KR102462608B1 - Caffeoyl-tetrapeptide having anti-inflammatory and skin soothing effects and composition containing the same - Google Patents
Caffeoyl-tetrapeptide having anti-inflammatory and skin soothing effects and composition containing the same Download PDFInfo
- Publication number
- KR102462608B1 KR102462608B1 KR1020200175373A KR20200175373A KR102462608B1 KR 102462608 B1 KR102462608 B1 KR 102462608B1 KR 1020200175373 A KR1020200175373 A KR 1020200175373A KR 20200175373 A KR20200175373 A KR 20200175373A KR 102462608 B1 KR102462608 B1 KR 102462608B1
- Authority
- KR
- South Korea
- Prior art keywords
- inflammatory
- tetrapeptide
- skin soothing
- caffeoyl
- formula
- Prior art date
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- A—HUMAN NECESSITIES
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Abstract
본 발명은 항염 및 피부진정 효과를 갖는 카페오일-테트라펩타이드 및 이를 포함하는 조성물에 관한 것이다.
본 발명에 따른 카페오일-테트라펩타이드는 하기 화학식 I의 구조를 갖는다.
[화학식 I]
본 발명의 신규한 카페오일-테트라펩타이드는 항염 및 피부진정 효과가 뛰어나므로, 인체 적용시 본래의 기능을 효과적으로 발휘할 수 있어, 의약, 화장품, 기능성 식품 분야에서 유용하게 이용될 수 있다.The present invention relates to a caffeoyl-tetrapeptide having anti-inflammatory and skin soothing effects and a composition comprising the same.
The caffeoyl-tetrapeptide according to the present invention has the structure of the following formula (I).
[Formula I]
Since the novel caffeoyl-tetrapeptide of the present invention has excellent anti-inflammatory and skin soothing effects, it can effectively exert its original function when applied to the human body, and thus can be usefully used in medicine, cosmetics, and functional food fields.
Description
본 발명은 항염 및 피부진정 효과를 갖는 카페오일-테트라펩타이드 및 이를 포함하는 조성물에 관한 것이다.The present invention relates to a caffeoyl-tetrapeptide having anti-inflammatory and skin soothing effects and a composition comprising the same.
펩타이드는 바이오의 핵심소재로 단백질의 기능적 최소 단위이며, 아미노산이 2개로부터 50개 이하로 구성된다. 적은량으로 우수한 효능을 보일 뿐만아니라 독성이 없어 의약품, 식품 및 화장품의 주요 원료로 많이 활용되고 있다. 특히 인체에 안전하고 효과가 좋은 펩타이드 화장품 소재는 날로 사용량이 늘어날 뿐만아니라 새로운 소재의 개발은 수입대체 효과 등 당 산업에서 매우 중요하다고 할 수 있다.Peptide is the core material of bio, the functional minimum unit of protein, and consists of 2 to 50 amino acids. Not only does it show excellent efficacy in a small amount, but also because it is non-toxic, it is widely used as a major raw material for pharmaceuticals, food and cosmetics. In particular, the use of peptide cosmetic materials that are safe and effective for the human body is increasing day by day, and the development of new materials is very important in the industry such as import substitution effect.
화장품 원료로 사용하는 펩타이드의 효능은 주로 콜라겐 증식, 미백 및 항염등의 효능을 단독으로 가지는 소재가 주를 이루고 있으며 비교적 고가 소재이기 때문에 사용량에 제한이 있는 실정이다. 이러한 항산화, 항염, 콜라겐 증식 등 다양한 효능을 하나의 펩타이드를 통해 발현할 수 있을 뿐만 아니라 비교적 짧은 서열로 구성되어 대량 생산을 통해 상업화가 가능하다면 관련 분야에서 다양하게 활용 가능하다.The efficacy of the peptide used as a cosmetic raw material is mainly composed of a material having the effects of collagen proliferation, whitening and anti-inflammatory, etc. alone, and since it is a relatively expensive material, there is a limitation in the amount used. If various effects such as antioxidant, anti-inflammatory, and collagen proliferation can be expressed through a single peptide, and it is composed of a relatively short sequence and can be commercialized through mass production, it can be used in various fields in related fields.
염증(inflammation)은 어떤 자극에 대한 생체조직의 방어반응의 하나로, 조직 변질, 순환장애와 삼출, 조직 증식의 세 가지를 병발하는 복잡한 병변을 일컫는다. 원인은 기계적 상해작용, 온도, 방사선 등의 물리적 인자, 독물 등의 화학적 인자, 세균감염 등의 기생체에 의한 것 등이며 이 중 세균에 의한 것이 가장 많다. 이러한 주요 원인 외에도, 여러 부수적 요인과 개체의 소인이나 면역 등에 의하여 그 발생은 복잡하다. Inflammation is one of the defense responses of biological tissues to certain stimuli, and refers to a complex lesion that combines three things: tissue deterioration, circulatory disorder and exudation, and tissue proliferation. Causes include mechanical injury, physical factors such as temperature and radiation, chemical factors such as poisons, and parasites such as bacterial infection, among which bacteria are the most common. In addition to these main causes, the occurrence is complicated by several incidental factors and the predisposition or immunity of the individual.
항염 효과를 갖는 다양한 연구가 진행되었는데, 대표적으로 한국공개특허 제2020-0135601호는 특정 아미노산 서열로 이루어지는 펩타이드, 또는 상기 펩타이드의 말단에 지방족 탄화수소가 축합된 화합물과 이를 포함하는 항염증 조성물을 개시하였고, 한국등록특허 제2146922호는 왕지네(Scolopendra subspinipes mutilans) 유래의 MKIKMHLIILKK-NH2 서열을 갖는 항염 펩타이드를 개시하였다.Various studies having an anti-inflammatory effect have been conducted, representatively, Korea Patent Application Publication No. 2020-0135601 discloses a peptide consisting of a specific amino acid sequence, or a compound in which an aliphatic hydrocarbon is condensed at the end of the peptide and an anti-inflammatory composition comprising the same. , Korean Patent No. 2146922 discloses an anti-inflammatory peptide having a MKIKMHLIILKK-NH 2 sequence derived from Wang centipede (Scolopendra subspinipes mutilans).
한편, 최근에는 환경오염, 특히 대기오염으로 인해 외부로 피부 노출시 피부트러블이 많이 발생할 수 있는데 이를 진정시키기 위한 의약품 이외 화장품의 개발은 미진한 실정이다.On the other hand, recently, many skin problems may occur when the skin is exposed to the outside due to environmental pollution, particularly air pollution.
따라서, 피부진정 효과를 갖는 펩타이드의 개발이 절실한 상황이다. Therefore, there is an urgent need to develop a peptide having a skin soothing effect.
이에, 본 발명자들은 특정 서열을 갖는 테트라펩타이드에 항산화 효능을 갖는 폴리페놀을 결합시킬 경우, 항염 및 피부진정 효과가 우수하다는 것을 확인하고, 본 발명을 완성하게 되었다.Accordingly, the present inventors confirmed that, when a polyphenol having an antioxidant effect is bound to a tetrapeptide having a specific sequence, the anti-inflammatory and skin soothing effects are excellent, and the present invention has been completed.
본 발명의 목적은 항염 및 피부진정 효과가 우수한 신규 펩타이드 및 이의 용도를 제공하는 데 있다.An object of the present invention is to provide a novel peptide having excellent anti-inflammatory and skin soothing effects and uses thereof.
본 발명의 다른 목적은 항염 및 피부진정용 조성물을 제공하는 데 있다.Another object of the present invention is to provide a composition for anti-inflammatory and skin soothing.
