KR101437641B1 - Hepatoprotective pharmaceutical composition comprising phenol compounds isolated from caryopteris incana - Google Patents
Hepatoprotective pharmaceutical composition comprising phenol compounds isolated from caryopteris incana Download PDFInfo
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- KR101437641B1 KR101437641B1 KR1020130069884A KR20130069884A KR101437641B1 KR 101437641 B1 KR101437641 B1 KR 101437641B1 KR 1020130069884 A KR1020130069884 A KR 1020130069884A KR 20130069884 A KR20130069884 A KR 20130069884A KR 101437641 B1 KR101437641 B1 KR 101437641B1
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Abstract
본 발명은 층꽃풀로부터 분리된 페놀계 화합물을 함유하는 간독성 질환 예방 및 치료용 조성물에 관한 것이다.
본 발명의 층꽃풀(Caryopteris incana) 추출물, 이의 분획물 및 이로부터 분리된 화합물은 제3급-부틸히드로퍼옥시드(t-BHP, tertiary-butyl hydroperoxide)와 같은 독성 물질에 의하여 간 독성이 유발되었을 때 간세포 보호 효과가 우수하므로 간 질환의 예방 및 치료에 탁월한 효과를 기대할 수 있다. The present invention relates to a composition for the prevention and treatment of hepatotoxic diseases containing a phenolic compound separated from a lamellipule.
The Caryopteris incana extract of the present invention, its fractions, and the compounds isolated therefrom are useful for the treatment of liver toxicity caused by toxic substances such as tert-butyl hydroperoxide (t-BHP) Since the hepatocyte protective effect is excellent, an excellent effect can be expected in prevention and treatment of liver disease.
Description
본 발명은 층꽃풀로부터 분리된 페놀계 화합물을 함유하는 간독성 질환 예방 및 치료용 조성물에 관한 것이다.
The present invention relates to a composition for the prevention and treatment of hepatotoxic diseases containing a phenolic compound separated from a lamellipule.
간은 인간의 신체 장기 중 생체 내 대사가 가장 활발하게 일어나는 장기로 인체 내 소화기계와 전신순환계 사이에 위치하면서 외부에서 들어온 생체 외 물질로부터 전신을 방어하는 기능을 수행하고 있다. 생체 내로 들어온 생체 외 물질은 일단 간을 통과하게 되므로 간은 영양소 이외에도 많은 독성물질에 노출될 위험이 다른 장기보다 많아 그 만큼 손상될 확률도 매우 높다. 그러나 간은 재생능력이 우수한 장기로 약간의 손상이 있을 경우에는 충분히 정상으로 회복되지만, 손상이 지속될 경우에는 간 조직의 일부가 완전히 파괴되고 간 기능도 저하되는 등 정상 간으로의 회복이 어려운 상태가 된다. 또한 우리의 몸은 산업화에 따른 공해물질, 유독물질에 항상 노출되어 있어 우리의 간은 끊임없이 해독작용에 시달리고 있는데 간독성을 유발하는 제3급-부틸히드로퍼옥시드(t-BHP, tertiary-butyl hydroperoxide), 사염화탄소, D-갈락토사민(D-galactosamine), 리포폴리사카라이드(LPS, lipopolysaccharide) 및 브로모벤젠(bromobenzene) 등과 같은 독성 유발물질 외에도 정신적 스트레스, 과음, 흡연 등은 간 손상을 가중시켜 인체가 방어 해독 작용을 하지 못해 면역 체계에 이상을 가져와 다른 질병의 원인이 되기도 한다. 간질환은 병이 생기는 원인에 따라 바이러스성 간질환, 알코올성 간질환, 약물독성 간질환, 지방간, 자가 면역성 간질환, 대사성 간질환 및 기타 간질환으로 구분된다. 간 질환은 초기에 자각증상이 없어 상당히 진행되어서야 발견되기 때문에, 우리나라뿐만 아니라 세계적으로도 사망원인의 수위를 차지하고 있으나, 효과적인 치료제 및 진단방법이 없는 실정이다. 종래 간질환 치료제로서 간 기능 보조제, 항바이러스제, 간세포 촉진제, 면역억제제, 섬유화억제제. 인터페론 등이 사용되고 있지만, 위와 같은 치료제들은 간질환에 효과적이지 못하고 부작용 및 재발의 위험이 높기 때문에 최근에는 천연물로부터 간 질환에 대해 유효하거나 간 보호활성을 가진 물질 탐색이 이루어지고 있다. The liver is the organ in which the metabolism of the body of the human body occurs most actively. It is located between the digestive system and the systemic circulatory system and functions to defend the whole body from the exogenous substance entered from the outside. Since the in vivo substance enters the liver once, the liver has a higher risk of being exposed to toxic substances than other organs in addition to nutrients. However, when the liver is regenerated, it is recovered to a normal state when there is some damage, but if the damage is sustained, the liver is completely destroyed and the hepatic function is lowered. do. In addition, our body is always exposed to pollutants and toxic substances by industrialization, and our liver is constantly detoxified. The tertiary-butyl hydroperoxide (t-BHP), which causes hepatotoxicity, In addition to toxic substances such as carbon tetrachloride, D-galactosamine, lipopolysaccharide and bromobenzene, mental stress, excessive drinking and smoking add to liver damage, Is unable to defend against the detoxifying function of the immune system, causing anomalies and other diseases. Liver disease is classified into viral liver disease, alcoholic liver disease, drug toxic liver disease, fatty liver, autoimmune liver disease, metabolic liver disease and other liver diseases depending on the cause of the disease. Since liver disease is not recognized until it has progressed considerably since it has no subjective symptoms at the beginning, it is the cause of death not only in Korea but also in the world. However, there is no effective treatment and diagnosis method. Conventional liver disease therapeutic agents include liver function supplements, antiviral agents, hepatocyte promoters, immunosuppressants, fibrosis inhibitors. Interferon have been used but these drugs are not effective for liver disease and have a high risk of side effects and recurrence.
현재까지 천연식물에서 추출되어 실제 임상에서 응용되고 있는 간 기능 보호제로서는 실리범 마리아넘(Silybum marianum)이라는 식물에서 추출된 실리빈(silybin), 실리디아민(silydiamine), 실리크리스틴(silycristine)등의 이성체로 구성된 실리마린(silymarin) 제제 정도가 있으나 이조차 효능의 증대가 필요하며, 실제로 치료제로서 현재 사용 중이거나 임상시험 중인 예는 소수에 불과하다. 이에 본 발명자들은 간 보호 효과를 가지는 물질을 탐색하여 식품 및 의약품에 활용하기 위한 목적으로 층꽃풀 추출물을 이용한 간 보호 활성을 조사하였다. To date, hepatoprotective agents that have been extracted from natural plants and applied in clinical practice include isomers such as silybin, silydiamine, silycristine, etc. extracted from plants called Silybum marianum . However, only a small number of patients are currently in clinical use or in clinical trials. Therefore, the present inventors have searched for a substance having liver-protecting effect and examined the liver-protecting activity using a herbal extract for the purpose of applying it to foods and medicines.
