KR102525843B1 - Anti-inflammatory composition comprising Liriodendron tulipifera extracts or alkamide isolated therefrom - Google Patents
Anti-inflammatory composition comprising Liriodendron tulipifera extracts or alkamide isolated therefrom Download PDFInfo
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- KR102525843B1 KR102525843B1 KR1020210088708A KR20210088708A KR102525843B1 KR 102525843 B1 KR102525843 B1 KR 102525843B1 KR 1020210088708 A KR1020210088708 A KR 1020210088708A KR 20210088708 A KR20210088708 A KR 20210088708A KR 102525843 B1 KR102525843 B1 KR 102525843B1
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- South Korea
- Prior art keywords
- compound
- inflammatory
- tulipiferamide
- isolated therefrom
- composition
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Abstract
본 발명은 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물에 관한 것으로, 구체적으로는 NO(Nitric Oxide) 형성을 억제하고 iNOS, COX-2 및 IL-1β의 발현을 억제하며 IRAK1 분해에 영향을 주지 않으면서 IKK 인산화를 억제하여 NF-κB 신호경로를 차단함으로써 항염활성을 갖는 것을 확인하였으며, 이를 이용하여 염증 예방 또는 치료에 기여할 것으로 기대된다.The present invention is a tulip tree ( Liriodendron tulipifera ) Relates to an anti-inflammatory composition containing an extract or a compound isolated therefrom, and specifically, inhibits NO (Nitric Oxide) formation, inhibits the expression of iNOS, COX-2 and IL-1β, and affects IRAK1 degradation. It was confirmed that it has anti-inflammatory activity by inhibiting IKK phosphorylation and blocking the NF-κB signaling pathway without giving it, and it is expected to contribute to the prevention or treatment of inflammation using this.
Description
본 발명은 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 Alkamide를 포함하는 항염증 조성물에 관한 것이다.The present invention is a tulip tree ( Liriodendron tulipifera ) extract or an anti-inflammatory composition containing Alkamide isolated therefrom.
염증 반응은 생체나 조직에 물리적 작용이나 화학적 물질, 세균 감염 등의 어떠한 기질적 변화를 가져오는 침습이 가해질 때 그 손상부위를 수복 재생하려는 기전으로, 일단 자극이 가해지면 국소적으로 히스타민, 세로토닌, 브라디키닌, 프로스타글란딘, HETE(hydroxyeicosatetraenoic acid), 류코트리엔과 같은 혈관 활성 물질이 유리되어 혈관 투과성이 증대되며, NF-κB에 의해 염증성 사이토카인이 증가하면서 염증을 유발한다. 이 염증은 정상 세포까지 손상시키고, 노화 유전자와 암 유전자 등 해로운 유전자를 깨우며, 만성 염증은 뇌졸중, 암, 비만, 관절염, 알츠하이머, 심장병, 우울증 등 각종 질환을 일으킬 수 있다.Inflammatory response is a mechanism to restore and regenerate the damaged area when a living organism or tissue is subjected to invasion that causes any organic change, such as physical action, chemical substance, or bacterial infection. Once stimulation is applied, histamine, serotonin, Vasoactive substances such as bradykinin, prostaglandin, HETE (hydroxyeicosatetraenoic acid), and leukotrienes are released to increase vascular permeability, and inflammatory cytokines are increased by NF-κB to induce inflammation. This inflammation damages even normal cells, awakens harmful genes such as aging genes and cancer genes, and chronic inflammation can cause various diseases such as stroke, cancer, obesity, arthritis, Alzheimer's, heart disease, and depression.
이러한 염증질환의 치료에는 고전적으로 프레드니솔론과 같은 스테로이드에 의한 염증 억제제, 나프록센과 같은 비스테로이드성 항염치료제(nonsteroidal anti-inflammatory drugs; NSAID) 및 사이클로스포린이나 FK506과 같이 칼슘 및 칼모듈린 의존성 단백인산화 효소인 칼시뉴린(calcineurin)에 결합하여 그 작용을 억제하는 면역억제제가 가장 많이 사용되어 왔다. 그러나 이러한 스테로이드를 비롯한 면역억제제들은 신독성, 감염, 임파종, 당뇨병, 진전(tremor), 두통, 설사, 고혈압, 오심, 신기능 장애 등의 부작용이 있어, 보다 안전한 천연물 유래 항염증제에 대한 연구가 활발히 진행되고 있다.Treatment of these inflammatory diseases has classically included steroidal anti-inflammatory drugs such as prednisolone, nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, and calcium- and calmodulin-dependent protein kinases such as cyclosporine or FK506. An immunosuppressive agent that binds to calcineurin and suppresses its action has been most commonly used. However, these steroids and other immunosuppressants have side effects such as renal toxicity, infection, lymphoma, diabetes, tremor, headache, diarrhea, high blood pressure, nausea, and renal dysfunction, so research on safer natural anti-inflammatory drugs is being actively conducted. there is.
튤립나무(Liriodendron tulipifera)는 목련목 목련과에 속하는 활엽교목. 북아메리카 원산으로 북아메리카 동부의 혼합 활엽수림에 분포한다. 큰 키로 자라고 가지 끝에 피는 꽃이 화초인 튤립과 매우 닮았다. 우리나라에는 고종 32년(1895)에 신작로 주변에 심을 가로수로 플라타너스(버즘나무), 양버들, 미루나무 등과 함께 수입되었다. 학명은 ‘백합꽃이 달리는 나무’라는 뜻이며, 뒷부분의 종명 역시 ‘커다란 튤립 꽃이 달린다’라는 뜻이다.Tulip tree ( Liriodendron) tulipifera ) is a broad-leaved arboreous tree belonging to the Magnoliaceae family. It is native to North America and is distributed in the mixed broad-leaved forests of eastern North America. The flowers that grow tall and bloom at the ends of branches are very similar to tulips. It was imported into Korea in the 32nd year of King Gojong (1895) as a street tree to be planted around Sinjak-ro, along with plane trees, sheep willows, and poplar trees. The scientific name means 'a tree with lily flowers', and the species name at the end also means 'a large tulip flower runs'.
튤립나무의 원산지는 미국 북부로, 나무 껍질은 아메리카 원주민에 의해 말라리아와 관련된 불규칙한 열을 치료하기 위한 약초로 사용되었다 (Graziosea 등, 2011). 세스퀴테르펜 락톤, 아포르핀 알칼로이드, 페닐프로파노이드 및 리그난 등이 튤립나무로부터 분리되었으며 (Muhammad 등, 1989; Lee 등, 2013), 이 중 코스투놀리드와 에피툴리피놀리드를 포함하는 세스퀴테르펜 락톤, 리리오데닌, 툴리페 롤린을 포함한 아포르핀 알칼로이드가이 식물에서 항산화 및 항암 활성을 나타내는 주요 성분으로 보고되었다 (Eliza 등, 2010; Nordin 등, 2015). 그러나, 오랜기간 약초로 사용되어 온 튤립나무의 생물학적 활성 연구와 이러한 활성을 갖는 화학물질의 분리 및 구조적 분석은 아직 미미한 실정이다. The tulip tree is native to the northern United States, and its bark was used as a medicinal herb by Native Americans to treat irregular fever associated with malaria (Graziosea et al., 2011). Sesquiterpene lactones, aporphine alkaloids, phenylpropanoids, and lignans have been isolated from tulip trees (Muhammad et al., 1989; Lee et al., 2013), among which sesquiterpenes including costunolide and epitulipinolide have been isolated. Aporphin alkaloids, including quinterpene lactone, liriodenine, and tuliperolin, have been reported as major components exhibiting antioxidant and anticancer activities in this plant (Eliza et al., 2010; Nordin et al., 2015). However, research on the biological activity of the tulip tree, which has been used as a medicinal herb for a long time, and the isolation and structural analysis of chemicals having this activity are still insignificant.
종래선행기술인 한국공개특허 제1020140147430호에는 튤립나무 잎에서 수득한 에센셜 오일을 함유하는 항산화 및 항염증 조성물이 기재되어 있으나, 본 발명의 튤립나무로부터 분리한 alkamide를 포함하는 항염증 조성물과는 그 구성 및 효과에서 차이가 있다. 한국등록특허 제1619710호에는 튤립나무 태좌 세포 배양 추출물을 함유한 항노화 피부 외용제 조성물이 기재되어 있으나, 역시 본 발명의 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 Alkamide를 포함하는 항염증 조성물은 기재되어 있지 않다.Korea Patent Publication No. 1020140147430, which is a prior art, describes an antioxidant and anti-inflammatory composition containing essential oil obtained from tulip leaves, but is different from the anti-inflammatory composition containing alkamide isolated from tulip trees according to the present invention. and there is a difference in effect. Korean Patent No. 1619710 describes an anti-aging composition for external application for skin containing an extract of placenta cell culture of the tulip tree, but the anti-inflammatory composition containing the extract of Liriodendron tulipifera or Alkamide isolated therefrom not listed
본 발명의 목적은 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물을 제공하는 데 있다.An object of the present invention is a tulip tree ( Liriodendron tulipifera ) to provide an anti-inflammatory composition comprising an extract or a compound isolated therefrom.
상기 과제를 해결하기 위하여 본 발명은 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물을 제공한다.In order to solve the above problems, the present invention is a tulip tree ( Liriodendron tulipifera ) An anti-inflammatory composition comprising an extract or a compound isolated therefrom is provided.
상기 튤립나무 추출물은, 튤립나무 뿌리를 물, C1~4의 저급 알코올, 아세톤(acetone), 에틸아세테이트(ethyl acetate), 디에틸아세테이트(diethyl acetate), 디에틸에테르(diethyl ether), 벤젠(benzene), 클로로포름(chloroform) 및 헥산(hexane)으로 이루어진 군에서 선택되는 1종 또는 이들의 혼합용매로 추출한 추출물일 수 있으며, 바람직하게는 물, C1~4의 저급 알코올로 추출한 추출물이며, 더욱 바람직하게는 메탄올로 추출한 추출물이다.The tulip tree extract is water, C1-4 lower alcohol, acetone, ethyl acetate, diethyl acetate, diethyl ether, benzene ), it may be an extract extracted with one or a mixed solvent selected from the group consisting of chloroform and hexane, preferably an extract extracted with water and C1-4 lower alcohol, more preferably is an extract extracted with methanol.
