KR20180057591A - Composition for Preventing or Treating Inflammatory Disease, Allergic Disease or Cancer Comprising Melatonin Derivative - Google Patents
Composition for Preventing or Treating Inflammatory Disease, Allergic Disease or Cancer Comprising Melatonin Derivative Download PDFInfo
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- KR20180057591A KR20180057591A KR1020180056550A KR20180056550A KR20180057591A KR 20180057591 A KR20180057591 A KR 20180057591A KR 1020180056550 A KR1020180056550 A KR 1020180056550A KR 20180056550 A KR20180056550 A KR 20180056550A KR 20180057591 A KR20180057591 A KR 20180057591A
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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- A—HUMAN NECESSITIES
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
- A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
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- A—HUMAN NECESSITIES
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
Abstract
Description
본 발명은 멜라토닌(melatonin) 유도체를 포함하는 염증성 질환, 알러지 질환 예방 또는 치료용 조성물과 암 질환 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating inflammatory diseases, allergic diseases, and a composition for preventing or treating cancer diseases, including melatonin derivatives.
염증은 물리적인 외상, 유해한 화학물질, 미생물에 의한 감염이나 생체 내 대사산물 중의 자극성 물질에 의하여 야기되는 조직손상에 반응해 국소적으로 나타나는 정상적이고 보호적인 생체 내 방어기전의 발현이다. 이러한 염증은 손상조직과 이동하는 세포(migrating cells)로부터 생산되는 다양한 화학매개인자에 의하여 촉발되며, 이들 화학매개인자들은 염증과정의 형태에 따라 매우 다양한 종류가 있는 것으로 알려져 있다. 정상적인 경우에 생체는 염증 반응을 통하여 발병 요인을 중화하거나 제거하고 상한 조직을 재생하여 정상적인 구조와 기능을 회복한다. Inflammation is the expression of a normal, protective in vivo defense mechanism that appears locally in response to physical trauma, harmful chemicals, infection by microorganisms, or tissue damage caused by irritants in metabolites in vivo. Such inflammation is triggered by various chemical mediators produced from damaged tissues and migrating cells, and these chemical mediators are known to be of a wide variety according to the type of inflammatory process. In a normal case, the living body neutralizes or removes pathogenic factors through an inflammatory reaction and regenerates damaged tissues to restore normal structure and function.
그러나 이러한 염증 반응이 비정상적으로 발생될 경우에는 만성 염증과 같은 질환으로 진행되기도 하며, 꽃가루와 같이 무해한 물질이나 천식, 류마티스성 관절염과 같은 자가 면역반응에 의해 부적절하게 염증이 촉발되는 경우에는 방어반응 자체가 오히려 조직을 손상시켜 다양한 질병을 일으킨다. However, if such an inflammatory reaction is abnormal, it may progress to a disease such as chronic inflammation, and if the inflammation is inappropriately triggered by an autoimmune reaction such as asthma or rheumatoid arthritis, or a harmless substance such as pollen, the defense response itself Rather, it damages tissues and causes various diseases.
일반적으로 거의 모든 임상질환에서 염증 반응을 관찰할 수 있는데, 이들 염증 질환 중에는 항생제 투여로 원인적 치료가 가능한 세균성 질환도 있지만 대부분은 그 발병이 자가 면역반응에 의한 조직손상에 기인하므로 특이적 치료법이 없는 난치병으로 알려져 있다. 이러한 염증의 발생 원인으로서는 다양한 생화학적인 현상이 관여하고 있는 바, 이를 억제하기 위한 다양한 기술들이 연구되었다.In general, inflammatory reactions can be observed in almost all clinical diseases. Among these inflammatory diseases, there are bacterial diseases that can be etiologically treated with antibiotics, but most of them are due to tissue damage caused by autoimmune reactions, so specific treatments are not required. There is no known incurable disease. Various biochemical phenomena are involved as causes of such inflammation, and various techniques for suppressing them have been studied.
예를 들어, 대식세포(Macrophage)는 화학적 자극에 반응해 여러 가지 사이토카인(cytokine)과 질소산화물(NO)을 생성하여 염증반응에서 중요한 역할을 하는 세포이다. 특히 대식세포에서 지질다당류(lipopolysaccharide, LPS)나 인터페론γ, 종양괴사인자-α(Tumor necrosis factor-α, TNF-α)와 같은 사이토카인 자극에 의해 발현되는 유도성 질소산화물 합성효소(iNOS)는 장시간 동안 다량의 질소 산화물(NO)을 생산하는데, 이러한 산화적 스트레스는 IκB에 의하여 억제되어 있는 염증 반응의 전사인자인 핵 인자 카파B(nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB) 활성을 촉진시키는 것으로 알려져 있다. 활성화된 NF-κB는 핵으로 이동하여 유도형 NO생성효소(inducible NO synthase, iNOS), 프로스타글란딘-엔도과산화물 합성효소-2(Prostaglandin-endoperoxide synthase-2, COX-2) 및 인터루킨-1β(Interleukin-1β, IL-1β)나 TNF-α와 같은 여러 종류의 사이토카인 등 염증반응을 유도하는 유전자 발현을 촉진시키며, 이들 인자들을 저해하면 염증 반응을 억제할 수 있는 것으로 알려져 있다(Baeuerle et al., Annu. Rev. Immunol., 12:141-179, 1994).For example, macrophages are cells that play an important role in inflammatory reactions by producing various cytokines and nitrogen oxides (NO) in response to chemical stimuli. In particular, in macrophages, inducible nitrogen oxide synthase (iNOS) is expressed by stimulation of cytokines such as lipopolysaccharide (LPS), interferon γ, and tumor necrosis factor-α (TNF-α). A large amount of nitrogen oxides (NO) is produced for a long time, and this oxidative stress is the nuclear factor kappa-light-chain-enhancer of activated B cells, NF, which is a transcription factor of the inflammatory response that is inhibited by IκB. It is known to promote -κB) activity. Activated NF-κB migrates to the nucleus and moves to the inducible NO synthase (iNOS), prostaglandin-endoperoxide synthase-2 (COX-2), and interleukin-1β (Interleukin- 1β, IL-1β) and various cytokines such as TNF-α promote the expression of genes that induce inflammatory reactions, and it is known that inhibition of these factors can suppress the inflammatory response (Baeuerle et al., Annu. Rev. Immunol., 12:141-179, 1994).
질소산화물(NO)은 세 가지 주요한 질소산화물 합성효소(NOS) 이성질체인 신경형 NOS(neuronal NOS, nNOS), 내피 NOS(endothelial NOS, eNOS), 유도형 NOS(inducible NOS, iNOS)에 의해 L-아르기닌(L-arginine)으로부터 생성된다. nNOS와 eNOS는 Ca2+/칼모듈린(calmodulin)에 의해 조절되지만, iNOS는 인터루킨(interleukin), 인터페론(interferon), LPS와 같은 염증성 자극에 의해 전사 수준에서 조절된다. nNOS나 eNOS에 의해 소량 생성된 질소산화물은 혈관확장, 신경전달, 병원체에 대한 세포파괴 등과 같은 정상적인 생리기능을 담당하지만, 대식세포에서 iNOS에 의해 과다 생성된 질소산화물은 염증과 암을 포함한 다양한 병리생리학적 과정에 관여하며, 수퍼옥사이드(superoxide)와 반응하여 퍼옥시니트라이트(peroxynitrite)를 형성하는 경우에는 강력한 산화제로 작용하여 세포에 손상을 입히고, 염증성 자극에 의해 활성화된 대식세포에서 NF-κB를 활성화시켜 염증 반응, 암, 동맥경화 등 만성질환에 관련하는 것으로 알려져 있다(Lawrence et al., Nat Med., 7:1291-1297, 2001; Riehemann et al., FEBS Lett., 442:89-94, 1999;Stamler et al., Science, 258:1898-1902, 1992).Nitrogen oxide (NO) is L-arginine by three major nitrogen oxide synthase (NOS) isomers: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). It is produced from (L-arginine). nNOS and eNOS are regulated by Ca 2+ /calmodulin, but iNOS is regulated at the transcription level by inflammatory stimuli such as interleukin, interferon, and LPS. Nitrogen oxides produced in small amounts by nNOS or eNOS are responsible for normal physiological functions such as vasodilation, neurotransmission, and cell destruction of pathogens, but nitrogen oxides produced in excess by iNOS in macrophages are various pathologies including inflammation and cancer. It is involved in physiological processes, and when it reacts with superoxide to form peroxynitrite, it acts as a strong oxidizing agent to damage cells, and NF-κB in macrophages activated by inflammatory stimulation. It is known to be related to chronic diseases such as inflammatory response, cancer, and arteriosclerosis by activating (Lawrence et al., Nat Med., 7:1291-1297, 2001; Riehemann et al., FEBS Lett., 442:89- 94, 1999; Stamler et al., Science, 258:1898-1902, 1992).
다면발현성의 사이토카인(pleiotropic cytokine)인 IL-6는 염증성 장 질환(inflammatory bowel disease), 관절염(arthritis), 실험적 자가면역 뇌수막염(experimental autoimmune encephalomyelitis), 다발성 캐슬만병(multicentric Castleman's disease), 프리스탄에 의해 유도된 루푸스(pristane-induced lupus) 및 형질세포종(plasmacytomas) 등에서 주요 원인 분자로 생각되고 있으며, COX-2는 주로 관절염, 루푸스의 원인분자로 생각되고 있다. 따라서 이들에 대한 선택적인 저해제는 널리 사용될 수 있다.IL-6, a pleiotropic cytokine, is found in inflammatory bowel disease, arthritis, experimental autoimmune encephalomyelitis, multicentric Castleman's disease, and Pristane. It is thought to be a major causative molecule in pristane-induced lupus and plasmacytomas, and COX-2 is considered to be a causative molecule mainly for arthritis and lupus. Therefore, selective inhibitors for them can be widely used.
그러나 아직까지는 염증 질환을 치료하기 위한 가장 일반적인 염증성 질환 예방 또는 치료용제로서 크게 스테로이드성 및 비스테로이드성 염증성 질환 예방 또는 치료용제를 사용하고 있는데, 이 중 합성 또는 치료용제는 대부분 주작용 이외에 여러 가지 부작용을 수반하는 경우가 많다는 문제점이 있다. However, as the most common inflammatory disease prophylactic or therapeutic agent for treating inflammatory diseases so far, however, steroidal and nonsteroidal inflammatory diseases prophylactic or therapeutic agents are largely used, among which synthetic or therapeutic solutions are mostly used for various side effects other than the main action. There is a problem in that it is often accompanied by.
따라서 효과가 탁월하며 부작용이 적은 새로운 염증성 질환의 개발이 절실히 요구되고 있는 실정이다. Therefore, there is an urgent need for the development of a new inflammatory disease with excellent effect and less side effects.