본 발명자들은 상기에 언급한 바와 같이 신규 펩타이드를 설계하고 제조하여 효능을 확인한 결과 항염 및 피부진정 효과가 우수함을 확인함으로써 본 발명을 완성하였다.The present inventors have completed the present invention by designing and manufacturing a novel peptide as described above and confirming that the efficacy is confirmed and the anti-inflammatory and skin soothing effects are excellent.
본 발명은 항염 및 피부진정 효과를 갖는 신규한 것으로써 하기 화학식 I로 표시되는 카페오일-테트라펩타이드를 제공하는 것을 목적으로 한다.An object of the present invention is to provide a caffeoyl-tetrapeptide represented by the following formula (I) as a novel thing having anti-inflammatory and skin soothing effects.
[화학식 I][Formula I]
상기 화학식 I의 펩타이드는 Caffeoyl-Gln-His-Gly-Val-OH의 서열을 가진 신규한 펩타이드 유도체이다.The peptide of formula (I) is a novel peptide derivative having the sequence of Caffeoyl-Gln-His-Gly-Val-OH.
본 발명에 있어서, 상기 화학식 I의 신규 펩타이드는 당 업계에 알려진 기술을 사용하여 제조할 수 있다. 대표적인 합성방법을 아래에 설명하고 있으나, 본 발명이 이러한 예에 제한되는 것은 아니며, 당 업계에 알려진 기술의 범위 내에서 당 업자가 적절히 변형하여 사용할 수 있다.In the present invention, the novel peptide of Formula I can be prepared using techniques known in the art. Representative synthesis methods are described below, but the present invention is not limited to these examples, and those skilled in the art can use it with appropriate modifications within the range of techniques known in the art.
상기 목적을 달성하기 위하여, 본 발명은 (a) 고체 지지체에 Fmoc-Val-OH를 결합하여 화학식 I-a로 표시되는 Fmoc-Val-O-Resin(2-Chlototrityl)을 얻는 단계; (b) 상기 단계 (a)에서 수득한 레진에 아미노산 (Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Gln(Trt)-OH, Caffeic acid 등)을 순서적으로 결합하여 화학식 I-b로 표시되는 보호기를 가진 레진에 결합된 펩타이드를 얻는 단계; (c) 상기 단계 (b)에서 수득한 보호화된 펩타이드가 결합된 레진으로부터 탈 보호화 공정을 거쳐 화학식 I-c로 표시되는 탈보호화된 Crude 펩타이드를 수득하는 단계; 및 (d) 상기 단계 (c)에서 수득한 비 정제 (Crude)된 펩타이드 유도체를 고성능액체크로마토그래피 (HPLC)로 정제하여 화학식 I로 표시되는 카페오일-테트라펩타이드를 얻는 단계를 포함하는 카페오일-테트라펩타이드의 제조방법을 제공한다.In order to achieve the above object, the present invention provides a method comprising: (a) binding Fmoc-Val-OH to a solid support to obtain Fmoc-Val-O-Resin (2-Chlototrityl) represented by Formula I-a; (b) amino acids (Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Gln(Trt)-OH, Caffeic acid, etc.) obtaining a peptide bound to a resin having a protecting group represented by I-b; (c) obtaining a deprotected crude peptide represented by Formula I-c through a deprotection process from the resin to which the protected peptide obtained in step (b) is bound; and (d) purifying the crude peptide derivative obtained in step (c) by high performance liquid chromatography (HPLC) to obtain caffeoyl-tetrapeptide represented by Formula I- It provides a method for producing a tetrapeptide.
[화학식 I-a][Formula I-a]
[화학식 I-b][Formula I-b]
[화학식 I-c][Formula I-c]
[화학식 I][Formula I]
본 발명에 있어서, 상기 화학식 I로 표시되는 카페오일-테트라펩타이드는 고체상 합성법으로 합성하는 것을 특징으로 한다.In the present invention, the caffeoyl-tetrapeptide represented by the formula (I) is characterized in that it is synthesized by a solid-phase synthesis method.
상기 화학식 I-b에서 R₁은 당 업계에서 통상적으로 이용하는 수소 또는 아민 보호기를 이용할 수 있다. 상기 아민 보호기는 아세트아미노메틸 (Acetaminomethyl)기, 벤질옥시카보닐 (Benzyloxycarbonyl)기, 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기, 아세틸 (acetyl)기, 벤조일 (Benzoyl)기, 파라-니트로벤조일 (para-Nitrobenzoyl)기, 파라-메톡시벤조일기 (para-Methoxybenzoyl) 등을 예시할 수 있으며, 벤질옥시카보닐 (Benzyloxycarbonyl)기, 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기가 바람직하며, 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기를 이용하는 것이 보다 바람직하지만 이에 국한되는 것은 아니다.In Formula Ib, R₁ may use hydrogen or an amine protecting group commonly used in the art. The amine protecting group is an acetaminomethyl group, a benzyloxycarbonyl group, a tert -butyloxycarbonyl group, an acetyl group, a benzoyl group, and a para-nitrobenzoyl group. ( para -Nitrobenzoyl) group, para-methoxybenzoyl group ( para -Methoxybenzoyl), etc. can be exemplified, and a benzyloxycarbonyl group, a tert -butyloxycarbonyl group is preferable, and a tert -Butyloxycarbonyl ( tert -Butyloxycarbonyl) group is more preferably used, but is not limited thereto.
상기 화학식 I-b에서 R₂는 당 업계에서 통상적으로 이용하는 수소 또는 방향족 아민 보호기를 이용할 수 있다. 상기 아민 보호기는 메톡시메틸 (Methoxymethyl)기, 벤질옥시메틸 (Benzyloxymethyl)기, 트리페닐메틸 (Triphenylmethyl)기, 터트-부틸디메틸실릴 (tert-Butyldimethylsilyl)기, 트리페닐실릴 (Triphenylsily)기, 트리이소프로필실릴 (Triispropylsilyl)기, 파라-메톡시벤질 (para-Methylxybenzyl)기, 테트라히드로피란 (Tetrahydropyran)기, 테트라히드로퓨란 (Tetrahydrofuran)기, 터트-부틸 (tert-Butyl)기, 디페닐메틸 (Diphenylmethyl)기, 2-클로로트리틸 (2-Chlorotrityl)기, 벤질 (Benzyl)기, 4-메톡시벤질 (4-Methoxybenzyl)기, 알릴 (Allyl)기, 터트-부틸옥시카르보닐 (tert-Butyloxycarbonyl)기, 아세틸 (Acetyl)기, 벤조일 (Benzoyl)기 등을 예시할 수 있으며, 메톡시메틸 (Methoxymethyl)기, 벤질옥시메틸 (Benzyloxymethyl)기, 트리페닐메틸 (Triphenylmethyl)기, 터트-부틸디메틸실릴 (tert-Butyldimethylsilyl)기, 트리페닐실릴 (Triphenylsily)기 또는 트리이소프로필실릴 (Triisopropylsilyl)기를 이용하는 것이 바람직하며, 2-클로로트리틸 (2-Chlorotrityl)기 또는 트리페닐메틸 (Triphenylmethyl)기를 이용하는 것이 보다 바람직하며, 아미드 보호기가 트리페닐메틸 (Triphenylmethyl)기를 이용하는 것이 가장 바람직하지만 이에 국한되는 것은 아니다.In Formula Ib, R 2 may be hydrogen or an aromatic amine protecting group commonly used in the art. The amine protecting group is a methoxymethyl group, a benzyloxymethyl group, a triphenylmethyl group, a tert -butyldimethylsilyl group, a triphenylsily group, and a triiso group. Triispropylsilyl group, para-methoxybenzyl ( para -Methylxybenzyl) group, tetrahydropyran (Tetrahydropyran) group, tetrahydrofuran (Tetrahydrofuran) group, tert-butyl ( tert -Butyl) group, diphenylmethyl ) group, 2-chlorotrityl (2-Chlorotrityl) group, benzyl (Benzyl) group, 4-methoxybenzyl (4-Methoxybenzyl) group, allyl (Allyl) group, tert -Butyloxycarbonyl group, acetyl (Acetyl) group, benzoyl group, etc. can be exemplified, and methoxymethyl (Methoxymethyl) group, benzyloxymethyl (Benzyloxymethyl) group, triphenylmethyl (Triphenylmethyl) group, tert-butyldimethylsilyl ( It is preferable to use a tert -Butyldimethylsilyl) group, a triphenylsily group, or a triisopropylsilyl group, and it is more preferable to use a 2-chlorotrityl group or a triphenylmethyl group. and it is most preferable to use a triphenylmethyl group as the amide protecting group, but is not limited thereto.