상기 튤립나무 추출물은, 하기 화학식 [1]로 표현되는 tulipiferamide A (화합물 1), tulipiferamide B (화합물 2), tulipiferamide C (화합물 3) 및 dehydrotemisin (화합물 4), N-acetylanonaine (화합물 5), N-acetylnornuciferin (화합물 6), tuliferoline (화합물 7), N-acetyl-3-methoxynornantenine (화합물 8), lysicamine (화합물 9), liriodenine (화합물 10), atherospermidine (화합물 11), liridine (화합물 12), oxoglaucine (화합물 13), oxophoebine (화합물 14), (±)-virolongin A (화합물 15), (±)-virolongin B (화합물 16), (-)-virolongin C (화합물 17), (+)-syringaresinol (화합물 18), (-)(7'S,8R,8'R)-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9'-ol-7-one (화합물 19), (7'S,8R,8'R)-lariciresinol (화합물 20), (2S,3R)-dihydrodehydrodiconiferyl alcohol (화합물 21), costunolide (화합물 22), eupatolide (화합물 23), epi-tulipinolide (화합물 24), trans-N-feruloyl tyramine (화합물 25), trans-N-feruloyl-3-methoxytyramine (화합물 26), sakuranetin (화합물 27), 5,6,7-trimethoxycoumarin (화합물 28), methoxyeugenol (화합물 29), N-phenethylbenzamide (화합물 30), N-phenethyl-N-methylacetamide (화합물 31), vanillin (화합물 32) 및 4-hydroxybenzaldehyde (33)로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것을 특징으로 하는 항염증 조성물을 제공한다.The tulip tree extract is represented by the following Chemical Formula [1]: tulipiferamide A (Compound 1), tulipiferamide B (Compound 2), tulipiferamide C (Compound 3) and dehydrotemisin (Compound 4), N -acetylanonaine (Compound 5), N -acetylnornuciferin (Compound 6), tuliferoline (Compound 7), N -acetyl-3-methoxynornantenine (Compound 8), lysicamine (Compound 9), liriodenine (Compound 10), atherospermidine (Compound 11), liridine (Compound 12), oxoglaucine (Compound 13), oxophoebine (Compound 14), (±)-virolongin A (Compound 15), (±)-virolongin B (Compound 16), (-)-virolongin C (Compound 17), (+)-syringaresinol ( Compound 18), (-)(7 'S , 8R , 8'R )-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9'-ol -7-one (Compound 19), (7 'S , 8R , 8'R )-lariciresinol (Compound 20), ( 2S , 3R )-dihydrodehydrodiconiferyl alcohol (Compound 21), costunolide (Compound 22), eupatolide (Compound 23), epi -tulipinolide (Compound 24), trans - N -feruloyl tyramine (Compound 25), trans - N -feruloyl-3-methoxytyramine (Compound 26), sakuranetin (Compound 27), 5,6,7- selected from the group consisting of trimethoxycoumarin (Compound 28), methoxyeugenol (Compound 29), N -phenethylbenzamide (Compound 30), N -phenethyl- N -methylacetamide (Compound 31), vanillin (Compound 32) and 4-hydroxybenzaldehyde (33) It provides an anti-inflammatory composition comprising one or more.
화학식 [1]formula [1]
상기 튤립나무 추출물은, tulipiferamide A (화합물 1), dehydrotemisin (화합물 4), tuliferoline (화합물 7), lysicamine (화합물 9), liriodenine (화합물 10), oxophoebine (화합물 14), eupatolide (화합물 23), epi-tulipinolide (화합물 24), sakuranetin (화합물 27) 로 이루어진 군으로부터 선택되는 1 이상을 포함할 수 있다.The tulip extract, tulipiferamide A (Compound 1), dehydrotemisin (Compound 4), tuliferoline (Compound 7), lysicamine (Compound 9), liriodenine (Compound 10), oxophoebine (Compound 14), eupatolide (Compound 23), epi -tulipinolide (Compound 24) and sakuranetin (Compound 27) may include one or more selected from the group consisting of.
상기 튤립나무 추출물의 추출 방법으로는 열수추출법, 냉침추출법, 환류냉각추출법, 용매추출법, 수증기증류법, 초음파추출법, 용출법, 압착법 등의 방법 중 어느 하나를 선택하여 사용할 수 있으며, 목적하는 추출물은 추가로 통상의 분획 공정을 수행할 수도 있으며, 통상의 정제 방법을 이용하여 정제될 수도 있다. 상기 제조된 튤립나무 추출물은 원심분리, 여과, 농축 후 동결 건조하여 냉장실에 보관하면서 그대로 사용할 수도 있다. 또한, 상기 추출물을 실리카 겔 컬럼 크로마토그래피(silica gel columnchromatography), 박층 크로마토그래피(thin layer chromatography), 고성능 액체 크로마토그래피(high performance liquid chromatography) 등과 같은 다양한 크로마토그래피를 이용하여 추가로 정제된 분획을 얻고, 이를 정제하여 상기 화합물을 얻을 수 있다.As the extraction method of the tulip tree extract, any one of methods such as hot water extraction, cold brew extraction, reflux cooling extraction, solvent extraction, steam distillation, ultrasonic extraction, elution, and compression may be selected and used, and the desired extract is In addition, a conventional fractionation process may be performed, and it may be purified using a conventional purification method. The prepared tulip tree extract may be used as it is while being stored in a refrigerating chamber after centrifugation, filtration, and concentration followed by freeze-drying. In addition, the extract is further purified by using various chromatography methods such as silica gel column chromatography, thin layer chromatography, and high performance liquid chromatography to obtain a further purified fraction. , It can be purified to obtain the above compound.
상기 항염증 조성물은 NO(Nitric oxide)의 생성을 억제하는 것일 수 있으며, iNOS, COX-2 및 IL-1β의 발현을 억제하는 것을 특징으로 하는 항염증 조성물이다. 상기 항염증 조성물은 TLR4 신호전달 경로의 IKK 업스트림 인산화효소인 IRAK1 분해에 영향을 주지 않으면서 IKK 인산화를 억제하여 NF-κB 를 특이적으로 억제하는 것일 수 있다.The anti-inflammatory composition may inhibit the production of nitric oxide (NO) and inhibit the expression of iNOS, COX-2 and IL-1β. The anti-inflammatory composition may specifically inhibit NF-κB by inhibiting IKK phosphorylation without affecting degradation of IRAK1, an IKK upstream kinase of the TLR4 signaling pathway.
본 발명의 튤립나무 추출물로부터 분리한 화합물은 알카마이드일 수 있다. 본 발명의 튤립나무 추출물로부터 분리한 알카마이드(Alkamide)는 상기 화학식 [1]로 표현되는 튤리피페라마이드 (tulipiferamide A, 화합물 1), tulipiferamide B (화합물 2) 및 tulipiferamide C (화합물 3)로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것일 수 있다.The compound isolated from the tulip tree extract of the present invention may be an alkamide. Alkamide isolated from the tulip extract of the present invention consists of tulipiferamide A (compound 1), tulipiferamide B (compound 2) and tulipiferamide C (compound 3) represented by the above formula [1]. It may include one or more selected from the group.
본 발명의 튤립나무 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물은 약학적 조성물로 제조될 수 있다. 상기 항염증 조성물의 약학적 조성물은 전체 약학적 조성물 총 중량에 대하여 바람직하게는 0.001~50 중량%, 더 바람직하게는 0.001~40 중량%, 가장 바람직하게는 0.001~30 중량%로 하여 첨가될 수 있다. An anti-inflammatory composition comprising the tulip tree extract or a compound isolated therefrom of the present invention can be prepared as a pharmaceutical composition. The pharmaceutical composition of the anti-inflammatory composition is preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight, most preferably 0.001 to 30% by weight based on the total weight of the total pharmaceutical composition. there is.
상기 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 액제, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균주사용액의 형태로 제형화하여 사용될 수 있다. 상기 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제, 감미제, 산미제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 튤립나무 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토즈, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제, 산미제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween)-61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical composition is formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, liquids, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, respectively. can Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants, sweeteners, and acidulants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient, For example, it is prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, preservatives, and acidulants are used. can be included Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. As a base for the suppository, witepsol, macrogol, tween-61, cacao butter, laurin paper, glycerogeratin, and the like may be used.
본 발명의 약학적 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중과, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여 경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 500㎎/㎏/일의 범위이다. 바람직한 투여량은 0.1㎎/㎏/일 내지 200㎎/㎏/일이며, 더 바람직한 투여량은 1㎎/㎏/일 내지 200㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the prescriber's judgment. Determination of dosage based on these factors is within the level of those skilled in the art, and generally dosages range from 0.01 mg/kg/day to approximately 500 mg/kg/day. A preferred dose is 0.1 mg/kg/day to 200 mg/kg/day, and a more preferred dose is 1 mg/kg/day to 200 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.
본 발명의 약학적 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사 및 피부 도포에 의해 투여될 수 있다. 본 발명의 튤립나무 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있는 약제이다.The pharmaceutical composition of the present invention can be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, eg oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection and dermal application. The anti-inflammatory composition containing the tulip tree extract or a compound isolated therefrom of the present invention has little toxicity and side effects, so it is a drug that can be safely used even when taken for a long period of time for preventive purposes.
본 발명은 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 건강기능식품을 제공한다. 상기 튤립나무 추출물로부터 분리한 화합물은 상기 화학식 [1]로 표현되는 tulipiferamide A (화합물 1), tulipiferamide B (화합물 2), tulipiferamide C (화합물 3) 및 dehydrotemisin (화합물 4), N-acetylanonaine (화합물 5), N-acetylnornuciferin (화합물 6), tuliferoline (화합물 7), N-acetyl-3-methoxynornantenine (화합물 8), lysicamine (화합물 9), liriodenine (화합물 10), atherospermidine (화합물 11), liridine (화합물 12), oxoglaucine (화합물 13), oxophoebine (화합물 14), (±)-virolongin A (화합물 15), (±)-virolongin B (화합물 16), (-)-virolongin C (화합물 17), (+)-syringaresinol (화합물 18), (-)(7'S,8R,8'R)-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9'-ol-7-one (화합물 19), (7'S,8R,8'R)-lariciresinol (화합물 20), (2S,3R)-dihydrodehydrodiconiferyl alcohol (화합물 21), costunolide (화합물 22), eupatolide (화합물 23), epi-tulipinolide (화합물 24), trans-N-feruloyl tyramine (화합물 25), trans-N-feruloyl-3-methoxytyramine (화합물 26), sakuranetin (화합물 27), 5,6,7-trimethoxycoumarin (화합물 28), methoxyeugenol (화합물 29), N-phenethylbenzamide (화합물 30), N-phenethyl-N-methylacetamide (화합물 31), vanillin (화합물 32) 및 4-hydroxybenzaldehyde (33)로 이루어진 군으로부터 선택되는 1 이상일 수 있다.The present invention is a tulip tree ( Liriodendron tulipifera ) Provides an anti-inflammatory health functional food containing an extract or a compound isolated therefrom. The compounds isolated from the tulip extract are tulipiferamide A (Compound 1), tulipiferamide B (Compound 2), tulipiferamide C (Compound 3) and dehydrotemisin (Compound 4), N -acetylanonaine (Compound 5) represented by Formula [1]. ), N -acetylnornuciferin (Compound 6), tuliferoline (Compound 7), N -acetyl-3-methoxynornantenine (Compound 8), lysicamine (Compound 9), liriodenine (Compound 10), atherospermidine (Compound 11), liridine (Compound 12) ), oxoglaucine (Compound 13), oxophoebine (Compound 14), (±)-virolongin A (Compound 15), (±)-virolongin B (Compound 16), (-)-virolongin C (Compound 17), (+) -syringaresinol (Compound 18), (-)(7 'S , 8R , 8'R )-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9 '-ol-7-one (Compound 19), (7' S ,8 R ,8' R )-lariciresinol (Compound 20), (2 S ,3 R )-dihydrodehydrodiconiferyl alcohol (Compound 21), costunolide (Compound 22 ), eupatolide (Compound 23), epi -tulipinolide (Compound 24), trans - N -feruloyl tyramine (Compound 25), trans - N -feruloyl-3-methoxytyramine (Compound 26), sakuranetin (Compound 27), 5,6 A group consisting of 7-trimethoxycoumarin (Compound 28), methoxyeugenol (Compound 29), N -phenethylbenzamide (Compound 30), N -phenethyl- N -methylacetamide (Compound 31), vanillin (Compound 32) and 4-hydroxybenzaldehyde (33) It may be one or more selected from.
상기 건강기능식품은 튤립나무 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물이 전체 식품 총 중량에 대하여 바람직하게는 0.001~50 중량%, 더 바람직하게는 0.001~30 중량%, 가장 바람직하게는 0.001~10중량%로 하여 첨가될 수 있다.The health functional food is preferably 0.001 to 50% by weight, more preferably 0.001 to 30% by weight, most preferably 0.001 to 30% by weight of the anti-inflammatory composition containing the tulip tree extract or a compound isolated therefrom, based on the total weight of the total food. It may be added as 0.001 to 10% by weight.