본 발명의 목적은 염증성 질환, 알러지 질환 및 암 질환을 효과적으로 예방 또는 치료하기 위하여, 생체 호르몬인 멜라토닌에서 유도된 신규한 화합물들을 포함하는 약학 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition comprising novel compounds derived from melatonin, a biological hormone, in order to effectively prevent or treat inflammatory diseases, allergic diseases and cancer diseases.
본 발명의 다른 목적은 염증성 질환, 알러지 질환 및 암 질환을 효과적으로 예방 또는 개선하기 위하여, 생체 호르몬인 멜라토닌에서 유도된 신규한 화합물을 포함하는 건강식품 또는 화장료 조성물을 제공하는 것이다.Another object of the present invention is to provide a health food or cosmetic composition comprising a novel compound derived from melatonin, a biological hormone, in order to effectively prevent or improve inflammatory diseases, allergic diseases and cancer diseases.
상기 목적을 달성하기 위하여, 본 발명은 멜라토닌 유도체를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases comprising a melatonin derivative as an active ingredient.
또한, 상기 다른 목적을 달성하기 위하여, 본 발명은 멜라토닌 유도체를 유효성분으로 포함하는 염증성 질환 예방 또는 개선용 건강식품을 제공한다.In addition, in order to achieve the above other object, the present invention provides a health food for preventing or improving inflammatory diseases comprising a melatonin derivative as an active ingredient.
상기 또 다른 목적을 달성하기 위하여, 본 발명은 멜라토닌 유도체를 유효성분으로 포함하는 염증성 질환 예방 또는 개선용 화장료 조성물을 제공한다.In order to achieve the above another object, the present invention provides a cosmetic composition for preventing or improving inflammatory diseases comprising a melatonin derivative as an active ingredient.
상기 또 다른 목적을 달성하기 위하여, 본 발명은 멜라토닌 유도체를 유효성분으로 포함하는 알러지 질환 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above another object, the present invention provides a pharmaceutical composition for preventing or treating allergic diseases comprising a melatonin derivative as an active ingredient.
상기 또 다른 목적을 달성하기 위하여, 본 발명은 멜라토닌 유도체를 유효성분으로 포함하는 알러지 질환 예방 또는 개선용 건강식품을 제공한다.In order to achieve the above another object, the present invention provides a health food for preventing or improving allergic diseases comprising a melatonin derivative as an active ingredient.
상기 또 다른 목적을 달성하기 위하여, 본 발명은 멜라토닌 유도체를 유효성분으로 포함하는 알러지 질환 예방 또는 치료용 화장료 조성물을 제공한다.In order to achieve the above another object, the present invention provides a cosmetic composition for preventing or treating allergic diseases comprising a melatonin derivative as an active ingredient.
상기 또 다른 목적을 달성하기 위하여, 본 발명은 멜라토닌 유도체를 유효성분으로 포함하는 암 질환 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above another object, the present invention provides a pharmaceutical composition for preventing or treating cancer diseases comprising a melatonin derivative as an active ingredient.
상기 또 다른 목적을 달성하기 위하여, 본 발명은 멜라토닌 유도체를 유효성분으로 포함하는 암 질환 예방 또는 개선용 건강식품을 제공한다.In order to achieve the above another object, the present invention provides a health food for preventing or improving cancer diseases comprising a melatonin derivative as an active ingredient.
상기 멜라토닌 유도체는 하기 화학식 1 또는 화학식 2로 표시된다.The melatonin derivative is represented by the following formula (1) or formula (2).
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
본 발명에 따른 멜라토닌 유도체는 염증 모델에 처리하면 NO의 생성 및 염증성 싸이토카인의 발현을 억제하는 항염 활성을 보이며, 비만세포(mast cell)에서 분비하는 히스타민을 억제하여 히스타민 매개 알러지 반응을 억제할 수 있고, 암세포에 처리 시 단백질인산화효소 B(AKT)와 세포외신호조절 인산화효소(Extracellular signal-regulated kinases, ERK)의 신호전달체계를 억제하며, 저산소 유도인자-1α(Hypoxia-inducible factor-1 alpha, HIF-1α)의 발현을 억제하는 항암 활성을 보이므로 염증성 질환, 알러지 질환 또는 암 질환 치료에 있어서 부작용이 적으면서도 효과가 우수한 치료제, 화장료 조성물 또는 건강식품으로 유용하게 사용할 수 있다.The melatonin derivative according to the present invention exhibits anti-inflammatory activity that inhibits the production of NO and the expression of inflammatory cytokines when treated in an inflammation model, and suppresses histamine secreted from mast cells, thereby inhibiting histamine-mediated allergic reactions. , When treated in cancer cells, it inhibits the signaling system of protein kinase B (AKT) and extracellular signal-regulated kinases (ERK), and hypoxia-inducible factor-1 alpha, As it shows anticancer activity that inhibits the expression of HIF-1α), it can be usefully used as a therapeutic agent, cosmetic composition, or health food with low side effects and excellent effect in the treatment of inflammatory diseases, allergic diseases or cancer diseases.
도 1은 멜라토닌 및 본 발명에서 합성한 멜라토닌 유도체들의 구조식을 나타낸 것이다;
도 2는 본 발명의 하나의 실시예에 따른 멜라토닌 유도체의 NO 생성 억제 효과를 나타낸 막대그래프이다;
도 3은 도 2의 실시예에 따른 멜라토닌 유도체의 염증인자 억제 효과를 나타낸 것이다;
도 4는 본 발명의 다른 실시예에 따른 멜라토닌 유도체의 히스타민 억제 효과를 나타낸 막대그래프이다;
도 5는 본 발명의 또 다른 실시예에 따른 멜라토닌 유도체의 대장암 세포에서의 항암 효과를 나타낸 표이다;
도 6은 도 5의 실시예에 따른 멜라토닌 유도체의 자궁경부암, 유방암, 폐암, 대장암 세포에서의 항암 효과를 나타낸 표이다;
도 7은 도 5의 실시예에 따른 멜라토닌 유도체의 항암 효과 기전을 분석한 결과를 나타낸 것이다; 및
도 8은 도 5의 실시예에 따른 멜라토닌 유도체의 대장암 세포에서의 저산소 유도인자-1α(Hypoxia-inducible factor 1-alpha, HIF-1α) 발현 억제 효과를 나타낸 것이다.1 shows the structural formula of melatonin and melatonin derivatives synthesized in the present invention;
Figure 2 is a bar graph showing the NO production inhibitory effect of a melatonin derivative according to an embodiment of the present invention;
Figure 3 shows the inhibitory effect of the inflammatory factor of the melatonin derivative according to the embodiment of Figure 2;
4 is a bar graph showing the histamine inhibitory effect of a melatonin derivative according to another embodiment of the present invention;
5 is a table showing the anticancer effect of a melatonin derivative in colon cancer cells according to another embodiment of the present invention;
6 is a table showing the anticancer effect of the melatonin derivative according to the embodiment of FIG. 5 in cervical cancer, breast cancer, lung cancer, and colon cancer cells;
Figure 7 shows the results of analyzing the anticancer effect mechanism of the melatonin derivative according to the embodiment of Figure 5; And
8 shows the effect of inhibiting the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in colon cancer cells of the melatonin derivative according to the embodiment of FIG. 5.
본 발명의 발명자는 멜라토닌 인돌 핵의 3번 위치에 곁사슬을 갖는 유도체와 2번 위치에 곁사슬을 갖는 유도체를 합성하고 상기 유도체가 항염증, 항알러지 및 항암 효과를 보이는 것을 확인하여 본 발명을 완성하였다.The inventors of the present invention synthesized a derivative having a side chain at
본 발명은 하기 화학식 1 또는 화학식 2의 멜라토닌 유도체를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases comprising the melatonin derivative of Formula 1 or Formula 2 as an active ingredient.
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
본 발명의 일 실시예에 따르면, LPS로 유도한 염증 모델에 상기 멜라토닌 유도체를 처리하였을 때, NO의 생성 및 염증성 싸이토카인인 단구주화성 단백질-1(monocyte chemoattractant protein-1, MCP-1), 인터루킨-6(Interleukin-6), COX-2 및 TNF-α의 발현이 크게 억제되었다. 즉, 상기 멜라토닌 유도체는 염증성 질환을 완화할 수 있는 효과적인 약학 조성물로 사용될 수 있다.According to an embodiment of the present invention, when the melatonin derivative is treated in an LPS-induced inflammation model, NO production and inflammatory cytokine monocyte chemoattractant protein-1 (MCP-1), interleukin The expression of -6 (Interleukin-6), COX-2 and TNF-α was greatly suppressed. That is, the melatonin derivative can be used as an effective pharmaceutical composition capable of alleviating inflammatory diseases.
이때, 상기 멜라토닌 유도체는 약학 조성물 총 100 중량부에 대하여, 0.1 내지 50 중량부로 포함될 수 있는 바, 0.1 중량부 미만으로 포함될 경우에는 멜라토닌 유도체의 항염 효과가 제대로 나타나지 않고, 50 중량부를 초과하여 포함될 경우에는 멜라토닌 유도체의 함량 증가량 대비 항염 효과가 현저히 감소하므로 바람직하지 않다.At this time, the melatonin derivative may be included in an amount of 0.1 to 50 parts by weight, based on a total of 100 parts by weight of the pharmaceutical composition.When it is included in less than 0.1 parts by weight, the anti-inflammatory effect of the melatonin derivative does not appear properly, and when it is included in excess of 50 parts by weight It is not preferable because the anti-inflammatory effect is significantly reduced compared to the increased amount of the melatonin derivative.
상기 약학 조성물이 적용될 수 있는 상기 염증성 질환으로는 부종, 피부염, 결막염, 치주염, 비염, 중이염, 인후염, 편도염, 폐렴, 위궤양, 위염, 크론병, 대장염, 치질, 통풍, 강직성 척추염, 류마티스 열, 루푸스, 섬유근통(fibromyalgia), 건선관절염, 골관절염, 류마티스 관절염, 견관절 주위염, 건염, 건초염, 건주위염, 근육염, 간염, 방광염, 신장염, 쇼그렌 증후군(sjogren’s syndrome), 다발성 경화증 및 급성 또는 만성 염증 질환으로 이루어지는 군으로부터 선택되는 하나 이상일 수 있으나, 이에 제한되지는 않는다.The inflammatory diseases to which the pharmaceutical composition can be applied include edema, dermatitis, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatic fever, lupus. , Fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, peri-shoulderitis, tendinitis, tendonitis, peritonitis, myositis, hepatitis, cystitis, nephritis, sjogren's syndrome, multiple sclerosis and acute or chronic inflammatory diseases It may be one or more selected from, but is not limited thereto.