이하, 상기 합성 방법을 단계별로 좀 더 상세히 설명한다.Hereinafter, the synthesis method will be described in more detail step by step.
고체상 펩타이드 합성방법은;Solid-phase peptide synthesis method;
1) 라이신이 결합된 레진을 Swelling하고 보호화된 두 번째 서열의 아미노산을 레진에 붙이는 단계;1) Swelling the lysine-bound resin and attaching the protected amino acid of the second sequence to the resin;
2) 아미노산 보호기(N-말단의 아미노기)를 염기(피페리딘)로 처리하여 제거하고 레진을 세척하는 단계;2) removing the amino acid protecting group (amino group at the N-terminus) by treatment with a base (piperidine) and washing the resin;
3) 결합을 위한 시약과 함께 보호화된 아미노산을 세척된 레진에 반응시켜 결합하는 단계;3) reacting the protected amino acid with a reagent for binding to the washed resin to bind;
4) 상기 2) 및 3)의 단계를 반복하여 서열 순서대로 합성하는 단계;4) repeating steps 2) and 3) to synthesize in sequence order;
5) 레진 및 구성 아미노산들의 보호기를 동시에 제거하는 단계; 5) simultaneously removing the protecting groups of the resin and constituent amino acids;
6) 펩타이드를 용매로 고체화하여 얻은 다음 정제하는 단계; 및6) a step of purifying the peptide obtained by solidifying it with a solvent; and
7) 정제된 펩타이드를 농축하고 동결건조하여 수득하는 단계를 포함할 수 있다. 7) concentrating the purified peptide and lyophilizing to obtain it.
단계 1)에 있어서, 사용할 수 있는 레진으로는 2-클로로트리틸클로라이드 레진 (2-Chlorotritylchloride Resin), 왕 레진 (Wang Resin), 디에이치피피 레진 (DHPP Resin, 4-(1',1'-dimethyl-1'-hydroxypropyl)phenoxyacetyl alanyl aminomethyl polystyrene), 피디디엠 레진 (PDDM Resin, Diphenyldiazomethane Resin), 사스린 레진 (SASRIN Resin, 2-Methoxy-4-alkoxybenzyl alcohol Resin)으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다. In step 1), the usable resin is 2-chlorotritylchloride resin, Wang Resin, DHPP Resin, 4-(1',1'- dimethyl-1'-hydroxypropyl)phenoxyacetyl alanyl aminomethyl polystyrene), PDDM Resin (PDDM Resin, Diphenyldiazomethane Resin), Sasrin resin (SASRIN Resin, 2-Methoxy-4-alkoxybenzyl alcohol Resin) at least one selected from the group consisting of can be heard
단계 1)에 있어서, 사용되는 용매로는 디클로로메탄 (Dichloromethane), N,N-디메틸포름아마이드 (N,N-Dimethylformamide), N,N-디메틸아세트아마이드 (N,N-Dimethylacetamide), N-메틸피롤리돈 (N-Methylpyrrolidone), 클로로포름 (Chloroform), 1,2-디클로로에탄 (1,2-Dichloroethane), 테트라히드로퓨란 (Tetrahydrofurane), 1,4-디옥산 (1,4-Dioxane), 아세토니트릴 (Acetonitrile), 메탄올 (Methanol), 에탄올 (Ethanol), 이소프로판올 (Isopropanol), 에틸렌 글리콜 (Ethylene glycol), 메틸 아세테이트 (Methyl acetate), 에틸 아세테이트 (Ethyl acetate) 등으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.In step 1), the solvent used is dichloromethane, N,N-dimethylformamide (N,N-Dimethylformamide), N,N-dimethylacetamide (N,N-Dimethylacetamide), N-methyl pyrrolidone (N-Methylpyrrolidone), chloroform (Chloroform), 1,2-dichloroethane (1,2-Dichloroethane), tetrahydrofurane (Tetrahydrofurane), 1,4-dioxane (1,4-Dioxane), aceto At least one selected from the group consisting of nitrile (Acetonitrile), methanol (Methanol), ethanol (Ethanol), isopropanol (Isopropanol), ethylene glycol (Ethylene glycol), methyl acetate (Methyl acetate), ethyl acetate (Ethyl acetate), etc. can be heard
단계 2)에 있어서, 사용되는 보호기를 제거하는 염기로는 피페리딘 (Piperidine), 피롤리딘 (Pyrrolidine), 피페라진 (Piperazine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), 4-메틸피페리딘 (4-Methylpiperidine), 몰포린 (Morpholine), 1-메틸-3-부틸이미다졸리윰 테트라플로오로보란 (1-methyl-3-butyl imidazolium BF4), 에탄올아민 (Ethanolamine), 시클로헥실아민 (Cyclohexylamine), 트리스(2-아미노에틸)아민 (Tris(2-aminoethyl)amine), 1,3-디시클로헥산비스-(메틸아민) (1,3-Dicyclohexanebis-(methylamine)), 1,4-비스-(3-아미노프로필)피페라진 (1,4-Bis-(3-aminopropyl)piperazine), 디에틸아민 (Diethylamine), 4-디메틸아미노피리딘 (4-Dimethylaminopyridine) 등의 유기 염기 및 수산화 리튬 (Lithium hydroxide), 수산화 나트륨 (Sodium Hydroxide), 수산화 칼슘 (Calcium Hydroxide), 수산화 칼륨 (Potassium Hydroxide) 등의 무기염기로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.In step 2), the base used to remove the protecting group is piperidine, pyrrolidine, piperazine, DBU (1,8-diazabicyclo[5.4.0]undec-7). -ene), 4-methylpiperidine, morpholine, 1-methyl-3-butylimidazolium tetrafluoroborane (1-methyl-3-butyl imidazolium BF4), ethanol Amine (Ethanolamine), cyclohexylamine (Cyclohexylamine), tris (2-aminoethyl) amine (Tris (2-aminoethyl) amine), 1,3-dicyclohexanebis- (methylamine) (1,3-Dicyclohexanebis- (methylamine)), 1,4-bis- (3-aminopropyl) piperazine (1,4-Bis- (3-aminopropyl) piperazine), diethylamine, 4-dimethylaminopyridine (4-Dimethylaminopyridine) ) and organic bases such as lithium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, and the like, and at least one selected from the group consisting of inorganic bases.