상기 건강기능식품은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 추출물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강기능성식품류 등이 있다.The health functional food includes the form of tablets, capsules, pills or liquids, and foods to which the extract of the present invention can be added include, for example, various foods, beverages, gum, tea, vitamin complexes, health functional foods, etc.
본 발명은 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 화장료 조성물을 제공한다. 본 발명의 튤립나무 추출물로부터 분리한 화합물은 상기 화합물 1 내지 33 으로 구성된 군으로부터 선택된 1 이상일 수 있다. 본 발명의 튤립나무 추출물로부터 분리한 화합물은 알카마이드일 수 있으며, 상기 화학식 [1]로 표현되는 알카마이드일 수 있다.The present invention is a tulip tree ( Liriodendron tulipifera ) Provides an anti-inflammatory cosmetic composition comprising an extract or a compound isolated therefrom. The compound isolated from the tulip tree extract of the present invention may be one or more selected from the group consisting of the
상기 화장료 조성물은 튤립나무 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물이 전체 식품 총 중량에 대하여 바람직하게는 0.001~50 중량%, 더 바람직하게는 0.001~30 중량%, 가장 바람직하게는 0.001~10 중량%로 하여 첨가될 수 있다.The cosmetic composition is preferably 0.001 to 50% by weight, more preferably 0.001 to 30% by weight, most preferably 0.001% by weight of the anti-inflammatory composition containing the tulip tree extract or a compound isolated therefrom, based on the total weight of the total food. ~10% by weight can be added.
상기 화장료 조성물은 화장품학 또는 피부과학적으로 허용가능한 매질 또는 기제를 함유한다. 이는 국소적용에 적합한 모든 제형으로, 예를 들면, 용액, 겔, 고체, 반죽 무수 생성물, 수상에 유상을 분산시켜 얻은 에멀젼, 현탁액, 마이크로에멀젼, 마이크로캡슐, 미세과립구, 또는 이온형(리포좀) 및 비이온형의 소낭 분산제의 형태로, 또는 크림, 스킨, 로션, 파우더, 연고, 스프레이 또는 콘실 스틱의 형태로 제공될 수 있다. 이들 조성물은 당해 분야의 통상적인 방법에 따라 제조될 수 있다. 본 발명에 따른 조성물은 또한 포말(foam)의 형태로 또는 압축된 추진제를 더 함유한 에어로졸 조성물의 형태로도 사용될 수 있다.The cosmetic composition contains a cosmetically or dermatologically acceptable medium or base. These are all formulations suitable for topical application, for example solutions, gels, solids, pasty anhydrous products, emulsions obtained by dispersing an oil phase in an aqueous phase, suspensions, microemulsions, microcapsules, microgranules, or ionic forms (liposomes) and It may be provided in the form of a non-ionic follicular dispersant, or in the form of a cream, toner, lotion, powder, ointment, spray or conceal stick. These compositions can be prepared according to conventional methods in the art. The composition according to the invention can also be used in the form of a foam or in the form of an aerosol composition further containing a compressed propellant.
본 발명의 화장료 조성물은 지방 물질, 유기용매, 용해제, 농축제, 겔화제, 연화제, 항산화제, 현탁화제, 안정화제, 발포제(foaming agent), 방향제, 계면활성제, 물, 이온형 또는 비이온형 유화제, 충전제, 금속이온봉쇄제, 킬레이트화제, 보존제, 비타민, 차단제, 습윤화제, 필수 오일, 염료, 안료, 친수성 또는 친유성 활성제, 지질 소낭 또는 화장품에 통상적으로 사용되는 임의의 다른 성분과 같은 화장품학 또는 피부과학 분야에서 통상적으로 사용되는 보조제를 함유할 수 있다. 상기 보조제는 화장품학 또는 피부과학 분야에서 일반적으로 사용되는 양으로 추가된다.The cosmetic composition of the present invention contains a fatty substance, an organic solvent, a solubilizing agent, a thickening agent, a gelling agent, a softening agent, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, water, ionic or nonionic Cosmetics such as emulsifiers, fillers, sequestering agents, chelating agents, preservatives, vitamins, blocking agents, humectants, essential oils, dyes, pigments, hydrophilic or lipophilic actives, lipid vesicles or any other ingredient commonly used in cosmetics or adjuvants commonly used in the field of dermatology. The adjuvant is added in an amount generally used in the field of cosmetology or dermatology.
본 발명의 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 화장료 조성물은 그 제형에 있어서 특별히 한정되는 바가 없으며, 예를 들면, 유연화장수, 수렴화장수, 영양화장수, 영양크림, 마사지크림, 에센스, 아이크림, 아이에센스, 클렌징크림, 클렌징폼, 클렌징워터, 팩, 파우더, 바디로션, 바디크림, 바디오일 및 바디에센스 등의 화장료로 제형화될 수 있다.Tulip tree of the present invention ( Liriodendron tulipifera ) The anti-inflammatory cosmetic composition containing an extract or a compound isolated therefrom is not particularly limited in its formulation, for example, softening lotion, astringent lotion, nutrient lotion, nutrient cream, massage cream, essence, eye cream , Eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil and body essence can be formulated into cosmetics.
본 발명은 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 화합물을 포함하는 항염증 조성물에 관한 것으로, 구체적으로는 NO(Nitric Oxide) 형성을 억제하고 iNOS, COX-2 및 IL-1β의 발현을 억제하며 IRAK1 분해에 영향을 주지 않으면서 IKK 인산화를 억제하여 NF-κB 신호경로를 차단함으로써 항염활성을 갖는 것을 확인하였으며, 이를 이용하여 염증 예방 또는 치료에 기여할 것으로 기대된다.The present invention is a tulip tree ( Liriodendron tulipifera ) Relates to an anti-inflammatory composition containing an extract or a compound isolated therefrom, and specifically, inhibits NO (Nitric Oxide) formation, inhibits the expression of iNOS, COX-2 and IL-1β, and affects IRAK1 degradation. It was confirmed that it has anti-inflammatory activity by inhibiting IKK phosphorylation and blocking the NF-κB signaling pathway without giving it, and it is expected to contribute to the prevention or treatment of inflammation using this.
도 1은 본 발명에 따른 화합물 1~3의 화학구조를 나타낸 것이다.
도 2는 본 발명에 따른 화합물 1~3의 주요 HMBC 와 COSY 관계 (A) 및 화합물 4의 화학구조 및 주요 HMBC, COSY 관계를 나타낸 것이다.
도 3은 본 발명에 따른 화합물 1~33의 RAW 264.7 세포에 대한 세포 독성 결과를 나타낸 것이다.
도 4는 RAW264.7 대식세포에서 LPS 유발 염증 반응에 대한 tulipiferamide A (LT-1, 화합물 1)의 효과를 나타낸 것이다. (A) RAW 264.7 대식세포를 30 분 동안 tulipiferamide A (30 μM)로 무처리(None) 또는 전처리(LT-1)된 후 표시된 시간(0, 3, 6, 12 시간) 동안 1 μM LPS로 처리된 각 샘플의 iNOS, COX-2, IL-1β에 대한 면역 블롯팅 결과 (B) (A)의 각 샘플 total RNA에서 iNOS, COX-2, IL-1β, TNFα, IL-6 및 GAPDH의 RT-PCR 결과
도 5는 RAW264.7 대식세포에서 LPS 유발 염증 반응에 대한 Tulipiferamide A (LT-1, 1)의 작용기전을 나타낸 것이다. (A) RAW 264.7 대식세포에 30 분 동안 tulipiferamide A (30 μM)를 부재(None) 또는 존재(LT-1) 하에 표시된 시간(0, 5, 15, 30, 60분) 동안 1 μM LPS로 처리된 각 샘플의 IRAK1, IKKα/β, p65, ERK, JNK, p38 및 인산화된 각 단백질의 면역 블롯팅 결과 (B) 플래그-태그된 IKKβ를 발현하는 플라스미드로 형질 감염된 HEK293 세포에 튤립페라미드 A (LT-1, 화합물 1) (30 μM)의 부재 또는 존재하에 24 시간 동안 처리된 후 면역 블롯팅 결과1 shows the chemical structures of
Figure 2 shows the main HMBC and COSY relationship of
Figure 3 shows the cytotoxicity results for RAW 264.7 cells of
Figure 4 shows the effect of tulipiferamide A (LT-1, Compound 1 ) on the LPS-induced inflammatory response in RAW264.7 macrophages. (A) RAW 264.7 macrophages were treated (None) or pre-treated (LT-1) with tulipiferamide A (30 µM) for 30 minutes and then treated with 1 µM LPS for the indicated times (0, 3, 6, 12 hours). (B) RT of iNOS, COX-2, IL-1β, TNFα, IL-6, and GAPDH in total RNA of each sample in (A) -PCR result
Figure 5 shows the mechanism of action of Tulipiferamide A (LT-1, 1) on the LPS-induced inflammatory response in RAW264.7 macrophages. (A) RAW 264.7 macrophages were treated with 1 μM LPS for the indicated times (0, 5, 15, 30, 60 min) in the absence (None) or presence (LT-1) of tulipiferamide A (30 μM) for 30 min. Immunoblotting results of IRAK1, IKKα/β, p65, ERK, JNK, p38, and each phosphorylated protein of each sample obtained (B) HEK293 cells transfected with a plasmid expressing flag-tagged IKKβ were treated with tulipperamide A ( Immunoblotting results after treatment for 24 hours in the absence or presence of LT-1, compound 1 ) (30 μM)
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the disclosure herein is provided so that it will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.
<< 실시예Example 1. 튤립나무( 1. Tulip tree ( LiriodendronLiriodendron tulipiferatulipifera ) 추출물 및 이로부터 분리된 화합물>) extracts and compounds isolated therefrom>
튤립나무(Liriodendron tulipifera)의 뿌리는 2016 년 8 월 충남대학교에서 채취되었으며, 바우처 표본 (CNU201608)은 대전 충남대학교 약학대학 약리학연구소에 기탁되었다.Tulip tree ( Liriodendron) tulipifera ) was collected at Chungnam National University in August 2016, and the voucher specimen (CNU201608) was deposited at the Pharmacology Research Institute, College of Pharmacy, Chungnam National University, Daejeon.
상기 튤립나무(Liriodendron tulipifera)의 뿌리 (15.0 kg)을 에탄올로 2 회 (7 days × 100 L) 추출하였다. 추출물을 회전 증발에 의해 감압하에 농축하여 튤립나무 조추출물(crude extract) 887.3 g을 얻었으며 이 중, 239.3g 을 실험에 사용하였다.The tulip tree ( Liriodendron tulipifera ) roots (15.0 kg) were extracted twice (7 days × 100 L) with ethanol. The extract was concentrated under reduced pressure by rotary evaporation to obtain 887.3 g of a crude extract of tulip tree, of which 239.3 g was used in the experiment.