층꽃풀(Caryopteris incana (Thunb.) Miq.)은 마편초과에 속하는 다년초로 주로 대한민국을 비롯하여 일본, 대만, 중국에서 자라며, 우리나라에서는 남부지방 산야에서 자란다(Ahn et al., 1998). 생약명은 '난향초'라 하여 지상부와 뿌리부분을 말하는데. 호흡기 감염증으로 인한 백일해, 기관지염에 유효하고, 풍습성으로 인한 관절염, 타박상에도 효력을 얻고, 산후의 어혈로 인한 하복부 동통을 치료하며 뱀에 물린데, 습진, 가려움증 등에 외용한다(Song et al., 1989). Caryopteris incana (Thunb.) Miq. Is a perennial herb that belongs to the genus Marchechida. It grows mainly in Korea, Japan, Taiwan, and China. In Korea, it grows in the south mountain area (Ahn et al., 1998). The generic name is "I am a herb" and refers to the root and the root part. It is effective for pertussis and bronchitis caused by respiratory infections. It is also effective for arthritis and bruises due to customs, treats lower abdominal pain due to postpartum hemorrhage, and is used for snakebite, eczema, itching, etc. (Song et al. 1989).
층꽃풀의 정유성분인 타우카디놀(taucadinol), 미르테닐 아세테이트(myrtenyl acetate), 피노카르본(pinocarvone), δ-3-카렌(δ-3-carene) 등이 세포독성이 있다고 보고되어 있으며, 다이터펜(diterpenoid)인 인카논(incanone)은 백혈병 세포(human leukemia cell)에서 세포독성이 있는 것으로 보고되어 있다(Kim et al., 2008). It has been reported that taucadinol, myrtenyl acetate, pinocarvone, and δ-3-carene, which are essential oil components of the grasses, are cytotoxic, The diterpenoid incanone has been reported to be cytotoxic in human leukemia cells (Kim et al., 2008).
그러나, 층꽃풀 추출물 및 이로부터 분리된 화합물들의 간 보호 활성에 관한 보고는 전혀 알려진 바가 없다.
However, there is no report on the hepatoprotective activity of lamellar larvae extract and compounds isolated therefrom.
이에 본 발명자들은 한국의 자생 식물을 대상으로 간 효과를 연구한 결과, 층꽃풀 추출물, 이의 분획물 및 이로부터 분리 동정하여 얻은 화합물이 우수한 간 보호 효과를 나타내어 간염, 지방간, 간경화 및 간장 독성과 같은 간 질환 등의 예방 및 치료제로 사용될 수 있음을 발견함으로써 본 발명을 완성하게 되었다. Accordingly, the inventors of the present invention have investigated the liver effect of Korean native plants. As a result, it has been found that the extracts of Fusarium oxysaccharum, fractions thereof and the compounds obtained by separation and identification thereof exhibit excellent liver protective effects and are useful as hepatitis, fatty liver, liver cirrhosis and liver toxicity And can be used as a preventive and therapeutic agent for diseases and the like.
따라서 본 발명의 목적은 층꽃풀 추출물 또는 이의 분획물을 유효성분으로 함유하는 간독성 질환 예방 및 치료용 약학 조성물을 제공하는데 있다. Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing and treating hepatotoxic diseases, which comprises an extract of Liliaceae or a fraction thereof as an active ingredient.
또한 본 발명의 목적은 층꽃풀 추출물 또는 분획물로부터 분리된 특정 화합물을 유효성분으로 함유하는 간독성 질환 예방 및 치료용 약학 조성물을 제공하는데 있다. It is also an object of the present invention to provide a pharmaceutical composition for preventing and treating hepatotoxic diseases, which comprises a specific compound isolated from the extracts or fractions of Staphylococcus aureus as an active ingredient.
또한 본 발명의 목적은 층꽃풀 추출물 또는 분획물로부터 분리된 신규의 화합물을 제공하는데 있다.
It is also an object of the present invention to provide a novel compound isolated from the extracts or fractions.
상기 목적을 달성하기 위하여, 본 발명은 층꽃풀 추출물, 분획물 또는 이로부터 분리한 화합물을 유효성분으로 함유하는 간독성 질환 예방 및 치료용 약학 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for prevention and treatment of hepatotoxic diseases, which comprises an extract of L. layer, fraction or a compound isolated therefrom as an active ingredient.
또한 본 발명은 층꽃풀 추출물 또는 분획물로부터 분리된 신규의 화합물을 제공한다.
The present invention also provides novel compounds isolated from the layer fennel extract or fractions.
본 발명의 층꽃풀(Caryopteris incana) 추출물, 이의 분획물 및 이로부터 분리된 화합물은 제3급-부틸히드로퍼옥시드(t-BHP, tertiary-butyl hydroperoxide)와 같은 독성 물질에 의하여 간 독성이 유발되었을 때 간세포 보호 효과가 우수하므로 간 질환의 예방 및 치료에 탁월한 효과를 기대할 수 있다.
The Caryopteris incana extract of the present invention, its fractions, and the compounds isolated therefrom are useful for the treatment of liver toxicity caused by toxic substances such as tert-butyl hydroperoxide (t-BHP) Since the hepatocyte protective effect is excellent, an excellent effect can be expected in prevention and treatment of liver disease.
도 1은 신규 화합물 카욥테로사이드 A(Caryopteroside A)의 1H-NMR 스펙트럼을 나타낸 것이다.
도 2는 신규 화합물 카욥테로사이드 A(Caryopteroside A)의 13C-NMR 스펙트럼을 나타낸 것이다.
도 3은 신규 화합물 카욥테로사이드 B(Caryopteroside B)의 1H-NMR 스펙트럼을 나타낸 것이다.
도 4는 신규 화합물 카욥테로사이드 B(Caryopteroside B)의 13C-NMR 스펙트럼을 나타낸 것이다.
도 5는 신규 화합물 인카노이드 A(Incanoid A)의 1H-NMR 스펙트럼을 나타낸 것이다.
도 6은 신규 화합물 인카노이드 A(Incanoid A)의 13C-NMR 스펙트럼을 나타낸 것이다.
도 7는 신규 화합물 인카노이드 B(Incanoid B)의 1H-NMR 스펙트럼을 나타낸 것이다.
도 8은 신규 화합물 인카노이드 B(Incanoid B)의 13C-NMR 스펙트럼을 나타낸 것이다.Figure 1 shows the 1 H-NMR spectrum of the novel compound Caryopteroside A.