또한, 본 발명은 하기 화학식 1 또는 화학식 2의 멜라토닌 유도체를 유효성분으로 포함하는 염증성 질환 예방 또는 개선용 건강식품을 제공한다.In addition, the present invention provides a health food for preventing or improving inflammatory diseases comprising the melatonin derivative of the following
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
또한, 본 발명은 하기 화학식 1 또는 화학식 2의 멜라토닌 유도체를 유효성분으로 포함하는 염증성 질환 예방 또는 개선용 화장료 조성물을 제공한다.In addition, the present invention provides a cosmetic composition for preventing or improving inflammatory diseases comprising the melatonin derivative of the formula (1) or (2) as an active ingredient.
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
또한, 본 발명은 하기 화학식 1 또는 화학식 2의 멜라토닌 유도체를 유효 성분으로 포함하는 알러지 질환 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating allergic diseases comprising the melatonin derivative of the following formula (1) or (2) as an active ingredient.
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
본 발명의 다른 실시예에 따르면, 본 발명에 따른 멜라토닌 유도체를 비만세포(mast cell)에 처리했을 때, Compound 48/80에 의해 유도되는 히스타민의 분비를 억제하는 효과를 나타내었다. Compound 48/80은 인간 비만세포에 처리하는 경우 탈과립(degranulation) 현상을 일으켜 비만세포가 원래부터 가지고 있는 히스타민이나 세로토닌뿐만 아니라 새롭게 합성된 전염증성 사이토카인, 프로스타글란딘, 류코트리엔(leukotriene) 등과 같은 염증인자들을 방출시키는 저분자 다중체이다. 이중 히스타민은 알러지 질환을 일으키는 주요한 원인 중 하나인 바, 본 발명의 멜라토닌 유도체를 포함하는 약학 조성물은 히스타민의 생성 또는 방출을 억제함으로써 알러지 질환을 완화시킬 수 있다.According to another embodiment of the present invention, when the melatonin derivative according to the present invention is treated on mast cells, it has the effect of inhibiting the secretion of histamine induced by Compound 48/80. Compound 48/80, when treated on human mast cells, causes degranulation, and not only histamine or serotonin, which mast cells originally possess, but also inflammatory factors such as newly synthesized pro-inflammatory cytokines, prostaglandins, and leukotriene. It is a low-molecular multimer that emits. Among them, histamine is one of the main causes of allergic diseases, and the pharmaceutical composition comprising the melatonin derivative of the present invention can alleviate allergic diseases by inhibiting the production or release of histamine.
이때, 상기 멜라토닌 유도체는 약학 조성물 총 100 중량부에 대하여, 0.1 내지 50 중량부로 포함될 수 있는 바, 상기 범위를 넘어서서 0.1 중량부 미만으로 포함되는 경우에는 멜라토닌 유도체의 항알러지 효과가 제대로 나타날 수 없고, 50 중량부를 초과하는 경우에는 멜라토닌 유도체의 함량 증가량 대비 항알러지 효과가 현저히 감소하게 되므로 바람직하지 않다.At this time, the melatonin derivative may be included in an amount of 0.1 to 50 parts by weight based on a total of 100 parts by weight of the pharmaceutical composition.When it is contained in an amount of less than 0.1 parts by weight beyond the above range, the anti-allergic effect of the melatonin derivative cannot be properly exhibited, If it exceeds 50 parts by weight, it is not preferable because the anti-allergic effect is significantly reduced compared to the amount of increase in the melatonin derivative.
상기 알러지 질환은 기관지 천식(asthma), 두드러기(urticaria), 아나필락시스(anaphylaxis), 음식물 알레르기(food allergy), 약 알레르기(drug allergy), 알레르기 비용혈성 수혈 반응, 아토피 피부염(atopic dermatitis). 알러지성 비염(allergic rhinitis), 알러지성 결막염, 알러지성 피부염, 알러지성 접촉성 피부염 및 담마진으로 이루어진 군에서 선택되는 하나 이상일 수 있으나 이에 제한되지는 않는다.The allergic diseases are bronchial asthma (asthma), urticaria (urticaria), anaphylaxis (anaphylaxis), food allergy (food allergy), drug allergy (drug allergy), allergic non-blood transfusion reaction, atopic dermatitis (atopic dermatitis). It may be one or more selected from the group consisting of allergic rhinitis, allergic conjunctivitis, allergic dermatitis, allergic contact dermatitis, and dammargin, but is not limited thereto.
또한, 본 발명은 하기 화학식 1 또는 화학식 2의 멜라토닌 유도체를 유효성분으로 포함하는 알러지 질환 예방 또는 개선용 건강식품을 제공한다.In addition, the present invention provides a health food for preventing or improving allergic diseases comprising the melatonin derivative of
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
또한, 하기 화학식 1 또는 화학식 2의 멜라토닌 유도체를 유효성분으로 포함하는 알러지 질환 예방 또는 개선용 화장료 조성물을 제공한다.In addition, it provides a cosmetic composition for preventing or improving allergic diseases comprising the melatonin derivative of the formula (1) or (2) as an active ingredient.
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
또한, 본 발명은 하기 화학식 1 또는 화학식 2의 멜라토닌 유도체를 유효성분으로 포함하는 암 질환 예방 또는 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer diseases comprising the melatonin derivative of the following formula (1) or formula (2) as an active ingredient.
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
본 발명의 또 다른 실시예에 따르면, 본 발명에 따른 멜라토닌 유도체를 폐암 또는 결장암 세포에 처리하였을 때, 상기 멜라토닌 유도체가 단백질인산화효소 B(AKT)와 세포외신호조절 인산화효소(Extracellular signal-regulated kinases, ERK)의 신호전달체계를 억제함으로써 상당한 항암 효과를 나타내었다. 따라서 본 발명에 따른 상기 멜라토닌 유도체는 우수한 치료 효과를 갖는 암 예방 또는 치료용 약학 조성물로 사용될 수 있다.According to another embodiment of the present invention, when the melatonin derivative according to the present invention is treated on lung or colon cancer cells, the melatonin derivative is protein kinase B (AKT) and extracellular signal-regulated kinases. , ERK) showed a significant anticancer effect by inhibiting the signaling system. Therefore, the melatonin derivative according to the present invention can be used as a pharmaceutical composition for preventing or treating cancer having an excellent therapeutic effect.
이때, 상기 멜라토닌 유도체는 약학 조성물 총 100 중량부에 대하여, 0.1 내지 50 중량부로 포함될 수 있는 바, 상기 범위를 벗어나게 되면 멜라토닌 유도체의 항암 효능이 제대로 나타나지 않거나, 함량 증가량 대비 치료 효능의 증가량이 미미하므로 바람직하지 않다.At this time, the melatonin derivative may be included in an amount of 0.1 to 50 parts by weight based on a total of 100 parts by weight of the pharmaceutical composition.If it is out of the above range, the anticancer effect of the melatonin derivative does not appear properly, or the amount of increase in the therapeutic effect relative to the amount of increase is insignificant Not desirable.
상기 암은 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강/부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 구강암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 직장암, 항문암, 방광암, 신장암, 남성생식기종양, 음경암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암 및 피부암으로 이루어진 군에서 선택된 하나 이상일 수 있으나 이에 제한되지는 않는다.The cancer is brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroma, endocranial tumor, episiocytoma, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal/sinus cancer, nasopharyngeal cancer, salivary gland Cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, Colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer And it may be one or more selected from the group consisting of skin cancer, but is not limited thereto.
또한, 본 발명은 하기 화학식 1 또는 화학식 2의 멜라토닌 유도체를 유효성분으로 포함하는 암 질환 예방 또는 개선용 건강식품을 제공한다.In addition, the present invention provides a health food for preventing or improving cancer diseases comprising the melatonin derivative of the following
[화학식 1][Formula 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,R 1 is at least one selected from the group consisting of hydrogen, (C2 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl,
[화학식 2][Formula 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.The R 2 is at least one selected from the group consisting of hydrogen, (C1 ~ C4) alkylcarbonyl, benzoyl (Benzoyl) and (C1 ~ C4) alkoxycarbonyl.
상기 약학 조성물은 통상적인 방법에 따라 겔제, 유제, 주사제, 산제, 과립제, 에어로솔제, 페이스트제, 경피흡수제 및 패치제로 이루어진 군에서 선택된 하나 이상의 제형으로 제공될 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition may be provided in one or more formulations selected from the group consisting of gels, emulsions, injections, powders, granules, aerosols, pastes, transdermal absorbers, and patches according to a conventional method, but is not limited thereto.
본 발명의 구체적인 실시예에서, 상기 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In a specific embodiment of the present invention, the pharmaceutical composition is a suitable carrier, excipient, disintegrant, sweetener, coating agent, swelling agent, lubricant, lubricant, flavoring agent, antioxidant, buffer solution, bacteriostatic agent commonly used in the manufacture of pharmaceutical compositions. , A diluent, a dispersant, a surfactant, a binder, and a lubricant may further include one or more additives selected from the group consisting of.
구체적으로, 담체, 부형제 및 희석제는 락토즈, 덱스트로즈, 수크로스, 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 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specifically, carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, undecided Vaginal cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil can be used, and solid preparations for oral administration include tablets, pills, powders, granules, Capsules and the like are included, and such solid preparations may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like in the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, etc.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as humectants, sweeteners, fragrances, and preservatives may be included. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like may be used. As a base material for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
상기 멜라토닌 유도체의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일 실시예에 따르면, 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The preferred dosage of the melatonin derivative may vary depending on the condition and weight of the subject, the type and extent of the disease, the form of the drug, the route and duration of administration, and may be appropriately selected by those skilled in the art. According to an embodiment of the present invention, although not limited thereto, the daily dosage may be 0.01 to 200 mg/kg, specifically 0.1 to 200 mg/kg, and more specifically 0.1 to 100 mg/kg. Administration may be administered once a day or may be divided into several doses, whereby the scope of the present invention is not limited.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the'subject' may be a mammal including a human, but is not limited to these examples.
상기 건강식품은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 건강식품은 유효성분인 멜라토닌 유도체 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다. The health food may be provided in the form of powder, granule, tablet, capsule, syrup or beverage, and the health food is used with other foods or food additives in addition to the melatonin derivative as an active ingredient, and is appropriately used according to a conventional method. I can. The mixing amount of the active ingredient may be appropriately determined according to the purpose of use, for example, prevention, health or therapeutic treatment.
상기 건강식품에 포함된 멜라토닌 유도체의 유효용량은 상기 약학조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the melatonin derivative contained in the health food may be used in accordance with the effective dose of the pharmaceutical composition, but in the case of long-term intake for the purpose of health and hygiene or health control, it may be less than the above range. , It is clear that the active ingredient can be used in an amount beyond the above range because there is no problem in terms of safety.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.There is no particular limitation on the kind of health food, for example, meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, Drinks, alcoholic beverages, and vitamin complexes.