상기 조추출물을 현탁하여 실리카겔 VLC에 적용하고, n-헥산 -에틸아세테이트(8:2, 5:5, 3:7, 1:9; 각 단계 6 L) 및 CHCl3-MeOH (9:1, 7:3, 5:5, 2:8; 각 단계 6 L; 최종 100% MeOH 10L로 세척)의 단계적 구배로 용출시켜 7개의 분획물(LT1_LT7)을 제조하였다. 분획물 LT2(24.1g)을 MeOH-H2O (7:3, 8:2, 9:1, 10:0, MeCN 100%)에서 단계별 용출로 역상 MPLC (Biotage SNAP cartridge, KP-C18-HS, 400 g) 를 통해 크로마토그래피하여 11개의 소분획물 (LT2-1 ~ LT2-11)을 얻었다. 화합물 32 (11.4 mg, t R = 37.2 min) 및 33 (3.6 mg, t R = 35.5 min)은 LT2-1 (115.5 mg)을 MeOH-H2O (40:60 → 50:50)의 용매조성으로 HPLC (Hector C18 column)를 실시하여 수득하였다. 화합물 28 (5.1 mg, t R = 31.4 min)는 분획물 LT2-2 (106.2 mg)를 MeCN-H2O (50:50 → 65:35)의 이동상으로 역상 HPLC (Hector C18 column)를 실시하여 수득하였다. 화합물 4 (49.3 mg, t R = 50.1 min), 23 (24.2 mg, t R = 51.9 min), 29 (74.0 mg, t R = 47.9 min), 및 30 (38.9 mg, t R = 49.5 min)은 분획물 LT2-3 (481.5 mg)을 MeCN-H2O (40:60 → 100:30) 의 선형구배 HPLC (Hector C18 column) 로 분리하였다. 분획물 LT2-4-1 (5.41 g) 및 LT2-5-1 (1.4 g) 는 메탄올 가용 분획 LT2-4 (8.5 g) 및 LT2-5 (2.5 g) 로부터 각각 얻었다. 분획물 LT2-4-1 는 n-hexane-EtOAc (8:2, 7:3, 5:5, MeOH 100%)의 단계구배 시스템으로 MPLC (Biotage SNAP Ultra cartridge, KP-Sil, 100 g) 에 의해 8개의 소분획 (LT2-4-1-1 ~ LT2-4-1-8) 으로 분리되었다. 이 중 LT2-4-1-5 (3.1 g)을 MeCN-H2O (50:50 → 60:40)의 구배 혼합으로 용출하는 HPLC (Phenomenex C18 column)로 순수분리하여 화합물 24 (10.5 mg, t R = 42.8 min)를 수득하였다.The crude extract was suspended and applied to silica gel VLC, and n-hexane-ethylacetate (8:2, 5:5, 3:7, 1:9; 6 L each step) and CHCl 3 -MeOH (9:1, Seven fractions (LT1_LT7) were prepared by elution with a stepwise gradient of 7:3, 5:5, 2:8; 6 L each step; final wash with 10 L 100% MeOH). Fraction LT2 (24.1 g) was purified by reverse - phase MPLC (Biotage SNAP cartridge, KP-C18-HS, 400 g) to obtain 11 small fractions (LT2-1 to LT2-11). Compounds 32 (11.4 mg, t R = 37.2 min) and 33 (3.6 mg, t R = 35.5 min) were obtained by preparing LT2-1 (115.5 mg) with a solvent composition of MeOH-H 2 O (40:60 → 50:50) It was obtained by performing HPLC (Hector C 18 column). Compound 28 (5.1 mg, t R = 31.4 min) was obtained by performing reverse-phase HPLC (Hector C 18 column) on fraction LT2-2 (106.2 mg) as a mobile phase of MeCN-H 2 O (50:50 → 65:35) obtained. Compounds 4 (49.3 mg, t R = 50.1 min), 23 (24.2 mg, t R = 51.9 min), 29 (74.0 mg, t R = 47.9 min), and 30 (38.9 mg, t R = 49.5 min) Fraction LT2-3 (481.5 mg) was separated by MeCN-H 2 O (40:60 → 100:30) linear gradient HPLC (Hector C 18 column). Fractions LT2-4-1 (5.41 g) and LT2-5-1 (1.4 g) were obtained from methanol-soluble fractions LT2-4 (8.5 g) and LT2-5 (2.5 g), respectively. Fraction LT2-4-1 was purified by MPLC (Biotage SNAP Ultra cartridge, KP-Sil, 100 g) with a step gradient system of n -hexane-EtOAc (8:2, 7:3, 5:5,
LT2-5-1는 n-haxane-EtOAc (8:2, 7:3, 5:5, 3:7, 1:9, MeOH 100%) 용출을 이용한 MPLC (Biotage SNAP Ultra cartridge, KP-Sil, 100 g) 로 수행하여 6개의 소분획 (LT2-5-1-1 ~ LT2-5-1-6)을 얻었으며, 이들 중, 분획 LT2-5-1-3 (732.6 mg) 및 LT2-5-1-4 (321.4 mg)을 역상 HPLC [Phenomenex, MeCN-H2O (60:40 → 70:30)] 하여 화합물 22 (235.4 mg, t R = 34.3 min) 및 27 (3.1 mg, t R = 19.3 min)을 수득하였다. 화합물 15 (19.3 mg, t R = 52.5 min) 및 16 (17.8 mg, t R = 50.3 min) 는 분획물 LT2-7 (238.3 mg)을 HPLC [Hector C18 column, MeCN-H2O (70:30 → 80:20)]를 통해 얻었다. 분획물 LT2-8 (264.6 mg) 에서는 MeCN-H2O (80:20 → 90:10)를 통한 역상 HPLC [Hector C18 column로 화합물 1 (17.1 mg, t R = 30.5 min), 2 (4.7 mg, t R = 35.6 min), 3 (5.1 mg, t R = 32.3 min), 및 17 (69.0 mg, t R = 36.8 min)이 분리되었다. LT2-5-1 was analyzed by MPLC (Biotage SNAP Ultra cartridge, KP-Sil, 100 g) to obtain 6 small fractions (LT2-5-1-1 to LT2-5-1-6), of which fractions LT2-5-1-3 (732.6 mg) and LT2-5 -1-4 (321.4 mg) was analyzed by reverse phase HPLC [Phenomenex, MeCN-H 2 O (60:40 → 70:30)] to give compounds 22 (235.4 mg, t R = 34.3 min) and 27 (3.1 mg, t R = 19.3 min). Compounds 15 (19.3 mg, t R = 52.5 min) and 16 (17.8 mg, t R = 50.3 min) were obtained by HPLC [Hector C 18 column, MeCN-H 2 O (70:30 → 80:20)]. In fractions LT2-8 (264.6 mg), MeCN-H 2 O (80:20 → 90:10) through reverse-phase HPLC [Hector C 18 column, compound 1 (17.1 mg, t R = 30.5 min), 2 (4.7 mg , t R = 35.6 min), 3 (5.1 mg, t R = 32.3 min), and 17 (69.0 mg, t R = 36.8 min) were isolated.
분획물 LT4 (20.7 g) 에서는 MeOH-H2O (5:5, 7:3, 9:1, 10:0, MeCN 100%)의 단계구배 혼합을 이용한 MPLC (Biotage SNAP cartridge, KP-C18-HS, 400 g)으로 화합물 6 (300.4 mg) 및 6개의 소분획물 (LT4-1 ~ LT4-6)을 수득하였다. 분획물 LT4-2 (2.9 g) 는 MPLC [Biotage SNAP cartridge, KP-C18-HS, 120 g, MeOH-H2O (3:7 → 5:5, 5:5 → 10:0, MeOH 100%)]를 통해 8개의 소분획물 (LT4-2-1 ~ LT4-2-8)을 수득하였으며, 이 중 분획물 LT4-2-3 (716.6 mg) 는 등용매 용매 MeOH-H2O (40:60)를 이용한 HPLC (Phenomenex C18 column) 에 의해 4개의 소분획물 (LT4-2-3-1 ~ LT4-2-3-4)로 분리되었다. 분획물LT4-2-3-2 (241.7 mg) 및 LT4-2-3-4 (101.5 mg)에서는 MeOH-H2O (40:60) 등용매 조건의 prep. HPLC (Phenomenex C18 column) 로 화합물 19 (57.7 mg, t R = 44.2 min) 및 20 (15.0 mg, t R = 51.6 min)이 수득되었다. 분획물 LT4-2-4 (610.1 mg)은 반복적인 MeOH-H2O (50:50 → 55:45) 선형구배의 HPLC (Hector C18 column)를 통해 화합물 18 (222.8 mg, t R = 42.3 min), 31 (12.1 mg, t R = 59.8 min), 및 다섯 개의 소분획물 (LT4-2-4-1 ~ LT4-2-4-3, LT4-2-4-5, LT4-2-4-6)로 분리되었으며, 이 중, LT4-2-4-3 (40.7 mg) 에서 MeOH-H2O (50:50) 용출 HPLC (Phenomenex C18 column)를 이용하여 화합물 21 (15.2 mg, t R = 58.3 min)을 수득하였다. 화합물 25 (16.8 mg, t R = 44.8 min) 및 26 (25.6 mg, t R = 46.0 min)은 HPLC [Hector phenyl column, MeOH-H2O (50:50 → 60:40)로 분획물 LT4-2-5 (236.2 mg)에서 얻었다. 분획물 LT4-4 (0.7 g)에서는 MeOH-H2O (80:20 → 90:10) 의 선형구배를 이용한 prep HPLC (Hector phenyl column) 에 적용하여 화합물 13 (75.4 mg, t R = 39.6 min)를 분리하였다. 분획물 LT4-5-1 (5.5 g) 는 MeOH-H2O (7:3, 8:2, 9:1, 10:0)의 단계적 구배 용리 MPLC (Biotage SNAP cartridge, KP-C18-HS, 400 g)로 7개의 소분획물 (LT4-5-1-1 ~ LT4-5-1-7)을 얻었고, 이 중, 분획물 LT4-5-1-5 (461.0 mg) 는 반복적인 MeOH-H2O (80:20 → 90:10) 구배 혼합 HPLC (Hector C18 column) 로 화합물 10 (62.1 mg, t R = 26.7 min), 12 (3.5 mg, t R = 39.9 min), 및 3개의 소분획물 (LT4-5-1-5-2 ~ LT4-5-1-5-4)로 분리되었다. 분획물 LT4-5-1-5-2 (31.1 mg), LT4-5-1-5-3 (41.0 mg), 및LT4-5-1-5-4 (207.1 mg) 에서는 HPLC [Hector phenyl column, MeOH-H2O (80:20 → 90:10)]를 통해 화합물 9 (6.5 mg, t R = 36.4 min), 8 (30.5 mg, t R = 40.1 min), 및 7 (63.4 mg, t R = 41.3 min)이 수득되었다. 화합물 5 (6.1 mg, t R = 40.8 min), 11 (2.6 mg, t R = 65.6 min), 및 14 (5.7 mg, t R = 60.9 min)은 MeOH-H2O (90:10)의 등용매 용매 용출되는 HPLC (Phenomenex biphenyl column)에 의해 분획물 LT4-5-1-6 (907.4 mg) 로부터 분리되었다.In fraction LT4 (20.7 g), MPLC (Biotage SNAP cartridge, KP-C18-HS) using step gradient mixing of MeOH-H 2 O (5:5, 7:3, 9:1, 10:0,
<< 실시예Example 2. 튤립나무로부터 분리된 화합물 분석> 2. Analysis of compounds isolated from tulip trees>
실시예 1에서 분리한 화합물 1~33을 분석하였다. 특정 회전은 JASCO DIP-370 편광계 (일본 도쿄)에서 측정되었다. 융점은 MPA100 melting point apparatus (Stanford Research Systems, U.S.A.)으로 측정하였다. UV 및 IR 스펙트럼은 각각 Shimadazu SPD-M20A PDA 검출기와 Thermo Scientific Nicolet iS10 분광기를 사용하여 기록되었으며, 1D 및 2D NMR 스펙트럼은 Bruker DMX 300 (1H-300MHz, 13C-75MHz) 및 Bruker DMX 600 (1H-600MHz, 13C-150MHz) 분광계에서 기록되었다. HRESIMS 데이터는 SYNAPT G2 질량 분석기 (Waters, U.K.) 및 Q Exactive mass spectrometer (Thermo Scientific, U.S.A.)에서 얻었다.