Figure 2 shows the 13 C-NMR spectrum of the novel compound Caryopteroside A;
Figure 3 shows the 1 H-NMR spectrum of the novel compound Caryopteroside B;
Fig. 4 shows the 13 C-NMR spectrum of the novel compound Caryopteroside B. Fig.
Figure 5 shows the 1 H-NMR spectrum of the novel compound incanoid A (Incanoid A).
6 shows a 13 C-NMR spectrum of a novel compound incanoid A (incanoid A).
Figure 7 shows the 1 H-NMR spectrum of a new compound incanoid B (Incanoid B).
8 shows the 13 C-NMR spectrum of the novel compound Incanoid B (Incanoid B).
이와 같은 본 발명을 더욱 상세하게 설명하면 다음과 같다. Hereinafter, the present invention will be described in detail.
본 발명은 층꽃풀(Caryopteris incana) 추출물 또는 이의 분획물을 유효성분으로 함유하는 간독성 질환 예방 및 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention and treatment of hepatotoxic diseases containing Caryopteris incana extract or a fraction thereof as an active ingredient.
본 발명의 층꽃풀 추출물은 하기와 같은 단계로 제조되는 것이 바람직하나 이에 한정되지 않는다;The layer foliar extract of the present invention is preferably, but not limited to, prepared by the following steps;
1) 건조한 층꽃풀에 추출 용매를 가하여 추출하는 단계;1) Extracting the dried grass layer with an extraction solvent;
2) 단계 1)의 추출물을 여과하는 단계; 및2) filtering the extract of step 1); And
3) 단계 2)의 여과한 추출물을 감압농축하여 추출물을 제조하는 단계.3) Step of extracting the filtered extract of step 2) by concentration under reduced pressure.
상기 층꽃풀은 식물 전체를 이용할 수 있고, 잎, 줄기, 뿌리, 꽃 등의 1 내지 2개 이상의 부위로 나누어 사용할 수 있으나, 이에 한정되는 것은 아니며, 바람직하게는 잎, 줄기, 꽃과 같은 지상부를 사용하는 것이 좋다.
The layer flower can be used as whole plants, and may be divided into one or two or more parts such as leaves, stems, roots, flowers, etc., but is not limited thereto. Preferably, the top part such as leaves, stems, It is good to use.
상기 추출 용매는 물, C1 ∼ C4의 알코올 또는 이들의 혼합 용매를 사용할 수 있으며, 메탄올 또는 에탄올 수용액으로 추출하는 것이 더욱 바람직하나, 이에 한정되는 것은 아니다. 상기 추출 용매의 양은 층꽃풀 건조 중량의 1 내지 30 배로 함이 바람직하고, 10 내지 20 배로 하는 것이 더 바람직하나, 이에 한정되는 것은 아니다. 추출시 온도는 10 내지 150℃ 인 것이 바람직하며, 20 내지 80℃ 인 것이 더욱 바람직하나 이에 한정되지 않는다. 상기 추출 시간은 1 내지 10일인 것이 바람직하나 이에 한정되지 않는다. The extraction solvent may be water, a C 1 to C 4 alcohol, or a mixed solvent thereof. Preferably, the extraction solvent is extracted with methanol or ethanol aqueous solution, but not limited thereto. The amount of the extraction solvent is preferably 1 to 30 times, more preferably 10 to 20 times, the dry weight of the layer foliage, but is not limited thereto. The extraction temperature is preferably 10 to 150 ° C, more preferably 20 to 80 ° C, but is not limited thereto. The extraction time is preferably 1 to 10 days, but is not limited thereto.
상기 추출물을 제조하는 방법은 초임계추출, 아임계추출, 고온추출, 고압추출 또는 초음파추출법 등의 추출장치를 이용한 방법 또는 XAD 및 HP-20을 포함한 흡착 수지를 이용하는 방법 등 당업계의 통상적인 추출방법을 사용할 수 있으며, 가온하며 환류 추출 또는 상온에서 추출하는 것이 바람직하나, 이에 한정하는 것은 아니다. 상기 추출 회수는 1회 내지 5회인 것이 바람직하며, 3회 반복 추출하는 것이 더욱 바람직하나 이에 한정되는 것은 아니다. The method for preparing the extract may be a conventional extraction method such as supercritical extraction, subcritical extraction, high-temperature extraction, high-pressure extraction, ultrasonic extraction, or the like using XAD and HP-20 adsorbent resins. Method may be used, and it is preferable to heat, reflux or extract at room temperature, but it is not limited thereto. The number of times of extraction is preferably one to five times, more preferably three times, but is not limited thereto.
상기 방법에 있어서, 단계 3)의 감압농축은 진공회전증발기를 이용하는 것이 바람직하나 이에 한정하지 않는다. 또한, 건조는 감압건조, 진공건조, 비등건조, 분무건조, 상온건조 또는 동결건조하는 것이 바람직하나 이에 한정하지 않는다. In the above method, it is preferable, but not limited, to use a vacuum rotary evaporator for the vacuum concentration in step 3). The drying is preferably, but not exclusively, reduced-pressure drying, vacuum drying, boiling drying, spray drying, room temperature drying or freeze-drying.
한편 층꽃풀 추출물의 분획물은 추가적으로 유기용매로 추출하여 얻을 수 있으며, 이때 유기용매는 디클로로메탄(CH2Cl2), 에틸아세테이트, 부탄올인 것이 바람직하나 이에 한정하지 않는다. 상기 분획물은 층꽃풀 추출물을 물에 현탁시킨 후 디클로로메탄(CH2Cl2), 에틸아세테이트 및 부탄올로 순차적으로 계통 분획하여 수득한 디클로로메탄 분획물, 에틸아세테이트 분획물, 에틸아세테이트 분획물, 부탄올 분획물 또는 물 분획물 중 어느 하나인 것이 바람직하며, 에틸아세테이트 분획물임이 더욱 바람직하나, 이에 한정하지 않는다. 상기 분획물은 상기 층꽃풀 추출물로부터 분획 과정을 1회 내지 5회, 바람직하게는 3회 반복하여 수득할 수 있고, 분획 후 감압 농축하는 것이 바람직하나 이에 한정하지 않는다.On the other hand, the fraction of Fusarium oxysporum extract can be obtained by further extracting with an organic solvent. The organic solvent is preferably dichloromethane (CH 2 Cl 2 ), ethyl acetate, butanol, but not limited thereto. The fractions were prepared by suspending the extracts in water and then sequentially fractionating the fractions with dichloromethane (CH 2 Cl 2 ), ethyl acetate and butanol. The dichloromethane fraction, ethyl acetate fraction, ethyl acetate fraction, butanol fraction or water fraction , And it is more preferable that it is an ethyl acetate fraction. However, it is not limited thereto. The fraction can be obtained by repeating the fractionation process from the layer fennel extract one to five times, preferably three times, and the fraction is preferably concentrated under reduced pressure, but not limited thereto.
