KR20240030256A - New Vitex A compound and Composition for anti-inflammation comprising Vitex A - Google Patents
New Vitex A compound and Composition for anti-inflammation comprising Vitex A Download PDFInfo
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- KR20240030256A KR20240030256A KR1020220109033A KR20220109033A KR20240030256A KR 20240030256 A KR20240030256 A KR 20240030256A KR 1020220109033 A KR1020220109033 A KR 1020220109033A KR 20220109033 A KR20220109033 A KR 20220109033A KR 20240030256 A KR20240030256 A KR 20240030256A
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- A23V2200/00—Function of food ingredients
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Abstract
본 발명은 화학식 1의 구조를 갖는 바이텍스 에이(Vitex A) 및 이의 염을 유효성분으로 포함하는 항염증용 조성물에 관한 것이다. 본 발명에 따른 신규한 화합물인 바이텍스 에이(Vitex A) 및 이의 염은 세포 독성이 없으면서 세포 내 NO 생성을 저해하고 염증성 사이토카인을 저해하는 효과를 나타내므로 염증을 예방 또는 치료하기 위한 조성물로서 약학적, 화장료, 또는 식품 조성물에 유용하게 사용할 수 있다.The present invention relates to an anti-inflammatory composition containing Vitex A having the structure of Formula 1 and a salt thereof as active ingredients. Vitex A and its salts, which are novel compounds according to the present invention, are non-cytotoxic and have the effect of inhibiting intracellular NO production and inhibiting inflammatory cytokines, so they are used as pharmaceutical compositions for preventing or treating inflammation. It can be usefully used in cosmetics, cosmetics, or food compositions.
Description
본 발명은 신규한 바이텍스 에이(Vitex A) 화합물, 및 상기 화합물 또는 이의 염을 포함하는 항염증용 조성물에 관한 것이다.The present invention relates to a novel Vitex A compound and an anti-inflammatory composition containing the compound or a salt thereof.
최근 경제 발전에 따른 의료기술의 발달 및 평균수명의 연장으로 고령자 비율이 계속하여 증가하고 있으며, 환경오염 및 스트레스 증가에 따른 면역계 이상으로 염증반응의 만성화가 진행되어 아토피, 천식 등의 만성 염증성 질환이 증가하고 있는 추세이다(Chang et al., 1994, Korean J. Gastroentrol., 26:907-918.; Heinzemann and Daser, 2002, Int. Arch. Allergy Immunol. 127:170-180.; Song et al., 1998, Korean J. Intern. Med., 55:158-168.; Sunget al., 2012, J. Ethnopharmacol. 144:94-100.).The proportion of elderly people continues to increase due to the development of medical technology and the extension of life expectancy due to recent economic development, and the inflammatory response becomes chronic due to immune system abnormalities due to environmental pollution and increased stress, leading to chronic inflammatory diseases such as atopy and asthma. There is an increasing trend (Chang et al., 1994, Korean J. Gastroentrol., 26:907-918.; Heinzemann and Daser, 2002, Int. Arch. Allergy Immunol. 127:170-180.; Song et al. , 1998, Korean J. Intern. Med., 55:158-168.; Sunget al., 2012, J. Ethnopharmacol. 144:94-100.).
염증 반응 (inflammatory response)은 생체나 조직 내 물리적 작용이나 화학적 물질, 박테리아 감염 등으로 인한 손상을 회복하기 위해 일어나는 반응으로 인체를 보호하는 긍정적인 역할을 하지만 염증의 정도가 심하거나 지속되게 되면 관절염, 알레르기, 질환, 고혈압 등의 질병을 일으키는 원인이 되기도 한다 (Moncada et al., 1991; Lee et al., 2014).The inflammatory response is a reaction that occurs to recover from damage caused by physical actions, chemical substances, or bacterial infections within the body or tissue, and plays a positive role in protecting the human body. However, if the degree of inflammation is severe or continues, arthritis, It can also cause diseases such as allergies, diseases, and high blood pressure (Moncada et al., 1991; Lee et al., 2014).
체내에서 일어나는 염증과정에서 염증매개 인자들인 NO(nitric oxide)와 PGE2(prostaglandin E2) 등이 과량 생성된다 (Posadas et al., 2000; Tsatsanis et al., 2006). 체내에서 NO는 염증반응 이외에도 방어기능, 혈관확장, 신호전달기능 등 다양한 생리적 기능을 가지고 있으며 NOSs(nitric oxide synthases)에 의해 L-arginine으로부터 생성된다 (Nathan 1997; Palmer 1987, Knowles and Moncada, 1994). NOS는 neuronal NOS (nNOS)와 endothelial NOS (eNOS), interferon-γ, lipopolysaccharide (LPS), cytokine과 같은 자극에 노출되는 경우에 발현되는 inducible NOS (iNOS) 등 세 가지 형태를 가진다 (Lee et al., 2004; Weisz et al., 1996).During the inflammatory process that occurs in the body, excessive amounts of inflammatory mediators such as NO (nitric oxide) and PGE2 (prostaglandin E2) are produced (Posadas et al., 2000; Tsatsanis et al., 2006). In the body, NO has various physiological functions such as defense function, vasodilation, and signal transmission function in addition to inflammatory response, and is produced from L-arginine by NOSs (nitric oxide synthases) (Nathan 1997; Palmer 1987, Knowles and Moncada, 1994). . NOS has three forms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), which is expressed when exposed to stimuli such as interferon-γ, lipopolysaccharide (LPS), and cytokines (Lee et al. , 2004; Weisz et al., 1996).
일반적인 염증 치료제로서 코르티코스테로이드(corticosteroid)와 같은 스테로이드성 약물은 강력한 항염증제로 이용되었지만 면역기능과 세포 활성을 억제하여 심각한 부작용을 가지고 체중 증가나 당뇨, 체액 저류 등의 독성 효과를 보이기도 한다 (Richard and Geoffrey, 2009). 이에 부작용이 적은 비스테로이성 소염 진통제 aspron, paracetamol, indomethacin, ibuprofen 등이 있지만 이들은 일시적으로 완화는 시켜주지만 근본적인 원인에는 영향을 미치지 않으며 염증과 관련된 COX 효소에 대해 비선택성으로 인한 부작용과 연관이 있고 선택성을 가지는 치료제들은 비용이 많이 든다. 따라서, 천연 원료로부터 안전하고 효과적인 항염증 치료제를 찾기 위한 연구가 계속되고 있다(Fava and Danese, 2011).As a general inflammatory treatment, steroid drugs such as corticosteroids have been used as powerful anti-inflammatory agents, but they have serious side effects by suppressing immune function and cell activity and can also exhibit toxic effects such as weight gain, diabetes, and fluid retention (Richard and Geoffrey) , 2009). There are non-steroidal anti-inflammatory painkillers with fewer side effects, such as aspron, paracetamol, indomethacin, and ibuprofen, but these provide temporary relief but do not affect the underlying cause. They are associated with side effects due to non-selectivity for the COX enzyme related to inflammation, and are selective. Treatments that have are expensive. Therefore, research is continuing to find safe and effective anti-inflammatory treatments from natural ingredients (Fava and Danese, 2011).