그 결과, 상기 화합물 1~33은 아포르핀 알칼로이드 (aporphine alkaloids) 10 종 (5-14), 리그난 (lignans) 7 종 (15-21), 세스퀴테르펜 락톤 (sesquiterperne lactones) 4 종 (4, 22-24), 페닐프로파노이드 (phenyl propanoids) 3 종 (25-26, 29), 플라 바논 (flavanone) 1 종 (27), 쿠마린 (coumarin) 1 종 (28), 펜에틸아민 (phenethylamine) 2종 (30-31), 페놀릭 알데하이드 (phenolic aldehyde) 2종 (32-33)과 함께 새로운 알카마이드 (alkamide ) 3종 (1-3)을 확인하고, 이를 표 1에 나타내었다. 이들 중 화합물 4은 천연물에서는 처음 분리된 것이다.As a result, the
본 발명의 튤립나무로부터 분리한 화합물은 tulipiferamide A (화합물 1), tulipiferamide B (화합물 2), tulipiferamide C (화합물 3), dehydrotemisin (화합물 4), N-acetylanonaine (화합물 5), N-acetylnornuciferin (화합물 6), tuliferoline (화합물 7), N-acetyl-3-methoxynornantenine (화합물 8), lysicamine (화합물 9), liriodenine (화합물 10), atherospermidine (화합물 11), liridine (화합물 12), oxoglaucine (화합물 13), oxophoebine (화합물 14), (±)-virolongin A (화합물 15), (±)-virolongin B (화합물 16), (-)-virolongin C (화합물 17), (+)-syringaresinol (화합물 18), (-)(7'S,8R,8'R)-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9'-ol-7-one (화합물 19), (7'S,8R,8'R)-lariciresinol (화합물 20), (2S,3R)-dihydrodehydrodiconiferyl alcohol (화합물 21), costunolide (화합물 22), eupatolide (화합물 23), epi-tulipinolide (화합물 24), trans-N-feruloyl tyramine (화합물 25), trans-N-feruloyl-3-methoxytyramine (화합물 26), sakuranetin (화합물 27), 5,6,7-trimethoxycoumarin (화합물 28), methoxyeugenol (화합물 29), N-phenethylbenzamide (화합물 30), N-phenethyl-N-methylacetamide (화합물 31), vanillin (화합물 32), 및 4-hydroxybenzaldehyde (33)로 이루어진 군으로부터 선택되는 1 이상을 포함한다.The compounds isolated from the tulip tree of the present invention are tulipiferamide A (Compound 1), tulipiferamide B (Compound 2), tulipiferamide C (Compound 3), dehydrotemisin (Compound 4), N -acetylanonaine (Compound 5), N -acetylnornuciferin (Compound 5). 6), tuliferoline (Compound 7), N -acetyl-3-methoxynornantenine (Compound 8), lysicamine (Compound 9), liriodenine (Compound 10), atherospermidine (Compound 11), liridine (Compound 12), oxoglaucine (Compound 13) , oxophoebine (Compound 14), (±)-virolongin A (Compound 15), (±)-virolongin B (Compound 16), (-)-virolongin C (Compound 17), (+)-syringaresinol (Compound 18), (-)(7 'S , 8R , 8'R )-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-7',9-epoxylignan-9'-ol-7-one (Compound 19), (7 'S , 8R , 8'R )-lariciresinol (Compound 20), ( 2S , 3R )-dihydrodehydrodiconiferyl alcohol (Compound 21), costunolide (Compound 22), eupatolide (Compound 23) , epi -tulipinolide (Compound 24), trans - N -feruloyl tyramine (Compound 25), trans - N -feruloyl-3-methoxytyramine (Compound 26), sakuranetin (Compound 27), 5,6,7-trimethoxycoumarin (Compound 28 ), methoxyeugenol (Compound 29), N -phenethylbenzamide (Compound 30), N -phenethyl- N -methylacetamide (Compound 31), vanillin (Compound 32), and at least one selected from the group consisting of 4-hydroxybenzaldehyde (33) include
본 발명의 튤립나무로부터 분리된 새로운 알카마이드 (alkamide) 화합물 1~3 및 천연물로부터 처음 분리된 화합물 4의 화학구조 및 주요 HMBC 및 COSY 관계를 도 1 내지 도 3에 나타내었다.The chemical structures and main HMBC and COZY relationships of the
튤리피페라미드 A (화합물 1) : 적색 오일; UV (MeOH) λmax (log ε) 277 (4.26), 251 (4.52), 210 (4.19); IR (KBr) vmax 3280, 2929, 2858, 1655, 1621, 1548, 1497, 1275 cm-1; 1H 및 13C NMR 데이터, 표 2 참조; HRESIMS m/z 272.2014 [M + H]+ (C18H26NO+, 272.2009), 294.1835 [M + Na]+ (C18H25NONa+, 294.1828). Tulipiperamide A (Compound 1) : Red oil; UV (MeOH) λ max (log ε) 277 (4.26), 251 (4.52), 210 (4.19); IR (KBr) vmax 3280, 2929, 2858, 1655, 1621, 1548, 1497, 1275 cm -1 ; 1 H and 13 C NMR data, see Table 2; HRESIMS m/z 272.2014 [M + H] + (C 18 H 26 NO + , 272.2009), 294.1835 [M + Na] + (C 18 H 2 5NONa + , 294.1828).
화합물 1은 분자에 해당하는 HRESIMS 스펙트럼에서 m/z 272.2014 [M + H]+ (계산치 272.2009) 및 294.1835 [M + Na]+ (계산치 294.1828)에서 분자 이온 피크를 나타내는 C18H25NO의 분자 공식의 옅은 적색을 띄는 황색 오일로 수득되었다. 1H NMR 스펙트럼 (표 2)에서 δ H 7.31 (2H, t, J = 7.4 Hz, H-3 "및 H-5"), 7.23 (1H, t, J = 7.4 Hz, H-4 "), 7.20 (2H, d, J = 7.4 Hz, H-2"및 H-6 "), 3.61 (2H, q, J = 6.7Hz, H2-2 ') 및 2.86 (2H, t, J = 6.7 Hz, H2-3 ')는 페닐에틸아민 부분의 존재를 나타냈다. δ H 7.54 (1H, dd, J = 11.5, 14.8 Hz, H-3), 6.05 (1H, t, J = 11.5 Hz, H-4), 5.79 (1H, m, H-5) 및 5.75 (1H, d, J = 14.8 Hz, H-2)에서의 올레핀 양성자 신호는 두 개의 이중 결합의 존재를 확인했다. 또한 δH 2.29 (2H, q, J = 7.5 Hz, H2-6), 1.40 (2H, m, H2-7), 1.30 (4H, m, H2-8 및 H2-9)에서의 4 개의 메틸렌 및 δ H 0.89 (3H, t, J = 6.8 Hz, H3-10)에서 하나의 메틸기가 관찰되었다. 13C NMR 데이터 (표 2)에서 16 개의 탄소 신호는 하나의 아미드카보닐 탄소 (δC 166.4), 하나의 벤젠 고리 (δ C 139.1, 128.9, 128.8, 126.7), 4 개의 올레핀 (δ C 140.6, 136.3, 126.4, 123.7), 6 개의 메틸렌 (δ C 40.8, 35.8, 31.6, 29.3, 28.3, 22.7) 및 하나의 메틸기 (δ C 14.2).에 해당한다. H-2/H-3에서 C-1로, 그리고 H-4에서 C-2/C-6으로의 HMBC 교차 피크는 C-2와 C-4에서 두 개의 이중 결합의 위치를 확인해 주었다 (도 2). 이것은 또한 화합물 1의 ESI-MS/MS 스펙트럼에서 m/z 105 및 151에서 두 개의 단편 이온 피크와도 일치했습니다. 이중 결합의 구성은 각각 14.8 Hz의 결합 상수 J H -2/H-3 및 11.5 Hz의 J H -4/H-5 에서 추론된 2E 및 4Z 인 것으로 밝혀졌다. 따라서 화합물 1은 deca-2E,4Z-dienoic acid 2-phenylethylamide 로, 튤리피페라미드 A (tulipiferamide A)로 명명하였다.
(14.8) 5.75,d
(14.8)
(11.3) 5.38,d
(11.3)
(7.4)2.16, t
(7.4)
(11.5, 14.8)7.54, dd
(11.5, 14.8)
(11.3)6.36, t
(11.3)
(7.4)2.34, q
(7.4)
(11.5)6.05, t
(11.5)
(11.3, 15.0)7.42, d.d.
(11.3, 15.0)
(7.5)2.29, q
(7.5)
(7.2)2.17, q
(7.2)
(7.2)2.01, q
(7.2)
(6.8)0.89, t
(6.8)
(7.0)0.88, t
(7.0)
(7.1)0.88, t
(7.1)
(6.7)3.61, q
(6.7)
(7.0)3.58, q
(7.0)
(6.9)3.52, q
(6.9)
(6.7)2.86, t
(6.7)
(7.0)2.85, t
(7.0)
(6.9)2.81, t
(6.9)
(7.4)7.20,d
(7.4)
(1.4, 7.7)7.21, d.d.
(1.4, 7.7)
(7.3)7.19,d
(7.3)
(7.4)7.31, t
(7.4)
(7.7)7.31, t
(7.7)
(7.3)7.31, t
(7.3)
(7.4)7.23, t
(7.4)
튤리피페라미드 B (화합물 2) : 황색 오일; UV (MeOH) λmax (log ε) 275 (4.24), 247 (4.45), 210 (4.26); IR (KBr) vmax 3338, 2929, 2858, 1669, 1541, 1454, 1369, 1238cm-1; 1H 및 13C NMR 데이터, 표 2 참조; HRESIMS m/z 272.2015 [M + H]+ (C18H26NO+, 272.2009), 294.1836 [M + Na]+ (C18H25NONa+, 294.1828). Tuliperamide B (Compound 2) : yellow oil; UV (MeOH) λ max (log ε) 275 (4.24), 247 (4.45), 210 (4.26); IR (KBr) v max 3338, 2929, 2858, 1669, 1541, 1454, 1369, 1238 cm -1 ; 1 H and 13 C NMR data, see Table 2; HRESIMS m/z 272.2015 [M + H] + (C 18 H 26 NO + , 272.2009), 294.1836 [M + Na] + (C 18 H 2 5NONa + , 294.1828).
화합물 2는 노란색 오일로, m/z 272.2015 [M + H]+에서 HRESIMS 이온을 기준으로 화합물 1과 동일한 분자식 C18H26NO를 가졌다 (C18H26NO+에 대한 계산치, 272.2009). 1H 및 13C NMR 공명은 δH 7.42 (1H, dd, J = 11.3, 15.0 Hz, H-4), 6.36 (1H, t, J = 11.3 Hz, H-3), 5.96 (1H, m, H-5), 5.38 (1H, d, J = 11.3 Hz, H-2) 에서 나타나는 올레핀 양성자의 공명을 제외하고는 화합물 1의 공명과 유사했음, 이는 화합물 2가 화합물 1의 기하이성질체임을 나타낸다. 화합물 2의 MS/MS 단편화 패턴은 화합물 1과 동일하였다. 2Z, 4E의 구성은 각각 11.3 Hz의 결합 상수 J H2/ H3 및 15.0 Hz의 J H4/ H5 에서 추론되었다. 따라서 화합물 2의 구조는 deca-2Z,4E-dienoic acid 2-phenylethylamide로 지정되었으며 튤리피페라미드 B (tulipiferamide B)로 명명되었습니다.