상기 화장료 조성물은 피부 외용연고, 기초 화장품, 메이크업 화장품, 바디 화장품 또는 면도용 화장품 등의 용도로 제공될 수 있으며, 상기 기초 화장품의 예로는 에센스, 로션, 크림, 젤, 화장수, 팩, 마사지 크림, 유액 등이 있을 수 있고, 상기 메이크업 화장품의 예로는 파운데이션, 립스틱, 아이섀도, 아이라이너, 마스카라, 아이브로우 펜슬, 메이크업 베이스 등이 있을 수 있으며, 바디 화장품으로는 비누, 액체 세정제, 입욕제, 썬 스크린 크림, 썬 오일 등이 있을 수 있고, 면도용 화장품으로는 애프터셰이브로션, 셰이빙 크림 등이 있다.The cosmetic composition may be provided for use such as skin ointment, basic cosmetics, makeup cosmetics, body cosmetics or shaving cosmetics, and examples of the basic cosmetics include essences, lotions, creams, gels, lotions, packs, massage creams, There may be emulsions, and examples of the makeup cosmetics may include foundation, lipstick, eye shadow, eye liner, mascara, eyebrow pencil, and makeup base, and body cosmetics include soap, liquid detergent, bath agent, and sunscreen. There may be creams and sun oils, and shaving cosmetics include aftershave lotions and shaving creams.
또한, 상기 화장료 조성물은 멜라토닌 유도체 외에 추가로 기능성 물질이나 물성 개선을 위한 부형제, 희석제 등의 물질이 포함될 수 있다.In addition, the cosmetic composition may further include a functional substance, an excipient for improving physical properties, a diluent, etc. in addition to the melatonin derivative.
구체적으로, 상기 화장품 조성물에는 물성 개선을 위하여 향료, 색소, 살균제, 산화방지제, 방부제, 보습제, 점증제, 무기염류 또는 합성 고분자 물질 등이 추가로 첨가될 수 있다. 이외에 첨가해도 되는 배합 성분으로 유지 성분, 에몰리엔트제, 계면 활성제, 유기 안료, 무기 안료, 유기 분체, 자외선 흡수제, pH 조정제, 알코올, 혈행 촉진제, 냉감제, 제한제 또는 정제수 등일 수 있다.Specifically, fragrances, pigments, disinfectants, antioxidants, preservatives, moisturizers, thickeners, inorganic salts or synthetic polymer substances may be additionally added to the cosmetic composition in order to improve physical properties. In addition, as a blending component that may be added, it may be a fat or oil component, an emollient agent, a surfactant, an organic pigment, an inorganic pigment, an organic powder, an ultraviolet absorber, a pH adjuster, an alcohol, a blood circulation accelerator, a cooling agent, a limiting agent, or purified water.
상기 유효성분 이외의 첨가해도 되는 배합 성분은 한정되지 않으며, 상기 어느 성분도 본 발명의 목적 및 효과를 손상시키지 않는 범위 내에서 배합 가능하다.The ingredients that may be added other than the active ingredient are not limited, and any of the ingredients may be blended within a range that does not impair the object and effect of the present invention.
또한, 상기 화장품 조성물은 용액, 유화물, 점성형 혼합물 등의 형상을 취할 수 있으며, 당업계에서 통상적으로 제조되는 어떠한 제형일 수 있고 일 예로 스프레이, 유액, 크림, 화장수, 팩, 파운데이션, 로션, 미용액, 모발화장료 등의 제형일 수 있다.In addition, the cosmetic composition may take the shape of a solution, emulsion, viscous mixture, etc., and may be any formulation commonly manufactured in the art. For example, spray, emulsion, cream, lotion, pack, foundation, lotion, essence , It may be a formulation such as hair cosmetics.
보다 구체적으로 본 발명의 화장품 조성물은 스프레이, 비누, 클렌징폼, 클렌징로션, 클렌징크림, 바디로션, 바디클린저, 스킨로션, 스킨소프너, 스킨토너, 아스트리젠트, 로션, 밀크로션, 모이스쳐 로션, 영양로션, 맛사지 크림, 영양크림, 모이스처크림, 핸드크림, 파운데이션, 에센스, 영양에센스 및 팩의 제형을 포함할 수 있다.More specifically, the cosmetic composition of the present invention is spray, soap, cleansing foam, cleansing lotion, cleansing cream, body lotion, body cleanser, skin lotion, skin softener, skin toner, astrigent, lotion, milk lotion, moisture lotion, nutrition lotion , Massage cream, nutritional cream, moisture cream, hand cream, foundation, essence, nutritional essence, and may include the formulation of the pack.
예를 들어, 본 발명의 제형이 스프레이 또는 파우더인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있으며, 특히 본 발명의 제형이 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.For example, when the formulation of the present invention is a spray or powder, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and in particular, when the formulation of the present invention is a spray. May additionally contain propellants such as chlorofluorohydrocarbon, propane/butane or dimethyl ether.
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물섬유, 식물섬유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as a carrier component. I can.
본 발명의 제형이 용액 또는 유탁액의 경우에는 담체 성분으로서 용매, 용매화제, 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르일 수 있다.When the formulation of the present invention is a solution or emulsion, a solvent, a solvating agent, or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, 1,3 -It may be butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline Cellulose, aluminum metahydroxide, bentonite, agar or tracant, and the like may be used.
본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코 시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 리놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is a surfactant containing cleansing, as a carrier component, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linoline derivatives or ethoxylated glycerol fatty acid esters may be used.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니며, 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공하는 것이다.Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples, and is provided to more completely describe the present invention to those with average knowledge in the art. will be.
<실시예 1> 멜라토닌 준비 및 멜라토닌 유도체 합성<Example 1> Preparation of melatonin and synthesis of melatonin derivatives
도 1에 도시된 멜라토닌 유도체인 화합물들을 제조하기 위하여, 화합물 1을 Tokyo Chemical Industry/Japan에서 구입한 후, 하기 반응식 1을 따라 반응시켜 화합물 3 내지 5를 합성하였다. 또한 멜라토닌(화합물 2)을 Sigam Aldrich에서 구입하여 준비하였다.In order to prepare compounds which are melatonin derivatives shown in FIG. 1,
[반응식 1][Scheme 1]
1. 화합물 3 합성1. Synthesis of
상기 반응식 1을 따라, 화합물 1인 5-메톡시트립타민(5-Methoxytryptamine, 100 mg, 0.53 mmol)에 트리에틸아민(triethylamine)과 뷰틸클로라이드(butylchloride, 0.83 mL, 0.79 mmol)를 첨가하여 한 시간 동안 상온에서 반응시킨 후, 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(실리카 겔(silica gel), Hx : EtOAC = 1 : 1)로 정제하여 화합물 3 (121.5 mg, 88.1% 수율)을 얻었다. According to
1H-NMR(500 MHz, CDCl3) δ 7.26~7.24 (m, 1H), 7.02~7.00 (m, 2H), 6.86~6.85 (m, 1H), 3.84 (s, 3H), 3.60~3.56 (m, 2H), 2.93~2.91 (m, 2H), 2.09~2.06 (m, 2H,), 1.63~ 1.58 (m, 2H), 0.91~0.88 (m, 2H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.26~7.24 (m, 1H), 7.02~7.00 (m, 2H), 6.86~6.85 (m, 1H), 3.84 (s, 3H), 3.60~3.56 ( m, 2H), 2.93~2.91 (m, 2H), 2.09~2.06 (m, 2H,), 1.63~ 1.58 (m, 2H), 0.91~0.88 (m, 2H) ppm.
2. 화합물 4 합성2. Synthesis of
상기 반응식 1을 따라, 화합물 1인 5-메톡시트립타민(5-Methoxytryptamine, 100 mg, 0.53 mmol)에 트리에틸아민(triethylamine)과 벤조일클로라이드(benzoylchloride, 0.92 mL, 0.79 mmol)를 첨가하여 한 시간 동안 상온에서 반응시킨 후 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, Hx : EtOAC = 1 : 1)로 정제하여 화합물 4 (111.6 mg, 73% 수율)를 얻었다. Following
1H-NMR(500 MHz, CDCl3) δ 7.87~7.86 (m, 2H), 7.67~7.64 (m, 1H), 7.59~7.56 (m, 2H), 7.47~7.45 (m, 1H), 7.25 (m, 1H), 7.08~7.05 (m, 1H), 6.49~6.47 (s, 1H), 4.01~3.98 (m, 2H), 3.97 (s, 3H), 3.27~3.25 (m, 2H,) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.87~7.86 (m, 2H), 7.67~7.64 (m, 1H), 7.59~7.56 (m, 2H), 7.47~7.45 (m, 1H), 7.25 ( m, 1H), 7.08~7.05 (m, 1H), 6.49~6.47 (s, 1H), 4.01~3.98 (m, 2H), 3.97 (s, 3H), 3.27~3.25 (m, 2H,) ppm.
3. 화합물 5 합성3. Synthesis of
상기 반응식 1을 따라, 화합물 1인 5-메톡시트립타민(5-Methoxytryptamine, 100 mg, 0.53 mmol)에 트리에틸아민(triethylamine)과 디-터트-뷰틸 디카보네이트(di-tert-butyl dicarbonate, 172 mg, 0.79 mmol)를 첨가하여 한 시간 동안 상온에서 반응시킨 후, 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, Hx : EtOAC = 1 : 1)로 정제하여 화합물 5(142.9 mg, 93% 수율)를 얻었다.According to
1H-NMR (500 MHz, CDCl3) δ 7.24~7.22 (m, 1H), 6.86~6.85 (m, 2H), 6.84 (m, 1H), 3.85 (s, 3H), 3.45~3.44 (m, 2H), 2.91~2.89 (m, 2H), 1.42 (s, 9H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.24~7.22 (m, 1H), 6.86~6.85 (m, 2H), 6.84 (m, 1H), 3.85 (s, 3H), 3.45~3.44 (m, 2H), 2.91-2.89 (m, 2H), 1.42 (s, 9H) ppm.
4. 화합물 6 합성4. Synthesis of
화합물 6은 이미 알려진 문헌(G. Spadoni 외 11명, J. Pineal Res. 2006, 40, 259269.)을 따라 합성하였고, 이를 기반으로 하기 반응식 2를 따라서 화합물 7 내지 10을 합성하였다.
[반응식 2][Scheme 2]
4. 화합물 7 합성4. Synthesis of
상기 반응식 2를 따라, 상기 화합물 6(100 mg, 0.53 mmol)에 트리에틸아민(triethylamine), 아세틸클로라이드(acetylchloride, 0.56 mL, 0.79 mmol)을 첨가하여 한 시간 동안 상온에서 반응시킨 후, 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, Hx : EtOAC = 1 : 1)로 정제하여 화합물 7(95.4 mg, 77.5% 수율)을 얻었다.Following
1H-NMR (500 MHz, CDCl3) δ 7.21~7.19 (m, 1H), 7.00~6.99 (m, 1H), 6.99~6.97 (m, 1H), 6.19 (s, 1H), 3.82 (s, 3H), 3.60~3.56 (m, 2H), 2.96~2.94 (m, 2H), 1.93 (s, 3H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.21~7.19 (m, 1H), 7.00~6.99 (m, 1H), 6.99~6.97 (m, 1H), 6.19 (s, 1H), 3.82 (s, 3H), 3.60~3.56 (m, 2H), 2.96~2.94 (m, 2H), 1.93 (s, 3H) ppm.