또한 본 발명은 층꽃풀 추출물 또는 이의 분획물로부터 분리한 하기 화학식 1 내지 10 으로 표시되는 화합물 중에서 선택된 1종 또는 2종 이상의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 간독성 질환 예방 및 치료용 약학 조성물을 제공한다.The present invention also relates to a method for the prevention and treatment of hepatotoxic diseases, which comprises, as an active ingredient, one or more compounds selected from the group consisting of compounds represented by the following formulas (1) to (10) A pharmaceutical composition is provided.
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
[화학식 6][Chemical Formula 6]
[화학식 7](7)
[화학식 8][Chemical Formula 8]
[화학식 9][Chemical Formula 9]
[화학식 10][Chemical formula 10]
상기 화학식 4에서, R1 및 R2는 각각 수소 또는 메틸기를 의미하며, 화학식 6에서 R은 하기 화학식 11의 카페오일기 또는 하기 화학식 12의 6,7-디히드로포리아멘토일기를 의미한다.In formula (4), R 1 and R 2 each represent hydrogen or a methyl group. In formula (6), R represents a caffeoyl group represented by the following formula (11) or a 6,7-dihydropoly mentoyl group represented by the following formula (12).
[화학식 11](11)
[화학식 12][Chemical Formula 12]
상기 화합물은 층꽃풀 추출물 또는 분획물을 세파덱스, 실리카겔 및 역상 칼럼크로마토그래피(RP-18) 등을 사용하여 화합물을 분리할 수 있다. 특히 이를 통하여 4종의 신규 화합물을 얻을 수 있었으며, 이를 각각 카욥테로사이드 A(Caryopteroside A, 화학식 1), 카욥테로사이드 B(Caryopteroside B, 화학식 2), 인카노이드 A(Incanoid A, 화학식 6, R은 카페오일기)및 인카노이드 B(Incanoid B, 화학식 6, R은 6,7-디히드로포리아멘토일기)이라 명명하였다. 상기 신규 화합물 이외에도, 5종의 페닐프로파노이드 배당체로서 6-O-카페오일플리노사이드 A(6-O-caffeoylphlinoside A, 화학식 3), 악테오사이드(acteoside, 화학식 4, R1 및 R2는 수소), 루코스셉터사이드 A(leucosceptoside A, 화학식 4, R1은 메틸기 및 R2는 수소), 지오노사이드 D(jionoside D, 화학식 4, R1은 수소 및 R2는 메틸기), 마티노사이드(Martynoside, 화학식 4, R1 및 R2는 메틸기), 6-카페오일-D-글루코즈(6-O-caffeoyl-D-glucose, 화학식 5), 1종의 이리도이드로서 8-O-아세틸-6′-O-카페오일하르파지드(8-O-acetyl-6'-O-caffeoylharpagide, 화학식 7), 3종의 플라보노이드로서 에리오딕티올-7-O-β-D-글루코피라노사이드(eriodictyol-7-O-β-D-glucopyranoside, 화학식 8), 루테올린 4′-O-β-D-글루코피라노사이드(luteolin 4'-O-β-D-glucopyranoside, 화학식 9), 로이폴린)(rhoifolin, 화학식 10)과 같은 화합물을 분리하였다. The compound can be isolated from the layer foliar extracts or fractions using Sephadex, silica gel and reverse phase column chromatography (RP-18). In particular, four new compounds could be obtained through this, and these were identified as Caryopteroside A (Formula 1), Caryopteroside B (Formula 2), Incanoid A (
상기 층꽃풀 추출물, 분획물 및 이로부터 분리된 화합물은 HepG2 세포에서의 세포독성 보호 효과로 인하여 간독성 질환, 구체적으로는 약물성 간 손상, 바이러스성 간 손상, 간염, 간경화, 간암, 간성혼수 등에 대한 예방 및 치료효과를 나타낸다.
The herbal extracts, fractions and the compounds isolated therefrom are useful for the prevention of hepatotoxic diseases, in particular, liver damage, viral liver damage, hepatitis, liver cirrhosis, liver cancer and hepatic coma due to the cytotoxic protective effect of HepG2 cells And therapeutic effects.
상기 본 발명의 층꽃풀 추출물, 이의 분획물 또는 이로부터 분리한 화합물을 포함하는 조성물은, 조성물 총 중량에 대하여 상기 층꽃풀 추출물, 이의 분획물 또는 이로부터 분리한 화합물을 0.1 내지 50 중량%로 포함하는 것이 바람직하나 이에 한정되지 않는다.The composition comprising the extract of the present invention, fractions thereof, or a compound isolated therefrom of the present invention comprises 0.1 to 50% by weight of the extract, the fraction thereof or the compound isolated therefrom, based on the total weight of the composition But is not limited thereto.
본 발명의 조성물은 약제의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The compositions of the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of medicaments.
본 발명에 따른 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 조성물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 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 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 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 composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method have. Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, (sucrose), lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.
본 발명의 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태, 체중, 연령, 성별, 식이, 배설율, 질환의 중증도, 약물형태, 투여시간, 투여방법, 투여경로 및 투여기간 등에 따라 그 범위가 다양하다. 1일 투여량은 본 발명에 따른 추출물, 분획물 또는 화합물을 동결건조하였을 때의 양으로 0.0001㎎/㎏ 내지 500㎎/㎏, 바람직하게는 0.001㎎/㎏ 내지 100㎎/㎏ 이며, 필요에 따라 일일 1회 내지 수회로 나누어 투여할 수 있다.
The composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the desired method, and the dose may be appropriately determined depending on the condition of the patient, The range varies depending on diet, excretion rate, severity of disease, drug type, administration time, administration method, administration route and administration period. The daily dose is 0.0001 mg / kg to 500 mg / kg, preferably 0.001 mg / kg to 100 mg / kg, when the extract, fraction or compound according to the present invention is lyophilized, It may be administered once to several times in divided doses.
또한, 본 발명은 층꽃풀 추출물 또는 이의 분획물을 유효성분으로 함유하는 간독성 질환 예방 또는 개선용 건강 식품을 제공한다.The present invention also provides a health food for preventing or ameliorating hepatotoxic diseases, which contains the extract of Aspergillus oryzae as an active ingredient.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소세지, 빵, 비스켓, 떡, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the foods to which the above substances can be added include dairy products including dairy products such as drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.
본 발명의 층꽃풀 추출물 또는 이의 분획물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합양은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 중의 상기 추출물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있다.The layer lamellar extract of the present invention or a fraction thereof can be directly added to food or used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to its use purpose (for prevention or improvement). Generally, the amount of the extract in the health functional food may be 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, the amount may be less than the above range.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12 g이다.The health functional beverage composition of the present invention has no particular limitation on the other ingredients other than the above-mentioned extract as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 층꽃풀 추출물 또는 이의 분획물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 층꽃풀 추출물 또는 이의 분획물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 층꽃풀 추출물 또는 이의 분획물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.