식물에서 유래한 화합물로 여러 분야에서 약물로서 효능을 가지는 triterpenoid나 flavonoid, tannin 등 다양한 화합물들이 분리 되었다. Triterpenoid는 항염증제, 간염, 기생충 및 바이러스 감염의 예방 및 치료에 사용되었고 flavonoid는 4천가지가 넘는 polyphenol 화합물로써 강력한 항산화제나 저밀도의 지단백질을 산화 시키는 것으로 알려져 있다. 이와 같이 천연물 유래 화합물은 많은 잠재력을 가지고 있다 (Hollman et al., 1997; Dzubak et al., 2006).Various compounds derived from plants, such as triterpenoids, flavonoids, and tannins, which are effective as drugs in various fields, have been isolated. Triterpenoids are used as anti-inflammatory agents, for the prevention and treatment of hepatitis, parasites, and viral infections, and flavonoids are over 4,000 polyphenol compounds known to be powerful antioxidants and to oxidize low-density lipoproteins. In this way, natural product-derived compounds have great potential (Hollman et al., 1997; Dzubak et al., 2006).
한편, 순비기나무(Vitex rotundifolia)는 제주도, 울릉도, 중부, 남부 지방의 해변 모래땅 바닷가에 흔하게 자라는 여러해살이 초본으로, 한국, 일본, 동남아시아, 태평양 연안, 오스트레일리아 등에 분포하는 방향성 식물이다. 상록관목으로서 향기가 나고 옆으로 자라다가 비스듬히 서며 전체에 회백색의 잔털이 있고, 관상용으로 심기도 하며, 한방에 이뇨, 신경통, 감기 등의 약재로 사용하기도 하였다.Meanwhile, Vitex rotundifolia is a perennial herb that commonly grows on the sandy beaches of Jeju Island, Ulleungdo Island, central and southern regions, and is an aromatic plant distributed in Korea, Japan, Southeast Asia, the Pacific coast, and Australia. It is an evergreen shrub with a fragrant scent, grows sideways and stands at an angle, and has gray-white fine hairs all over. It is also planted as an ornamental plant, and is also used as a medicinal herb for diuresis, neuralgia, and colds.
순비기나무와 관련하여 한국 등록특허 제10-1877401호(2018.07.12. 공고)는 순비기나무의 잎을 효소 가수분해 처리 및 초고압 균질화 처리하여 불용성 섬유질 성분을 가용화한 순비기나무 잎 추출물의 항비만용 조성물을 개시하고 있고, 한국 등록특허 제10-1127929호(2012.03.23. 공고)는 순비기나무 20 내지 50 g을 에탄올 0.2 내지 1.0ℓ로 18 내지 30시간 추출하여 수득되는 순비기나무 추출물을 조성물의 총 중량에 대해 건조 중량으로 5 내지 30 중량% 함유하는 화장료 조성물을 개시하고 있고, 한국 공개특허 제10-2022-0029479호(2022.03.08. 공개)는 순비기나무의 열매 추출물을 포함하는 여성 갱년기 증상 예방 또는 치료용 약학적 조성물을 개시하고 있다.In relation to Sunbigi tree, Korean Patent No. 10-1877401 (announced on July 12, 2018) describes the extract of Sunbigi tree leaves obtained by solubilizing the insoluble fiber components by enzymatic hydrolysis and ultra-high pressure homogenization of the leaves of Sunbigi tree. Disclosing a composition for obesity, Korean Patent No. 10-1127929 (announced on March 23, 2012) is an extract obtained by extracting 20 to 50 g of Siberia chinensis with 0.2 to 1.0 L of ethanol for 18 to 30 hours. Discloses a cosmetic composition containing 5 to 30% by weight in dry weight relative to the total weight of the composition, and Korean Patent Publication No. 10-2022-0029479 (published on March 8, 2022) includes an extract of the fruit of the Sunbigi tree. A pharmaceutical composition for preventing or treating female menopausal symptoms is disclosed.
이에 본 발명자들은 천연물 유래 화합물(phytochemical)로서 인체에 안전하면서도 항염증 효과가 우수한 물질을 개발하기 위해 연구를 진행하던 중, 순비기나무의 가지로부터 신규 화합물을 발견하였고, 상기 신규 화합물은 세포독성을 나타내지 않으며 우수한 항염증 활성을 나타내므로 염증의 예방, 개선, 및 치료 용도로서 유용하게 사용할 수 있음을 발견하고 본 발명은 완성하게 되었다.Accordingly, while conducting research to develop a natural product-derived compound (phytochemical) that is safe for the human body and has an excellent anti-inflammatory effect, the present inventors discovered a new compound from the branches of the Siberia tree, and the new compound has cytotoxicity. The present invention was completed after discovering that it can be usefully used for the prevention, improvement, and treatment of inflammation because it exhibits excellent anti-inflammatory activity.
본 발명의 하나의 목적은 세포독성을 나타내지 않으며, 우수한 항염증 활성을 가지는 신규 화합물을 제공하는 것이다.One object of the present invention is to provide a new compound that is not cytotoxic and has excellent anti-inflammatory activity.
본 발명의 다른 하나의 목적은 상기 신규 화합물 또는 이의 염을 유효성분으로 포함하는 항염증용 조성물을 제공하는 것이다.Another object of the present invention is to provide an anti-inflammatory composition containing the novel compound or a salt thereof as an active ingredient.
본 발명의 또 다른 하나의 목적은 상기 조성물을 포함하는 염증 예방 또는 치료용 약학적, 화장료, 또는 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical, cosmetic, or food composition for preventing or treating inflammation comprising the composition.
하나의 양태로서, 본 발명은 세포독성을 나타내지 않으며, 우수한 항염증 활성을 가지는 신규 화합물을 제공한다.In one aspect, the present invention provides a novel compound that is not cytotoxic and has excellent anti-inflammatory activity.
본 발명에서 사용되는 용어 "항염증"은 염증을 예방 또는 치료하는 것을 의미한다. 여기서, 상기 염증은 외부 감염원(박테리아, 곰팡이, 바이러스, 다양한 종류의 알레르기 유발 물질 등)의 침입에 의하여 유발되는 질환을 말하며, 상기 질환으로는 아토피성 피부염, 알러지성 피부염, 염증성 장질환, 위궤양, 또는 천식 등이 있으나, 이에 특별히 제한되지는 않는다.The term “anti-inflammatory” used in the present invention means preventing or treating inflammation. Here, the inflammation refers to a disease caused by the invasion of external infectious agents (bacteria, mold, viruses, various types of allergy-causing substances, etc.), and the diseases include atopic dermatitis, allergic dermatitis, inflammatory bowel disease, gastric ulcer, or asthma, etc., but is not particularly limited thereto.
본 발명에서 사용되는 용어 "예방"은 질환 또는 질병을 보유하고 있다고 진단된 적은 없으나, 이러한 질환 또는 질병에 걸리기 쉬운 경향이 있는 개체에서 질환 또는 질병의 발생을 억제하는 것을 의미한다.The term “prevention” as used in the present invention refers to suppressing the occurrence of a disease or disease in an individual who has not been diagnosed as having the disease or disease but is prone to such disease or disease.