튤리피페라미드 C (화합물 3) : 황색 오일; UV (MeOH) λmax (log ε) 259 (2.58), 255 (2.53), 200 (4.03); IR (KBr) vmax 3330, 2928, 2856, 1645, 1550, 1454, 1228, 1030 cm-1; 1H 및 13C NMR 데이터, 표 2 참조; HRESIMS m/z 274.2172 [M + H]+ (C18H28NO+에 대한 계산치, 274.2165), 296.1991 [M + Na]+ (C18H27NONa+에 대한 계산치, 296.1985). Tulipiperamide C (Compound 3) : yellow oil; UV (MeOH) λ max (log ε) 259 (2.58), 255 (2.53), 200 (4.03); IR (KBr) v max 3330, 2928, 2856, 1645, 1550, 1454, 1228, 1030 cm -1 ; 1 H and 13 C NMR data, see Table 2; HRESIMS m/z 274.2172 [M + H] + (calculated for C 18 H 28 NO + , 274.2165), 296.1991 [M + Na] + (calculated for C 18 H 27 NONa + , 296.1985).
화합물 3은 MS 및 NMR 분광 데이터에 기초하여 알카미드로 확인되었다. 화합물 3의 분자식 C18H27NO은 HRESIMS에 의해 m/z 274.2172에서 양성자화된 분자 [M + H]+로부터 추론되었다. 화합물 1과 화합물 2 (C18H25NO)와 비교하여 두 질량 단위의 차이는 이중 결합 중 하나가 포화되어야 함을 나타낸다. 이중 결합의 위치는 HMBC와 COSY 상관 관계에 의해 명확하게 위치되었다 (도 2). H2-3에서 C-1 및 C-5, H2-2 및 H2-6에서 C-4로 HMBC 교차 피크는 C-4에서 이중 결합의 위치를 확인했다 (도 2). 페닐 메탄 및 데카-4-에나미드 골격에 해당하는 2 개의 MS 단편 이온 (m/z 91 및 168)이 ESI-MS/MS 스펙트럼에서 검출되었다. Z 배열은 알릴 메틸렌 탄소 δ C 27.3 (C-6) 및 23.6 (C-3)의 화학적 이동에 의해 확인되었다. Z 배열의 경우, 알릴 탄소의 일반적인 화학적 이동은 δ C 27-30에 가깝고 E 배열의 알릴 탄소의 화학적 이동은 δ C 32-35.7에 가깝기 때문에 화합물 3의 구조는 deca-4Z-enoic acid phenylethylamide로 결정되고 튤리피페라미드 C (tulipiferamide C)로 명명되었다.
디하이드로테미신 (화합물 4) : 무색 결정 바늘; mp 141.8 °C; [α]22 D +147.7 (c 0.10, MeOH); 1H NMR (CDCl3, 600MHz) δ H 6.18 (1H, d, J = 3.0 Hz, H2-13a), 5.98 (1H, J = 3.0 Hz, H2-13b), 5.80 (1H, m, H-1), 5.06 (1H, s, H2-3a), 5.03 (1H, d, J = 10.8 Hz, H2-2a), 4.98 (1H, d, J = 17.4 Hz, H2-2b), 4.71 (1H, brs , H2-3b), 4.12 (1H, d, J = 11.3 Hz, H-6), 4.08 (1H, dd, J = 3.7, 10.9 Hz, H-8), 2.61 (1H, tt, J = 3.0, 10.8 Hz, H-7), 2.37 (1H, d, J = 11.7 Hz, H-5), 1.84 (1H, dd, J = 4.1, 13.0 Hz, H2-9a), 1.79 (3H, s, H3- 15), 1.66 (1H, m, H2-9b), 1.09 (3H, s, H3-14); 13C NMR (CDCl3, 150MHz) δ C 170.2 (C-12), 146.9 (C-1), 140.0 (C-4), 137.7 (C-11), 120.4 (C-13), 116.2 (C- 3), 112.1 (C-2), 78.8 (C-6), 67.8 (C-8), 55.6 (C-5), 55.0 (C-7), 50.0 (C-9), 42.4 (C-10), 23.9 (C-15), 19.8 (C-14); HRESIMS m/z 247.1333 [M - H]- (C15H19O3 - 에 대한 계산치, 247.1340).Dihydrothemycin (Compound 4): Colorless crystalline needles; mp 141.8 °C; [α] 22 D +147.7 ( c 0.10, MeOH); 1 H NMR (CDCl 3 , 600 MHz) δ H 6.18 (1H, d, J = 3.0 Hz, H 2 -13a), 5.98 (1H, J = 3.0 Hz, H 2 -13b), 5.80 (1H, m, H -1), 5.06 (1H, s, H 2 -3a), 5.03 (1H, d, J = 10.8 Hz, H 2 -2a), 4.98 (1H, d, J = 17.4 Hz, H 2 -2b), 4.71 (1H, brs, H 2 -3b), 4.12 (1H, d, J = 11.3 Hz, H-6), 4.08 (1H, dd, J = 3.7, 10.9 Hz, H-8), 2.61 (1H, tt, J = 3.0, 10.8 Hz, H-7), 2.37 (1H, d, J = 11.7 Hz, H-5), 1.84 (1H, dd, J = 4.1, 13.0 Hz, H 2 -9a), 1.79 (3H, s, H 3 - 15), 1.66 (1H, m, H 2 -9b), 1.09 (3H, s, H 3 -14); 13 C NMR (CDCl 3 , 150 MHz) δ C 170.2 (C-12), 146.9 (C-1), 140.0 (C-4), 137.7 (C-11), 120.4 (C-13), 116.2 (C- 3), 112.1 (C-2), 78.8 (C-6), 67.8 (C-8), 55.6 (C-5), 55.0 (C-7), 50.0 (C-9), 42.4 (C-10) ), 23.9 (C-15), 19.8 (C-14); HRESIMS m/z 247.1333 [M - H] - (calcd for C 15 H 19 O 3 - , 247.1340).
화합물 4은 엘레만 세스퀴 테르펜락톤으로, 천연물에서는 처음으로 분리되었다. 화합물 4의 1H 및 13C NMR 스펙트럼의 검사는 elemane-type sesquiterpene lactone에 대한 특징적인 신호를 보여 주었다. α- 메틸렌 γ- 락톤 그룹의 존재는 δ H 6.18 (1H, d, J = 3.0 Hz, H2-13a), 5.98 (1H, d, J = 3.0 Hz, H2-13b)에서 1H NMR 공명 및 δC 170.2 (C-12), 137.7 (C-11), 120.4 (C-13)에서 13C NMR 공명에 의해 확인되었다. 1H NMR 스펙트럼에서 δ H 5.80 (1H, m, H-1), 5.03 (1H, d, J = 10.8Hz, H2-2a), 4.98 (1H, d, J = 17.4Hz, H2-2b)에서의 올레핀 신호는 말단 비닐 그룹을 나타내었다. δ H 5.06 (1H, s, H2-3a), 4.71 (1H, brs, H2-3b)에서의 또다른 올레핀 양성자 클러스터 및 δ H 1.79 (3H, s, H3-15)에서 메틸은 이소프로페닐 골격을 나타냈다. δ H 4.12 (1H, d, J = 11.3 Hz, H-6) 및 4.08 (1H, dd, J = 3.7, 10.9 Hz, H-8)에서 다운 필드 이동된 양성자 신호는 두 개의 산소 치환기의 존재를 나타낸다. 추가적으로, 두 개의 메틴 (δ H 2.37, 2.61), 하나의 메틸렌 (δH 1.84, 1.66) 및 하나의 메틸 (δH 1.09)기가 관찰되었다. HSQC 및 HMBC 교차 피크는 elemane 골격에 대한 NMR 할당을 완료하기 위해 광범위하게 사용되었다 (도 3). 화합물 4에서 5 개의 입체센터의 상대적 구성은 NOESY 상관 관계의 해석에 의해 추론되었습니다. H3-14와 H-6/H-8 사이의 NOE 상관 관계는 같은 쪽에 위치를 제안한 반면, H2-9b와 H-1/H-7 사이에는 반대쪽에 위치를 나타낸다 (도 3). Demir 등(2017)에 의하면 모든 엘레마놀리드의 H-7은 α 방향으로 기록되었다. 따라서 화합물 4에 대한 실험적인 비 회전 값은 +147.7 (c 0.10, MeOH)이었다. 결과적으로 화합물 4의 구조는 디하이드로테미신 (dehydrotemisin) 으로 확립되었으며, 이는 천연물로부터는 처음 분리된 것이다.
<< 실시예Example 3. 튤립나무로부터 분리된 화합물이 NO 생성에 미치는 영향 확인> 3. Confirmation of the effect of compounds isolated from tulip trees on NO production>
3-1. 세포 배양 및 생존력 확인3-1. Cell culture and viability check
RAW 264.7 세포는 10% 열-불활성화 소태아혈청 (HyClone FBS, GE Healthcare, 미국 일리노이 주) 및 1% L-글루타민이 보충된 둘베코의 변형된 이글 배지 (DMEM, 대한민국 경산시 웰진)로 5 % CO2에서 37℃에서 배양되었다. 세포 생존력을 결정하기 위해 RAW 264.7 세포를 75 % 세포의 합류 밀도로 96-웰 플레이트에 시드하고 밤새 배양한 후, 세포를 표시된 화합물 또는 다양한 농도의 시료로 30 분 동안 처리한 다음 1 μg/ml LPS로 24 시간 동안 자극하였다. MTT 분석은, 5 mg/ml MTT 용액 (Sigma-Aldrich, Miamisburg, OH, USA)을 첨가하여 세포 생존율을 결정하고 플레이트를 37℃에서 1 시간 동안 배양했다. 상청액을 제거하고 100μl DMSO를 각 웰에 첨가한 다음 마이크로 플레이트 리더 (Bio-Rad Laboratories, Inc., Hercules, CA, USA)를 사용하여 590 nm에서 측정하여 그 결과를 도 3에 나타내었다. 도 3에서 보는 바와 같이, 화합물 10 및 24는 20 μM 농도에서 강한 세포독성이 나타났으며, 이 외의 화합물은 40 μM 농도까지 세포독성을 나타내지 않았다.RAW 264.7 cells were maintained at 5% in Dulbecco's modified Eagle's medium (DMEM, Wellgene, Gyeongsan-si, Korea) supplemented with 10% heat-inactivated fetal bovine serum (HyClone FBS, GE Healthcare, IL, USA) and 1% L-glutamine. Incubated at 37°C in CO2. To determine cell viability, RAW 264.7 cells were seeded in 96-well plates at a confluency of 75% cells and incubated overnight, then cells were treated with the indicated compounds or samples at various concentrations for 30 min followed by 1 μg/ml LPS stimulated for 24 hours. For the MTT assay, cell viability was determined by adding 5 mg/ml MTT solution (Sigma-Aldrich, Miamisburg, OH, USA) and the plates were incubated at 37°C for 1 hour. After removing the supernatant, 100 μl of DMSO was added to each well, and then measured at 590 nm using a microplate reader (Bio-Rad Laboratories, Inc., Hercules, CA, USA), and the results are shown in FIG. 3 . As shown in FIG. 3, compounds 10 and 24 showed strong cytotoxicity at a concentration of 20 μM, and the other compounds showed no cytotoxicity up to a concentration of 40 μM.