단계 3)에 있어서, 보호화된 아미노산이 결합할 때 사용하는 시약으로는 DCC (N,N-Dicyclohexylcarbodiimide), DIC (N,N-Diisopropylcarbodiimide), BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate), PyBrOP (Bromo-tripyrrolidino-phosphonium hexafluorophosphate), PyAOP (7-Aza-benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate), PyOxim (Ethyl cyano(hydooxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate), HBTU (O-Benzotriazole-N,N,N',N'-tetramethyluroniumhexafluorophosphate), HCTU (2-(6-Chloro-1H-benzotriazol-1-yl)-N,N,N',N',-tetramethylaminium hexafluorophosphate), HDMC (N-[(5-chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium hexafluorophosphate N-oxide), TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate), HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphatemethanaminium), TATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroboratemethanaminium), CDI (carbonyldiimidazole), COMU (1-[1-(Cyano-2-ethoxy-2-oxoethylidene-aminooxy)-dimethylamino-morpholino]-uronium hexafluorophosphate), TOTT (2-(1-Oxy-pyridin-2-yl)-1,1,3,3-tetramethyl-isothiouronium tetrafluoroborate), EDCㅇHCl (N-(3-dimethylaminopropyl)-N`-ethylcarbodiimide hydrochloride), TFFH (Tetramethylfluoroformamidinium hexafluorophosphate), EEDQ (N-Ethoxycarbony-2-ethoxy-1,2-dihydro-quinoline), T3P (2-Propanephosphonic acid anhydride), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), Oxyma (Ethyl cyanohydroxyiminoacetate), HOBt (1-Hydroxybenzotriazole), HOOBt(HODhbt, Hydroxy-3,4-dihydro-4-ox-1,2,3-benzo-triazine), BTC (bis-Trichloromethylcarbonate or Triphosgene), CDI (1,1'-Carbonyldiimidazole), 6-ClHOBt (1-Hydroxy-6-chloro-benzotriazole), HOAt (1-Hydroxyazabenzotriazole) HOSu (N-Hydroxysuccinimide) 등으로 구성된 군에서 선택되는 1 이상의 것을 들 수 있다.In step 3), the reagent used when the protected amino acid binds is DCC (N,N-Dicyclohexylcarbodiimide), DIC (N,N-Diisopropylcarbodiimide), BOP (Benzotriazole-1-yl-oxy-tris-( dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate), PyBrOP (Bromo-tripyrrolidino-phosphonium hexafluorophosphate), PyAOP (7-Aza-benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate), PyOxim (hydooxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphate), HBTU (O-Benzotriazole-N,N,N',N'-tetramethyluroniumhexafluorophosphate), HCTU (2-(6-Chloro-1H- benzotriazol-1-yl)-N,N,N',N',-tetramethylaminium hexafluorophosphate), HDMC (N-[(5-chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uronium hexafluorophosphate N- oxide), TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate), HATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3, 3-tetramethyluroniumhexafluorophosphatemethanaminium), TATU (2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3 -tetramethyluroniumtetrafluoroboratemethanaminium), CDI (carbonyldiimidazole), COMU (1-[1-(Cyano-2-ethoxy-2-oxoethylidene-aminooxy)-dimethylamino-morpholino]-uronium hexafluorophosphate), TOTT (2-(1-Oxy-pyridin- 2-yl)-1,1,3,3-tetramethyl-isothiouronium tetrafluoroborate), EDC∙HCl (N-(3-dimethylaminopropyl)-N`-ethylcarbodiimide hydrochloride), TFFH (Tetramethylfluoroformamidinium hexafluorophosphate), EEDQ (N-Ethoxycarbony- 2-ethoxy-1,2-dihydro-quinoline), T3P (2-Propanephosphonic acid anhydride), DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), Oxyma (Ethyl cyanohydroxyiminoacetate) ), HOBt (1-Hydroxybenzotriazole), HOOBt (HODhbt, Hydroxy-3,4-dihydro-4-ox-1,2,3-benzo-triazine), BTC (bis-Trichloromethylcarbonate or Triphosgene), CDI (1,1) and at least one selected from the group consisting of '-Carbonyldiimidazole), 6-ClHOBt (1-Hydroxy-6-chloro-benzotriazole), HOAt (1-Hydroxyazabenzotriazole) HOSu (N-Hydroxysuccinimide), and the like.
단계 5)에 있어서, 레진 및 아미노산의 보호기를 동시에 제거하는 과정은 산성 용액의 존재 하에서 수행한다. 상기 산성 용액은 TFA/phenol/water/TIPS (88/5/5/2), TFA/phenol/water/thioanisole/EDT (82.5/5/5/5/2.5), TFA/phenol/water/thioanisole/1-decanethiol (82.5/5/5/5/2.5), TFA/DTT/water/TIPS (88/5/5/2), TFA-DODT-TIS-anisole-water (183:5:2:5:5, v/v), TFA/phenol (95/5), TFA/phenol/Methanesulfonic acid (95/2.5/2.5), TFA/thioanisole/EDT/anisole (90/5/3/2), TFA/TES (95/5), TFA/water (95/5), TFA/DCM/indole (70/28/2), TFA/TIPS/water (95/2.5/2.5) 등의 용액을 예시할 수 있다.In step 5), the process of simultaneously removing the protecting groups of the resin and the amino acid is performed in the presence of an acidic solution. The acid solution is TFA/phenol/water/TIPS (88/5/5/2), TFA/phenol/water/thioanisole/EDT (82.5/5/5/5/2.5), TFA/phenol/water/thioanisole/ 1-decanethiol (82.5/5/5/5/2.5), TFA/DTT/water/TIPS (88/5/5/2), TFA-DODT-TIS-anisole-water (183:5:2:5: 5, v/v), TFA/phenol (95/5), TFA/phenol/Methanesulfonic acid (95/2.5/2.5), TFA/thioanisole/EDT/anisole (90/5/3/2), TFA/TES (95/5), TFA/water (95/5), TFA/DCM/indole (70/28/2), and TFA/TIPS/water (95/2.5/2.5) solutions can be exemplified.
단계 6)에 있어서, Crude 펩타이드를 정제할 때 사용하는 용매로는 메탄올 (Methanol), 에탄올 (Ethanol), 이소프로판올 (Isopropanol), 아세토니트릴 (Acetonitrile) 및 정제수의 혼합용액이며, 이때 사용하는 산으로는 삼불화아세트산 (Trifluoroacetic acid), 아세트산 (Acetic acid), 포름산 (Formic acid)를 0.1% 내지 5% 이내로 사용하여 정제할 수 있다. In step 6), the solvent used when purifying the crude peptide is a mixed solution of methanol, ethanol, isopropanol, acetonitrile and purified water, and the acid used at this time is Trifluoroacetic acid, acetic acid, and formic acid may be used in an amount of 0.1% to 5%.
상기 작용기에 대한 보호기는 "Protecting Groups in Organic Synthesis (Greene and Wuts, John Wiley & Sons, 1991)"에 상세히 기재되어 있다.Protecting groups for these functional groups are described in detail in "Protecting Groups in Organic Synthesis (Greene and Wuts, John Wiley & Sons, 1991)".
본 명세서에서 용어 "펩타이드"는 펩타이드 결합에 의해 아미노산 잔기들이 서로 결합되어 형성된 선형의 분자를 의미한다.As used herein, the term “peptide” refers to a linear molecule formed by bonding amino acid residues to each other by peptide bonds.
본 발명에 따른 카페오일-테트라펩타이드는 발현 사이토카인 발현억제능(도 2) 및 피부진정 효과(도 3 및 도 4)가 있었다.The caffeoyl-tetrapeptide according to the present invention had the ability to inhibit expression of cytokine expression (FIG. 2) and a skin soothing effect (FIG. 3 and FIG. 4).
따라서, 또 하나의 양태로서, 본 발명은 본 발명의 카페오일-테트라펩타이드를 포함하는 항염 및 피부진정용 조성물에 관한 것이다. 본 발명의 카페오일-테트라펩타이드를 유효성분으로 함유하는 항염 및 피부진정용 조성물은 약학용, 화장용 또는 건강기능식품용으로 활용 가능하다.Accordingly, as another aspect, the present invention relates to an anti-inflammatory and skin soothing composition comprising the caffeoyl-tetrapeptide of the present invention. The composition for anti-inflammatory and skin soothing containing caffeoyl-tetrapeptide of the present invention as an active ingredient can be used for pharmaceutical, cosmetic, or health functional food.