본 명세서에서 사용되는 용어 "치료"는 개체에서 (a) 질환 또는 질병의 발전의 억제 (b) 질환 또는 질병의 경감 및 (c) 질환 또는 질환의 제거를 의미한다.As used herein, the term “treatment” means (a) inhibiting the development of a disease or condition, (b) alleviating the disease or condition, and (c) eliminating the disease or condition in an individual.
본 명세서에서 사용되는 용어 "개체"는 본 발명의 상기 조성물을 투여하여 증상이 호전될 수 있는 질환을 가진 인간을 포함한 원숭이, 소, 말, 돼지, 양, 개, 고양이, 랫드, 마우스, 침팬지 등의 포유동물을 의미한다.The term "individual" used herein refers to monkeys, cows, horses, pigs, sheep, dogs, cats, rats, mice, chimpanzees, etc., including humans, whose symptoms can be improved by administering the composition of the present invention. means mammals.
본 발명에 있어서, 상기 신규 화합물은 하기 화학식 1의 구조를 가지는 바이텍스 에이(Vitex A) 화합물이다.In the present invention, the novel compound is Vitex A compound having the structure of the following formula (1).
본 발명에 있어서, 상기 화학식 1의 구조를 가지는 화합물은 식물, 바람직하게는 바이텍스(Vitex) 속 식물, 보다 바람직하게는 순비기나무(Vitex rotundifolia), 보다 더 바람직하게는 순비기나무의 가지로부터 분리되거나 화학적으로 합성된 것이거나 형질전환된 미생물에 의한 배양물로부터 유래된 화합물일 수 있다.In the present invention, the compound having the structure of Formula 1 is obtained from a plant, preferably from a plant of the genus Vitex , more preferably from Vitex rotundifolia , and even more preferably from a branch of the genus Vitex. The compounds may be isolated, chemically synthesized, or derived from cultures of transformed microorganisms.
하나의 구체적 예로서, 상기 화학식 1의 화합물은 순비기나무 가지의 에탄올 추출물을 헥산, 클로로포름, 에틸아세테이트, 부탄올, 및 물로 분획하고, 상기 부탄올 분획물을 순상 컬럼크로마토그래피 (클로로포름 (C) 및 메탄올 (MeOH), 물의 혼합용매 (50:1:0.001 부피비)에서 100 % 메탄올 (MeOH))로 소분획하고 그 소분획물 중의 5번째 소분획물을 겔투과 크로마토그래피(물 및 메탄올 (MeOH)의 혼합용매 (1:1 부피비))로 소분획하여 5번째 소분획물을 역상 고성능액체크로마토그래피 (물 및 아세토니트릴 (ACN)의 혼합용매 (95:5 부피비)에서 100% 아세토니트릴 (ACN))로 소분획하고, 그 소분획물 중의 8번째 소분획물을 역상 고성능액체크로마토그래피 (물 및 아세토니트릴 (ACN)의 혼합용매 (80:20 부피비)에서 100% 아세토니트릴 (ACN))로 분획하여 분리할 수 있다.As a specific example, the compound of Formula 1 was obtained by fractionating the ethanol extract of the branches of the S. vulgaris tree with hexane, chloroform, ethyl acetate, butanol, and water, and subjecting the butanol fraction to normal phase column chromatography (chloroform (C) and methanol ( MeOH) and water mixed solvent (50:1:0.001 volume ratio) was sub-fractionated with 100% methanol (MeOH)), and the fifth sub-fraction among the sub-fractions was subjected to gel permeation chromatography (mixed solvent of water and methanol (MeOH) ( Sub-fractionated with 1:1 volume ratio) and the 5th sub-fraction was sub-fractionated with reverse-phase high-performance liquid chromatography (100% acetonitrile (ACN) in a mixed solvent of water and acetonitrile (ACN) (95:5 volume ratio)) , the 8th subfraction among the subfractions can be separated by fractionation using reverse-phase high-performance liquid chromatography (100% acetonitrile (ACN) in a mixed solvent of water and acetonitrile (ACN) (80:20 volume ratio)).
본 발명의 화학식 1의 구조를 갖는 바이텍스 에이(Vitex A) 화합물은 세포독성을 나타내지 않으며, 세포 내 NO 활성을 저해하는 효과를 가진다.The Vitex A compound having the structure of Formula 1 of the present invention does not exhibit cytotoxicity and has the effect of inhibiting intracellular NO activity.
또한, 본 발명의 화학식 1의 구조를 갖는 바이텍스 에이(Vitex A) 화합물은 염증성 사이토카인의 생성 저해 효과를 가진다.In addition, the Vitex A compound having the structure of Formula 1 of the present invention has an effect of inhibiting the production of inflammatory cytokines.
따라서, 본 발명의 화학식 1의 구조를 갖는 바이텍스 에이(Vitex A) 화합물은 염증을 예방, 개선, 또는 치료하기 위한 용도로 유용하게 사용할 수 있다.Therefore, the Vitex A compound having the structure of Formula 1 of the present invention can be usefully used to prevent, improve, or treat inflammation.
다른 하나의 양태로서, 본 발명은 화학식 1의 구조를 갖는 바이텍스 에이(Vitex A) 화합물 또는 이의 염을 유효성분으로 포함하는 항염증용 조성물을 제공한다.In another aspect, the present invention provides an anti-inflammatory composition containing Vitex A compound having the structure of Formula 1 or a salt thereof as an active ingredient.
상기 화학식 1의 화합물 또는 이의 염은 전체 조성물의 총 중량을 기준으로 0.001 내지 50 중량%, 바람직하게는 0.01 내지 30 중량%, 보다 바람직하게는 0.01 내지 10 중량%의 함량으로 포함될 수 있다. 상기 화학식 1의 화합물 또는 이의 염의 함량이 0.001 중량% 미만일 경우 항염증 효과가 미약하고, 50 중량%를 초과하는 경우 함량 증가에 따른 효과 증가가 비례적이지 않아 비효율적일 수 있으며, 제형상의 안정성이 확보되지 않는 문제가 있다.The compound of Formula 1 or its salt may be included in an amount of 0.001 to 50% by weight, preferably 0.01 to 30% by weight, and more preferably 0.01 to 10% by weight, based on the total weight of the entire composition. If the content of the compound of Formula 1 or its salt is less than 0.001% by weight, the anti-inflammatory effect is weak, and if it exceeds 50% by weight, the increase in effect due to increase in content is not proportional and may be ineffective, and the stability of the formulation may be reduced. There is a problem that cannot be secured.
본 발명에 있어서, 상기 화학식 1의 화합물의 염은 약학적, 화장학적, 또는 식품학적으로 허용되는 염의 형태일 수 있다. 그와 같은 염으로는 약학적, 화장학적, 또는 식품학적으로 허용되는 유리산(free acid)에 의해 형성되는 산부가염 또는 염기에 의해 형성되는 금속염이 유용하다. 예를 들어, 유리산으로는 무기산과 유기산을 사용할 수 있다. 무기산으로는 염산, 황산, 브롬산, 아황산 또는 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레인산, 후마산, 글루콘산, 메탄술폰 산 등을 사용할 수 있다. 또한, 금속염으로는 알칼리 금속염, 알칼리 토금속염, 나트륨, 칼륨 또는 칼슘염을 사용할 수 있다. 그러나 특별히 이로 제한되지는 않는다.In the present invention, the salt of the compound of Formula 1 may be in the form of a pharmaceutically, cosmetically, or foodologically acceptable salt. As such salts, acid addition salts formed by free acids or metal salts formed by bases that are pharmaceutically, cosmetically, or foodologically acceptable are useful. For example, inorganic acids and organic acids can be used as free acids. Hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid, or phosphoric acid can be used as inorganic acids, and citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, etc. can be used as organic acids. Additionally, as the metal salt, alkali metal salt, alkaline earth metal salt, sodium, potassium or calcium salt can be used. However, it is not particularly limited thereto.