5. 화합물 8 합성5. Synthesis of
상기 반응식 2를 따라, 상기 화합물 6(100 mg, 0.53 mmol)에 트리에틸아민(triethylamine), 뷰틸 클로라이드(butylchloride, 0.83 mL, 0.79 mmol)을 첨가하여 한 시간 동안 상온에서 반응시킨 후 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, Hx : EtOAC = 1 : 1)로 정제하여 화합물 8(99.3 mg, 72% 수율)을 얻었다.Following
1H-NMR (500 MHz, CDCl3) δ 7.20~7.18 (m, 1H), 6.99 (m, 1H), 6.78~6.77 (m, 1H), 6.18 (s, 1H), 3.82 (s, 3H), 3.61~3.57 (m, 2H), 2.96~2.93 (m, 2H), 2.11~2.08 (m, 2H), 1.64~1.57 (m, 2H), 0.90~0.87 (m, 3H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.20~7.18 (m, 1H), 6.99 (m, 1H), 6.78~6.77 (m, 1H), 6.18 (s, 1H), 3.82 (s, 3H) , 3.61~3.57 (m, 2H), 2.96~2.93 (m, 2H), 2.11~2.08 (m, 2H), 1.64~1.57 (m, 2H), 0.90~0.87 (m, 3H) ppm.
6. 화합물 9 합성6. Synthesis of
상기 반응식 2를 따라, 상기 화합물 6(100 mg, 0.53 mmol)에 트리에틸아민(triethylamine), 벤조일클로라이드(benzoylchloride, 0.92 mL, 0.79 mmol)을 첨가하여 한 시간 동안 상온에서 반응시킨 후, 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, Hx : EtOAC = 1 : 1)로 정제하여 화합물 9(138.5 mg, 87 % 수율)를 얻었다.Following
1H-NMR (500 MHz, CDCl3) δ 7.69~7.67 (m, 2H), 7.48~7.46 (m, 1H), 7.40~7.37 (m, 2H), 7.20~7.19 (m, 1H), 7.00 (m, 1H), 6.79~6.77 (m, 1H), 6.24 (s, 1H), 3.82 (s, 3H), 3.80~3.77 (m, 2H), 3.08~3.05 (m, 2H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.69~7.67 (m, 2H), 7.48~7.46 (m, 1H), 7.40~7.37 (m, 2H), 7.20~7.19 (m, 1H), 7.00 ( m, 1H), 6.79~6.77 (m, 1H), 6.24 (s, 1H), 3.82 (s, 3H), 3.80~3.77 (m, 2H), 3.08~3.05 (m, 2H) ppm.
7. 화합물 10 합성7. Synthesis of
상기 반응식 2를 따라, 상기 화합물 6(100 mg, 0.53 mmol)에 트리에틸아민(triethylamine), 디-터트-뷰틸 디카보네이트(di-tert-butyl dicarbonate, 172 mg, 0.79 mmol)를 첨가하여 한 시간 동안 상온에서 반응시킨 후, 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, Hx : EtOAC = 1 : 1)로 정제하여 화합물 10(131 mg, 85 % 수율)을 얻었다.According to
1H-NMR (500 MHz, CDCl3) δ 7.19~7.14 (m, 1H), 7.00 (m, 1H), 6.78~6.76 (m, 1H), 6.19 (s, 1H), 3.82 (s, 3H), 3.47~3.45 (m, 2H), 2.94~2.92 (m, 2H), 1.41 (s, 9H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.19~7.14 (m, 1H), 7.00 (m, 1H), 6.78~6.76 (m, 1H), 6.19 (s, 1H), 3.82 (s, 3H) , 3.47-3.45 (m, 2H), 2.94-2.92 (m, 2H), 1.41 (s, 9H) ppm.
8. 대조 화합물 합성8. Synthesis of control compounds
하기 반응식 3을 따라서 대조 화합물인 MB-2 및 MB-3을 합성하였다.Control compounds MB-2 and MB-3 were synthesized according to
[반응식 3][Scheme 3]
8-1) 화합물 MB-2 합성8-1) Synthesis of compound MB-2
상기 반응식 3을 따라, 상기 화합물 2(157 mg, 0.67 mmol)에 테트라하이드로퓨란(tetrahydrofuran, THF, 5 mL) 및 리튬 알루미늄 수소화물(lithium aluminium hydride, 1.4 mL, 1.35 mmol)을 첨가하고 한 시간 동안 가열하면서 교반하여 반응시킨 뒤, 물(2.5 mL)을 첨가하여 반응을 종결시켰다. 이를 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, 디클로로메탄(CH2Cl2) : 메탄올(MeOH) = 9 : 1 (1% 암모니아(NH3OH)))로 정제하여 흰색 고체의 MB-2(89.7 mg, 61 % 수율)를 얻었다.Following
1H-NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 7.21 (s, 1H) 7.06 (m, 1H) 7.01 (m, 1H), 6.81~6.79 (m, 1H), 3.26~3.23 (m, 2H), 3.14~3.11 (m, 2H), 2.98~ 2.93 (m, 2H), 1.36~1.33 (m, 3H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.22 (s, 1H), 7.21 (s, 1H) 7.06 (m, 1H) 7.01 (m, 1H), 6.81~6.79 (m, 1H), 3.26~3.23 (m, 2H), 3.14~3.11 (m, 2H), 2.98~ 2.93 (m, 2H), 1.36~1.33 (m, 3H) ppm.
8-2) 화합물 MB-3 합성8-2) Synthesis of compound MB-3
상기 반응식 3을 따라, 상기 화합물 3(386 mg, 1.48 mmol)에 테트라하이드로퓨란(tetrahydrofuran, THF, 5 mL) 및 리튬 알루미늄 수소화물(lithium aluminium hydride, 1.4 mL, 2.94 mmol)을 첨가하여 한 시간 동안 가열하면서 교반하여 반응시킨 뒤 물(2.5 mL)을 첨가하여 반응을 종결시켰다. 이를 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, CH2Cl2 : MeOH = 9 : 1 (1% NH3OH))로 정제하여 흰색 고체의 MB-3(231.4 mg, 63.4% 수율)를 얻었다.Following
1H-NMR (500 MHz, CDCl3) δ 7.18 (s, 1H), 7.24~7.20 (m, 2H), 7.04~6.75 (m, 1H), 6.85 (s, 1H), 6.75~6.73(m, 1H), 3.73(s, 1H), 3.12~3.11(m, 2H), 2.98~2.95(m, 2H), 2.70~2.67(m, 2H), 1.63~1.56(m, 2H), 1.24~1.20(m, 4H), 0.79~0.76(m, 3H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.18 (s, 1H), 7.24~7.20 (m, 2H), 7.04~6.75 (m, 1H), 6.85 (s, 1H), 6.75~6.73(m, 1H), 3.73(s, 1H), 3.12~3.11(m, 2H), 2.98~2.95(m, 2H), 2.70~2.67(m, 2H), 1.63~1.56(m, 2H), 1.24~1.20( m, 4H), 0.79 to 0.76 (m, 3H) ppm.
더불어 하기 반응식 4를 따라서 대조 화합물인 MLB-2 및 MLB-3을 합성하였다.In addition, control compounds MLB-2 and MLB-3 were synthesized according to
[반응식 4][Scheme 4]
8-3) 화합물 MLB-2 합성8-3) Synthesis of compound MLB-2
상기 반응식 4를 따라, 상기 화합물 7(150 mg, 0.64 mmol)에 테트라하이드로퓨란(tetrahydrofuran, THF, 5 mL) 및 리튬 알루미늄 수소화물(lithium aluminium hydride, 1.3 mL, 1.29 mmol)을 첨가하여 한 시간 동안 가열하면서 교반하여 반응시킨 뒤 물(2.5 mL)을 첨가하여 반응을 종결시켰다. 이를 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, CH2Cl2 : MeOH = 9 : 1 (1% NH3OH))로 정제하여 갈색 고체의 MLB-2(84 mg, 60 % 수율)를 얻었다.Following
1H-NMR (500 MHz, CDCl3) δ 7.24~7.19 (m, 2H), 7.04 (s, 1H), 6.93 (s, 1H), 6.77~6.75 (m, 1H), 3.75 (s, 3H), 3.20~3.18 (m, 2H), 3.08~3.07 (m, 2H), 2.91~2.90(m, 2H), 1.32~1.30 (m, 3H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.24~7.19 (m, 2H), 7.04 (s, 1H), 6.93 (s, 1H), 6.77~6.75 (m, 1H), 3.75 (s, 3H) , 3.20-3.18 (m, 2H), 3.08-3.07 (m, 2H), 2.91-2.90 (m, 2H), 1.32-1.30 (m, 3H) ppm.
8-4) 화합물 MLB-3 합성8-4) Synthesis of compound MLB-3
상기 반응식 4를 따라, 상기 화합물 8(200 mg, 0.76 mmol)에 테트라하이드로퓨란(tetrahydrofuran, THF, 5 mL) 및 리튬 알루미늄 수소화물(lithium aluminium hydride, 1.5 mL, 1.52 mmol)을 첨가하여 한 시간 동안 가열하면서 교반하여 반응시킨 뒤 물(2.5 mL)을 첨가하여 반응을 종결시켰다. 이를 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, CH2Cl2 : MeOH = 9 : 1 (1% NH3OH))로 정제하여 갈색 고체의 MLB-3(109.9 mg, 63.4% 수율)를 얻었다.Following
1H-NMR (500 MHz, CDCl3) δ 7.23 (s, 1H), 7.10~7.09 (m, 1H), 7.04 (s, 1H), 3.81 (s, 3H), 3.34~3.32 (m, 2H), 3.21~3.17 (m, 2H), 2.93~2.89 (m, 2H), 1.34~1.30 (m, 4H), 0.85~0.82 (m, 3H) ppm. 1 H-NMR (500 MHz, CDCl 3 ) δ 7.23 (s, 1H), 7.10~7.09 (m, 1H), 7.04 (s, 1H), 3.81 (s, 3H), 3.34~3.32 (m, 2H) , 3.21~3.17 (m, 2H), 2.93~2.89 (m, 2H), 1.34~1.30 (m, 4H), 0.85~0.82 (m, 3H) ppm.