In addition to the above-mentioned ingredients, the extracts of the layer foliar extracts or fractions thereof can be used as flavoring agents such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates such as cheese and chocolate, Salts of alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks and the like. In addition, the layer foliar extract or fraction thereof of the present invention may contain flesh for the production of natural fruit juice and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of from 0.1 to about 20 parts by weight per 100 parts by weight of the layer foliar extract or fraction thereof of the present invention.
이하, 본 발명을 실시예 및 제조예에 의해 상세히 설명한다. Hereinafter, the present invention will be described in detail with reference to Examples and Production Examples.
단 하기 실시예 및 제조예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 제조예에 의해 한정되지 않는다.
EXAMPLES The following examples and preparations are merely illustrative of the present invention, and the contents of the present invention are not limited by the following examples and preparative examples.
제조예 1 : 층꽃풀 지상부 추출물 및 이의 분획물의 제조Production Example 1: Preparation of a ground-layer extract of a layered grass and its fractions
음건한 층꽃풀의 지상부(꽃을 포함한 잎과 줄기) 6.13 kg을 세절한 후 25.5 L의 메탄올에 침적시키고 4일 동안 실온에서 추출한 후 추출액을 여과하였다. 추출액을 여과한 후 남은 잔사에 다시 25.5 L의 메탄올을 가하고 4일 동안 실온에서 추출하는 방법을 추가로 2회 반복한 뒤, 이를 35 ℃에서 감압 농축하여 메탄올 추출물 760.1 g을 수득하였다. 상기 메탄올 추출물을 증류수 7.5 L에 현탁시키고, 분별깔때기를 이용하여 디클로로메탄(70.5 L × 3), 에틸아세테이트(7.5 L × 3) 및 부탄올(7.5 L ×3)로 분획하였으며, 그 결과 디클로로메탄 분획물(90.2 g), 에틸아세테이트 분획물(42.6 g), 부탄올 분획물(248.5 g) 및 물 분획물을 얻을 수 있었다.
6.13 kg of the ground part (leaf and stem including flower) of the shrub layer was subjugated and immersed in 25.5 L of methanol, extracted at room temperature for 4 days, and then the extract was filtered. 25.5 L of methanol was added to the remaining residue after filtration of the extract, and the mixture was further extracted twice at room temperature for 4 days. The mixture was concentrated under reduced pressure at 35 ° C to obtain 760.1 g of a methanol extract. The methanol extract was suspended in 7.5 L of distilled water and fractionated into dichloromethane (70.5 L x 3), ethyl acetate (7.5 L x 3) and butanol (7.5 L x 3) using a separating funnel. As a result, the dichloromethane fraction (90.2 g), ethyl acetate fraction (42.6 g), butanol fraction (248.5 g) and water fraction.
제조예 2 : 층꽃풀 추출물의 분획물로부터 유효성분의 분리Production Example 2: Isolation of Active Ingredients from the Fraction of Lycopersiconazole Extract
상기 층꽃풀의 메탄올 추출물로부터 분획한 에틸아세테이트 분획물 20 g을 메탄올을 전개용매로 사용하여 세파덱스 LH-20 컬럼크로마토그래피를 실시하였다. 각각의 분획들은 TLC로 확인하여 유사한 분획들을 모아 7개의 소분획(980E1 ∼ 980E7)으로 나누었다. 20 g of the ethyl acetate fraction fractionated from the methanol extract of the layer fennel was subjected to Sephadex LH-20 column chromatography using methanol as a developing solvent. Each fraction was identified by TLC and similar fractions were pooled into seven small fractions (980E1 to 980E7).
이후, 소분획 E3(13.5 g)은 세파덱스 LH-20을 이용하여 컬럼 크로마토그래피를 실시하였다. 전개용매로는 70% 메탄올을 사용하였으며, 마지막은 100% 메탄올을 사용하여 11개의 소분획(980E3-1 ∼ 980E3-11)을 얻을 수 있었다. Subsequently, small fraction E3 (13.5 g) was subjected to column chromatography using Sephadex LH-20. 70% methanol was used as the developing solvent, and 11 small fractions (980E3-1 ~ 980E3-11) were obtained using 100% methanol.
소분획 980E3-2(382.6 mg)을 취하여, 실리카겔을 이동상으로 한 컬럼 크로마토그래피를 수행하였다. 용매 조건은 CH2Cl2:MeOH:H2O(부피비 7:1:0.1 → 4:1:0.1)의 혼합용매를 사용하여 전개시켰으며 10 개의 소분획(980E3-2a ∼ 980E3-2j)으로 나누었다. The small fraction 980E3-2 (382.6 mg) was subjected to column chromatography using silica gel as a mobile phase. The solvent conditions were developed using a mixed solvent of CH 2 Cl 2 : MeOH: H 2 O (volume ratio 7: 1: 0.1 → 4: 1: 0.1) and 10 small fractions (980E3-2a to 980E3-2j) I divided it.
소분획 980E3-2i(84.1 mg)는 Licroprep RP-18 컬럼 크로마토그래피를 수행하여 다시 소분획 9 개(980E3-2i1 ∼ 980E3-2i9)를 얻었으며, 그 중 5 와 7 분획에서 각각 화합물 1(17.9 ㎎)과 2(15.1 ㎎)를 얻었다. The small fraction 980E3-2i (84.1 mg) was subjected to Licroprep RP-18 column chromatography to obtain nine small fractions (980E3-2i1 to 980E3-2i9), and in the 5th and 7th fractions, compound 1 (17.9 Mg) and 2 (15.1 mg).
소분획 980E3-4(5.2 g)는 CH2Cl2:MeOH:H2O(부피비 7:1:0.1→4:1:0.1)의 혼합용매를 사용하여 실리카겔을 이용한 컬럼 크로마토그래피를 수행하여 15개의 소분획(980E3-4-1 ∼ 980E3-4-15)으로 분리하였다. 이 중 분획 980E3-4-11(3 g)은 35% 메탄올에서 70% 메탄올까지 전개용매로서 사용하여 Lichroprep RP-18 컬럼 크로마토그래피를 수행하였으며, 이로부터 순수한 화합물 4(1.93 g)와 12(83.5 ㎎)를 얻었다.The small fraction 980E3-4 (5.2 g) was subjected to column chromatography using silica gel using a mixed solvent of CH 2 Cl 2 : MeOH: H 2 O (volume ratio 7: 1: 0.1 → 4: 1: 0.1) (980E3-4-1 to 980E3-4-15). Fraction 980E3-4-11 (3 g) was subjected to Lichroprep RP-18 column chromatography using 35% methanol to 70% methanol as a developing solvent, from which pure compound 4 (1.93 g) and 12 Mg).