본 발명의 하나의 구체적 용도로서, 본 발명의 조성물은 염증을 예방 또는 치료하기 위한 약학적 조성물로 사용될 수 있다.As one specific use of the present invention, the composition of the present invention can be used as a pharmaceutical composition for preventing or treating inflammation.
본 발명의 조성물이 약학적 조성물로 사용되는 경우, 유효성분으로서 화학식 1의 화합물 및 상기 화합물의 약학적으로 허용 가능한 염 이외에 약학적으로 허용되는 담체를 추가로 포함할 수 있다.When the composition of the present invention is used as a pharmaceutical composition, it may further include a pharmaceutically acceptable carrier in addition to the compound of Formula 1 and a pharmaceutically acceptable salt of the compound as an active ingredient.
본 발명의 약학적 조성물에 포함되는 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 탄수화물류 화합물(예: 락토스, 아밀로스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 셀룰로스 등), 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 염 용액, 알코올, 아라비아 고무, 식물성 기름(예: 옥수수 기름, 목화 종자유, 두유, 올리브유, 코코넛유), 폴리에틸렌 글리콜, 메틸 셀룰로스, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다.Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in preparation, and include carbohydrate compounds (e.g. lactose, amylose, dextrose, sucrose, sorbitol, mannitol, starch, cellulose, etc.) , acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, salt solution, alcohol, gum arabic, vegetable oils (e.g. corn oil, cotton seed oil) , soy milk, olive oil, coconut oil), polyethylene glycol, methyl cellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil, but are not limited thereto.
본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.In addition to the above ingredients, the pharmaceutical composition of the present invention may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.
본 발명의 약학적 조성물은 통상의 방법에 따라 산제, 과립제, 캡슐제, 현탁액, 에멀젼, 시럽제, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액 등의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterilized injection solutions according to conventional methods.
상기 약학적 조성물은 염증을 예방 또는 치료할 수 있는데, 치료 방법은 상기 약학적 조성물을 약학적 유효량으로 쥐, 생쥐, 가축, 인간 등의 포유동물 내에 다양한 경로로 투여하는 것을 포함한다. 상기 투여 방법은 모든 방식으로 이루어질 수 있는데, 예를 들어, 경구, 직장 또는 정맥 내 주입, 복강 내 투여, 근육 내 투여, 피하 투여 또는 도포에 의한 국부 투여 등으로 투여될 수 있다.The pharmaceutical composition can prevent or treat inflammation, and the treatment method includes administering the pharmaceutical composition in a pharmaceutically effective amount into mammals such as rats, mice, livestock, and humans through various routes. The administration method may be carried out in any manner, for example, oral, rectal or intravenous injection, intraperitoneal administration, intramuscular administration, subcutaneous administration or local administration by application, etc.
상기 약학적 조성물의 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성별, 병적 상태 등의 요인에 따라 달라질 수 있다. 본 발명의 약학적 조성물의 투여량은 성인 기준으로 0.001-100 ㎎/kg 범위 내이다. 다만, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것이 아니다.The dosage of the pharmaceutical composition may vary depending on factors such as formulation method, administration method, patient's age, weight, gender, and pathological condition. The dosage of the pharmaceutical composition of the present invention is within the range of 0.001-100 mg/kg for adults. However, the above dosage does not limit the scope of the present invention in any way.
본 발명의 다른 하나의 구체적 용도로서, 본 발명의 조성물은 염증을 예방 또는 개선하기 위한 화장료 조성물로 사용될 수 있다.As another specific use of the present invention, the composition of the present invention can be used as a cosmetic composition to prevent or improve inflammation.
본 발명의 조성물이 약학적 조성물로 사용되는 경우, 유효성분으로서 화학식 1의 화합물 및 상기 화합물의 약학적으로 허용 가능한 염 이외에 화장료 조성물에 통상적으로 이용되는 성분들을 추가적으로 포함할 수 있다. 예컨대, 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제 및 담체를 포함할 수 있다.When the composition of the present invention is used as a pharmaceutical composition, it may additionally contain ingredients commonly used in cosmetic compositions in addition to the compound of Formula 1 and a pharmaceutically acceptable salt of the compound as active ingredients. For example, it may contain conventional auxiliaries and carriers such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings.
상기 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 영양 크림, 수렴 화장수, 유연 화장수, 로션, 에센스, 영양젤 또는 마사지 크림 등의 제형으로 제조될 수 있다.The cosmetic composition can be prepared in any formulation commonly prepared in the art, for example, solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil. , may be formulated as powder foundation, emulsion foundation, wax foundation, spray, etc., but is not limited thereto. More specifically, it can be manufactured in formulations such as nutritional cream, astringent lotion, softening lotion, lotion, essence, nutritional gel, or massage cream.
상기 화장료 조성물의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라가칸트검, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the cosmetic composition is a paste, cream or gel, the carrier ingredients include animal oil, vegetable oil, wax, paraffin, starch, gum tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide, etc. This can be used.
상기 화장료 조성물의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation of the cosmetic composition is powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder can be used as the carrier ingredient. In particular, in the case of spray, chlorofluorohydrocarbon, May contain propellants such as propane/butane or dimethyl ether.
상기 화장료 조성물의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 가용화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation of the cosmetic composition is a solution or emulsion, a solvent, solubilizer, or emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, These include 1,3-butyl glycol oil, glycerol aliphatic esters, polyethylene glycol or fatty acid esters of sorbitan.
상기 화장료 조성물의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라가칸트 등이 이용될 수 있다.When the formulation of the cosmetic composition is a suspension, the carrier ingredients include water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester, and polyoxyethylene sorbitan ester, and miso. Crystalline cellulose, aluminum metahydroxide, bentonite, agar, or tragacanth can be used.
상기 화장료 조성물의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 라놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the cosmetic composition is a cleansing agent containing a surfactant, the carrier ingredients include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, and fatty acid. Amide ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester can be used.
본 발명의 다른 하나의 구체적 용도로서, 본 발명의 조성물은 염증을 예방 또는 개선하기 위한 식품 조성물로 사용될 수 있다.As another specific use of the present invention, the composition of the present invention can be used as a food composition to prevent or improve inflammation.
본 발명의 조성물이 식품 조성물로 사용되는 경우, 유효성분으로서 화학식 1의 화합물 및 이의 식품학적으로 허용 가능한 염 이외에 식품 제조 시에 통상적으로 첨가되는 성분, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 추가로 포함할 수 있다.When the composition of the present invention is used as a food composition, in addition to the compound of Formula 1 and its foodologically acceptable salts as active ingredients, ingredients commonly added during food production, such as proteins, carbohydrates, fats, nutrients, Seasonings and flavoring agents may additionally be included.