8-5) 화합물 MC-1 합성8-5) Synthesis of compound MC-1
[반응식 5][Scheme 5]
상기 반응식 5을 따라, 화합물 1인 5-메톡시트립타민(5-Methoxytryptamine, 500 mg, 2.63 mmol)에 N-카보벤조일옥시글리신(N-carbobenzoxyglycine, 1.1 g, 5.3 mmol), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, EDCI, 1.0 g, 5.3 mmol), 트리에틸아민(triethylamine, 364.3 μl, 2.6 mmol), 4-디메틸아미노피리딘(4-dimethylaminopyridine, DMAP, 32.1 mg, 0.26 mmol) 및 디클로로메탄(dichloromethane, 13 mL)을 첨가하고 상온에서 30분간 반응시켰다. 그 후 이를 아세트산에틸(ethyl acetate)과 브라인(brine)으로 추출하고 무수 MgSO4로 건조 및 여과하였다. 여과물을 농축하고 컬럼 크로마로그래피(silica gel, Hx : EtOAC = 1 : 1)로 정제하여 갈색 고체의 화합물 11(901 mg, 90% 수율)을 얻었다.According to
상기 화합물 11(300 mg, 0.79 mmol)과 Pd(OH)2/C(11.1 mg, 0.08 mmol)을 혼합하고, 메탄올(2.6 mL)과 수소(H2)를 주입하였다. 2시간 후 진공 여과 깔대기에 셀라이트(Cellite)를 충진하고 MeOH(100 mL)로 감압 여과하였다. 여과물을 진공 조건하에 농축한 후 디클로로메탄(5 mL)과 메탄올(1 mL), 아세틸클로라이드(1 mL)을 교반하여 제조한 염화수소(hydrogen chloride, 1 mL)을 천천히 주입하였다. 그런 후 이를 아세트산에틸(100 mL)로 한 번 더 감압 여과하여 흰색 고체의 MC-1(189.4 mg, 97% 수율)를 얻었다. The compound 11 (300 mg, 0.79 mmol) and Pd(OH) 2 / C (11.1 mg, 0.08 mmol) were mixed, and methanol (2.6 mL) and hydrogen (H 2 ) were injected. After 2 hours, Celite was filled in a vacuum filtration funnel, and filtered under reduced pressure with MeOH (100 mL). After the filtrate was concentrated under vacuum conditions, hydrogen chloride (1 mL) prepared by stirring dichloromethane (5 mL), methanol (1 mL), and acetyl chloride (1 mL) was slowly injected. Then, it was filtered under reduced pressure with ethyl acetate (100 mL) once more to obtain MC-1 (189.4 mg, 97% yield) as a white solid.
<실시예 2> 멜라토닌 및 멜라토닌 유도체의 항염증 효과 확인<Example 2> Confirmation of anti-inflammatory effects of melatonin and melatonin derivatives
상기 멜라토닌 및 실시예 1에서 합성한 멜라토닌 유도체의 항염증 효과를 확인하기 위하여, 먼저 Raw 264.7 세포를 한국 세포주 은행(Korean Cell Line Bank; KCLB)에서 얻어 10% 태아소혈청(Fetal bovine serum, FBS, Gibco BRL), 페니실린 100 U/ml / 스트렙토마이신 100 μg/ml)이 포함된 배지(Dulbecco's Modified Eagle's, DMEM, Gibco BRL)에 배양하였다. 지질다당류(Lipopolysaccharide, LPS) 및 그리스(Griess) 시약은 시그마(Sigma-Aldrich)에서 구입하여 사용하였다. 1 μg/mL LPS 존재하에 Raw 264.7 세포를 시약 처리군과 비처리군으로 분리하여 처리군에는 상기 멜라토닌 및 실시예 1에서 합성한 멜라토닌 유도체를 24시간 동안 처리하여 염증모델을 준비하였다. In order to confirm the anti-inflammatory effect of the melatonin and the melatonin derivative synthesized in Example 1, Raw 264.7 cells were first obtained from Korean Cell Line Bank (KCLB) and 10% fetal bovine serum (FBS, Gibco BRL), penicillin 100 U / ml /
1. NO 생성 억제 효과 및 세포 독성 확인1. Confirmation of NO production inhibitory effect and cytotoxicity
상기에서 준비한 염증모델에 상기 실시예 1에서 준비한 멜라토닌 및 멜라토닌 유도체를 농도별로 처리하고 배양 배지 내 아질산염(nitrite) 양을 그리스(Griess) 시약을 이용하여 540 nm 흡광도에서 측정하여 항염증 효과를 확인하였다. 산화질소(NO) 생성 분석은 이미 공지되어 있는 방법(Hwang, S.J., Y.W. Kim, Y. Park, H.J. Lee, K.W. Kim. 2014 Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells. Inflammation research 63:81-90.)으로 수행하였다.In the inflammation model prepared above, the melatonin and melatonin derivatives prepared in Example 1 were treated by concentration, and the amount of nitrite in the culture medium was measured at 540 nm absorbance using a Grease reagent to confirm the anti-inflammatory effect. . The analysis of nitric oxide (NO) production is a known method (Hwang, SJ, YW Kim, Y. Park, HJ Lee, KW Kim. 2014 Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells.Inflammation research 63 :81-90.).
그 결과 도 2와 같이, 도 1의 화합물 2인 멜라토닌을 제외한 모든 멜라토닌 유도체들은 기존 멜라토닌보다 농도 의존적으로 NO의 생성을 억제하는 효과가 뛰어났다.As a result, as shown in FIG. 2, all melatonin derivatives except for melatonin, which is
또한 멜라토닌 유도체의 NO 생성 억제 효과가 세포 독성에 의한 것인지 확인하기 위해, 세포생존율을 확인하였다. 이미 공지되어 있는 방법(Hwang, S.J., Y.W. Kim, Y. Park, H.J. Lee, K.W. Kim. 2014 Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells. Inflammation research 63:81-90.)으로 세포 생존율 분석을 수행하였다. Raw 264.7 세포에 각 실험에 바람직한 양의 멜라토닌 유도체를 처리하고 24시간 후 20 μl 세포역가 96 수용성 원 용액 시약(celltiter 96 Aqueous One Solution Reagent, Promega, Madison, WI)을 첨가하여 490 nm 흡광도에서 세포 생존율을 측정하였다. 그 결과, 멜라토닌 유도체 4, 5, 6, 8, 9 및 10번의 세포독성이 관찰되었다. 따라서 멜라토닌 유도체 1, 3, 7번이 세포독성 없이 NO 생성 억제 효과를 나타내는 것으로 확인되었다.In addition, in order to confirm whether the NO production inhibitory effect of the melatonin derivative is due to cytotoxicity, cell viability was confirmed. Cells by a known method (Hwang, SJ, YW Kim, Y. Park, HJ Lee, KW Kim. 2014 Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells.Inflammation research 63:81-90.) Viability analysis was performed. Cell viability at 490 nm absorbance by adding 20 μl cell titer 96 Aqueous One Solution Reagent (celltiter 96 Aqueous One Solution Reagent, Promega, Madison, WI) 24 hours after treating Raw 264.7 cells with the desired amount of melatonin derivative for each experiment. Was measured. As a result, cytotoxicity of
2. 염증인자 억제 효과 확인2. Confirmation of inhibitory effect on inflammatory factors
상기 실시예 2에서 준비한 염증 모델에 멜라토닌 유도체 1, 3 또는 7을 처리한 후, 염증성 싸이토카인인 단구주화성 단백질-1(monocyte chemoattractant protein-1, MCP-1), IL-6, IL-1β, COX-2 및 TNF-α의 발현을 RT-PCR로 확인하였다.After treatment with
RT-PCR 분석을 이미 공지되어 있는 방법(Hwang, S.J., Y.W. Kim, Y. Park, H.J. Lee, K.W. Kim. 2014 Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells. Inflammation research 63:81-90.)으로 수행하였다. 본 발명에서 사용된 PCR 프라이머는 하기 표 1과 같으며, 바이오니아(Bioneer)에서 구입하였다.RT-PCR analysis is a known method (Hwang, SJ, YW Kim, Y. Park, HJ Lee, KW Kim. 2014 Anti-inflammatory effects of chlorogenic acid in lipopolysaccharide-stimulated RAW 264.7 cells.Inflammation research 63:81- 90.). The PCR primers used in the present invention are shown in Table 1 below, and were purchased from Bioneer.
PCR 증폭 확인을 위해서, β-액틴을 내부 대조군으로 사용하여 PCR 산물을 1.5% 아가로스 겔에 분리시킨 후 레드세이프 핵산 염색(RedSafe nucleic acid staining, Intron, Korea)으로 시각화하고 UV를 조사하여 확인하였다.To confirm PCR amplification, the PCR product was separated on a 1.5% agarose gel using β-actin as an internal control, visualized with RedSafe nucleic acid staining (Intron, Korea) and confirmed by UV irradiation. .
그 결과, 도 3에 도시된 같이, MCP-1, IL-6, COX-2, TNF-α의 발현이 크게 저하된 것으로 나타났다. 따라서 본 발명에 따른 멜라토닌 유도체들은 멜라토닌에 비해 탁월한 항염효과를 나타내는 것을 확인하였다.As a result, as shown in Figure 3, it was found that the expression of MCP-1, IL-6, COX-2, TNF-α significantly decreased. Therefore, it was confirmed that the melatonin derivatives according to the present invention exhibit excellent anti-inflammatory effects compared to melatonin.
<실시예 3> 비만 세포에서 Compound 48/80으로 유도된 히스타민 분비 억제효과 확인<Example 3> Confirmation of histamine secretion inhibitory effect induced by Compound 48/80 in mast cells
상기 멜라토닌 유도체의 히스타민에 대한 억제 효과를 알아보기 위하여, 먼저 전북대학교 의과대학 면역학교실에서 사람 비만세포주 HMC-1를 분양받았으며, 10% 태아우혈청(fetal bovine serum, FBS)과 1% 페니실린/스트렙토마이신(penicillin/streptomycin)이 함유된 IMEM(Iscove's Modified Dulbecco's Media)을 배양액으로 하여 37℃와 5% CO₂조건에서 배양하였다.In order to investigate the inhibitory effect of the melatonin derivative on histamine, the human mast cell line HMC-1 was first distributed in the Department of Immunology, Chonbuk National University College of Medicine, and 10% fetal bovine serum (FBS) and 1% penicillin/strepto. IMEM (Iscove's Modified Dulbecco's Media) containing mycin (penicillin/streptomycin) was used as a culture medium and cultured at 37°C and 5% CO₂.
이렇게 배양된 HMC-1 3×106개에 상기 실시예 1에서 준비한 멜라토닌 및 멜라토닌 유도체를 처리하여 37℃에서 30분 동안 배양한 다음, Compound 48/80을 300 μg/ml만큼 첨가하여 20분 동안 반응시켰다. Compound 48/80을 처리한 세포는 가볍게 원심 분리하여 상층액을 수거하였고, 상층액에 포함된 히스타민은 O-프탈알데하이드(O-phthaladehyde, OPT)와 반응시킨 후 측정하였다. The melatonin and melatonin derivatives prepared in Example 1 were treated with 3×10 6 HMC-1s thus cultured, incubated at 37°C for 30 minutes, and then Compound 48/80 was added by 300 μg/ml for 20 minutes. Reacted. The cells treated with Compound 48/80 were lightly centrifuged to collect the supernatant, and the histamine contained in the supernatant was measured after reacting with O-phthaladehyde (OPT).