상기 펩티드를 포함하는 약학용 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition containing the peptide is formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions, respectively, according to a conventional method. may be used, but is not limited thereto.
본 발명의 카페오일-테트라펩타이드를 함유하는 약학용 조성물에 함유될 수 있는 담체, 부형제 및 희석제로는 락토오즈, 덱스트로즈, 수크로스, 덱스트린, 말토덱스트린, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들수 있으나, 이에 제한되지 않는다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제되나, 이에 제한되지 않는다.Carriers, excipients and diluents that may be included in the pharmaceutical composition containing the caffeoyl-tetrapeptide of the present invention include lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol , starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but is not limited thereto. In the case of formulation, it is usually prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant, but is not limited thereto.
상기 카페오일-테트라펩타이드를 포함하는 화장료 조성물은 피부, 두피 등에 사용할 수 있고, 항염 및 피부진정 효과를 위하여 사용할 수 있다.The cosmetic composition containing the caffeo oil-tetrapeptide can be used for skin, scalp, etc., and can be used for anti-inflammatory and skin soothing effects.
본 발명의 화장료 조성물에 포함되는 카페오일-테트라펩타이드의 함량은 용도, 적용 형태, 사용 목적 및 소망하는 효과에 따라서 적절히 조절 가능하며, 함량 대비 효과를 고려하여, 예컨대 전체 조성물 중량에 대하여 0.0001 내지 99.9 중량% 이내에서 사용할 수 있다.The content of caffeoyl-tetrapeptide contained in the cosmetic composition of the present invention can be appropriately adjusted according to the use, application form, purpose of use and desired effect, and in consideration of the effect compared to the content, for example, 0.0001 to 99.9 based on the total weight of the composition. It can be used within % by weight.
본 발명의 항염 및 피부진정용 조성물은 비경구로 투여할 수 있으며, 경피에 도포에 의한 국부 투여 (Topical application) 방식으로 적용될 수 있다.The anti-inflammatory and skin soothing composition of the present invention may be administered parenterally, and may be applied in a topical application method by percutaneous application.
상기 화장료 조성물은 피부 및 두피에 경피적으로 적용되고, 기초 화장품, 가슴 및 둔부 전용 크림, 메이크업 화장품, 바디 제품, 면도용 제품, 모발 제품 등을 포함한 모든 화장품 제품의 제조에 사용 가능한 조성물을 의미하는 것으로, 경구제, 스프레이, 현탁액, 유액, 크림, 젤, 폼 등의 형태로 제제화된 것일 수 있으나 그 형태에 특별한 제한이 없다.The cosmetic composition is applied transdermally to the skin and scalp, and refers to a composition that can be used in the manufacture of all cosmetic products including basic cosmetics, creams for chest and buttocks, makeup cosmetics, body products, shaving products, hair products, etc. , oral preparations, sprays, suspensions, emulsions, creams, gels, foams, etc. may be formulated in the form, but the form is not particularly limited.
또한, 상기 화장료 조성물은 유연 화장수, 수렴화장수, 영양화장수, 영양 크림, 마사지크림, 아이크림, 아이 에센스, 에센스, 클렌징크림, 클렌징로션, 클렌징폼, 클렌징 워터, 팩, 파우더, 보디로션, 보디 크림, 보디 에센스, 보디 세정제, 자외선 차단 크림, 염모제, 샴푸, 린스, 치약, 구강 청정제, 로션, 연고, 젤, 크림, 패치 및 분무제로 이루어진 군으로부터 선택되는 제형을 가지는 것을 포함한다.In addition, the cosmetic composition is a flexible lotion, astringent lotion, nourishing lotion, nourishing cream, massage cream, eye cream, eye essence, essence, cleansing cream, cleansing lotion, cleansing foam, cleansing water, pack, powder, body lotion, body cream , body essence, body wash, sunscreen cream, hair colorant, shampoo, rinse, toothpaste, mouthwash, lotion, ointment, gel, cream, patch, and spray.
또한, 상기 화장료 조성물은 부틸렌글라이콜, 1,2-헥산다이올, 글리세린, 나이아신아마이드, 병풀뿌리추출물, 카페오일-테트라펩타이드, 시호뿌리추출물, 황금추출물, 병풀추출물, 티트리잎추출물, 소듐하이알루로네이트, 아크릴레이트/C10-30알킬아크릴레이트크로스폴리머, 트로메타딘, 아데노신, 에틸헥실글리세린 등을 더욱 포함할 수 있다.In addition, the cosmetic composition is butylene glycol, 1,2-hexanediol, glycerin, niacinamide, Centella asiatica root extract, caffeo oil-tetrapeptide, Shiho root extract, golden extract, Centella asiatica extract, tea tree leaf extract, sodium Hyaluronate, acrylate/C10-30 alkyl acrylate crosspolymer, tromethadine, adenosine, ethylhexylglycerin, and the like may be further included.
상기 카페오일-테트라펩타이드를 포함하는 기능성 식품 조성물은 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다. The functional food composition containing the caffeoyl-tetrapeptide can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, and the like.
본 발명의 건강기능식품이라 함은, 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The health functional food of the present invention refers to a food manufactured and processed using raw materials or ingredients useful for the human body according to the Health Functional Food Act No. 6727, and contains nutrients for the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulation or physiological action.
본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards.
상기 식품 첨가물 공전에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류 첨가 알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 포함하나, 이에 제한되지 않는다.The items listed in the Food Additives Codex include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations such as sodium L-glutamate preparations, noodles-added alkalis, preservatives, and tar dye preparations are included, but are not limited thereto.
또한, 상기 본 발명의 항염 및 피부진정용 조성물은 상기 유효성분 이외에 통상의 제품화 및 제제화에 사용 가능한 모든 종류의 성분, 예컨대 향료, 색소, 살균제, 산화 방지제, 방부제, 보습제, 점증제, 부형제, 희석제, 무기염류 및 합성 고분자 물질 등을 추가로 포함할 수 있으며, 그 종류와 함량은 최종 산물의 용도 및 사용 목적에 따라 적절하게 조절할 수 있다.In addition, the anti-inflammatory and skin soothing composition of the present invention includes all kinds of ingredients that can be used for general commercialization and formulation in addition to the active ingredients, such as fragrances, pigments, bactericides, antioxidants, preservatives, moisturizers, thickeners, excipients, and diluents. , inorganic salts, synthetic polymers, etc. may be additionally included, and the type and content may be appropriately adjusted according to the purpose and purpose of the final product.
본 발명의 신규한 카페오일-테트라펩타이드는 항염 및 피부진정 효과가 뛰어나므로, 인체 적용시 본래의 기능을 효과적으로 발휘할 수 있어, 의약, 화장품, 기능성 식품 분야에서 유용하게 이용될 수 있다.Since the novel caffeoyl-tetrapeptide of the present invention has excellent anti-inflammatory and skin soothing effects, it can effectively exert its original function when applied to the human body, and thus can be usefully used in medicine, cosmetics, and functional food fields.
도 1은 본 발명의 실시 예에 따른 항염 및 피부진정 효능을 가진 카페오일-테트라펩타이드를 합성하는 공정도이다.
도 2는 본 발명에 따른 카페오일-테트라펩타이드의 항염 효과 실험 결과이다.
도 3은 본 발명에 따른 카페오일-테트라펩타이드의 경피수분손실량과 피부 붉은기 변화를 시험한 결과이다.
도 4는 본 발명에 따른 카페오일-테트라펩타이드의 자외선 조사 후 피부진정 효능의 시험 사진이다.1 is a process diagram of synthesizing caffeoyl-tetrapeptide having anti-inflammatory and skin soothing effects according to an embodiment of the present invention.
