 6 of ascorbic acid , an ascorbic acid derivative in which a hydroxyl group at a specific position is substituted with a carboxyl group can be synthesized.

Optionally, after adding a halogenated aryl or fatty acid ester such as benzylbromoacetate to ascorbic acid in which the hydroxyl group at positions 5 and 6 is protected, esterification of the end of the hydroxyl group at positions 2 and/or 3 is performed, By adding ethyl acetate or the like, a carboxyl group can be finally induced at the corresponding position.

Then, the N-terminus of the synthesized peptide and ascorbic acid modified with a carboxyl group at a specific position are combined (conjugation). When the carboxyl group present at the terminal of ascorbic acid and the amino group at the N-terminus of ditide react, an amide-bonded ascorbic acid derivative can be synthesized by dehydration and condensation. This reaction may be performed, for example, in a state in which a peptide and a resin are coupled, thereby generating polymer beads. For example, after the amino acid constituting the peptide or its analog is coupled, the N-terminal amino group is an acyl activator having a desired alkyl group, for example, acylanhydride and DMAP (4-(N, N-dimethylamino)pyridine)) together to form an amide bond at the N-terminus of the peptide, or ascorbic acid carboxylic acid which is conjugated with N,N-diisopropylcarbodiimide (DIC), 1-hydroxy Roxy-7-azabenzotriazole (HOAt) or 1-hydroxybenzotriazole (HOBt) can be used together to form an amide bond.

In this way, when ascorbic acid carboxylic acid is bound to the peptide coupled to the resin, an aqueous acid solution such as trifluoroacetic acid (TPA) is used to cut and separate the peptide-bound ascorbic acid derivative from the solid support resin. If necessary, diethyl ether is added to crystallize the synthesized ascorbic acid derivative, and analysis and purification processes using filtration, drying, HPLC, etc. are performed, and processes such as freeze-drying and packaging are additionally performed for storage and sale. can proceed.

For example, in Formula 2, amino acids having R ₃ as a first group as a neutral or hydrophobic side branch and analogs thereof are alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M) ), natural amino acids such as phenylalanine (F), tyrosine (Y) and tryptophan (W); modified amino acids in which the side branches constituting these natural amino acids are partially substituted (for example, modified amino acids having as a side branch an aryl group substituted with at least one alkyl or heteroaryl group); It includes, but is not limited to, amino acids with side branch modifications such as L-2-naphthylalanine and L-biphenylalanine.

In addition, in Formula 2, the unit amino acid having R ₃ as a second group having a positively charged side branch and its analogs are natural amino acids such as arginine (R), histidine (H) and lysine (K) as well as natural amino acids constituting these natural amino acids. including, but not limited to, modified amino acids in which side branches are partially or fully substituted. For example, the positively charged side branch that may be included in the second group may include C ₁ to C ₂₀ polyamines.

C ₁ ~ C ₂₀ polyamines capable of forming positively charged side branches as natural amino acid analogs include alkyl diamines such as putrescine and cadaverine; Bis(3-aminopropyl)amine (bis(3-aminopropyl)amine), spermidine, N,N'-bis(3-aminopropyl)-1,3-propanediamine (N,N'-bis Linear having one or more amino groups in the middle of an aliphatic chain, such as (3-aminopropyl)-1,3-propanediamine), spermine, thermospermine, caldopentamine and caldohexamine alkyl polyamines; branched alkyl polyamines such as, but not limited to, tris(3-aminopropyl)amine and tetrakis(3-aminopropyl)ammonium. When the polyamine forms a side branch as the second group, an appropriate anion such as a halogen anion may be incorporated, and below is an example in which spermine is linked to the amino acid backbone as a side branch. However, the structure in which the polyamine side branch is linked to the amino acid backbone is not limited to those exemplified below.

As shown in Formulas 1 and 2, the peptide constituting the ascorbic acid derivative consists of 6 to 20, for example 6 to 15, preferably 6 to 12 amino acid residues or analogs thereof, Amino acids and their analog residues having positively charged side branches and amino acids and their derivative residues having neutral or hydrophobic side branches are each linked via an amide bond. An ascorbic acid derivative having a positively charged amino acid or an analog residue thereof has improved permeability to a cell membrane, for example, a skin cell membrane. In addition, if an amino acid residue stably forming the alpha-chain of the peptide is included, such as arginine (R) or lysine (K) as a positively charged amino acid residue and/or alanine (A) as a hydrophobic amino acid residue, the alpha constituting the peptide -Since the chain is maintained firmly, the stability of the ascorbic acid derivative linked to the peptide can be improved.

On the other hand, the peptide having the structure of Formula 2 includes an amino acid or a derivative thereof having a neutral (neutral) or hydrophobic (hydrophobic) side branch. As the side branches constituting these hydrophobic amino acids or derivative residues thereof are oriented by hydrophobic interaction, a peptide structure having a rigid alpha-helical conformation is induced. Accordingly, a stable ascorbic acid derivative can be synthesized while the ascorbic acid moiety having the structure of Formula 1 and the peptide moiety having the structure of Formula 2 are combined.

A peptide having a positively charged amino acid residue and a hydrophobic amino acid residue is electrostatically bound to negatively charged molecules in bacterial cell membranes such as lipopolysaccharide and teichoic acid, and the peptide is inserted into the lipid bilayer constituting the bacterial cell membrane. Then, a hole is made in the cell membrane of the bacteria, the potential of the cell membrane is lost, and antibacterial activity is exhibited.

In an exemplary embodiment, in Formula 2, the unit amino acid having a first group in which R ₃ is a hydrophobic or neutral branch or a derivative thereof is 30 to 70%, for example 40 to 60%, preferably from the total amino acids constituting the peptide. may be included in a proportion of 45 to 55%.

In addition, the ascorbic acid moiety and the peptide moiety are linked via an amide bond. The ascorbic acid moiety and the peptide moiety constituting the ascorbic acid derivative administered to the living body may be separated into respective moieties by a peptide degrading enzyme or the like. Accordingly, while maintaining a stable structure in vitro, the ascorbic acid derivative can exhibit physiological activity unique to ascorbic acid while being decomposed into an ascorbic acid moiety in the body. For example, the ascorbic acid moiety and the unit amino acid or derivative thereof constituting the peptide or derivative thereof may each be L-form, but is not limited thereto.