즉, 상층액 속에 포함된 히스타민(histamine)의 양을 측정하기 위해 상층액 500 μl에 0.5N 과염소산(HClO4) 2ml을 넣고 혼합한 후 12,000 rpm에서 20분간 원심분리하였다. 원심 분리한 상층액 2 ml에 6N 수산화나트륨(NaOH) 0.2 ml, 부탄올-클로로포름(buthanol-chloroform (3:2)) 3.3 ml와 염화나트륨(NaCl)을 넣고 3,000 rpm에서 10분간 다시 원심 분리했다. 이후 원심 분리한 상층액의 윗층 3 ml에 n-헵탄(n-heptane) 3 ml와 0.1N 염화수소(HCl) 1.2 ml을 넣고 혼합한 후 100℃에서 10분간 끓인 다음 3,000 rpm에서 5분 간 원심 분리하여 아래층을 파스퇴르 피펫으로 수거하였다. 수거한 용액에 0.1N HCl 1 ml과 1N NaOH 0.3 ml, 0.2% OPT 0.2 ml 넣고 냉암소에서 45분 간 반응시킨 다음, 0.5N 황산(H2SO4) 0.28 ml을 넣어 반응을 종결 시킨 뒤 형광광도 측정기(Spectrofluorophotometer, Shimadzu, Japan)로 여기(excitation) 350 nm, 방출(emission) 440 nm에서 석영 큐벳을 사용하여 형광량을 측정하였다.That is, in order to measure the amount of histamine contained in the supernatant , 2 ml of 0.5N perchloric acid (HClO 4 ) was added to 500 μl of the supernatant, mixed, and centrifuged at 12,000 rpm for 20 minutes. To 2 ml of the centrifuged supernatant, 0.2 ml of 6N sodium hydroxide (NaOH), 3.3 ml of buthanol-chloroform (3:2), and sodium chloride (NaCl) were added, followed by centrifugation at 3,000 rpm for 10 minutes. Thereafter, 3 ml of n-heptane and 1.2 ml of 0.1N hydrogen chloride (HCl) were added to the upper 3 ml of the centrifuged supernatant, mixed, boiled at 100°C for 10 minutes, and then centrifuged at 3,000 rpm for 5 minutes. The lower layer was collected with a Pasteur pipette. Add 1 ml of 0.1N HCl, 0.3 ml of 1N NaOH, and 0.2 ml of 0.2% OPT to the collected solution, react in a cool and dark place for 45 minutes, and then add 0.28 ml of 0.5N sulfuric acid (H 2 SO 4 ) to terminate the reaction, and then fluorescence. The amount of fluorescence was measured using a quartz cuvette at excitation 350 nm and emission 440 nm with a photometer (Spectrofluorophotometer, Shimadzu, Japan).
그 결과, 도 4에 나타나 있는 바와 같이 멜라토닌 유도체 1, 3, 7번의 히스타민 억제 효과가 관찰되었고, 특히 멜라토닌 유도체 7번의 경우 멜라토닌보다 우월한 히스타민 억제 효과를 나타내는 것을 확인하였다. As a result, as shown in FIG. 4, the histamine inhibitory effect of
<실시예 4> 멜라토닌 및 멜라토닌 유도체의 항암 효과 확인<Example 4> Confirmation of anticancer effect of melatonin and melatonin derivatives
1. 시험관 내에서 대장암 세포주인 HCT116에서 항암 효과 확인1. Confirmation of anticancer effect in HCT116, a colon cancer cell line, in vitro
상기 실시예 1에서 준비한 멜라토닌 및 멜라토닌 유도체의 HCT-116 대장암 세포주에 대한 항암효과를 검증하기 위하여 티아졸일 블루 테트라졸리움 브로마이드(Thiazolyl Blue Tetrazolium Bromide, MTT) 분석법으로 세포 생존율을 측정하였으며, 이를 위해 공지된 문헌(Lee H-Y et al., (2013) Cancer Lett. 332:102-109)에 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다. 대장암 세포주 HCT-116은 한국 세포주 은행에서 분양받았다. HCT-116 세포는 열에 의해 불활성화 된 10% 소태아혈청 (Fetal Bovine Serum, FBS), 100 units/mL 페니실린(penicillin), 100 μg/mL 스트렙토마이신(streptomycin)과 250 ng/mL 암포테리신 B(amphotericin B)가 포함되어 있는 RPMI 1640 배지를 이용하여 37℃, 5% 이산화탄소(CO2)조건에서 1주일에 1 내지 2회 계대 배양하였다. 모든 세포는 액체질소로부터 녹인 다음 3회 이상 계대를 거치고 나서 실험에 이용하였다. In order to verify the anticancer effect of the melatonin and melatonin derivatives prepared in Example 1 on the HCT-116 colorectal cancer cell line, the cell viability was measured by the Thiazolyl Blue Tetrazolium Bromide (MTT) assay, and known for this purpose. The experiment was performed as follows by applying the method described in the document (Lee HY et al., (2013) Cancer Lett. 332:102-109). The colorectal cancer cell line HCT-116 was purchased from the Korean Cell Line Bank. HCT-116 cells were heat-inactivated 10% fetal bovine serum (FBS), 100 units/mL penicillin, 100 μg/mL streptomycin and 250 ng/mL amphotericin B. Using RPMI 1640 medium containing (amphotericin B), it was subcultured 1 to 2 times a week at 37° C. and 5% carbon dioxide (CO 2 ). All cells were dissolved in liquid nitrogen, passed through three or more passages, and used in the experiment.
상기 대장암 세포주를 96-웰 플레이트의 각 웰에 200 ㎕씩(2 x 104cells/ml) 분주하여 하루 동안 배양하였다. 다음날 디메틸설폭시화물(Dimethyl sulfoxide, DMSO)에 멜라토닌 및 멜라토닌 유도체를 0.125 mM 내지 2 mM의 농도로 첨가하고 3일간 배양하였다. 단, DMSO는 배지의 10%가 넘지 않도록 사용하였다. 시료 없이 DMSO만 처리한 군을 음성대조군(zero-day control)으로 사용하였다. 배양한 세포에 5 mg/ml의 MTT 용액 20 μl를 처리하고 추가로 4시간 배양하였고, 이후 배지를 제거하고 인산완충식염수(phosphate buffered saline, PBS)로 불순물을 제거한 다음 DMSO 200 μl를 가하였다. 15분 동안 교반기에서 교반한 다음 590 nm에서 흡광도를 측정하였다. 10% DMSO에서 배양한 경우를 대조군으로 하여 각 시험 물질처리에 따른 세포 생존율을 하기 수학식 1을 이용하여 측정하였다.The colon cancer cell line was dispensed into each well of a 96-well plate by 200 µl (2 x 10 4 cells/ml) and cultured for one day. The next day, melatonin and a melatonin derivative were added to dimethyl sulfoxide (DMSO) at a concentration of 0.125 mM to 2 mM, and cultured for 3 days. However, DMSO was used so as not to exceed 10% of the medium. The group treated with only DMSO without a sample was used as a negative control (zero-day control). The cultured cells were treated with 20 μl of 5 mg/ml MTT solution and cultured for an additional 4 hours, after which the medium was removed, impurities were removed with phosphate buffered saline (PBS), and then 200 μl of DMSO was added. After stirring in a stirrer for 15 minutes, the absorbance was measured at 590 nm. When cultured in 10% DMSO was used as a control, the cell viability according to the treatment of each test substance was measured using
[수학식 1][Equation 1]
% 생존율 = (OD(시료) - OD(0-day))/ (OD(10% DMSO) - OD(0-day)) X 100 % Survival rate = (OD(sample)-OD(0-day))/ (OD(10% DMSO)-OD(0-day))
시료를 처리하지 않은 대조군을 100%로 하였을 때, 시료 처리군의 값을 대조군에 대한 백분율로 나타내었으며, 각 시험물질 처리는 이중 혹은 삼중 시험의 평균값 ± SEM으로 구하였다. IC50값은 50% 생존율에 대한 시험 물질의 농도이다. When 100% of the control group was not treated with the sample, the value of the sample treatment group was expressed as a percentage of the control group, and each test substance treatment was calculated as the mean value ± SEM of the double or triple test. The IC 50 value is the concentration of the test substance for 50% survival.
그 결과, 도 5와 같이 멜라토닌 유도체 7, MB-2, MC-1을 제외하고 모두 기존의 멜라토닌보다 더 뛰어난 항암 효과를 보였다. 특히 1 mM 이하의 저농도에서도 상당한 항암활성을 나타내었으며 그 중 10번 유도체가 상당한 항암 활성을 나타내었다. As a result, as shown in FIG. 5, except for
2. 자궁경부암, 유방암, 폐암, 대장암 세포주에 대한 항암 효과 확인2. Confirmation of anticancer effect on cervical cancer, breast cancer, lung cancer, and colon cancer cell lines
상기 실시예에서 확인한 멜라토닌 10번 유도체에 대하여 인간 자궁경부암, 유방암, 폐암 및 대장암 세포주에 대한 항암 효과를 상기 실시예 4 중 1의 MTT (Thiazolyl Blue Tetrazolium Bromide) 분석법으로 확인하였다. 인간 자궁암 세포주 HeLa, 폐암 세포주 A549와 유방암 세포주 MDA-MB-231은 미국 세포주 은행 (ATCC, Manassas, VA, USA)에서 분양 받았다. HCT116, HeLa, A549 및 MDA-MB-231 세포는 열에 의해 불활성화된 10% 소태아혈청(Fetal Bovine Serum, FBS), 100 units/mL 페니실린(penicillin), 100 μg/mL 스트렙토마이신(streptomycin)과 250 ng/mL 암포테리신 B(amphotericin B)가 포함되어 있는 RPMI 1640 배지를 이용하여 37℃, 5% CO2 조건에서 1주일에 1회 내지 2회 계대 배양하였다. 모든 세포는 액체질소로부터 녹인 다음 3회 이상 계대를 거치고 나서 실험에 이용하였다. The anticancer effect on human cervical cancer, breast cancer, lung cancer, and colon cancer cell lines with respect to the melatonin derivative No. 10 identified in the above Example was confirmed by the MTT (Thiazolyl Blue Tetrazolium Bromide) analysis method of Example 4 above. Human cervical cancer cell line HeLa, lung cancer cell line A549 and breast cancer cell line MDA-MB-231 were pre-sale from the American cell line bank (ATCC, Manassas, VA, USA). HCT116, HeLa, A549 and MDA-MB-231 cells were thermally inactivated with 10% Fetal Bovine Serum (FBS), 100 units/mL penicillin, 100 μg/mL streptomycin and Using RPMI 1640 medium containing 250 ng/mL amphotericin B, it was subcultured once to twice a week at 37°C and 5% CO 2. All cells were dissolved in liquid nitrogen, passed through three or more passages, and used in the experiment.