한편, 소분획 980E3-4-14(126.7 ㎎)는 Lichroprep RP-18 column chromatography로 30% 메탄올에서 40% 메탄올까지 극성을 올리면서 전개시켜 10개의 소분획(980E3-4-14a ∼ 980E3-4-14j)으로 나누었다. 그 중 소분획 980E3-4-14c(20 ㎎)는 50% 메탄올을 전개용매로 사용한 preparative RP-18 TLC를 실시하여 순수한 화합물 8(15.6 ㎎)을 얻었으며, 소분획 980E3-4-14h(11.3 ㎎)는 50% 메탄올을 전개용매로 이용한 preparative RP-8 TLC를 수행하여, 순수한 화합물 3(7.7 ㎎)을 얻었다. On the other hand, the small fraction 980E3-4-14 (126.7 mg) was developed by increasing the polarity from 30% methanol to 40% methanol by Lichroprep RP-18 column chromatography to obtain 10 small fractions (980E3-4-14a to 980E3-4- 14j). A small fraction of 980E3-4-14c (20 mg) was subjected to preparative RP-18 TLC using 50% methanol as a developing solvent to obtain pure compound 8 (15.6 mg). The fraction 980E3-4-14h (11.3 Mg) was subjected to preparative RP-8 TLC using 50% methanol as a developing solvent to obtain pure compound 3 (7.7 mg).
한편 소분획 980E3-4-10(903.2 ㎎)은 Lichroprep RP-18 컬럼 크로마토그래피를 수행하여 10개의 소분획(980E3-4-10.1 ∼ 980E3-4-10.10)으로 나누었다. 사용한 전개용매는 30% 메탄올에서 50% 메탄올까지 사용하였으며, 그 중 4번째 소분획 980E3-4-10.4로부터 세파덱스 LH-20을 이용하여 화합물 5(326.5 ㎎)를 얻었다. 또한 첫 번째 소분획 980E3-4-10.1로부터 전개용매를 30% 메탄올에서 50% 메탄올까지 극성을 높이면서 Lichroprep RP-18 컬럼 크로마토그래피를 수행하여 화합물 7(20.6 ㎎)을 얻었다. 그리고 다섯 번째 소분획 980E3-4-10.5(89.1 ㎎)로부터 50% 메탄올를 전개용매로 이용한 preparative RP-18 TLC를 실시한 결과 화합물 6(9.4 ㎎)과 9(28 ㎎)를 얻었다. On the other hand, the small fraction 980E3-4-10 (903.2 mg) was subjected to Lichroprep RP-18 column chromatography and divided into 10 small fractions (980E3-4-10.1 to 980E3-4-10.10). The developing solvent used was 30% methanol to 50% methanol. Compound 5 (326.5 mg) was obtained from the fourth small fraction 980E3-4-10.4 using Sephadex LH-20. Further, from the first small fraction 980E3-4-10.1, the developing solvent was subjected to Lichroprep RP-18 column chromatography with increasing polarity from 30% methanol to 50% methanol to obtain Compound 7 (20.6 mg). The compound 6 (9.4 mg) and 9 (28 mg) were obtained from the fifth small fraction 980E3-4-10.5 (89.1 mg) by preparative RP-18 TLC using 50% methanol as a developing solvent.
한편, 소분획 980E3-2e(49 ㎎)는 HPLC를 이용한 RP-18(7 ㎛, 250-10, Merck) preparative HPLC를 실시하였다. 36% 메탄올에서 60% 메탄올까지의 혼합 용매를 사용하였으며, 이를 통하여 화합물 10(5.1 ㎎)과 11(10.5 ㎎)을 얻었다. On the other hand, RP-18 (7 ㎛, 250-10, Merck) preparative HPLC was performed on the fraction 980E3-2e (49 mg) by HPLC. Compound 10 (5.1 mg) and 11 (10.5 mg) were obtained from a mixed solvent of 36% methanol and 60% methanol.
한편, 소분획 980E3-1(1.51 g)을 실리카겔을 이동상으로 한 컬럼 크로마토그래피를 수행하였다. 용매 조건은 CH2Cl2:MeOH:H2O(부피비 7:1:0.1 → 5:1:0.1)의 혼합용매를 사용하여 전개시켰으며, 16 개의 소분획(980E3-1a ∼ 980E3-1p)로 나누었고, 11번째 분획인 소분획 980E3-1k(478.7 ㎎)는 Lichroprep RP-18 컬럼 크로마토그래피로 30% 메탄올에서 60% 메탄올까지 극성을 올리면서 전개용매를 사용하여 순수한 화합물 13 (109.1 ㎎)을 얻었다. On the other hand, column chromatography using a small fraction of 980E3-1 (1.51 g) with silica gel as a mobile phase was carried out. The solvent conditions were developed using a mixed solvent of CH 2 Cl 2 : MeOH: H 2 O (volume ratio 7: 1: 0.1 → 5: 1: 0.1) and 16 small fractions (980E3-1a to 980E3-1p) And the 11th fraction, 980E3-1k (478.7 mg), was purified by Lichroprep RP-18 column chromatography from 30% methanol to 60% methanol, and pure compound 13 (109.1 mg) was isolated using a developing solvent .
또한, 소분획 980E3-3(2.2 g)은 세파덱스 LH-20을 이용하여 컬럼 크로마토그래피를 실시하였다. 전개용매로 100% 메탄올을 사용하여 6개의 소분획(980E3-3a ∼ 980E3-3f)으로 나누었다. 소분획 980E3-3b(176 mg)은 CH2Cl2:MeOH:H2O(부피비 7:1:0.1)의 혼합용매를 사용하여 실리카겔을 이용한 컬럼 크로마토그래피와 분취용 RP-18 TLC(50% MeOH)를 실시하여 순수한 화합물 14(17.3 ㎎)를 얻었다.
Further, the fraction 980E3-3 (2.2 g) was subjected to column chromatography using Sephadex LH-20. It was divided into six small fractions (980E3-3a to 980E3-3f) using 100% methanol as developing solvent. The small fraction 980E3-3b (176 mg) was purified by column chromatography on silica gel using a mixed solvent of CH 2 Cl 2 : MeOH: H 2 O (volume ratio 7: 1: 0.1) MeOH) to obtain pure compound 14 (17.3 mg).
제조예 3 : 분리된 화합물의 구조 결정Preparation Example 3: Determination of the structure of separated compounds
상기 제조예 2에서 얻은 각 성분들에 대한 물리적 특성 및 1H-NMR(400 MHz)과 13C-NMR(100 MHz) 스펙트럼을 측정하였다. 각 피크의 화학 이동값(chemical shift)을 측정용매인 메탄올의 화학이동값(3.3 ppm, 49.8 ppm)에 대한 상대값으로 나타내었다.