In one exemplary embodiment, peptides and analogs thereof that bind to ascorbic acid have an amino acid having a positively charged side branch and an amino acid having a hydrophobic side branch linked via an amide bond, or an amino acid having a positively charged side branch or a hydrophobic side branch. Amino acids can be linked in series via amide bonds. Such a peptide or an analog thereof may have the structure of Formula 3 below.

[Formula 3]

In Formula 3, R ₄ is the same as defined in Formula 2; any one of R ₅ and R ₆ is the first group defined in Formula 2, and the other of R ₅ and R ₆ is the second group defined in Formula 2; q, r, s and t are each independently an integer from 1 to 5, and q + r + s + t is an integer from 6 to 20; x and y are 0, 1, or 2, respectively, and x + y = 2.

For example, in Formula 3, q and s may be different, and r and t may be different, and the ratio of the unit units represented by q and s in the entire molecule may be 30 to 70%, for example 40 to 60%. .

In another exemplary embodiment, the peptide binding to ascorbic acid may have a structure in which an amino acid having a positively charged side branch or an analog thereof and an amino acid having a hydrophobic or neutral side branch are alternately linked in series via an amide bond. Such a peptide or an analog thereof may have the structure of Formula 4 below.

[Formula 4]

In Formula 4, R ₄ is the same as defined in Formula 2; R ₅ and R ₆ are each the same as defined in Formula 3; Z is an integer from 3 to 10.

On the other hand, collagen is a major structural block of connective tissue in animals including the human body, and provides high tensile strength to connective tissue, including skin, as well as the ability to overcome deformation. In particular, type I collagen, which is the most type of collagen present in the body, is a substance that provides skin tension and elasticity together with elastin in the skin tissue, and protects the skin from UV rays and suppresses the formation of wrinkles in the skin.

Ascorbic acid promotes collagen synthesis by inducing the production of hydroxyproline, a major amino acid constituting collagen. It is known that intracellular delivery of ascorbic acid in skin tissue occurs through sodium-dependent vitamin C transporter 1 (SVCT1) and SVCT2, but the expression of skin cells is lower than that of other epithelial tissue cells. However, since the ascorbic acid derivative of the present invention has good bioefficiency, it can efficiently induce collagen synthesis even at a lower concentration than ascorbic acid (see FIGS. 3 and 8 ).

On the other hand, melanin is a phenolic high molecular compound widely present in nature, and is a black pigment present in the epidermal layer of the skin. Melanin absorbs the light energy of ultraviolet (UV) light to protect the skin from UV damage, and it protects the skin from external harmful factors such as amines, free radicals, harmful oxygen and pre-radicals generated within the skin. to protect If melanin does not disappear because melanin is synthesized excessively or keratinization of the skin does not occur normally, it not only damages the skin, but also causes pigmentation of the skin to form spots and freckles, and can cause skin cancer.

Melanocytes, cells that make melanin, exist in the basal layer located at the bottom of the epidermis. When the skin is stimulated by excessive ultraviolet rays, an enzyme called tyrosinase oxidizes tyrosine in the melanocytes, and the oxidized tyrosine makes melanin. As the newly created skin cells push up the old skin cells, the old cells become keratin and fall off. As new skin cells containing the generated melanin pass through the granular layer and the stratum corneum to the stratum corneum, the skin appears black. Since there is no enzyme to break down melanin in the human body, melanin is removed from the skin when keratinocytes are separated from the epidermis. Therefore, in order to prevent darkening of the skin, it is necessary to reduce melanin pigment or suppress melanin production. The ascorbic acid derivative of the present invention inhibits the production of melamine, and acts on skin whitening. In particular, since it inhibits the production of melamine even at a low concentration compared to the ascorbic acid derivative, the ascorbic acid derivative of the present invention has excellent cell permeability, cell efficiency and bioefficiency (see FIG. 4 ).

In addition, the ascorbic acid derivative according to the present invention not only inhibits the secretion of TNF-α, which is an important factor in the inflammatory response (see Fig. 5), soft tissue infection (cellulitis, pyogenic myositis), suppurative arthritis, suppurative osteomyelitis, otitis media, It also shows good antibacterial activity against Staphylococcus aureus ( S. aureus ), a representative strain that causes pneumonia, post-operative wound infection, bacteremia, endocarditis, food poisoning, atopic dermatitis, and the like (see FIG. 6).

In particular, compared to pure ascorbic acid, the ascorbic acid derivative of the present invention is not easily decomposed even in an external environment such as heat, and thus has excellent stability (see FIG. 7 ), and the skin tissue permeability is greatly improved (see FIG. 8 ). Therefore, it can be used in various industrial fields such as pharmaceuticals, food, cosmetics, etc. by supplementing the disadvantages of ascorbic acid.

[Composition comprising an ascorbic acid derivative]

As described above, the ascorbic acid derivative not only has excellent stability and tissue and cell permeability, but also exhibits antibacterial and anti-inflammatory activity, promotes collagen synthesis, and inhibits melamine production.

Accordingly, the present invention includes an antibacterial composition, an anti-inflammatory composition, and an anti-inflammatory composition comprising an ascorbic acid derivative having the structure of the aforementioned Chemical Formulas 1 to 4, a pharmaceutically, food engineering and/or cosmetically acceptable salt thereof as an active ingredient. It relates to antibacterial/anti-inflammatory drugs, health functional foods and cosmetics. For example, these compositions may be a pharmaceutical composition, a food composition, and a cosmetic composition, respectively, and may be applied to treat and/or prevent atopic dermatitis or to alleviate atopic dermatitis.

In another aspect, the present invention relates to a functional cosmetic composition and cosmetics comprising as an active ingredient an ascorbic acid derivative or a cosmetically acceptable salt thereof having the structures of Chemical Formulas 1 to 4 described above. For example, the functional cosmetic composition may have functions such as skin aging improvement, skin wrinkle improvement, and/or skin whitening.

Pharmaceutically, food engineering and/or cosmetically acceptable salts may include acid addition salts or basic salts formed with pharmaceutically, food engineering and/or cosmetically acceptable free acids, but not limited Acid addition salts can be prepared by conventional methods, for example, by dissolving an ascorbic acid derivative in an excess of an aqueous acid solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. have. Equal molar amounts of compound and acid or alcohol (eg glycolmonomethyl ether) in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.

Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Pharmaceutical/food engineering and/or cosmetically non-toxic salts are sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate Chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate , succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β -hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

Optionally, bases can be used to make pharmaceutically/food engineering and/or cosmetically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving an ascorbic acid derivative in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. Also, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

For example, the content of ascorbic acid derivatives and salts thereof in the above composition is not particularly limited, but is included in a concentration of 0.1 to 1000 μM, for example, a concentration of 1.0 to 500 μM, preferably 1.0 to 200 μM. can

For example, the pharmaceutical composition related to antibacterial and/or anti-inflammatory may include, as an active ingredient, an ascorbic acid derivative having a structure of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof alone, and other formulations, use Depending on the method and purpose of use, additional ingredients, that is, pharmaceutically or nutritionally acceptable carriers, excipients, diluents or sub-components may be additionally included.

For example, a pharmaceutical composition comprising an ascorbic acid derivative and a pharmaceutically acceptable salt thereof can be prepared according to a conventional method for oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, It can be formulated and used in the form of suppositories and sterile injectable solutions. For example, ascorbic acid derivatives or pharmaceutically acceptable salts thereof may be administered in various oral or parenteral formulations during clinical administration. When formulated, commonly used fillers, extenders, binders, wetting agents, surfactants , may further include diluents or excipients such as anti-aggregating agents, lubricants, wetting agents, fragrances, emulsifiers or preservatives, and may be used orally or parenterally.

For example, carriers, excipients and diluents that may be included in a pharmaceutical composition comprising an ascorbic acid derivative or a pharmaceutically acceptable salt thereof include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch. , acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. , dextrin, calcium carbonate, propylene glycol, liquid paraffin, and may be one or more selected from the group consisting of physiological saline, but is not limited thereto, and all conventional carriers, excipients or diluents may be used. Ingredients other than the active ingredient may be added independently or in combination.

More specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include ascorbic acid derivatives or pharmaceutically acceptable salts thereof with one or more excipients, for example, starch , calcium carbonate, sucrose or lactose, gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, solutions, emulsions and syrups, and various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As a base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, glycerogelatin, and the like can be used. When administered parenterally, the pharmaceutical composition of the present invention may be administered through subcutaneous injection, intravenous injection or intramuscular injection.

Forms for parenteral administration include toothpaste, mouthwash, topical administration agents (creams, ointments, dressing solutions, sprays, other coating agents, etc.). As an example of the formulation of the topical administration agent, a pharmaceutical composition containing an active ingredient may be impregnated in a carrier such as gauze made of natural or synthetic fibers.

In the case of a cream or ointment, it may be suitable for direct application to the affected area or inflamed area related to atopic dermatitis. In the case of a spray, except that it contains an active ingredient, it can be prepared by a conventional spray preparation method, and it is filled and packaged in a compression container or other spray container and sprayed frequently on the affected area or inflamed area caused by inflammatory diseases or bacteria disease can be prevented or treated. In the case of a dressing solution, except that it contains an active ingredient, it can be prepared by a conventional method for preparing a dressing solution, and is used for dressings in diseased areas or other bacterially infected areas, and diseases caused by inflammatory diseases or bacteria can be prevented or treated.

In addition, the dosage form of the pharmaceutical composition of the present invention may be in a preferred form depending on the method of use, particularly by adopting a method known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. can be formulated. Examples of specific formulations include warning agents, granules, lotions, liniments, limonades, powders, syrups, eye ointments, liquids, aerosols, EXTRACTS, elixils, ointments, fluid extracts, emulsions, suspensions, ointments, infusions, eye drops, tablets, suppositories, injections, spirits, capsules, creams, pills, soft or hard gelatin capsules, and the like.

Optionally, the pharmaceutical composition may contain, in addition to the active ingredient, nutrients, vitamins, electrolytes, flavoring agents, coloring agents, thickeners, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives , glycerin, alcohol, a carbonation agent used in carbonated beverages, and the like may be additionally contained.

For example, the pharmaceutical composition of the present invention may be administered to mammals such as rats, mice, livestock, and humans by various routes. Any mode of administration can be envisaged, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

The preferred dosage of the pharmaceutical composition comprising the ascorbic acid derivative of the present invention or a pharmaceutically acceptable salt thereof varies depending on the patient's condition and body weight, the degree of disease, drug form, administration route and period, may be appropriately selected. For example, the pharmaceutical composition comprising an ascorbic acid derivative or a pharmaceutically acceptable salt thereof may be administered at 0.0001 to 100 mg/kg per day, preferably at 0.001 to 100 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.

On the other hand, food compositions and health functional foods for alleviating inflammation and/or antibacterial include ascorbic acid derivatives having the structures of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient. Examples of the food composition of the present invention include food, food additives, beverages or beverage additives. In the present specification, food may include all of food, food additives, health functional food, and beverage.

For example, foods containing ascorbic acid derivatives or food engineering acceptable salts thereof include meat, sausage, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gums, and dairy products including ice cream. , various soups, beverages, teas, drinks, alcoholic beverages and vitamin complexes, and includes all health foods in the ordinary sense. In addition, in the present invention, food includes special nutritional food (eg, formula milk, infant/infant food, etc.), processed meat products, fish meat products, tofu, jelly, noodles (eg, ramen, noodles, etc.), health supplements, seasoned foods ( Ex, soy sauce, soybean paste, red pepper paste, mixed soy sauce, etc.), sauces, sweets (eg snacks), dairy products (eg fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various kimchi, pickles, etc.), beverages ( Examples include, but are not limited to, fruit and vegetable beverages, soy milk, fermented beverages, ice cream, etc.), natural seasonings (eg, ramen soup, etc.), vitamin complexes, alcoholic beverages, alcoholic beverages and other health supplements. The food, beverage or food additive may be prepared by a conventional manufacturing method.

The food composition and/or health functional food may include food engineering-acceptable food supplement additives in addition to the active ingredient, and may further include appropriate carriers, excipients and diluents commonly used in the manufacture of functional food.

As an example, the health functional food of the present invention may include the form of tablets, capsules, pills, liquids, etc., as an active ingredient, other than containing an ascorbic acid derivative or a cosmetically acceptable salt thereof, special ingredients There is no limitation, and it may contain food supplement additive ingredients such as flavoring agents or natural carbohydrates as additional ingredients.