2 is a result of an anti-inflammatory effect of caffeoyl-tetrapeptide according to the present invention.
3 is a result of testing the amount of percutaneous moisture loss and skin redness of caffeoyl-tetrapeptide according to the present invention.
4 is a test photograph of the skin soothing effect after UV irradiation of caffeoyl-tetrapeptide according to the present invention.
본 명세서에서 특별한 표시가 없는 한, 아미노산 및 보호기의 지정에 사용되는 약어는 IUPAC-IUB의 생화학 용어 위원회 (Commission of Biochemical Nomenclature)에서 권장하는 용어에 기초한다 (Biochemistry, 11:1726-1732(1972); Pure & Appl. Chem., Vol. 56, No. 5, pp. 595-624, 1984).Unless otherwise indicated herein, abbreviations used for designation of amino acids and protecting groups are based on terms recommended by the IUPAC-IUB Commission of Biochemical Nomenclature ( Biochemistry, 11:1726-1732 (1972)) ( Pure & Appl. Chem., Vol. 56, No. 5, pp. 595-624, 1984).
본 명세서에서 사용한 보호기 및 아미노산의 약어는 다음과 같다:Abbreviations of protecting groups and amino acids used herein are as follows:
DCM: 디클로로메탄 (Dichloromethane)DCM: Dichloromethane
DMSO: 디메틸설폭시드 (Dimethylsulfoxide)DMSO: Dimethylsulfoxide
DTT: 디티올쓰레이톨 (Dithiolthreitol)DTT: Dithiolthreitol
EDT: 1,2-에탄디티올 (1,2-Ethanedithiol)EDT: 1,2-ethanedithiol (1,2-Ethanedithiol)
Gln: 글루타민 (Glutamine)Gln: Glutamine
Gly: 글라이신 (Glycine)Gly: Glycine
His: 히스티딘 (Histidine)His: Histidine
HPLC: 고성능액체크로마토그래피 (High Performance Liquid Chromatography)HPLC: High Performance Liquid Chromatography
Lys: 라이신 (Lysine)Lys: Lysine
Boc: 터트-부틸옥시카르보닐기 (tert-Butyloxycarbonyl)Boc: tert-butyloxycarbonyl group ( tert -Butyloxycarbonyl)
OtBu: O-터트-부틸(O-tert-Butyl)OtBu: O- tert -Butyl
t-Bu: 터트-부틸 (tert-Butyl)t-Bu: tert -Butyl
Fmoc: 9-플루오레닐옥시카보닐 (9-Fluorenyloxycarbonyl)Fmoc: 9-fluorenyloxycarbonyl (9-Fluorenyloxycarbonyl)
Trt: 트리페닐메틸 (또는 트리틸) (Triphenylmethyl or Trityl)Trt: triphenylmethyl (or trityl) (Triphenylmethyl or Trityl)
Pbf: 2,2,4,6,7-펜타메틸-디히드로벤조퓨란-5-설포닐 (2,2,4,6,7-Pentamethyl-dihydrobenzofuran-5-sulfonyl)Pbf: 2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl (2,2,4,6,7-Pentamethyl-dihydrobenzofuran-5-sulfonyl)
Pmc: 2,2,5,7,8-펜타메틸크로만-6-설포닐 (2,2,5,7,8-Pentamethylchroman-6-sulfonyl)Pmc: 2,2,5,7,8-pentamethylchroman-6-sulfonyl (2,2,5,7,8-Pentamethylchroman-6-sulfonyl)
Mtr: 4-메톡시-2,3,6-트리메틸페닐-설포닐 (4-Methoxy-2,3,6-trimethylphenyl-sulfonyl)Mtr: 4-Methoxy-2,3,6-trimethylphenyl-sulfonyl (4-Methoxy-2,3,6-trimethylphenyl-sulfonyl)
Tos: 파라-톨루엔설포닐 (para-Toluenesulfonyl)Tos: para-toluenesulfonyl (para-Toluenesulfonyl)
TES: 트라이에틸실란 (Triethylsilane)TES: Triethylsilane
TFA: 트라이플루오로아세틱 엑시드 (Trifluoroacetic acid)TFA: Trifluoroacetic acid
TIPS: 트리이소프로필실란 (Triisopropylsilane)TIPS: Triisopropylsilane
Val: 발린 (Valine)Val: Valine
이하, 본 발명을 실시 예에 의해 더욱 상세히 설명하고자 한다. 이들 실시 예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시 예에 의해 제한되지 않는다는 것은 당 업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail by way of examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시 예. 화학식 I로 표시되는 카페오일-테트라펩타이드의 제조Example. Preparation of caffeoyl-tetrapeptide represented by formula (I)
본 명세서 전체에 거쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 "%"는 별도의 언급이 없는 한 고체/고체는 (중량/중량) %, 고체/액체는 (중량/부피) %, 그리고 액체/액체는 (부피/부피) %이다.Throughout this specification, "%" used to indicate the concentration of a specific substance is (weight/weight) % for solids/solids, (weight/volume) % for solids/liquids, and liquids unless otherwise specified. /liquid is (volume/volume) %.
실시 예 1 : H-Val-O-레진(2-클로로트리틸)의 제조Example 1: Preparation of H-Val-O-resin (2-chlorotrityl)
[화학식 2][Formula 2]
여과막이 장착된 고체상 (solid-phase) 합성 반응기에 2-클로로트리틸 클로라이드 레진 (치환율 = 1.41 mmol/g의 레진, 200 mmole) 및 디클로로메탄 (1000 ml, 이하 DCM)를 넣고, 15분간 레진을 팽창시킨 후, 감압 하에서 여과막을 통하여 용매를 제거하였다. Fmoc-Val-OH (분자량 = 339.4 g/mol) (135.76 g, 400 mmol, 2.0 당량)이 포함된 DCM (1000 ml)을 넣고, 이어서 DIPEA (분자량 = 129.25 g/mol) (129.25 g, 1000 mmol, 2.5 당량)를 첨가한 후, 실온에서 4시간 동안 반응시켰다. 감압 여과하여 반응액을 제거하고, 레진에 DCM : 메탄올 : DIPEA = 17 : 2 : 1 (1000 ml)을 넣고 20분간 교반시켰다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리한다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반한다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리한다. DMF 1000 ml으로 총 6회 레진을 세척한 후, 화학식 2로 표시되는 H-Val-O-레진(2-클로로트리틸)을 수득하였다 (치환율: 0.5 mmol/g, 수율 >99%).In a solid-phase synthesis reactor equipped with a filtration membrane, 2-chlorotrityl chloride resin (resin with a substitution rate = 1.41 mmol/g, 200 mmole) and dichloromethane (1000 ml, hereafter DCM) were put, and the resin was incubated for 15 minutes. After expansion, the solvent was removed through a filtration membrane under reduced pressure. DCM (1000 ml) with Fmoc-Val-OH (molecular weight = 339.4 g/mol) (135.76 g, 400 mmol, 2.0 equiv) was added, followed by DIPEA (molecular weight = 129.25 g/mol) (129.25 g, 1000 mmol) (129.25 g, 1000 mmol) , 2.5 equivalents), and then reacted at room temperature for 4 hours. The reaction solution was removed by filtration under reduced pressure, DCM : methanol : DIPEA = 17 : 2 : 1 (1000 ml) was added to the resin and stirred for 20 minutes. The reaction solution is removed by filtration under reduced pressure, and the resin is treated in the same way once more. After washing the resin twice with 1000 ml of DMF, 1000 ml of a 20% piperidine/DMF solution is added and stirred for 15 minutes. The reaction solution is removed by filtration under reduced pressure, and the resin is treated in the same way once more. After washing the resin a total of 6 times with 1000 ml of DMF, H-Val-O-resin (2-chlorotrityl) represented by
실시 예 2 : H-Gly-Val-O-레진(2-클로로트리틸)의 제조Example 2: Preparation of H-Gly-Val-O-resin (2-chlorotrityl)
[화학식 3][Formula 3]
H-Val-O-레진(2-클로로트리틸)(100 mmole)이 들어있는 반응기에 Fmoc-Gly-OH (분자량 = 297.3 g/mol, 89.19 g, 300 mmole)과 Oxyma (분자량 = 142.11 g/mol, 46.90 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.7 g, 330 mmole)을 적가한 다음 상온에서 5시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 3으로 표시되는 H-Gly-Val-O-레진(2-클로로트리틸)을 수득하였다 (수율 >99%).In a reactor containing H-Val-O-resin (2-chlorotrityl) (100 mmole), Fmoc-Gly-OH (molecular weight = 297.3 g/mol, 89.19 g, 300 mmole) and Oxyma (molecular weight = 142.11 g/molecular weight = 142.11 g/ mol, 46.90 g, 330 mmole) was dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.7 g, 330 mmole) was added dropwise to the mixed reaction solution, followed by slow stirring at room temperature for 5 hours. After the resin was washed twice with 1000 ml of DMF, 1000 ml of a 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated in the same way once more. After washing the resin a total of 6 times with 1000 ml of DMF, H-Gly-Val-O-resin (2-chlorotrityl) represented by