Physical properties and 1 H-NMR (400 MHz) and 13 C-NMR (100 MHz) spectra of the respective components obtained in Preparation Example 2 were measured. The chemical shift of each peak was expressed as a relative value relative to the chemical shift value (3.3 ppm, 49.8 ppm) of methanol as a measurement solvent.
제조예 3-1 : 화합물 1의 구조분석Production Example 3-1: Analysis of Structure of
[α]20 D -44.1° (c 0.44, MeOH) [α] 20 D -44.1 ° ( c 0.44, MeOH)
HRESMS(positive-ion mode):m/z = 787.2462(Calcd. for C38H43O18: 787.2449)HRESMS (positive-ion mode): m / z = 787.2462 ( Calcd . For C 38 H 43 O 18 : 787.2449)
1H-NMR (400 MHz, CD3OD): δ 1.09(3H, d, J=6.2 Hz, H-r6), 2.79(2H, brt, J=6.9 Hz, H-7), 2.29(1H, t, J=9.7 Hz, H-r4), 3.42(1H, t, J=8.7 Hz, H-g2), 3.54(1H, m, H-r5), 3.58(1H, dd, J=3.7, 9.9 Hz, H-r3), 3.73(1H, q, J=8.0 Hz, H-8a), 3.79(1H, m, H-g5), 3.84(1H, t, J=9.0 Hz, H-g3), 3.93(1H, br, H-r2), 3.97(1H, q, J=8.0 Hz, H-8b), 4.24(1H, brd, J=4.0 Hz, H-g6), 4.41(1H, d, J=7.9 Hz, H-g1), 5.04(1H, t, J=9.6 Hz, H-g4), 5.19(1H, d, J=1.0 Hz, H-r1), 6.22(1H, d, J=15.9 Hz, H-8″), 6.27(1H, d, J=15.9 Hz, H-8′), 6.65(1H, dd, J=1.8, 8.1 Hz, H-6), 6.54(1H, d, J=8.0 Hz, H-5), 6.68(1H, d, J=1.9 Hz, H-2), 6.71(1H, d, J=8.2 Hz, H-5″), 6.75(1H, d, J=8.2 Hz, H-5′), 6.81(1H, dd, J=1.8, 8.3 Hz, H-6″), 6.93(1H, dd, J=1.8, 8.2 Hz, H-6′), 6.98(1H, d, J=1.8 Hz, H-2″), 7.04(1H, d, J=1.8 Hz, H-2′), 7.53(1H, d, J=15.9 Hz, H-7″), 7.59(1H, d, J=15.9 Hz, H-7′). 1 H-NMR (400 MHz, CD 3 OD): δ 1.09 (3H, d, J = 6.2 Hz, H-r6), 2.79 (2H, brt, J = 6.9 Hz, H-7), 2.29 (1H, t, J = 9.7 Hz, H -r4), 3.42 (1H, t, J = 8.7 Hz, H-g2), 3.54 (1H, m, H-r5), 3.58 (1H, dd, J = 3.7, 9.9 Hz, H-r3), 3.73 (1H, q, J = 8.0 Hz, H-8a), 3.79 (1H, m, H-g5), 3.84 (1H, t, J = 9.0 Hz, H-g3), 3.93 (1H, br, H- r2), 3.97 (1H, q, J = 8.0 Hz, H-8b), 4.24 (1H, brd, J = 4.0 Hz, H-g6), 4.41 (1H, d, J = 7.9 Hz, H-g1) , 5.04 (1H, t, J = 9.6 Hz, H-g4), 5.19 (1H, d, J = 1.0 Hz, H-r1), 6.22 (1H, d, J = 15.9 Hz, H-8 "), 6.27 (1H, d, J = 15.9 Hz, H-8 '), 6.65 (1H, dd, J = 1.8, 8.1 Hz, H-6), 6.54 (1H, d, J = 8.0 Hz, H-5) , 6.68 (1H, d, J = 1.9 Hz, H-2), 6.71 (1H, d, J = 8.2 Hz, H-5 "), 6.75 (1H, d, J = 1.8 Hz, H-5 '), 6.81 (1H, dd, J = 1.8,8.3 Hz, H-6''), 6.93 (1H, dd, J = , d, J = 1.8 Hz, H-2 "), 7.04 (1H, d, J = 1.8 Hz, H-2 '), 7.53 (1H, d, J = 15.9 Hz, H-7"), 7.59 ( 1H, d, J = 15.9Hz, H-7 ').
13C-NMR (100 MHz, CD3OD): δ 18.5(C-r6), 36.6(C-7), 64.1(C-g6), 70.5(C-r4), 70.9(C-g4), 72.0(C-r3), 72.3(C-r2), 72.5(C-8), 73.1(C-g5), 73.7(C-r4), 76.1(C-g2), 81.5(C-g3), 103.1(C-r1), 104.4(C-g1), 114.6(C-8′,8″), 115.3(C-2′,2″), 116.4(C-5), 116.5(C-5′,5″), 117.1(C-2), 121.3(C-6), 123.0(C-6″), 123.3(C-6′), 127.6(C-1′,1″), 131.4(C-1), 144.6(C-4), 146.1(C-3), 146.7(C-3″), 146.8(C-3′), 147.4(C-7″), 148.1(C-7′), 149.6(C-4″), 149.8(C-4′), 168.1(C-9″), 168.8(C-9′).