Examples of natural carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose, sucrose and the like; Common sugars such as polysaccharides such as dextrin and cyclodextrin, as well as sugar alcohols such as xylitol, sorbitol, and erythritol. natural flavoring/sweetening agents such as taumatine, stevia extract (eg rebaudioside A, glycyrrhizin) as flavoring or sweetening agents other than those described above; Synthetic flavoring/sweetening agents such as saccharin and aspartame may be used.

In addition, food compositions and/or health functional foods contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and salts thereof , alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, carbonation agents used in alcoholic carbonated drinks, and the like. In addition, the food composition according to the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages. These components may be used independently or in combination.

For example, the antibacterial and/or anti-inflammatory composition of the present invention contains carbohydrates, proteins, lipids, vitamins and minerals in addition to the active ingredient ascorbic acid derivative or a pharmaceutically/food engineering and/or cosmetically acceptable salt thereof. can do. The carbohydrates, proteins, lipids, vitamins or minerals may be appropriately selected according to the purpose and use thereof, for example, the carbohydrates are honey, dextrin, sucrose, palatinose, glucose, fructose, starch syrup, sugar alcohol. , sorbitol, xylitol, maltitol, and the protein is a milk-derived protein such as casein and whey protein, soybean protein, an animal-derived enzyme such as trypsin and pepsin of these proteins, and neutrase ), may be a hydrolyzate by alkilase, and the lipid is sunflower oil, rapeseed oil, olive oil, safflower oil, corn oil including a primary saturated fatty acid and polyunsaturated fatty acid. , soybean oil, palm oil, various plant-derived oils such as palm oil, middle-chain fatty acids, EPA, DHA, soybean-derived phospholipids, and milk-derived phospholipids, and the minerals include potassium phosphate, potassium carbonate , potassium chloride, sodium chloride, calcium lactate, calcium gluconate, calcium pantothenate, calcium caseinate, magnesium chloride, ferrous sulfate, sodium hydrogen carbonate, but is not particularly limited by each example.

On the other hand, functional cosmetic compositions and cosmetics for anti-inflammatory, antibacterial, skin wrinkle improvement, skin aging prevention and/or skin whitening include ascorbic acid derivatives having structures of Formulas 1 to 4 or a cosmetically acceptable salt thereof. The cosmetic composition contains a cosmetically and/or dermatologically acceptable medium, ie a medium suitable for the skin, mucous membranes, hair and scalp. It is in any cosmetic dosage form suitable for topical application, in particular in aqueous, aqueous/alcoholic or oily solutions, or in aqueous, aqueous/alcoholic or oily gels, or solid or kneaded dry products, emulsions obtained by dispersing the oily phase in an aqueous phase (O/ W) or vice versa (W/O), in the form of suspensions, microemulsions, microcapsules, microgranules or ionic (liposomes) and/or non-ionic vesicular dispersions. These compositions can be prepared according to conventional methods in the art. The composition according to the invention can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.

Ethanol, glycerin, butylene glycol, propylene glycol, glycereth-26, methylgluceth-20, isocetyl myristate, isocetyl octanoate, octyldodecyl myristate, octyl as a solvent to prepare a functional cosmetic composition At least one selected from decanol, isostearyl isostearate, cetyl octanoate and neopentyl glycol dicaprate may be used. When the cosmetic composition of the present invention is prepared using such a solvent, the solubility of the compound in the solvent is slightly different depending on the type of the compound and the mixing ratio of the solvent. Depending on the type of solvent and the amount used can be appropriately selected.

In addition, the cosmetic composition according to the present invention may further include an excipient for cosmetics. In the range that does not impair the effects of the present invention, that is, anti-inflammatory, antibacterial, skin wrinkle improvement, skin aging prevention, and/or skin whitening effects, known ingredients used in conventional cosmetics, for example, moisturizers, powder ingredients, UV absorbers , antioxidants, cosmetic ingredients, glycolipids, plant extracts, preservatives, fragrances, pH adjusters, pigments, viscosity modifiers or gelling agents, etc. may be included as auxiliary components.

Non-limiting examples of humectants include propylene glycol, isoprene glycol, 1,2-heptanediol, 1,3-butylene glycol, dipropylene glycol, hexanediol, polyethylene glycol glycerin, glycerin, diglycerin, triglycerin, polyglycerin, Glycols such as neopentyl glycol, sorbitol, erythritol, pentaerythritol, glucose, and galactose, fructose, sucrose, maltose, xylose, xylobiose, reduced products of oligosaccharides, protein, mucopolysaccharide, collagen, elastin, keratin, or and triethanolamine.

Non-limiting examples of powder components include white inorganic pigments such as titanium oxide, siliconized titanium oxide, zinc oxide and barium sulfate, colored inorganic pigments such as iron oxide, carbon black, titanium/titanium oxide sintered product and ultramarine blue, talc, silicone treatment Talc, muscovite, kaolin, silicon carbide, bentonite, smectite, silicic anhydride, aluminum oxide, magnesium oxide, zirconium oxide, diatomaceous earth, calcium silicate, barium silicate, magnesium silicate, calcium carbonate, magnesium carbonate, hydroxyapatite and boron nitride White sieving powder, titanium dioxide coated mica, iron oxide mica titanium, siliconized mica titanium, young gourd, polyethylene-based resin, fluorine-based resin, cellulose-based resin, and organic polymer resin powder such as silicone resin, zinc stearate and N-acylysine Organic low molecular weight powder, natural organic powder such as starch, silk powder and cellulose powder, organic pigment powder such as Red No. 201, Red No. 202, Orange No. 203, Orange No. 204, Blue No. 404 and Yellow No. 401, Red No. 3 , Red No. 104, Red No. 106, Orange No. 205, Yellow No. 4, Yellow No. 5, Green No. 3 and Blue No. 1. Organic powder pigments such as zirconium, barium or aluminum lake, gold foil powder such as mica, gold powder, and It may be a composite powder, such as titanium oxide-coated microparticles|fine-particles mica titanium.

Non-limiting examples of the ultraviolet absorber may be benzophenone derivatives, paraaminobenzoic acid derivatives, methoxycinnamic acid derivatives, urokanic acid, and the like. Non-limiting examples of antioxidants may be BHT, BHA, vitamin C, vitamin E, derivatives thereof, salts thereof, and the like. Non-limiting examples of the cosmetic ingredient may be vitamins including the above vitamins, derivatives thereof and salts thereof, anti-inflammatory agents, herbal medicines, and the like. Non-limiting examples of glycolipids may be sphingoglycolipids and the like. Non-limiting examples of the plant extract may be extracts of aloe vera, witch hazel, hammeris, cucumber, lemon, lavender and rose. Non-limiting examples of the preservative may be methyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and ethanol.