그 결과, 도 6과 같이 멜라토닌 10번 유도체는 폭넓은 항암 효과를 보였다. 특히 폐암 세포주를 제외한 나머지 대장암, 유방암, 자궁경부암 세포주에서는 멜라토닌에 비해서 상당히 우월한 항암활성을 나타내었다.As a result, as shown in FIG. 6, the
3. 멜라토닌 유도체가 나타내는 항암 효과의 분자적 기전 분석3. Molecular mechanism analysis of anticancer effects of melatonin derivatives
멜라토닌 유도체가 나타내는 항암 효과의 분자적 기전을 분석하기 위하여 대장암 세포주인 HCT-116에 상기 실시예 1에서 준비한 멜라토닌 및 멜라토닌 유도체 1 내지 10를 처리하고 이의 항암 효과를 웨스턴 블롯(western blot)으로 확인하였다. 웨스턴 분석은 이미 공지되어 있는 방법(2014, Inflammation research 63:81-90.)으로 수행하였다. 구체적으로 웨스턴 블롯은 하기와 같이 수행하였다: 인산화된 단백질인산화효소 B(phospho-AKT, pAKT, Cell Signaling), AKT (Cell Signaling) 단백질에 특이적인 일차 항체를 사용하였다. 항-래빗 홀스래디쉬 퍼옥시다제(rabbit horseradish peroxidase) 결합 이차 항체는 피어스 케미칼(Pierce Chemical Co.)에서 구입하였으며, 전기화학발광(Electrogenerated ChemiLuminescence) 플러스 시약(ECL Plus reagent, Amersham Biosciences, USA)로 발색한 후 퓨전(Fusion) 장비(Vilber Lourmat, FR)를 이용하여 검출하였다. 폰소 S(Ponceau S) 용액은 시그마(Sigma)에서 구입하였다.In order to analyze the molecular mechanism of the anticancer effect exhibited by the melatonin derivative, the colon cancer cell line HCT-116 was treated with the melatonin and
그 결과 도 7과 같이, 멜라토닌 유도체의 항암 효과는 세포의 세포사멸(Apoptosis) 억제 및 세포증식 촉진 등의 역할을 하는 단백질인산화효소 B(AKT)의 신호전달체계를 억제하기 때문인 것을 확인하였다. 특히 가장 뛰어난 항암활성을 보였던 유도체 10번은 AKT의 인산화를 억제하는 능력도 가장 우수하였다.As a result, as shown in FIG. 7, it was confirmed that the anticancer effect of the melatonin derivative is because it inhibits the signaling system of protein kinase B (AKT), which plays a role in inhibiting apoptosis and promoting cell proliferation. In particular, derivative No. 10, which showed the most excellent anticancer activity, also showed the best ability to inhibit phosphorylation of AKT.
많은 암세포는 저산소 상태에 관계없이 HIF-1α의 활성이 증가되어 있다. 급속한 증식으로 일부 암세포가 저산소의 상태가 되어 그 적응으로 HIF-1α의 활성이 높아지는 것이지만, 실제로는 저산소 상태가 아니어도 유전자 변이 등에 의하여 증식신호 전달체계가 항시적으로 증가되어 있어, 지속적인 HIF-1α의 활성 증가 상태를 보인다. 따라서 암 세포 치료에서 HIF-1α의 발현 감소는 매우 중요하다.In many cancer cells, the activity of HIF-1α is increased regardless of hypoxia. Although some cancer cells become hypoxic due to rapid proliferation, and their adaptation increases the activity of HIF-1α, even if they are not in a hypoxic state, the proliferation signal transduction system is constantly increased due to genetic mutation, etc. It shows a state of increased activity. Therefore, it is very important to reduce the expression of HIF-1α in the treatment of cancer cells.
상기 실시예의 도 3에서 상대적으로 항암 활성은 낮은 것으로 보였던 멜라토닌 유도체 1, 3, 7, 8을 HCT-116 세포주에 처리한 후, 저산소 유도인자-1α(Hypoxia-inducible factor-1 alpha, HIF-1α)의 발현을 확인하였다.After treating the
구체적으로 웨스턴 블롯은 하기와 같이 수행하였다: HIF-1a (BD), 튜불린(Tubulin, Santa Cruz) 단백질에 특이적인 일차 항체를 사용하였다. 항 마우스 홀스래디쉬 퍼옥시다제(mouse horseradish peroxidase) 결합 이차 항체는 피어스 케미칼(Pierce Chemical Co.)에서 구입하였으며, 전기화학발광(Electrogenerated ChemiLuminescence) 플러스 시약(ECL Plus reagent, Amersham Biosciences, USA)로 발색한 후 퓨전(Fusion) 장비(Vilber Lourmat, FR)를 이용하여 검출하였다. 폰소 S(Ponceau S) 용액은 시그마(Sigma)에서 구입하였다.Specifically, Western blot was performed as follows: HIF-1a (BD), tubulin (Tubulin, Santa Cruz) protein-specific primary antibodies were used. Anti-mouse horseradish peroxidase-binding secondary antibody was purchased from Pierce Chemical Co., and developed with Electrogenerated ChemiLuminescence Plus reagent (ECL Plus reagent, Amersham Biosciences, USA). Then, it was detected using a fusion equipment (Vilber Lourmat, FR). Ponceau S solution was purchased from Sigma.
그 결과 도 8과 같이, 멜라토닌 유도체를 처리한 경우 HIF-1α의 발현이 유의적으로 감소한 것을 확인하였으며, 특히 유도체 3번과 8번은 기존 멜라토닌보다 HIF-1α의 발현을 더 억제시키는 것을 확인하였다.As a result, as shown in FIG. 8, when the melatonin derivative was treated, the expression of HIF-1α was significantly reduced, and in particular,
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시예일 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 described above, specific parts of the present invention have been described in detail, and for those of ordinary skill in the art, it will be apparent that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Therefore, it will be said that the practical scope of the present invention is defined by the appended claims and their equivalents.
<110> inje university industry-academic cooperation foundation <120> Composition for Preventing or Treating Inflammatory Disease, Allergic Disease or Cancer Comprising Melatonin Derivative <130> ADP-2018-0135 <160> 12 <170> KoPatentIn 3.0 <210> 1 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 1 aagggctgct tccaaacctt tgac 24 <210> 2 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 2 tgcctgaagc tcttgttgat gtgc 24 <210> 3 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 3 catcttctca aaattcgagt gacaa 25 <210> 4 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 4 tgggagtaga caaggtacaa ccc 23 <210> 5 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 5 ttcaaaagaa gtgctggaaa aggt 24 <210> 6 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 6 gatcatctct acctgagtgt cttt 24 <210> 7 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 7 gaggatacca ctcccaacag acc 23 <210> 8 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 8 aagtgcatca tcgttgttca taca 24 <210> 9 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 9 cttctgggcc tgctgttca 19 <210> 10 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 10 ccagcctact cattgggatc a 21 <210> 11 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 11 gagctgaacg ggaagctact gg 22 <210> 12 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 12 ccaccttctt gatgtcatca t 21 <110> inje university industry-academic cooperation foundation <120> Composition for Preventing or Treating Inflammatory Disease, Allergic Disease or Cancer Comprising Melatonin Derivative <130> ADP-2018-0135 <160> 12 <170> KoPatentIn 3.0 <210> 1 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 1 aagggctgct tccaaacctt tgac 24 <210> 2 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 2 tgcctgaagc tcttgttgat gtgc 24 <210> 3 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 3 catcttctca aaattcgagt gacaa 25 <210> 4 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 4 tgggagtaga caaggtacaa ccc 23 <210> 5 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 5 ttcaaaagaa gtgctggaaa aggt 24 <210> 6 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 6 gatcatctct acctgagtgt cttt 24 <210> 7 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 7 gaggatacca ctcccaacag acc 23 <210> 8 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 8 aagtgcatca tcgttgttca taca 24 <210> 9 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 9 cttctgggcc tgctgttca 19 <210> 10 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 10 ccagcctact cattgggatc a 21 <210> 11 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 11 gagctgaacg ggaagctact gg 22 <210> 12 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> primer <400> 12 ccaccttctt gatgtcatca t 21
Claims (4)
[화학식 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,
[화학식 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.1. A pharmaceutical composition for preventing or treating cancer, comprising a melatonin derivative represented by the following formula (1) or (2) as an active ingredient.
[Chemical Formula 1]
Wherein R 1 is at least one member selected from the group consisting of hydrogen, (C 2 -C 4) alkylcarbonyl, benzoyl and (C 1 -C 4) alkoxycarbonyl,
(2)
Wherein R 2 is at least one selected from the group consisting of hydrogen, (C 1 -C 4) alkylcarbonyl, benzoyl and (C 1 -C 4) alkoxycarbonyl.
상기 멜라토닌 유도체는 약학 조성물 총 100 중량부에 대하여, 0.1 내지 50 중량부로 포함되는 것을 특징으로 하는 암 질환 예방 또는 치료용 약학 조성물.The method according to claim 1,
Wherein the melatonin derivative is contained in an amount of 0.1 to 50 parts by weight based on 100 parts by weight of the total amount of the pharmaceutical composition.
상기 암은 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강/부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 구강암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 직장암, 항문암, 방광암, 신장암, 남성생식기종양, 음경암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암 및 피부암으로 이루어진 군에서 선택된 하나 이상인 것을 특징으로 하는 암 질환 예방 또는 치료용 약학 조성물.The method according to claim 1,
Wherein the cancer is selected from the group consisting of brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial lesion, ependymoma, brain tumor, head and neck tumor, laryngeal cancer, Cancer, breast cancer, breast cancer, gastric cancer, liver cancer, gallbladder cancer, biliary cancer, pancreatic cancer, small bowel cancer, pancreatic cancer, breast cancer, pancreatic cancer, cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non- Ovarian cancer, uterine sarcoma, vaginal cancer, female germ cell cancer, female urethral cancer, colon cancer, colon cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, And skin cancer. ≪ RTI ID = 0.0 > 11. < / RTI >
[화학식 1]
상기 R1은 수소, (C2~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상이며,
[화학식 2]
상기 R2는 수소, (C1~C4)알킬카르보닐, 벤조일(Benzoyl) 및 (C1~C4)알콕시카르보닐로 이루어진 군에서 선택된 하나 이상임.A health food for preventing or ameliorating cancer diseases, which comprises a melatonin derivative represented by the following formula (1) or (2) as an active ingredient.
[Chemical Formula 1]
Wherein R 1 is at least one member selected from the group consisting of hydrogen, (C 2 -C 4) alkylcarbonyl, benzoyl and (C 1 -C 4) alkoxycarbonyl,
(2)
Wherein R 2 is at least one selected from the group consisting of hydrogen, (C 1 -C 4) alkylcarbonyl, benzoyl and (C 1 -C 4) alkoxycarbonyl.
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