실시 예 3 : H-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)의 제조Example 3: Preparation of H-His(Trt)-Gly-Val-O-resin (2-chlorotrityl)
[화학식 4][Formula 4]
H-Gly-Val-O-레진(2-클로로트리틸)(100 mmole)이 들어있는 반응기에 Fmoc-His(Trt)-OH (분자량 = 619.7 g/mol, 185.91 g, 300 mmole)과 Oxyma (분자량 = 142.11 g/mol, 46.90 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.7 g, 330 mmole)을 적가한 다음 상온에서 5시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반하였다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리하였다. DMF 1000 ml으로 총 6회 레진을 세척한 후 화학식 4로 표시되는 H-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)을 수득하였다 (수율 >99%).In a reactor containing H-Gly-Val-O-resin (2-chlorotrityl) (100 mmole), Fmoc-His(Trt)-OH (molecular weight = 619.7 g/mol, 185.91 g, 300 mmole) and Oxyma ( Molecular weight = 142.11 g/mol, 46.90 g, 330 mmole) was dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.7 g, 330 mmole) was added dropwise to the mixed reaction solution, followed by slow stirring at room temperature for 5 hours. After the resin was washed twice with 1000 ml of DMF, 1000 ml of a 20% piperidine/DMF solution was added and stirred for 15 minutes. The reaction solution was removed by filtration under reduced pressure, and the resin was treated in the same way once more. After washing the resin a total of 6 times with 1000 ml of DMF, H-His(Trt)-Gly-Val-O-resin (2-chlorotrityl) represented by Chemical Formula 4 was obtained (yield >99%).
실시 예 4 : H-Gln(Trt)-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)의 제조Example 4: Preparation of H-Gln(Trt)-His(Trt)-Gly-Val-O-resin (2-chlorotrityl)
[화학식 5][Formula 5]
H-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)(100 mmole)이 들어있는 반응기에 Fmoc-Gln(Trt)-OH (분자량 = 610.7 g/mol, 183.21 g, 300 mmole)과 Oxyma (분자량 = 142.11 g/mol, 46.90 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.7 g, 330 mmole)을 적가한 다음 상온에서 5시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 2회 세척한 후, 20% 피페리딘/DMF 용액 1000 ml를 더하고 15분 동안 교반한다. 감압 여과하여 반응액을 제거하고, 레진을 동일하게 1회 더 처리한다. DMF 1000 ml으로 총 6회 레진을 세척한 후 H-Gln(Trt)-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)을 수득하였다 (수율 >99%).Fmoc-Gln(Trt)-OH (molecular weight = 610.7 g/mol, 183.21 g, 300 mmole) and Oxyma (molecular weight = 142.11 g/mol, 46.90 g, 330 mmole) were dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.7 g, 330 mmole) was added dropwise to the mixed reaction solution, followed by slow stirring at room temperature for 5 hours. After washing the resin twice with 1000 ml of DMF, 1000 ml of a 20% piperidine/DMF solution is added and stirred for 15 minutes. The reaction solution is removed by filtration under reduced pressure, and the resin is treated in the same way once more. After washing the resin a total of 6 times with 1000 ml of DMF, H-Gln(Trt)-His(Trt)-Gly-Val-O-resin (2-chlorotrityl) was obtained (yield >99%).
실시 예 5 : Caffeoyl-Gln(Trt)-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)의 제조Example 5: Preparation of Caffeoyl-Gln(Trt)-His(Trt)-Gly-Val-O-resin (2-chlorotrityl)
[화학식 6][Formula 6]
H-Gln(Trt)-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)(100 mmole)이 들어있는 반응기에 Caffeic acid (분자량 = 180.16 g/mol, 54.05 g, 300 mmole)과 Oxyma (분자량 = 142.11 g/mol, 46.90 g, 330 mmole)을 DMF 1000 ml에 용해한 다음 투입하였다. 혼합된 반응액에 DIC (분자량 = 126.2 g/mol, 41.7 g, 330 mmole)을 적가한 다음 상온에서 4시간 동안 서서히 교반하였다. 레진을 DMF 1000 ml으로 6회 세척한 후 화학식 6으로 표시되는 Caffeoyl-Gln(Trt)-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)을 수득하였다 (수율 >99%).Caffeic acid (molecular weight = 180.16 g/mol, 54.05 g, 300 mmole) in a reactor containing H-Gln(Trt)-His(Trt)-Gly-Val-O-resin(2-chlorotrityl) (100 mmole) ) and Oxyma (molecular weight = 142.11 g/mol, 46.90 g, 330 mmole) were dissolved in 1000 ml of DMF and then added. DIC (molecular weight = 126.2 g/mol, 41.7 g, 330 mmole) was added dropwise to the mixed reaction solution, followed by slow stirring at room temperature for 4 hours. After the resin was washed 6 times with 1000 ml of DMF, Caffeoyl-Gln(Trt)-His(Trt)-Gly-Val-O-resin (2-chlorotrityl) represented by
실시 예 6 : Crude Caffeoyl-Gln-His-Gly-Val-OH의 제조Example 6: Preparation of Crude Caffeoyl-Gln-His-Gly-Val-OH
[화학식 7][Formula 7]
Caffeoyl-Gln(Trt)-His(Trt)-Gly-Val-O-레진(2-클로로트리틸)을 반응기에 투입하고 냉각된 TFA/TIPS/water (95/2.5/2.5) 용액 3 L를 서서히 부어 넣은 다음 상온에서 4시간 동안 교반하였다. 반응액을 받아낸 다음 냉각된 디에틸에테르 12 L에 반응액을 서서히 적가하여 펩타이드를 석출시켰다. 실온에서 30분 동안 교반한 다음 여과하여 펩타이드를 회수하였다. 최대한 용매를 감압 제거한 다음 진공 건조기에서 5시간 동안 건조시켜 거의 백색이고, 화학식 7로 표시되는 Crude Caffeoyl-tetrapeptide 75.44 g을 수득하였다. (분자량 601.61g/mol, Crude peptide 순도 74.3%, 수율 125.4%)Caffeoyl-Gln(Trt)-His(Trt)-Gly-Val-O-resin (2-chlorotrityl) was put into the reactor, and 3 L of cooled TFA/TIPS/water (95/2.5/2.5) solution was slowly added. After pouring, the mixture was stirred at room temperature for 4 hours. After receiving the reaction solution, the reaction solution was slowly added dropwise to 12 L of cooled diethyl ether to precipitate the peptide. After stirring at room temperature for 30 minutes, the peptide was recovered by filtration. After removing the solvent under reduced pressure as much as possible, it was dried in a vacuum dryer for 5 hours to obtain 75.44 g of crude caffeoyl-tetrapeptide, which is almost white and represented by Chemical Formula 7. (Molecular weight 601.61g/mol, Crude peptide purity 74.3%, Yield 125.4%)
실시 예 7 : Caffeoyl-Gln-His-Gly-Val-OH의 제조Example 7: Preparation of Caffeoyl-Gln-His-Gly-Val-OH
[화학식 I][Formula I]
상기 실시 예 6에서 수득한 화학식 7로 표시되는 Crude Caffeoyl-tetrapeptide 75.44 g을 정제수에 용해한 다음 0.46μm membrane 여과하였다. 여과액을 산업용 HPLC (220 nm, 10 ml/분, 10 미크론 C18 컬럼에서 20분 내에 0.1% TFA 내 아세토니트릴 초기농도 8%에서 55%로 증가)로 반복 주입한 후 main fraction 부분을 분획하여 화학식 I로 표시되는 Caffeoyl-tetrapeptide, 44 g (수율: 58.3%, 순도: 98.3%)을 수득하였다.75.44 g of crude caffeoyl-tetrapeptide represented by Chemical Formula 7 obtained in Example 6 was dissolved in purified water, and then filtered with a 0.46 μm membrane. After repeatedly injecting the filtrate with industrial HPLC (220 nm, 10 ml/min, acetonitrile initial concentration in 0.1% TFA increased from 8% to 55% in 20 minutes on a 10 micron C18 column), the main fraction was fractionated to obtain the chemical formula Caffeoyl-tetrapeptide represented by I, 44 g (yield: 58.3%, purity: 98.3%) was obtained.