Non-limiting examples of the fragrance may be camphor oil, tangerine oil, peppermint oil, jasmine absolute, pine oil, lime oil, lavender oil, rose oil and musk oil. Non-limiting examples of pH adjusting agents may be edetic acid, sodium edetate, sodium chloride, quenic acid, sodium quenate, sodium hydroxide, potassium hydroxide, triethanolamine, and the like. Non-limiting examples of the pigment may be Blue No. 1, Blue No. 204, Red No. 3 and Yellow No. 201, and the like.

Non-limiting examples of viscosity modifiers include polyvinyl alcohol (PVA), methylcellulose (MC), ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, other cellulose derivatives, polyvinylpyrilidone (PVP), Carboxymethyl cellulose, xanthan gum, alginic acid or its salt, carrageenan, quince seed pod, alkaligenes-produced polysaccharide, carboxyvinyl polymer, acrylate, acrylic acid polymer (chain type, crosslinked type) and acrylic acid/alkyl methacrylate copolymer etc.

Non-limiting examples of gelling agents include (behenic acid/eicoic acid diacid) glyceryl and (behenic acid/eicoic acid diacid) polyglyceryl-10, fatty acid metal salts, hydroxystearic acid, dextrin fatty acid esters, inulin fatty acid esters, sugar fatty acids Hydrocarbon wax such as ester, acylated cellulose, dibenzylidene sorbitol, amino acid gelling agent, silicic anhydride, organomodified clay mineral, fumed silica, alumina, crosslinked organopolysiloxane, polyethylene wax or paraffin wax, carnauba wax, or Vegetable waxes such as candelilla wax, agar, and gelatin may be used.

The cosmetic composition of the present invention may be prepared in any formulation conventionally prepared in the art, for example, a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing agent , oil, powder foundation, emulsion foundation, wax foundation, spray, etc., but is not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, a nourishing lotion, a cream, a nourishing cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray, or a powder.

In addition, the cosmetic composition of the present invention may further include one or more cosmetically acceptable carriers to be formulated in cosmetics, and conventional ingredients include, for example, oil, water, surfactant, humectant, lower alcohol, and thickener. , a chelating agent, a colorant, a preservative, a fragrance, and the like may be appropriately mixed, but the present invention is not limited thereto. The cosmetically acceptable carrier included in the cosmetic composition of the present invention varies depending on the formulation.

When the cosmetic formulation according to the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide, etc. this can be used When the formulation of the cosmetic according to the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, additional chlorofluorohydro It may contain a propellant such as carbon, propane/butane or dimethyl ether. In addition, when the cosmetic formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, There are propylene glycol and 1,3-butyl glycol oil, and in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol fatty ester, fatty acid ester of polyethylene glycol or sorbitan, etc. may be used. can

In addition, when the cosmetic formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester , microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracanth may be used. In addition, when the cosmetic formulation of the present invention is a surfactant-containing cleansing agent, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate as carrier components , fatty acid amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative or ethoxylated glycerol fatty acid ester and the like can be used.

On the other hand, cosmetics according to the present invention are skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nourishing lotion, massage cream, nourishing cream, moisture cream, hand cream, essence, nourishing essence, pack, soap , shampoo, cleansing foam, cleansing lotion, cleansing cream, body lotion, body cleanser, emulsion, press powder, loose powder or eye shadow.

Hereinafter, the present invention will be described through exemplary embodiments, but the present invention is not limited to the technical ideas described in the following examples.

Synthesis example: ascorbic acid derivative synthesis

(1) Synthesis of Intermediate 1-1

NaHCO3 (2.91g, 34.7mmol) was added to a DMSO solution (30ml) in which L-Ascorbic acid Acetonide (5g, 23.1mmol) was dissolved, reacted at room temperature for 20 minutes, and after addition of benzyl bromoacetate (6.36g, 4.35mmol) 8 stirred for hours. The reaction solution was diluted with DW, extracted with EtoAc, the organic solvent layer was washed with brine, anhydrous MgSO ₄ was added, and then dried under reduced pressure. Intermediate 1-1 (Benzyl 2-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)-4- hydroxy-5-oxo-2,5-dihydrofuran-3-yl)oxy)acetate) (yield: 85%) was obtained.

1H NMR (500 MHz, CDCl ₃ ): 7.4-7.1(m, 5H), 5.18(s, 2H), 4.78(d, 1H), 4.57(s, 2H), 4.26(dt(1H), 4.17(dd) , 1H), 4.05 (dd, 1H), 1.37 (s, 6H).

(2) Synthesis of Intermediate 1-2

Intermediate 1-1 (1 g, 2.74 mmole) was dissolved in AcOEt (50 mL), 10% Pd/C (0.1 g) was added, and the mixture was stirred in a hydrogen atmosphere for 5 hours. The catalyst was filtered and dried under reduced pressure, and intermediate 1-2 (2-((2-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-5-oxo-2,5-dihydrofuran) -3-yl)oxy)acetic acid) was obtained.

1 H NMR (500 MHz, MeOD ): 5.09 (d, 1H), 4.95 (d, 1H), 4.33 (m, 1H), 4.22 (m, 1H), 4.05 (m, 1H), 1.37 (s, 3H), 1.35(s, 3H).

(3) Synthesis of Intermediate 1-3 (2,5,7-Tris-butyl-L-tryptophan)

H-Trp-OH (10.0 g) was dissolved in trifluoroactic acid (TFA, 245 mL), and then tert-BuOH (47 mL, 10eq) was added. The reaction mixture was stirred at room temperature for 3 days and then concentrated under reduced pressure to remove the solvent. After dissolving in toluene and concentration again under reduced pressure to completely remove TFA, 50 mL of DW was added to the compound from which TFA was completely removed to form a gum-like precipitate, and then saturated aqueous NaHCO3 solution was added to the mixture to pH 7 was titrated and water was removed. The resulting solid was completely dissolved with EtOH and recrystallized at 4° C. with distilled water to obtain Intermediate 1-3.