3-2. 산화질소(NO) 생산에 미치는 영향 확인3-2. Check the effect on nitric oxide (NO) production
Griess Reagent Kit (Sigma-Aldrich, Miamisburg, OH, USA)를 사용하여 세포 상청액의 아질산염 농도를 NO 생성 지표로 평가하였다. RAW 264.7 세포를 75 % 세포의 합류 밀도로 96-웰 플레이트에 시드하고 밤새 배양한 후, 세포를 실시예 1의 화합물 1~33을 0, 1, 2.5, 5, 10, 20, 40, 80, 100 μM 농도로 30 분 동안 처리한 다음 1 μM LPS로 24 시간 동안 자극하였다. 이후, 100 μl의 상청액을 96-well plate에서 100μl의 Griess 시약과 혼합한 다음 실온에서 30 분 동안 배양하였다. 흡광도는 마이크로 플레이트 리더 (Bio-Rad Laboratories, Inc., Hercules, CA, USA)를 사용하여 540 nm에서 측정되었다. 아질산 농도는 아질산 나트륨의 표준 용액에서 회귀하여 계산하고, 이를 무처리 대조군과 비교하여 IC50을 계산하여 표 3에 나타내었다.The nitrite concentration in the cell supernatant was evaluated as an indicator of NO production using the Griess Reagent Kit (Sigma-Aldrich, Miamisburg, OH, USA). RAW 264.7 cells were seeded in a 96-well plate at a confluence of 75% cells and cultured overnight, and then the cells were treated with
각 값은 세 가지 결정의 평균 ± SEM을 나타냄. a : 세포 독성 효과는 MTT 분석에 의해 20μM에서 관찰됨, b : 양성 대조군 화합물, L-NMMA (산화질소 합성효소 억제제).Each value represents the mean ± SEM of three determinations. a : Cytotoxic effect observed at 20 μM by MTT assay, b : Positive control compound, L-NMMA (nitric oxide synthase inhibitor).
표 3에서 보는 바와 같이, 화합물 1, 4, 7, 9, 10, 14, 23, 24 및 27이 LPS로 자극된 RAW 264.7 세포에서 산화질소의 생성을 효과적으로 억제하였다. 그러나, 화합물 10 및 24는 농도 20 μM 에서 강한 세포독성을 나타내었다. 결과적으로 시험 화합물 중 7 종 화합물 1, 4, 7, 9, 14, 23, 및 27로 RAW264.7 대식세포를 전처리한 결과, 형태학적 징후없이 IC50 값이 50μM 미만으로 LPS 유도 NO 생성이 유의하게 억제되는 것을 확인하였다. 이때 양성 대조군 인 NG-monomethyl-L-arginine monoacetate, L-NMMA 은 IC50 값이 35.5 μM 이었다.As shown in Table 3, compounds 1, 4, 7, 9, 10, 14, 23, 24 and 27 effectively inhibited the production of nitric oxide in LPS-stimulated RAW 264.7 cells. However, compounds 10 and 24 showed strong cytotoxicity at a concentration of 20 μM. As a result, as a result of pre-treatment of RAW264.7 macrophages with 7
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실시예Example
4. 화합물 1의 항염활성 확인> 4. Confirmation of anti-inflammatory activity of
상기 실시예 3에서 튤립나무로부터 분리한 화합물 1, 4, 7, 9, 14, 23, 및 27이 LPS 유도 NO 생성을 억제하는 점을 확인하였으며, 이들 중, 이전까지 알려지지 않은 신규 물질인 tulipiferamide A (화합물 1)의 항염활성을 조사하였다. It was confirmed that
화합물 1이 NF-κB 표적 유전자인 iNOS, COX-2, IL-1β 발현에 미치치는 효과를 확인하였다. 상기 실시예 3-1과 동일한 방법으로 RAW264.7 대식세포를 유지시키고, RAW 264.7 대식세포를 30 분 동안 화합물 1 (tulipiferamide A) 30 μM로 처리 또는 무처리 후, 0, 3, 6, 12 시간 동안 1μM LPS로 처리하였다. 이후, 샘플의 전체 세포의 용해물을 10 % SDS-PAGE로 분리하고 iNOS, COX-2, IL-1β 및 β-actin 항체로 면역 블롯팅을 수행하여 그 결과를 도 4A에 나타내었다.The effect of
도 4A에서 보는 바와 같이, LPS는 RAW264.7 대식세포에서 iNOS, COX-2 및 IL-1β의 발현을 증가시켰으며, 이러한 증가는 화합물 1에 의하여 억제되었다. 특히 iNOS 및 COX-2는 LPS 처리 시간에 따라 발현이 지속적으로 증가하였으며 이는 화합물 1에 의해 억제되었다. IL-1β는 LPS 처리 후, 6시간째에 발현이 가장 증가하였고, 점차 발현량이 감소하였으며, 화합물 1은 이러한 IL-1β의 증가도 억제하였다.As shown in Figure 4A, LPS increased the expression of iNOS, COX-2 and IL-1β in RAW264.7 macrophages, and this increase was suppressed by
화합물 1의 NF-κB 표적 유전자인 iNOS, COX-2, IL-1β, TNFα 및 IL-6의 발현은 RT-PCR 분석으로 분석하였다. RAW 264.7 대식세포를 30 분 동안 화합물 1 (tulipiferamide A) 30 μM로 처리 또는 무처리 후, 0, 2, 4 시간 동안 1μM LPS로 처리하였다. 이후, easy-BLUE total RNA 추출 키트 (iNtRON Biotechnology, Inc., Seongnam, Korea)를 사용하여 total RNA를 준비한 후, oligo (dT)-primed cDNA를 RT-PCR kit (Promega, Madison, CA, USA)를 사용하여 합성하였다. PCR은 각 마우스 유전자에 대한 하기 프라이머 쌍을 사용하여 수행하였다 (m iNOS F: 5’-CGAAACGCTTCACTTCCAA-3’ R: 5’-TGAGCCTATATTGCTGTGGCT-3’; m Cox2 F: 5’-AACCGCATTGCCTCTGAAT- 3’ R: 5’- CATGTTCCAGGAGGATGGAG-3’; m IL-1β F: 5’-ATGGCAACTGTTCCTGAACTCAACT-3’ R: 5’-CAGGACAGGTATAGATTCTTTCCTTT-3’; m TNFα F: 5’-TTCTGTCTACTGAACTTCGGGGTGATCGGTCC-3’ R: 5’-GTATGAGATAGCAAATCGGCTGACGGTGTGGG-3’; m IL-6 F: 5’-ACATCCTCGACGGCATCT-3’ R: 5’-GCCTCTTTGCTGCTTTCAC-3’; m GAPDH, 5’-GACCCCTTCTTGACCTC-3’ and 5’-GCCATCCACAGTCTTCTG-3’). PCR 증폭 후, 생성물을 아가로스 겔 전기영동으로 분리하고 에티듐 브로마이드 염색을 사용하여 시각화하여 도 4B에 나타내었다.The expression of iNOS, COX-2, IL-1β, TNFα and IL-6, which are NF-κB target genes of
도 4B에서 보는 바와 같이, LPS는 RAW264.7 대식세포에서 iNOS, COX-2, IL-1β, TNFα 및 IL-6의 발현을 증가시켰으며, 이러한 증가는 화합물 1에 의하여 억제되었다. 이를 통하여 본 발명의 튤립나무 추출물로 분리한 신규 물질인 화합물 1은 NF-κB 매개 염증경로를 억제하는 것을 확인하였다.As shown in Figure 4B, LPS increased the expression of iNOS, COX-2, IL-1β, TNFα and IL-6 in RAW264.7 macrophages, and this increase was suppressed by
화합물 1의 매개 염증 반응 억제와 관련된 분자 메커니즘을 결정하기 위해 NF-κB 신호 전달의 관여하는 단백질의 발현을 체계적으로 모니터링하였다. RAW 264.7 대식세포를 화합물 1 (tulipiferamide A) 30 μM로 처리 또는 무처리 후, 0, 5, 15, 30, 60 분 동안 1μM LPS로 처리하였다. 이후, 수확한 세포를 용해하여 SDS-PAGE로 분리하고 NC 막으로 옮긴 다음, JNK1, Phospho-p38, p38 및 ERK (Santa Cruz, CA, USA); IKBα, Phospho-IKBα, Phospho-IKKα/β, Phospho-ERK, Phospho-JNK, Phospho-p65, p65, 및 IRAK1 (Cell Signaling Technology, Beverly, MA, USA); IKKβ (Upstate Biotech, Waltham, MA, USA); 및 β-actin (Sigma-Aldrich, Miamisburg, OH, USA) 의 1차 항체를 4℃에서 24 시간 동안 유지한 후, 멤브레인을 HRP-접합된 2 차 항체와 함께 실온에서 1 시간 동안 배양했다. 이후 밴드를 강화된 화학 발광 웨스턴 블로팅 검출 시약 (WestGlow; Biomax, Inc., Seoul, Korea)을 사용하여 검출하고 이를 도 5A에 나타내었다.Expression of proteins involved in NF-κB signaling was systematically monitored to determine the molecular mechanisms involved in compound 1-mediated inhibition of the inflammatory response. RAW 264.7 macrophages were treated with or without 30 μM of Compound 1 (tulipiferamide A) and then treated with 1 μM LPS for 0, 5, 15, 30, or 60 minutes. Then, the harvested cells were lysed, separated by SDS-PAGE, and transferred to NC membranes, followed by JNK1, Phospho-p38, p38 and ERK (Santa Cruz, CA, USA); IKBα, Phospho-IKBα, Phospho-IKKα/β, Phospho-ERK, Phospho-JNK, Phospho-p65, p65, and IRAK1 (Cell Signaling Technology, Beverly, MA, USA); IKKβ (Upstate Biotech, Waltham, MA, USA); and β-actin (Sigma-Aldrich, Miamisburg, OH, USA) primary antibodies were maintained at 4°C for 24 hours, and then the membrane was incubated with HRP-conjugated secondary antibodies for 1 hour at room temperature. Then, the band was detected using an enhanced chemiluminescence western blotting detection reagent (WestGlow; Biomax, Inc., Seoul, Korea) and is shown in FIG. 5A.
도 5A에서 보는 바와 같이, 화합물 1 (30μM)은 IKKα/β, IkBα and relA (p65)의 인산화를 통하여 NF-κB 활성화를 현저히 억제함으로써 화합물 1의 항염증 활성을 나타내었다. 게다가 LPS에 의한 MAPKs (ERK, JNK 및 p38)의 인산화가 화합물 1에 의하여 영향을 받지 않으며, 화합물 1의 억제 효과는 NF-κB 에 특이적인 것을 확인하였다. 더욱 중요한 점은 화합물 1은 TLR4 신호전달 경로의 IKK 업스트림 인산화효소인 IRAK1 분해에 영향을 주지 않으면서 IKK 인산화를 억제한다는 것이다. 이는 화합물 1이 LPS 유도 NF-κB 신호경로를 IKK 활성을 타켓팅함으로써 제한하는 것을 의미한다. 즉, IKKβ의 이소성 발현에 의한 IKK 인산화는 화합물 1에 의하여 현저히 억제되어 화합물 1이 IRAK1과 같은 업스트림 인산화효소와 관계없이 IKKβ의 수준에서 억제하는 것을 의미한다.As shown in FIG. 5A , compound 1 (30 μM) significantly inhibited NF-κB activation through phosphorylation of IKKα/β, IkBα and relA (p65), thereby exhibiting anti-inflammatory activity of
상기와 같이 본 발명자들은 튤립나무의 뿌리에서 33가지 화합물을 분리하고 IKKβ의 활성을 표적으로 하여 유발 염증 반응을 억제하는 강력한 효능을 갖는 새로운 알카마이드 성분을 확인하였다. 이러한 결과로부터 IKK-NF-κB 신호 전달 캐스케이드의 비정상적인과 활성화를 포함하는 염증성 질환의 치료에 본 발명의 튤립나무로부터 분리한 신규 화합물 튤립페라미드 A를 이용할 수 있음을 확인하였다.As described above, the present inventors isolated 33 compounds from the roots of the tulip tree and identified a new alkamide component having a strong effect of inhibiting the inflammatory response induced by targeting the activity of IKKβ. From these results, it was confirmed that the novel compound tulipperamide A isolated from the tulip tree of the present invention can be used for the treatment of inflammatory diseases including abnormal overactivation of the IKK-NF-κB signaling cascade.