상기 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등)] 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.Examples of such carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, oligosaccharides, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As a flavoring agent, natural flavoring agents [thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)] and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
상기 식품의 종류에는 특별한 제한이 없다. 본 발명의 화학식 1의 화합물 및 이의 식품학적으로 허용 가능한 염을 첨가할 수 있는 식품의 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 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There are no particular restrictions on the type of food. Examples of foods to which the compound of Formula 1 of the present invention and its foodologically acceptable salt can be added include meat, sausages, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gum, and ice cream. It includes dairy products, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes, and includes all health foods in the conventional sense.
본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 화학식 1의 화합물 또는 이의 식품학적으로 허용 가능한 염 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙 등을 추가로 포함시킬 수 있다.When the food composition of the present invention is manufactured as a drink, in addition to the compound of formula 1 of the present invention or a foodologically acceptable salt thereof, citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, etc. may be additionally included. .
또한, 상기 식품 조성물은 상술한 성분 외에 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 식품 조성물은 천연 과일쥬스, 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다.In addition, the food composition contains, in addition to the above-mentioned ingredients, various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, and glycerin. , alcohol, and carbonating agents used in carbonated beverages. In addition, the food composition of the present invention may contain pulp for the production of natural fruit juice, beverages, and vegetable beverages. These ingredients can be used independently or in combination.
한편, 본 발명의 구체적 실시예에서 화학식 1의 화합물은 세포독성이 없는 무해한 물질임이 확인되었다. 따라서, 본 발명의 유효성분인 화학식 1의 화합물 또는 이의 염은 독성이 거의 없어 장기간 사용시에도 안심하고 사용할 수 있으며, 특히 상기한 바와 같은 약학적, 화장료, 또는 식품 조성물에 유용하게 사용할 수 있다.Meanwhile, in a specific example of the present invention, the compound of Formula 1 was confirmed to be a harmless substance without cytotoxicity. Therefore, the compound of Formula 1 or its salt, which is the active ingredient of the present invention, has little toxicity and can be used safely even for long-term use, and can be particularly useful in pharmaceutical, cosmetic, or food compositions as described above.
본 발명의 화학식 1의 구조를 갖는 바이텍스 에이(Vitex A) 화합물은 신규 화합물이며, 상기 화학식 1의 바이텍스 에이(Vitex A) 및 이의 염은 세포 독성이 없으면서 세포 내 NO 생성을 저해하고 염증성 사이토카인을 저해하는 효과를 나타내므로 염증을 예방 또는 치료하기 위한 조성물로서 약학적, 화장료, 또는 식품 조성물에 유용하게 사용할 수 있다.The Vitex A compound having the structure of Formula 1 of the present invention is a new compound, and Vitex A of Formula 1 and its salts inhibit intracellular NO production without cytotoxicity and inhibit inflammatory cytotoxicity. Since it has the effect of inhibiting cain, it can be usefully used in pharmaceutical, cosmetic, or food compositions as a composition for preventing or treating inflammation.
도 1은 본 발명의 일 실시예에 따른 순비기나무의 가지로부터 추출물 및 분획물을 제조하는 공정을 도시한 그림이다.
도 2는 본 발명의 일 실시예에 따른 순비기나무 에탄올 추출물의 부탄올 분획물로부터 화학식 1의 바이텍스 에이(Vitex A) 화합물을 분리하는 방법을 도시한 그림이다.
도 3은 본 발명의 일 실시예에 따른 화학식 1의 화합물의 동정에 대한 성상, 분자량, 질량분석, 1H-NMR스펙트럼 및 13C-NMR스펙트럼 측정 결과를 나타낸 그림이다.
도 4는 본 발명의 일 실시예에 따른 화학식 1의 화합물의 RAW 264.7 세포 내 NO 생성 억제 정도를 나타낸 그림이다.
도 5는 본 발명의 일 실시예에 따른 화학식 1의 화합물의 RAW 264.7 세포에 대한 세포 독성 정도를 나타낸 그림이다.
도 6은 본 발명의 일 실시예에 따른 화학식 1의 화합물의 염증성 사이토카인 IL-8의 저해 효과를 나타낸 그림이다.
도 7은 본 발명의 일 실시예에 따른 화학식 1의 화합물의 HT-29 세포에 대한 세포 독성 정도를 나타낸 그림이다.Figure 1 is a diagram illustrating a process for producing extracts and fractions from branches of Sunbigi tree according to an embodiment of the present invention.
Figure 2 is a diagram illustrating a method for separating the Vitex A compound of Formula 1 from the butanol fraction of the ethanol extract of Siberia chinensis according to an embodiment of the present invention.
Figure 3 is a diagram showing the measurement results of property, molecular weight, mass spectrometry, 1 H-NMR spectrum, and 13 C-NMR spectrum for the identification of the compound of Formula 1 according to an embodiment of the present invention.
Figure 4 is a diagram showing the degree of inhibition of NO production in RAW 264.7 cells by the compound of Formula 1 according to an embodiment of the present invention.
Figure 5 is a diagram showing the degree of cytotoxicity of the compound of Formula 1 on RAW 264.7 cells according to an embodiment of the present invention.
Figure 6 is a diagram showing the inhibitory effect of the compound of Formula 1 on the inflammatory cytokine IL-8 according to an embodiment of the present invention.
Figure 7 is a diagram showing the degree of cytotoxicity of the compound of Formula 1 to HT-29 cells according to an embodiment of the present invention.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, to aid understanding of the present invention, it will be described in detail through examples. However, the embodiments according to the present invention may be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
실시예 1: 화합물의 분리 및 동정Example 1: Separation and identification of compounds
1-1. 화합물의 분리1-1. Separation of compounds
순비기 가지 분말(건조 중량 2 kg)에 80% EtOH를 가하여 90분 동안 37 ℃에서 초음파 기기를 이용하여 추출하고 여과와 감압농축하여 에탄올 추출물 약 39.68 g을 얻었다. 상기 순비기 추출물을 증류수에 현탁시킨 후, 도 1에 제시된 바와 같이 용매의 극성에 따라 헥산 분획물(1.0 g), 클로로포름 분획물 (1.53 g), 에틸아세테이트 분획물 (9.88 g), 부탄올 분획물(9.79 g), 및 물 분획물 (15.33 g)을 얻었다.80% EtOH was added to pure boiled eggplant powder (dry weight 2 kg), extracted using an ultrasonic device at 37°C for 90 minutes, filtered, and concentrated under reduced pressure to obtain about 39.68 g of ethanol extract. After suspending the pure boiling extract in distilled water, hexane fraction (1.0 g), chloroform fraction (1.53 g), ethyl acetate fraction (9.88 g), and butanol fraction (9.79 g) according to the polarity of the solvent as shown in Figure 1. , and water fraction (15.33 g) were obtained.