), 3.43 (1H, dd, J = 8.6 and 5.1 Hz, H-α), 2.98 (1 H, dd, J = 14.8 and 8.6 Hz), 1.47 (9H, s, tBu), 1.45 (9H , s, tBu), 1.32 (9H, s, tBu).1H NMR (500 MHz, DMSO-d6) δ: 8.70 (1H, br s), 7.44 (1H, br s, Indole-H), 7.00 (1H, br s, Indole-H) 3.52 (1 H, dd, J = 14.8 and 5.1 Hz, HA-

), 3.43 (1H, dd, J = 8.6 and 5.1 Hz, H-α), 2.98 (1 H, dd, J = 14.8 and 8.6 Hz), 1.47 (9H, s, tBu), 1.45 (9H , s, tBu), 1.32 (9H, s, tBu).

(4) Synthesis of Intermediate 1-4

Intermediate 1-3 (2.23 g) was dissolved in MeCN-H 2 O (5:1; 115 mL) at 60° C. followed by addition of Et 3 N (1.7 mL, 2 eq). After the reaction mixture was stirred until a clear color, a solution of Fmoc-Cl (1.54 g, 1 eq) dissolved in MeCN was slowly added to react. After stirring for about 1 hour, MeCN was removed by concentration under reduced pressure, dissolved in EtOAc (90 mL), and extracted using 1M HCl (70 mL) and brine (70 mL). The EtOAc layer was dried over Na ₂ SO ₄ , filtered, and then concentrated under reduced pressure. The produced crude product was purified using silica gel chromatography (Cy/EtOAc/AcOH, 100:0:1~50:50:1) to obtain Intermediate 1-4.

), 3.11 (1H, dd, J=14.8 and 8.3Hz, HB-

), 1.47 (9H, s, tBu), 1.44 (9H, s, tBu), 1.29 (9H, s, tBu).1H NMR (500 MHz, DMSO-d6) δ: 12.60 (1H, br s, COOH), 8.70 (1H, s), 7.88 (1H, d, J = 7.5 Hz), 7.87 (1H, d, J = 7.7 Hz), 7.78 (1H, d, J = 7.5 Hz), 7.68 (1H, d, J = 7.5 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.47 (1H, d, J = 1.5 Hz) , 7.41 (1H, t, J = 7.5 Hz), 7.39 (1H, d, J = 7.5 Hz), 7.30 (1H, br t, J = 7.5 Hz), 7.23 (1H, br t, J = 7.5 Hz) , 7.00 (1H, d, 1.5 Hz), 4.19-4.13 (4H, m, H-α, Fmoc-CH, Fmoc-CH2), 3.38 (1H, dd, J=14.8 and 5.8 Hz, HA-

), 3.11 (1H, dd, J=14.8 and 8.3Hz, HB-

), 1.47 (9H, s, tBu), 1.44 (9H, s, tBu), 1.29 (9H, s, tBu).

(5) ascorbic acid-peptide conjugated derivative synthesis

Rink amide MBHA resin was put into the reactor of the synthesizer, DCM was slowly added to the reactor, the resin was sufficiently inflated by stirring, and DMF was added to the remaining resin, followed by stirring, and the solvent was removed. After the piperidine solution was added, stirred and removed, DMF solvent was added to the remaining resin and stirred to wash the resin. This process was repeated 5 more times, followed by washing. Tryptophan (Fmoc-Tbt-OH) modified to have an indole group substituted with tert-butyl constituting the C-terminus of the peptide was dissolved in DMF, injected into the reactor, and HBTU (Hexafluorophosphate Benzotriazole Tetramethyl Uronium) dissolved in DMF and N- Methylmorpholine was injected sequentially and reacted for 1 hour. After draining the reaction solution, adding DMF to the resin, stirring, and repeating the coupling process to remove the solvent, coupling was performed up to the N-terminal amino acid, Fmoc-arginine-OH. After the piperidine solution was added and stirred and removed, DMF solvent was added to the remaining resin, stirred, and the resin was washed. This process was repeated 5 more times, and then washed.

After dissolving Intermediate 1-2 in DMF, it was injected into the reactor, and HOBt (hydroxybenzotriazole) and DIC (N,N'-diisopropylcarbodiimide) dissolved in DMF were sequentially injected into the reactor and reacted overnight. After the reaction solution was drained, DMF was added to the resin and stirred, the solvent was removed, and DMF solvent was added to the remaining resin, followed by stirring, and the resin was washed. This process was repeated 3 more times, and then washed. After stirring by adding DCM to the resin, the solvent was removed. After adding the cleavage solution to the resin, stirring, and concentrating the cleavage solution under reduced pressure, the ascorbic acid derivative bound to the peptide was precipitated in cold ether. The precipitated ascorbic acid derivative was filtered using a pressure reducing device, and the dried ascorbic acid derivative was recovered and vacuum dried. Hereinafter, the ascorbic acid derivative synthesized in this synthesis example is referred to as 'AA-RB109'.

The synthesized ascorbic acid derivative was analyzed by HPLC and MS, and the results of each analysis are shown in Table 1 and FIGS. 1 and 2 below. With respect to MS analysis, the expected molecular weight of the ascorbic acid derivative was 1428.7 Da, and it was analyzed to have 1428.0 Da. HPLC analysis conditions are as follows.

Column: C18 analytical column; Gradient: 5-65% B buffer in 30 min; Buffer: A buffer, 0.05% TFA/HO; B buffer 0.05% TFA/acetonitrile; Flow rate: 1 ml/min; Wavelength: 230 nm; Injection volume: 10 μl (0.5 mg/ml).

Ascorbic acid derivative HPLC peak (detector A 230 nm) Peak No. Retention Time Area Area (%) One 25.388 13423 0.410 2 25.555 3206370 97.830 3 25.746 35065 1.070 4 27.467 5 31.931 Total

Example 1: Induction of collagen synthesis by ascorbic acid derivatives

HDF, a human fibroblast cell line, was plated on a 96-well plate at a concentration of 5×10 ³ cells/well, and treated with ascorbic acid and AA-RB109 at concentrations ranging from 0.08 to 10 μM, respectively. After culturing in serum-free medium (DMEM) for 72 hours, the conditioned media was collected. ELISA analysis (Procollagen Type 1 C-peptide EIA Kit, MK101) was performed to confirm the concentration of Type 1 collagen in the conditioned media. The analysis results are shown in FIG. 3 . Pure ascorbic acid did not show collagen synthesis-inducing activity at a concentration lower than 2 μM, but AA-RB109 showed an inducing activity even at a low concentration of 80 nM. It was indirectly confirmed that AA-RB109 had superior cell permeability and cell efficiency compared to ascorbic acid.