실험 예 1 : 카페오일-테트라펩타이드의 항염 활성평가: 발현 사이토카인 억제능 분석Experimental Example 1: Evaluation of anti-inflammatory activity of caffeoyl-tetrapeptide: expression cytokine inhibitory ability analysis
펩타이드 소재의 항염 활성을 평가하기 위하여 세포주에 LPS (lipopolysaccharides)를 처리하여 유도하는 Mouse TNFa ELISA(Cat. N.: 558534)를 통해 사이토카인을 RT-PCR (reverse transcription polymerase chain reaction) 기법을 이용하여 분석하였다. 또한, 이에 LPS에 염증 유도 후 사이토카인 억제 효과를 알아보기 위해 Raw 264.7 cell에 LPS 염증 유도 후 시험물질을 농도별(0 ~ 100μg/mL)로 처리하여 Mouse TNFa ELISA를 통해 사이토카인의 양상을 측정하였다. 이때 대조구로 Dexamethasone, 비교예로 caffeoyl기가 붙지 않은 테트라펩타이드(NH2-Gln-His-Gly-Val-OH)를 각각 처리하였다.In order to evaluate the anti-inflammatory activity of the peptide material, the cell line was treated with LPS (lipopolysaccharides) to induce cytokines through Mouse TNFa ELISA (Cat. N.: 558534) using RT-PCR (reverse transcription polymerase chain reaction) technique. analyzed. In addition, in order to investigate the cytokine inhibitory effect after inducing inflammation in LPS, after inducing LPS inflammation in Raw 264.7 cells, the test substance was treated at each concentration (0 ~ 100μg/mL), and the cytokine pattern was measured through Mouse TNFa ELISA. did. At this time, dexamethasone as a control and tetrapeptide (NH 2 -Gln-His-Gly-Val-OH) without a caffeoyl group as a comparative example were treated, respectively.
실험 예 2 : 피부진정 효능평가Experimental Example 2: Evaluation of skin soothing efficacy
피부진정 효능 평가는 1) 자외선인공 조사기, 2) 광량 측정기, 3) Tewameter TM-300, 4) Chromameter CR-400, 5) ANTERA 3D® 장비를 사용하여 경피수분손실량 및 피부 붉은기를 총 22명에 대하여 평가하였다. The skin soothing effect was evaluated using 1) artificial UV irradiator, 2) light quantity meter, 3) Tewameter TM-300, 4) Chromameter CR-400, 5) ANTERA 3D ® equipment, and transdermal moisture loss and skin redness were evaluated in a total of 22 people. was evaluated.
시험 대상자의 내측 상완부에 자외선 조사 면적을 35㎠로 하여 0.8cm x 0.8cm 크기의 면적을 갖는 6개의 정사각형 조사 주위를 구획한 다음 빛을 조사한 후, 하기와 같이 펩타이드 제형의 적당량을 도포한 경우와 도포하지 않은 경우에 대해 경피수분손실량 및 피부 붉은기를 각각 평가하였다.In the case of applying an appropriate amount of the peptide formulation as follows after dividing the area around 6 square irradiations having an area of 0.8 cm x 0.8 cm with an ultraviolet irradiation area of 35 cm on the inner upper arm of the test subject and irradiating light as follows For the non-applied case, the amount of transdermal moisture loss and skin redness were evaluated, respectively.
1) Tewameter를 이용한 경피수분손실량 평가: 피부장벽이 손상된 시험 부위와 대조 부위의 시료 사용 전 후, 경피수분손실량 변화를 Tewameter를 이용하여 측정하였다.1) Evaluation of transdermal moisture loss using Tewameter: Changes in transdermal moisture loss were measured using Tewameter before and after the use of samples in the test and control regions with damaged skin barrier.
2) Chromameter를 이용한 피부 붉은기 평가: 피부 장벽이 손상된 시험 부위와 대조 부위의 시료 사용 전 후, 피부 붉은기 변화를 색차계를 이용하여 측정하였다.2) Evaluation of skin redness using Chromameter: Changes in skin redness were measured using a colorimeter before and after the use of samples in the test and control areas with damaged skin barrier.
도 3 및 도 4에 도시된 바와 같이, 본 발명에 따른 카페오일-테트라펩타이드는 자외선 조사 후 대조구 대비 경피수분손실량이 감소하고, 피부 붉은기도 줄어들어 피부진정 효과가 우수하다는 것을 확인할 수 있었다.As shown in Figures 3 and 4, the caffeoyl-tetrapeptide according to the present invention decreased the amount of transdermal moisture loss compared to the control after UV irradiation, and it was confirmed that the skin redness was reduced, and thus the skin soothing effect was excellent.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당 업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, it is clear that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Accordingly, it is intended that the substantial scope of the present invention be defined by the appended claims and their equivalents.
Claims (11)
[화학식 I]
An anti-inflammatory and skin soothing composition comprising a caffeoyl-tetrapeptide having a structure of the following formula (I).
[Formula I]
[화학식 I]
A pharmaceutical composition for anti-inflammatory and skin soothing comprising caffeoyl-tetrapeptide having a structure of the following formula (I).
[Formula I]
[화학식 I]
A health food composition for anti-inflammatory and skin soothing comprising caffeoyl-tetrapeptide having the structure of the following formula (I).
[Formula I]
[화학식 I]
A cosmetic composition for anti-inflammatory and skin soothing comprising caffeoyl-tetrapeptide having the structure of the following formula (I).
[Formula I]
According to claim 8, wherein the composition is a softening lotion, astringent lotion, nutrient lotion, nutrition cream, massage cream, eye cream, eye essence, essence, cleansing cream, cleansing lotion, cleansing foam, cleansing water, pack, powder, body lotion Anti-inflammatory and A cosmetic composition for skin soothing.
The cosmetic composition for anti-inflammatory and skin soothing according to claim 8, further comprising a substance having skin soothing activity.
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