상기 부탄올 분획물을 대상으로 순상 컬럼 크로마토크래피 (클로로포름 (C) 및 메탄올 (MeOH), 물의 혼합용매 (50:1:0.001 부피비) → 100 % 메탄올 (MeOH))를 이용하여 8개의 분획물 (B1-B8)을 얻었다. 이 중 B5 분획물을 겔 투과 크로마토그래피 (물 및 메탄올 (MeOH)의 혼합용매 (1:1 부피비))를 이용하여 11개의 분획물 (B5A-B5K)을 얻었다. 얻은 B5A 분획물을 역상 고성능액체크로마토그래피 (물 및 아세토니트릴 (ACN)의 혼합용매 (95:5 부피비) → 100% 아세토니트릴 (ACN))를 이용하여 5 mL/ min 유속으로 분리하면서 254 nm에서 UV검출기로 분석하여, 10개의 소분획물을 얻었고, 이 중 B5A8 소분획물을 역상 고성능액체크로마토그래피 (물 및 아세토니트릴 (ACN)의 혼합용매 (80:20 부피비) → 100 % 아세토니트릴 (ACN))를 이용하여 3 mL/min 유속으로 분리하면서 254 nm에서 UV검출기로 분석하여, 최종적으로 화합물 1 (2.9 mg)을 분리하였고, 상기 화합물의 용출 시간은 22.8 분이었다 (도 2 참조).For the butanol fraction, eight fractions (B1- B8) was obtained. Among these, 11 fractions (B5A-B5K) were obtained for the B5 fraction using gel permeation chromatography (mixed solvent of water and methanol (MeOH) (1:1 volume ratio)). The obtained B5A fraction was separated using reverse-phase high-performance liquid chromatography (mixed solvent of water and acetonitrile (ACN) (95:5 volume ratio) → 100% acetonitrile (ACN)) at a flow rate of 5 mL/min and UV at 254 nm. By analyzing with a detector, 10 small fractions were obtained, of which the B5A8 small fraction was subjected to reverse-phase high-performance liquid chromatography (mixed solvent of water and acetonitrile (ACN) (80:20 volume ratio) → 100% acetonitrile (ACN)). Compound 1 (2.9 mg) was finally separated by separation at a flow rate of 3 mL/min and analysis with a UV detector at 254 nm, and the elution time of the compound was 22.8 minutes (see Figure 2).
1-2. 화합물 1의 동정1-2. Identification of Compound 1
상기 실시예 1-1에서 분리된 화합물의 구조 동정을 위하여, 성상, 분자량, 질량분석, 1H-NMR 스펙트럼 및 13C-NMR 스펙트럼을 측정하였다. 도 3에 나타난 바와 같이, 실시예 1-1에서 분리된 화합물 1은 무색의 무정형 상태로 얻어졌으며, 화합물의 1H-NMR 스펙트럼, 13C-NMR 스펙트럼 및 질량분석을 토대로 분자식은 C26H36O12, 분자량은 540.2207으로 결정하였다. 또한 UV 스펙트럼의 256 nm 파장에서 강한 흡수를 보여 이 화합물은 이리도이드 계열의 화합물임을 추정할 수 있었다.To identify the structure of the compound isolated in Example 1-1, properties, molecular weight, mass spectrometry, 1 H-NMR spectrum, and 13 C-NMR spectrum were measured. As shown in Figure 3, Compound 1 isolated in Example 1-1 was obtained in a colorless amorphous state, and the molecular formula was C 26 H 36 based on the 1 H-NMR spectrum, 13 C-NMR spectrum, and mass spectrometry of the compound. O 12 , molecular weight was determined to be 540.2207. In addition, it showed strong absorption at a wavelength of 256 nm in the UV spectrum, making it possible to assume that this compound was an iridoid series compound.
1H-NMR 스펙트럼에서 iridoid proton signal [δH 5.08 (1H, d, J = 6.1 Hz, H-1), 4.87 (1H, overlap, H-3), 2.00 (2H, m, H-4), 2.47 (1H, m, H-5), 4.67 (1H, d, J = 7.9 Hz, H-6), 5.79 (1H, brs, H-7), 2.92 (1H, t, J = 6.9 Hz, H-9), 5.01 (1H, d, J = 14.8 Hz, H-10a), 4.89 (1H, overlap, H-10b)]이 확인되었다. 또한 glycopyranosyl proton signal [δH 4.67 (1H, d, J = 7.9 Hz, H-1′), 3.22 (1H, dd, J = 9.2, 7.9 Hz, H-2′), 3.36 (1H, m, H-3′), 3.27 (overlap, H-4′), 3.28 (1H, m, H-5′), 3.85 (1H, m, H-6′a), 3.63 (1H, m, H-6′b)]과 [δ H 7.91 (2H, d, J = 8.9 Hz, H-2′′, 6′′), 6.84 (2H, d, J= 8.9 Hz, H-3′′,5′′)]을 통해 p-hydroxy benzoic을 확인하였고, methylene proton signal [δH 3.65 (1H, m, H-1′′′a), 3.49 (1H, m, H-1′′′b), 1.59 (1H, q, J = 6.6 Hz, H-2′′′), 1.40 (2H, m, H-3′′′)]과 methyl proton signal [δH 0.94 (3H, t, J = 7.4 Hz, H-4′′′)]이 관찰되었다. 1 In the H-NMR spectrum, iridoid proton signal [δ H 5.08 (1H, d, J = 6.1 Hz, H-1), 4.87 (1H, overlap, H-3), 2.00 (2H, m, H-4), 2.47 (1H, m, H-5), 4.67 (1H, d, J = 7.9 Hz, H-6), 5.79 (1H, brs, H-7), 2.92 (1H, t, J = 6.9 Hz, H -9), 5.01 (1H, d, J = 14.8 Hz, H-10a), 4.89 (1H, overlap, H-10b)] were confirmed. Additionally, the glycopyranosyl proton signal [ δH 4.67 (1H, d, J = 7.9 Hz, H-1′), 3.22 (1H, dd, J = 9.2, 7.9 Hz, H-2′), 3.36 (1H, m, H -3′), 3.27 (overlap, H-4′), 3.28 (1H, m, H-5′), 3.85 (1H, m, H-6′a), 3.63 (1H, m, H-6′) b)] and [ δ H 7.91 (2H, d, J = 8.9 Hz, H-2′′, 6′′), 6.84 (2H, d, J = 8.9 Hz, H-3′′,5′′) ], p -hydroxy benzoic was confirmed, and methylene proton signal [δ H 3.65 (1H, m, H-1′′′a), 3.49 (1H, m, H-1′′′b), 1.59 (1H , q, J = 6.6 Hz, H-2′′′), 1.40 (2H, m, H-3′′′)] and methyl proton signal [ δH 0.94 (3H, t, J = 7.4 Hz, H- 4′′′)] was observed.