Example 2: Inhibition of Melamine Synthesis of Ascorbic Acid Derivatives

Melanoma cell line B16F10 cells were plated on a 6-well plate at a concentration of 1× ^{10 5} cells/well, and then treated with α-MSH (melanocyte stimulating hormone) to induce melanin synthesis by ascorbic acid and AA-RB109 5 It was treated in a concentration range of ~40 μM. After culturing for 120 hours (DMEM, 10% FBS), cells were harvested using a cell scraper, dissolved at 95°C using 10% DMSO (in 1N NaOH) solution, and absorbance was measured at OD490. The measurement result is shown in FIG. The absorbance value of the control group not treated with α-MSH, a negative control, was regarded as 100%, and the relative value of each test group was expressed as % of control value. Ascorbic acid did not show melanin synthesis inhibitory activity at a concentration lower than 40 μM, but AA-RB109 showed a concentration-dependent inhibitory activity in a concentration range of 10 to 40 μM. It was confirmed that AA-RB109 had superior cell permeability and cell efficiency compared to ascorbic acid.

Example 3: Anti-inflammatory effect of ascorbic acid derivatives

Monocyte cell line RAW264.7 (KCLB No 40071) cells were plated on a 96-well plate at a concentration of 5×10 ⁴ cells/well, and then treated with LPS (lipopolysaccharide) to induce TNF-α synthesis in the model inducing TNF-α synthesis with ascorbic acid and AA -RB109 was treated in a concentration range of 2.5 to 150 μM. After culturing for 4 hours (DMEM, 10% FBS), the conditioned media was collected and the TNF-α content in the conditioned media was measured using a mouse TNF-α ELISA Kit. The measurement result is shown in FIG. Ascorbic acid showed an inhibitory effect of about 23.4% at a high concentration of 150 μM, but AA-RB109 showed an inhibitory effect of about 44% even at a concentration of 10 μM. It was confirmed again that the cell permeability and cell efficiency of AA-RB109 were excellent compared to ascorbic acid.

Example 4: Antibacterial effect of ascorbic acid derivatives

Strain S. aureus was inoculated into LB medium and cultured with shaking for 18 hours at 37°C and 180 rpm. After the cultured bacterial solution was diluted 1000 times with LB medium (10 ⁵ ~ 10 ⁶ CFU/ml), the diluted bacterial solution and LB medium containing AA-RB109 were mixed, and then again at 37°C and 180 rpm for 18 hours. Shake culture. The absorbance value of the cultured bacterial solution was measured at OD 610 to determine the concentration (MIC) at which the growth of the bacteria did not occur. The analysis results are shown in FIG. 6 . The growth of S. aureus was confirmed through absorbance analysis at OD610, and at a concentration of 1000 nM or higher, it showed strong antibacterial activity. Regarding the excellent antibacterial effect on S. aureus , which shows the most correlation with the imbalance of skin flora, the possibility of ascorbic acid derivatives as a material for application to atopic-related skin diseases was confirmed.

Example 5: Thermal stability of ascorbic acid derivatives

In order to confirm the thermal stability of AA-RB109, the thermal stability for up to 30 days under a harsh condition of 40 °C was confirmed. For comparison, the thermal stability of pure ascorbic acid was evaluated under the same conditions. An evaluation result is shown in FIG. Ascorbic acid was completely oxidized from the 7th day and the target peak could not be confirmed, and it was confirmed that AA-RB109 was stable by about 89.7% or more even after 30 days at 40°C. Despite the bioavailability of ascorbic acid, it is difficult to apply to various products in the food, cosmetic, and pharmaceutical fields due to its weak thermal stability.

Example 6: Skin permeability of ascorbic acid derivatives

In order to check the skin permeability of AA-RB109, an in vitro skin permeation experiment using Franz Diffusion Cell Assay was performed. For comparison, the skin permeability of pure ascorbic acid was measured under the same conditions. The measurement result is shown in FIG. Ascorbic acid could not confirm the skin permeability until 24 hours, the test period, but AA-RB109 showed an excellent skin permeability of 26.6%. Despite the bioavailability of ascorbic acid, it is difficult to apply it to various products in the cosmetic and pharmaceutical fields due to its weak skin permeability. did.

In the above, the present invention has been described based on exemplary embodiments and examples of the present invention, but the present invention is not limited to the technical ideas described in the above embodiments and examples. Rather, those of ordinary skill in the art to which the present invention pertains can easily propose various modifications and changes based on the above-described embodiments and examples. However, it is clear from the appended claims that all such modifications and changes fall within the scope of the present invention.

Claims (4)

A compound having the structure of Formula 1 below.
[Formula 1]

In Formula 1, R ₁ and R ₂ are each independently hydrogen or a structure of Formula 2 below, and at least one of R ₁ and R ₂ has a structure of Formula 2 below.
[Formula 2]

In Formula 2, R ₃ is a C ₁ ~ C ₂₀ alkyl group, C ₂ ~ C ₂₀ alkenyl group, C ₂ ~ C ₂₀ alkynyl group, C ₁ ~ C ₂₀ alkyl disulfide group, C ₄ ~ C ₃₀ alicyclic group ), as a first group selected from the group consisting of C ₆ ~ C ₃₀ aryl group and C ₃ ~ C ₃₀ heteroaryl group, the alicyclic, aryl group and hetero aryl group are each independently unsubstituted or at least one C ₁ -C ₂₀ alkyl group, C ₆ -C ₂₀ aryl group and C ₃ -C ₃₀ first group substituted with a functional group selected from the group consisting of heteroaryl group, or C ₁ -C ₂₀ alkyl amino group, C ₁ -C ₂₀ alkyl As a second group selected from the group consisting of a guanidyl group, a C ₁ -C ₂₀ alkyl polyamine, and a C ₀ -C ₃₀ heteroaryl group connected directly or through a C ₁ -C ₂₀ alkylene group and having at least one nitrogen atom, , The C ₁ -C ₂₀ heteroaryl group having at least one nitrogen atom is a second group unsubstituted or substituted with at least one C ₁ -C ₂₀ alkylamino group, and among the entire molecules having the structure of Formula 2, the first the proportion of unit units having groups is 30 to 70%; R ₄ is a hydroxyl group or an amino group; L is a direct bond, C ₁ ~ C ₂₀ alkylene group, C ₆ ~ C ₃₀ arylene group, or C ₃ ~ C ₃₀ hetero arylene group; p is an integer from 6 to 20; A functional cosmetic composition comprising a compound having the structure of Formula 1 below or a cosmetically acceptable salt thereof as an active ingredient.
[Formula 1]