<< 제제예formulation example 1. 약학적 제제> 1. Pharmaceutical preparations>
1.1. 정제의 제조1.1. manufacture of tablets
본 발명의 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 튤리피페라마이드 A 200㎎을 락토즈 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄하여 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활성 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다. Tulip tree of the present invention ( Liriodendron tulipifera ) extract or 200 mg of tulipiferamide A isolated therefrom was mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. After adding 10% gelatin solution to this mixture, it was pulverized and passed through a 14 mesh sieve. It was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of active agent, and 5 g of magnesium stearate was made into tablets.
1.2. 주사액제의 제조1.2. Preparation of injection solution
본 발명의 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 튤리피페라마이드 A 100㎎, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다. Tulip tree of the present invention (
<< 제제예formulation example 2. 건강기능식품의 제조> 2. Manufacture of health functional food>
2.1. 건강기능식품의 제조2.1. Manufacture of health functional food
본 발명의 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 튤리피페라마이드 A 2g, 비타민 혼합물 적량, 비타민 A 아세테이트 70㎍, 비타민 E 1.0㎎, 비타민 B1 0.13㎎, 비타민 B2 0.15㎎, 비타민 B6 0.5㎎, 비타민 B12 0.2㎍, 비타민 C 10㎎, 비오틴 10㎍, 니코틴산아미드 1.7㎎, 엽산 50㎍, 판토텐산 칼슘 0.5㎎, 무기질 혼합물 적량, 황산제1철 1.75㎎, 산화아연 0.82㎎, 탄산 마그네슘 25.3㎎, 제1인산칼륨 15㎎, 제2인산칼슘 55㎎, 구연산칼륨 90㎎, 탄산칼슘 100㎎, 염화마그네슘 24.8㎎을 섞어 과립으로 제조하였으나, 용도에 따라 다양한 제형으로 변형시켜 제조할 수 있다. 또한, 상기의 비타민 및 미네랄 혼합물의 조성비를 임의로 변형 실시하여도 무방하며, 통상의 건강기능식품 제조방법에 따라 상기의 성분을 혼합하여 제조할 수 있다.Tulip tree of the present invention ( Liriodendron tulipifera ) extract or Tulipiferamide A 2g isolated therefrom, proper amount of vitamin mixture, vitamin A acetate 70μg, vitamin E 1.0mg, vitamin B1 0.13mg, vitamin B2 0.15mg, vitamin B6 0.5mg, vitamin B12 0.2μg, Vitamin C 10mg, Biotin 10μg, Nicotinamide 1.7mg, Folic Acid 50μg, Calcium Pantothenate 0.5mg, Mineral Mixture Appropriate amount, Ferrous Sulfate 1.75mg, Zinc Oxide 0.82mg, Magnesium Carbonate 25.3mg, Potassium Phosphate Monobasic 15mg , 55 mg of dibasic calcium phosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride were mixed to form granules, but it can be prepared by transforming into various formulations depending on the use. In addition, the composition ratio of the vitamin and mineral mixture may be arbitrarily modified, and it may be prepared by mixing the above components according to a conventional health functional food manufacturing method.
2.2. 건강기능성 음료의 제조2.2. Manufacture of health functional beverages
본 발명의 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 튤리피페라마이드 A 1g, 구연산 0.1g, 프락토올리고당 100g, 정제수 900g을 섞어 통상의 음료 제조방법에 따라 교반, 가열, 여과, 살균, 냉장하여 음료를 제조하였다.Tulip tree of the present invention ( Liriodendron A beverage was prepared by mixing 1 g of tulipifera ) extract or tulippiperamide A isolated therefrom, 0.1 g of citric acid, 100 g of fructooligosaccharide, and 900 g of purified water, followed by stirring, heating, filtering, sterilization, and refrigeration according to a conventional beverage manufacturing method.
<< 제제예formulation example 3. 3. 화장료의cosmetic 제조> manufacturing>
2.1. 스킨로션의 제조2.1. Manufacture of skin lotion
본 발명의 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 튤리피페라마이드 A 0.1g, 부틸렌글리콜 2.0g, 프로필렌글리콜 2.0g, 카르복시비닐폴리머 0.1 g, 피이지-12 노닐페닐에테르 0.2g, 폴리솔베이트 80 0.4g, 에탄올 10.0g, 트리에탄올아민 0.1g, 방부제, 색소, 향료 적당량, 정제수 잔량을 혼합하여 스킨로션을 제조하였다.Tulip tree of the present invention ( Liriodendron tulipifera ) extract or isolated therefrom, 0.1 g of tulippiperamide A, 2.0 g of butylene glycol, 2.0 g of propylene glycol, 0.1 g of carboxyvinyl polymer, PEG-12 nonylphenyl ether 0.2 g, 0.4 g of
2.2. 마사지크림의 제조2.2. Manufacture of massage cream
본 발명의 튤립나무(Liriodendron tulipifera) 추출물 또는 이로부터 분리한 튤리피페라마이드 A 0.1g, 밀납 10.0g, 폴리솔베이트 60 1.5g, 피이지 60 경화피마자유 2.0g, 솔비탄세스퀴올레이트 0.8g, 유동파라핀 40.0g, 스쿠알란 5.0g, 글리세린 5.0g, 부틸렌글리콜 3.0g, 프로필렌글리콜 3.0g, 트리에탄올아민 0.2g, 방부제, 색소, 향료 적당량, 정제수 잔량을 혼합하여 마사지크림을 제조하였다.Tulip tree of the present invention ( Liriodendron tulipifera ) extract or Tulipiferamide A isolated therefrom 0.1 g, beeswax 10.0 g,
Claims (13)
상기 튤립나무 뿌리 추출물 또는 이로부터 분리한 화합물은, 하기 화학식 [1]로 표현되는 tulipiferamide A (화합물 1) 및 dehydrotemisin (화합물 4), tuliferoline (화합물 7), lysicamine (화합물 9), liriodenine (화합물 10), oxophoebine (화합물 14), eupatolide (화합물 23), epi-tulipinolide (화합물 24) 및 sakuranetin (화합물 27) 로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것을 특징으로 하는 항염증 조성물.
화학식 [1]
Tulip tree ( Liriodendron tulipifera ) In the anti-inflammatory composition comprising a root extract or a compound isolated therefrom,
The tulipifera root extract or a compound isolated therefrom is represented by the following formula [1]: tulipiferamide A (Compound 1) and dehydrotemisin (Compound 4), tuliferoline (Compound 7), lysicamine (Compound 9), liriodenine (Compound 10) ), oxophoebine (Compound 14), eupatolide (Compound 23), epi-tulipinolide (Compound 24) and sakuranetin (Compound 27) Anti-inflammatory composition comprising at least one selected from the group consisting of.
Formula [1]
상기 튤립나무 뿌리 추출물은, 튤립나무 뿌리를 물, C1~4의 저급 알코올, 아세톤(acetone), 에틸아세테이트(ethyl acetate), 디에틸아세테이트(diethyl acetate), 디에틸에테르(diethyl ether), 벤젠(benzene), 클로로포름(chloroform) 및 헥산(hexane)으로 이루어진 군에서 선택되는 1종 또는 이들의 혼합용매로 추출한 추출물인 것을 특징으로 하는 항염증 조성물.According to claim 1,
The tulip tree root extract is obtained from water, C1-4 lower alcohol, acetone, ethyl acetate, diethyl acetate, diethyl ether, benzene ( benzene), chloroform (chloroform) and hexane (hexane) selected from the group consisting of one or a mixed solvent of these extracts characterized in that the anti-inflammatory composition.
상기 항염증 조성물은 NO(Nitric oxide)의 생성을 억제하는 것을 특징으로 하는 항염증 조성물.According to claim 1 or 2,
The anti-inflammatory composition is an anti-inflammatory composition, characterized in that for suppressing the production of NO (nitric oxide).
상기 항염증 조성물은 iNOS, COX-2 및 IL-1β의 발현을 억제하는 것을 특징으로 하는 항염증 조성물.According to claim 1 or 2,
The anti-inflammatory composition is an anti-inflammatory composition, characterized in that inhibiting the expression of iNOS, COX-2 and IL-1β.
상기 튤립나무 뿌리 추출물로부터 분리한 화합물은 튤리피페라마이드 A (tulipiferamide A, 화합물 1), 튤리피페라마이드 B(tulipiferamide B, 화합물 2) 및 튤리피페라마이드 C(tulipiferamide C, 화합물 3)로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것을 특징으로 하는 항염증 조성물.According to claim 1,
The compound isolated from the tulip tree root extract consists of tulipiferamide A (compound 1), tulipiferamide B (compound 2) and tulipiferamide C (tulipiferamide C, compound 3). Anti-inflammatory composition comprising at least one selected from the group.
상기 튤립나무 뿌리 추출물 또는 이로부터 분리한 화합물은, tulipiferamide A (화합물 1), dehydrotemisin (화합물 4), tuliferoline (화합물 7), lysicamine (화합물 9), liriodenine (화합물 10), oxophoebine (화합물 14), eupatolide (화합물 23), epi-tulipinolide (화합물 24) 및 sakuranetin (화합물 27) 로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것을 특징으로 하는 항염증 건강기능식품.In the anti-inflammatory health functional food containing a Liriodendron tulipifera root extract or a compound isolated therefrom,
The tulipifera root extract or a compound isolated therefrom is, tulipiferamide A (Compound 1), dehydrotemisin (Compound 4), tuliferoline (Compound 7), lysicamine (Compound 9), liriodenine (Compound 10), oxophoebine (Compound 14), An anti-inflammatory health functional food comprising at least one selected from the group consisting of eupatolide (Compound 23), epi-tulipinolide (Compound 24) and sakuranetin (Compound 27).
상기 튤립나무 뿌리 추출물 또는 이로부터 분리한 화합물은, tulipiferamide A (화합물 1), dehydrotemisin (화합물 4), tuliferoline (화합물 7), lysicamine (화합물 9), liriodenine (화합물 10), oxophoebine (화합물 14), eupatolide (화합물 23), epi-tulipinolide (화합물 24) 및 sakuranetin (화합물 27) 로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것을 특징으로 하는 항염증 화장료 조성물.Tulip tree ( Liriodendron tulipifera ) In the anti-inflammatory cosmetic composition comprising a root extract or a compound isolated therefrom,
The tulipifera root extract or a compound isolated therefrom is, tulipiferamide A (Compound 1), dehydrotemisin (Compound 4), tuliferoline (Compound 7), lysicamine (Compound 9), liriodenine (Compound 10), oxophoebine (Compound 14), An anti-inflammatory cosmetic composition comprising at least one selected from the group consisting of eupatolide (Compound 23), epi-tulipinolide (Compound 24) and sakuranetin (Compound 27).
상기 항염증 화장료 조성물은 유연화장수, 수렴화장수, 영양화장수, 영양크림, 마사지크림, 에센스, 아이크림, 아이에센스, 클렌징크림, 클렌징폼, 클렌징워터, 팩, 파우더, 바디로션, 바디크림, 바디오일 및 바디에센스로 이루어진 군으로부터 선택되는 제형을 가지는 것임을 특징으로 하는 항염증 화장료 조성물.According to claim 10,
The anti-inflammatory cosmetic composition is a softening lotion, astringent lotion, nutrient lotion, nutrient cream, massage cream, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, body lotion, body cream, body oil And an anti-inflammatory cosmetic composition characterized in that it has a formulation selected from the group consisting of body essence.
화학식 [1]
From the group consisting of tulipiferamide A (compound 1), tulipiferamide B (compound 2) and tulipiferamide C (compound 3) represented by the following formula [1] One new compound of choice.
formula [1]
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