13C-NMR 스펙트럼에서 9개의 iridoid carbon signal [δC 98.7 (C-1), 100 (C-3), 30.7 (C-4), 45.6 (C-5), 80.8 (C-6), 132.7 (C-7), 143.1 (C-8), 49 (C-9), 63.4 (C-10)]과 6개의 glycopyranosyl carbon signal [δC 99.2 (C-1′), 75 (C-2′), 78.3 (C-3′), 71.5 (C-4′), 78.2 (C-5′), 62.8 (C-6′)]과 1개의 carbonyl carbon signal [δ C 166.8 (C-7′′)], 6개의 p-hydroxy benzoic carbon signal [δ C 122.1 (C-1′′), 132.9 (C-2′′,6′′), 116.3 (C-3′′,5′′), 163.7 (C-4′′)], 3개의 methylene carbon signal [δ C 69.6 (C-1′′′), 32.9 (C-2′′′), 20.3 (C-3′′′)], 1개의 methyl carbon signal [δ C 14.3 (C-4′′′)], 신호를 확인하여 총 26개의 탄소신호를 확인하였다. 13 In the C-NMR spectrum, nine iridoid carbon signals [δ C 98.7 (C-1), 100 (C-3), 30.7 (C-4), 45.6 (C-5), 80.8 (C-6), 132.7 (C-7), 143.1 (C-8), 49 (C-9), 63.4 (C-10)] and six glycopyranosyl carbon signals [δ C 99.2 (C-1′), 75 (C-2′) ), 78.3 (C-3′), 71.5 (C-4′), 78.2 (C-5′), 62.8 (C-6′)] and one carbonyl carbon signal [ δ C 166.8 (C-7′′) )], six p -hydroxy benzoic carbon signals [ δC 122.1 (C-1′′), 132.9 (C-2′′ , 6′′), 116.3 (C-3′′,5′′), 163.7 (C-4′′′)], three methylene carbon signals [ δC 69.6 (C-1′′′), 32.9 (C-2′′′), 20.3 (C-3′′′)], one A total of 26 carbon signals were confirmed by checking the methyl carbon signal [ δ C 14.3 (C-4′′′)].
2D NMR COSY, HMQC, HMBC 스펙트럼을 통해 H-3와 C-1'''의 상관관계로 butyl 부분이 iridoid 골격의 C-3에 연결된 것을 확인하였고, p-hydroxy benzoic 그룹의 H-2′′, 6′′와 iridoid 골격의 H-10 교차 피크를 통해 carbonyl의 C-7′′에 연결됨을 확인하였다. 그리고 H-1' [δH 4.67 (1H, d, J = 7.9 Hz, H-1′)]과 C-1의 상관관계를 통하여 glycopyranosyl 그룹이 iridoid 골격의 C-1번에 위치함을 확인하였다.Through 2D NMR COZY, HMQC, and HMBC spectra, it was confirmed that the butyl portion was connected to C-3 of the iridoid skeleton through the correlation between H-3 and C-1''', and H-2'' of the p -hydroxy benzoic group. , it was confirmed that it was connected to C-7'' of carbonyl through the 6'' and H-10 cross peaks of the iridoid skeleton. And through the correlation between H-1' [δ H 4.67 (1H, d, J = 7.9 Hz, H-1′)] and C-1, it was confirmed that the glycopyranosyl group is located at position C-1 of the iridoid skeleton. .
또한 [C-1 (δC 98.7; δH 5.08 (1H, d, J = 6.1 Hz, H-1)]의 Chemical shift 값이 의자형 입체구조를 가지는 A 고리에서[C-1 (δC 98.7; δH 5.11 d, J = 5.5 Hz)]나타나는 값과 비슷하고, 보트형 입체구조를 가지는 A고리에서 보이는[C-1 (δC 95.5; δH 5.18 d, J = 6.7 Hz, H-1)] 값과 다른 값을 보여 이 화합물의 A 고리가 의자형 입체구조를 가짐을 확인하였다. H-1의 선택적인 1D-NOE irradiation에서 H-3과 H-6의 신호 변화를 나타내어 비교화합물인 Nisindaside와 비교했을 때 이 proton 들은 α-방향성을 가짐을 확인하였다. H-1과 H-6의 동일한 방향성과 H-5와 H-9의 교차피크는 NOESY의 상관관계에 의해 관찰되었다.In addition, the chemical shift value of [C-1 (δ C 98.7; δ H 5.08 (1H, d, J = 6.1 Hz, H-1)] is [C-1 (δ C 98.7) in the A ring, which has a chair-shaped three-dimensional structure. ; δ H 5.11 d, J = 5.5 Hz)], which is similar to the value shown in the A ring, which has a boat-shaped three-dimensional structure [C-1 (δ C 95.5; δ H 5.18 d, J = 6.7 Hz, H-1 )] value, which was different from the value, confirming that the A ring of this compound has a chair-shaped three-dimensional structure. Selective 1D-NOE irradiation of H-1 showed signal changes in H-3 and H-6, which were the comparative compounds. Compared to nisindaside, these protons were confirmed to have α -orientation. The same orientation of H-1 and H-6 and the cross peaks of H-5 and H-9 were observed by NOESY correlation.
이상의 결과를 문헌상의 데이터와 비교하여 화합물 1의 구조는 이리도이드 글리코시드(iridoid glycoside) 계열인 니신다시드(Nishindaside)와 유사하지만 1H-NMR 스펙트럼 및 13C-NMR 스펙트럼에서 Nishindaside에서 나타나는 methoxy proton signal 대신 methylene proton signal [δH 3.65 (1H, m, H-1′′′a), 3.49 (1H, m, H-1′′′b), 1.59 (1H, q, J = 6.6 Hz, H-2′′′), 1.40 (2H, m, H-3′′′)], methyl proton signal [δH 0.94 (3H, t, J = 7.4 Hz, H-4′′′)]의 부틸에스터 잔기가 2D NMR을 통해 확인되었고, 1D-NOE와 2D-NOESY를 통해 입체구조를 확인하였다. 이는 천연에서 처음 분리 보고되는 물질이며, 상기 분리 및 동정한 화합물을 바이텍스 에이(Vitex A)로 결정하였다.Comparing the above results with literature data, the structure of compound 1 is similar to Nishindaside, a member of the iridoid glycoside series, but the methoxy proton appearing in Nishindaside in the 1 H-NMR spectrum and 13 C-NMR spectrum Instead of signal, methylene proton signal [δ H 3.65 (1H, m, H-1′′′a), 3.49 (1H, m, H-1′′′b), 1.59 (1H, q, J = 6.6 Hz, H -2′′′), 1.40 (2H, m, H-3′′′)], butyl ester with methyl proton signal [δ H 0.94 (3H, t, J = 7.4 Hz, H-4′′′)] The residue was confirmed through 2D NMR, and the three-dimensional structure was confirmed through 1D-NOE and 2D-NOESY. This is the first substance isolated and reported from nature, and the isolated and identified compound was determined to be Vitex A.
실시예 2: 화합물의 염증 억제 활성 평가Example 2: Evaluation of anti-inflammatory activity of compounds
2-1. RAW 264.7 와 HT-29 세포주의 배양2-1. Culture of RAW 264.7 and HT-29 cell lines
마우스 유래 대식세포인 RAW 264.7 세포주와 인간 대장암 세포주인 HT-29는 한국 세포주 은행에서 구입하여 37 ℃ 배양기에서 공기(95%)와 이산화탄소(5%)의 혼합기체를 지속적으로 공급하며 10% FBS, 100 IU/mL penicillin, 100 ㎍/mL streptomycin을 포함하는 DMEM 배지로 배양하였다. 75T 플라스크에 배양하고 80% confluent 할 때 2일마다 교환하였다.RAW 264.7 cell line, a mouse-derived macrophage cell line, and HT-29, a human colon cancer cell line, were purchased from the Korean Cell Line Bank and continuously supplied with a mixture of air (95%) and carbon dioxide (5%) in an incubator at 37°C and 10% FBS. , 100 IU/mL penicillin, and 100 ㎍/mL streptomycin were cultured in DMEM medium. Cultured in 75T flasks and exchanged every 2 days when 80% confluent.