In Formula 1, R ₁ and R ₂ are each independently hydrogen or a structure of Formula 2 below, and at least one of R ₁ and R ₂ has a structure of Formula 2 below.
[Formula 2]

In Formula 2, R ₃ is a C ₁ ~ C ₂₀ alkyl group, C ₂ ~ C ₂₀ alkenyl group, C ₂ ~ C ₂₀ alkynyl group, C ₁ ~ C ₂₀ alkyl disulfide group, C ₄ ~ C ₃₀ alicyclic group ), as a first group selected from the group consisting of C ₆ ~ C ₃₀ aryl group and C ₃ ~ C ₃₀ heteroaryl group, the alicyclic, aryl group and hetero aryl group are each independently unsubstituted or at least one C ₁ -C ₂₀ alkyl group, C ₆ -C ₂₀ aryl group and C ₃ -C ₃₀ first group substituted with a functional group selected from the group consisting of heteroaryl group, or C ₁ -C ₂₀ alkyl amino group, C ₁ -C ₂₀ alkyl As a second group selected from the group consisting of a guanidyl group, a C ₁ -C ₂₀ alkyl polyamine, and a C ₀ -C ₃₀ heteroaryl group connected directly or through a C ₁ -C ₂₀ alkylene group and having at least one nitrogen atom, , The C ₁ -C ₂₀ heteroaryl group having at least one nitrogen atom is a second group unsubstituted or substituted with at least one C ₁ -C ₂₀ alkylamino group, and among the entire molecules having the structure of Formula 2, the first the proportion of unit units having groups is 30 to 70%; R ₄ is a hydroxyl group or an amino group; L is a direct bond, C ₁ ~ C ₂₀ alkylene group, C ₆ ~ C ₃₀ arylene group or C ₃ ~ C ₃₀ hetero arylene group; p is an integer from 6 to 20; An antibacterial composition comprising a compound having the structure of Formula 1 below, a pharmaceutically acceptable salt thereof, a food engineering acceptable salt thereof, or a cosmetically acceptable salt thereof as an active ingredient.
[Formula 1]

In Formula 1, R ₁ and R ₂ are each independently hydrogen or a structure of Formula 2 below, and at least one of R ₁ and R ₂ has a structure of Formula 2 below.
[Formula 2]

In Formula 2, R ₃ is a C ₁ ~ C ₂₀ alkyl group, C ₂ ~ C ₂₀ alkenyl group, C ₂ ~ C ₂₀ alkynyl group, C ₁ ~ C ₂₀ alkyl disulfide group, C ₄ ~ C ₃₀ alicyclic group ), as a first group selected from the group consisting of C ₆ ~ C ₃₀ aryl group and C ₃ ~ C ₃₀ heteroaryl group, the alicyclic, aryl group and hetero aryl group are each independently unsubstituted or at least one C ₁ -C ₂₀ alkyl group, C ₆ -C ₂₀ aryl group and C ₃ -C ₃₀ first group substituted with a functional group selected from the group consisting of heteroaryl group, or C ₁ -C ₂₀ alkyl amino group, C ₁ -C ₂₀ alkyl As a second group selected from the group consisting of a guanidyl group, a C ₁ -C ₂₀ alkyl polyamine, and a C ₀ -C ₃₀ heteroaryl group connected directly or through a C ₁ -C ₂₀ alkylene group and having at least one nitrogen atom, , The C ₁ -C ₂₀ heteroaryl group having at least one nitrogen atom is a second group unsubstituted or substituted with at least one C ₁ -C ₂₀ alkylamino group, and among the entire molecules having the structure of Formula 2, the first the proportion of unit units having groups is 30 to 70%; R ₄ is a hydroxyl group or an amino group; L is a direct bond, C ₁ ~ C ₂₀ alkylene group, C ₆ ~ C ₃₀ arylene group or C ₃ ~ C ₃₀ hetero arylene group; p is an integer from 6 to 20; An anti-inflammatory composition comprising a compound having the structure of Formula 1 below, a pharmaceutically acceptable salt thereof, a food engineering acceptable salt thereof, or a cosmetically acceptable salt thereof as an active ingredient.
[Formula 1]

In Formula 1, R ₁ and R ₂ are each independently hydrogen or a structure of Formula 2 below, and at least one of R ₁ and R ₂ has a structure of Formula 2 below.
[Formula 2]

In Formula 2, R ₃ is a C ₁ ~ C ₂₀ alkyl group, C ₂ ~ C ₂₀ alkenyl group, C ₂ ~ C ₂₀ alkynyl group, C ₁ ~ C ₂₀ alkyl disulfide group, C ₄ ~ C ₃₀ alicyclic group ), as a first group selected from the group consisting of C ₆ ~ C ₃₀ aryl group and C ₃ ~ C ₃₀ heteroaryl group, the alicyclic, aryl group and hetero aryl group are each independently unsubstituted or at least one C ₁ -C ₂₀ alkyl group, C ₆ -C ₂₀ aryl group and C ₃ -C ₃₀ first group substituted with a functional group selected from the group consisting of heteroaryl group, or C ₁ -C ₂₀ alkyl amino group, C ₁ -C ₂₀ alkyl As a second group selected from the group consisting of a guanidyl group, a C ₁ -C ₂₀ alkyl polyamine, and a C ₀ -C ₃₀ heteroaryl group connected directly or through a C ₁ -C ₂₀ alkylene group and having at least one nitrogen atom, , The C ₁ -C ₂₀ heteroaryl group having at least one nitrogen atom is a second group unsubstituted or substituted with at least one C ₁ -C ₂₀ alkylamino group, and among the entire molecules having the structure of Formula 2, the first the proportion of unit units having groups is 30 to 70%; R ₄ is a hydroxyl group or an amino group; L is a direct bond, C ₁ ~ C ₂₀ alkylene group, C ₆ ~ C ₃₀ arylene group or C ₃ ~ C ₃₀ hetero arylene group; p is an integer from 6 to 20;

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