2-2. 염증 유도 및 추출물 처리2-2. Inflammation induction and extract treatment
마우스 유래 대식세포 RAW 264.7와 인간 대장암 세포 HT-29를 10% FBS, 100 IU/mL penicillin, 100 ㎍/mL streptomycin을 포함하는 DMEM 배지로 96 well plate에 각각(2x105, 3x105 cells/well)에 분주하고 24시간 안정화하였다. 상기 실시예 1-2에서 분리 및 동정한 화합물을 100 uM 농도로 처리하고 1시간 후 Lipopolysaccharide (LPS) 처리하고 각각 20시간, 12시간 배양하였다.Mouse-derived macrophages RAW 264.7 and human colon cancer cells HT-29 were cultured in DMEM medium containing 10% FBS, 100 IU/mL penicillin, and 100 ㎍/mL streptomycin in a 96-well plate (2x10 5 , 3x10 5 cells/well). ) and stabilized for 24 hours. The compounds isolated and identified in Example 1-2 were treated at a concentration of 100 uM, and after 1 hour, they were treated with lipopolysaccharide (LPS) and cultured for 20 hours and 12 hours, respectively.
2-3. NO 생성 억제능 측정2-3. Measurement of NO production inhibition ability
RAW 264.7 마우스 대식세포를 LPS로 자극한 후 샘플을 처리하였을 때의 NO 생성 억제능을 확인하였다. 샘플과 염증반응을 유도시킨 24시간 후 상층액을 96 well plate로 100 μL씩 옮긴 후 Griess reagent A와 B를 동량으로 혼합하여 10분 동안 암실에서 상온 반응시켜 microplate reader를 이용해 540 nm에서의 흡광을 측정하여 하기 실험식 1에 따라 NO 생성 저해 활성을 판단하였다.The ability to inhibit NO production was confirmed when RAW 264.7 mouse macrophages were stimulated with LPS and then treated with samples. After 24 hours of inducing the sample and inflammatory reaction, 100 μL of the supernatant was transferred to a 96 well plate, mixed with equal amounts of Griess reagent A and B, reacted at room temperature in the dark for 10 minutes, and absorbance was measured at 540 nm using a microplate reader. The NO production inhibitory activity was determined according to the following empirical formula 1.
[실험식 1][Empirical Formula 1]
그 결과, 도 4에 도시된 바와 같이, 본 발명에 따른 바이텍스 에이(Vitex A)는 100 μM 농도에서 13.8%의 NO 저해활성을 갖는 것을 확인하였다.As a result, as shown in FIG. 4, it was confirmed that Vitex A according to the present invention had a NO inhibitory activity of 13.8% at a concentration of 100 μM.
2-4. RAW 264.7 세포 생존률 측정2-4. RAW 264.7 cell viability measurement
마우스 대식세포 RAW 264.7에 염증반응을 유도시킨 24시간 후 혈청이 제거된(serum free) DMEM으로 교환한다. MTT 용액은 1/100의 부피로 0.5 mg/mL 농도로 처리하였고, 암실의 37 ℃ 환경에서 2시간 후 배지를 제거하고 200 μL의 DMSO를 이용해 formazan을 용해하였다. 540 nm에서의 흡광(absolbanse; Abs)을 측정하였고, 대조군과 비교하여 세포 생존률(%)을 하기 실험식 2로 계산하였다.After 24 hours of inducing an inflammatory response in mouse macrophages RAW 264.7, the cells were replaced with serum-free DMEM. The MTT solution was treated at a concentration of 0.5 mg/mL at 1/100 the volume, and after 2 hours in a dark room at 37°C, the medium was removed and formazan was dissolved using 200 μL of DMSO. Absorbance (Abs) at 540 nm was measured, and cell survival rate (%) compared to the control group was calculated using the following empirical formula 2.
[실험식 2][Empirical Formula 2]
그 결과, 도 5에 도시된 바와 같이, 바이텍스 에이(Vitex A)는 100 μM 농도에서 세포독성이 없음을 확인할 수 있었다.As a result, as shown in Figure 5, it was confirmed that Vitex A had no cytotoxicity at a concentration of 100 μM.
2-5. IL-8 생성 억제능 측정2-5. Measurement of IL-8 production inhibition ability
HT-29 인간 대장암세포를 LPS로 자극한 후 샘플을 처리하였을 때의 IL-8 생성 억제능을 확인하였다. 샘플과 염증반응을 유도시킨 12시간 후 상층액을 96 well plate로 100 μL씩 옮긴 후 ELISA Kit를 이용하여 진행 뒤 microplate reader를 이용해 540 nm에서 흡광을 측정하여 IL-8 생성 저해 활성을 판단하였다.The ability to inhibit IL-8 production was confirmed when HT-29 human colon cancer cells were stimulated with LPS and then treated with samples. After 12 hours of inducing the inflammatory response with the sample, 100 μL of the supernatant was transferred to a 96 well plate and processed using an ELISA kit. Then, absorbance was measured at 540 nm using a microplate reader to determine IL-8 production inhibitory activity.
[실험식 3][Empirical Formula 3]
그 결과, 도 6에 도시된 바와 같이, 본 발명에 따른 바이텍스 에이(Vitex A)는 100 μM 농도에서 55.49 %의 IL-8 저해활성을 갖는 것을 확인하였다.As a result, as shown in Figure 6, it was confirmed that Vitex A according to the present invention had an IL-8 inhibitory activity of 55.49% at a concentration of 100 μM.
2-6. HT-29 세포 생존률 측정2-6. HT-29 cell viability measurement
인간 대장암 세포 HT-29에 염증반응을 유도시킨 24시간 후 혈청이 제거된(serum free) DMEM으로 교환하였다. MTT 용액은 1/100의 부피로 0.5 mg/mL 농도로 처리하였고, 암실의 37 ℃ 환경에서 2시간 후 배지를 제거하고 200 μL의 DMSO를 이용해 formazan을 용해하였다. 540 nm에서의 흡광(absolbanse; Abs)을 측정하였고, 대조군과 비교하여 세포 생존률(%)을 상기 실험식 2로 계산하였다.After 24 hours of inducing an inflammatory response in human colon cancer cells HT-29, the cells were replaced with serum-free DMEM. The MTT solution was treated at a concentration of 0.5 mg/mL at 1/100 the volume, and after 2 hours in a dark room at 37°C, the medium was removed and formazan was dissolved using 200 μL of DMSO. Absorbance (absorbanse; Abs) at 540 nm was measured, and cell survival rate (%) compared to the control group was calculated using the above empirical formula 2.
도 7에 도시된 바와 같이, 본 발명에 따른 바이텍스 에이(Vitex A)는 100 μM 농도에서 세포독성이 없음을 확인할 수 있었다.As shown in Figure 7, it was confirmed that Vitex A according to the present invention had no cytotoxicity at a concentration of 100 μM.
Claims (4)
[화학식 1]
Vitex A compound having the structure of Formula 1 below.
[Formula 1]
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