13 C-NMR (100 MHz,
무정형의 분말인 상기 화합물은 1H-NMR 스펙트럼에서 δ 7.53(1H, d, J=15.9 Hz, H-7″), 7.59(1H, d, J=15.9 Hz, H-7′)와 6.22(1H, d, J=15.9 Hz, H-8″), 6.27(1H, d, J=15.9 Hz, H-8′)에서의 피크는 서로 커플링 하고 있으며, 커플링 상수로(coupling constant)로 trans 비닐(vinyl)기가 2개 존재하는 것을 알 수 있었다. δ 6.65(1H, dd, J=1.8, 8.1 Hz, H-6)에서의 doublet of doublet 피크는 6.54(1H, d, J=8.0 Hz, H-5) 피크와 ortho 커플링을 하고 6.68(1H, d, J=1.9 Hz, H-2) 피크와 meta 커플링을 하고 있어, 방향족 고리가 ABX system으로 치환된 화합물임을 알 수 있었다. δ 6.71(1H, d, J=8.2 Hz, H-5″) 피크가 6.81(1H, dd, J=1.8, 8.3 Hz, H-6″) 피크와 ortho 커플링을 하고 6.98(1H, d, J=1.8 Hz, H-2″) 피크와는 meta 커플링을 하고 있어, 다른 방향족 고리가 ABX system으로 치환된 화합물임을 알 수 있었다. δ 6.93(1H, dd, J=1.8, 8.2 Hz, H-6′)에서의 doublet of doublet 피크는 6.75(1H, d, J=8.2 Hz, H-5′) peak와 ortho 커플링을 하고 7.04(1H, d, J=1.8 Hz, H-2′) 피크와는 meta 커플링을 하고 있어 ABX system으로 치환된 방향족 고리가 3개 존재하는 화합물임을 알 수 있었다. δ 5.19에서의 넓은 doublet 피크(J=1.0 Hz)와 1.09(3H, d, J=6.2 Hz, H-r6)에서의 doublet 피크는 람노오스(rhamnose)에서 기인하는 전형적인 피크로 각각 아노머 수소(anomeric proton)과 람노오스의 6번 수소에서 기인하는 피크임을 알 수 있었다. 또한 δ 5.04 에서의 triplet 피크는 당에서 기인하는 피크로 치환기가 결합하고 있음을 예상할 수 있고, δ 4.41(1H, d, J=7.9 Hz)에서의 doublet 피크는 당의 아노머 수소에서 기인한 것으로 그 커플링 상수로서 β-form임을 알 수 있었다. 따라서 이 화합물은 3개의 방향족 고리, 2개의 trans 비닐기 및 2개의 당이 존재하며 그 중 하나는 람노오스임을 확인할 수 있었다. Powder of the compound of the amorphous from 1 H-NMR spectrum δ 7.53 (1H, d, J = 15.9 Hz, H-7 "), 7.59 (1H, d, J = 15.9 Hz, H-7 ') and 6.22 ( 1H, a d, J = 15.9 Hz, H -8 "), 6.27 (1H, d, J = 15.9 Hz, H-8 ') peak is, and coupling with each other, the coupling constant (coupling constant) in There were two trans vinyl groups. The doublet of doublet peak at δ 6.65 (1H, dd, J = 1.8, 8.1 Hz, H-6) was ortho- coupled with 6.54 (1H, d, J = 8.0 Hz, H- , d, J = 1.9 Hz, H-2) peaks and meta coupling, indicating that the aromatic ring was substituted with the ABX system. δ 6.71 (1H, d, J = 8.2 Hz, H-5 ") peak at 6.81 (1H, dd, J = 1.8, 8.3 Hz, H-6") peak and ortho coupling and 6.98 (1H, d, J = 1.8 Hz, H-2 ") peak was meta -coupled, indicating that the other aromatic rings were substituted with the ABX system. δ 6.93 (1H, dd, J = 1.8, 8.2 Hz, H-6 ') doublet of doublet peak, 6.75 (1H, d, J = 8.2 Hz, H-5 in') peak and ortho coupling to 7.04 (1H, d, J = 1.8 Hz, H-2 ') peak was meta- coupled with three aromatic rings substituted with the ABX system. δ broad doublet doublet peak at peak (J = 1.0 Hz) and 1.09 (3H, d, J = 6.2 Hz, H-r6) at 5.19 is ramno agarose (rhamnose) each anomeric hydrogen in typical peak resulting from ( anomeric proton) and the 6th hydrogen of rhamnose. The triplet peak at δ 5.04 can be expected to have substituents attached to the sugar-derived peak, and the doublet peak at δ 4.41 (1H, d, J = 7.9 Hz) is due to the anomeric hydrogen of the sugar It was found that the coupling constant was β-form. Therefore, this compound has three aromatic rings, two trans vinyl groups, and two sugars, one of which can be confirmed to be laminose.
13C-NMR 스펙트럼에서 δ 168.1(C-9″)과 168.8(C-9′)에서의 피크로 2개의 카보닐기를 나타내는 것이며, 이는 2개의 카페오일(caffeoyl)기에서 기인한 것임을 알 수 있었다. δ 60-80사이의 피크들은 2개의 당에서 기인한 피크로 그 화학 이동 값을 통하여 각각 글루코오스와 람노오스임을 확인할 수 있었다(Steaven et al., 1990, Leroy et al., 1972). Dept(135°) 스펙트럼에서 δ 72.3(C-8)과 36.7(C-7) 피크는 CH2기 임을 알 수 있었으며 지방족기(aliphatic group)에서 기인한 것임을 알 수 있었다. It was found that two carbonyl groups in the 13 C-NMR spectrum showed peaks at δ 168.1 (C-9 ") and 168.8 (C-9 '), which were attributed to two caffeoyl groups . Peaks between δ 60-80 were peaks attributable to the two sugars, and their chemical shifts were confirmed to be glucose and rhamnose, respectively (Steaven et al., 1990, Leroy et al., 1972). In the Dept (135 °) spectrum, peaks δ 72.3 (C-8) and 36.7 (C-7) were found to be CH 2 groups and were attributed to aliphatic groups.
1H-1HCOSY에서 2개의 당 들의 정확한 위치를 알 수 있었으며, 비닐기와 방향족 고리의 연결관계, 결합 위치를 확인하였다. 또한, 이들의 결합위치를 정확하게 확인하기 위하여 HMBC와 HMQC 실험을 수행하였으며, HMQC에서는 탄소와 수소간의 정확한 피크들을 동정할 수 있으며, HMBC에서는 치환기들의 정확한 위치를 알 수 있었다. 즉, 글루코오스의 6번에서 기인하는 δ 4.24 에서의 피크는 δ 168.8에서의 카보닐기와 상관관계가 나타나고, δ 5.04 에서의 triplet 피크는(C-g4)는 δ 168.1(C-9″)에서의 다른 카보닐기와 상관관계가 나타나며, 두 개의 카페오일기는 글루코오스의 4번과 6번에 각각 결합하고 있음을 알 수 있었다. 또한 글루코오스의 1번 수소에서 기인하는 δ 4.41(1H, d, J=7.9 Hz)에서의 doublet 피크는 δ 72.5에서의 8번 탄소와 상관관계가 나타나고, 람노오스의 1번 수소에서 기인하는 δ 5.19에서의 넓은 doublet 피크가 δ 81.5에서의 글루코오스 3번 탄소와 상관관계가 나타나고 있어, 글루코오스 1번에 펜에틸(phenethyl)기가, 3번 위치에 람노오스가 결합하고 있음을 확인할 수 있었다. The exact positions of the two sugars in 1 H- 1 HCOSY were determined, and the linking and bonding positions between vinyl groups and aromatic rings were confirmed. HMBC and HMQC experiments were carried out to confirm their bonding positions accurately. In HMQC, exact peaks between carbon and hydrogen could be identified, and exact positions of substituents were found in HMBC. That is, the peak at δ 4.24 originating from glucose No. 6 exhibited a correlation with the carbonyl group at δ 168.8, and the triplet peak at δ 5.04 (C-g 4) was correlated with the peak at δ 168.1 (C-9 " And the two caffeoyl groups were found to bind to
상기 분석 결과를 종합하여 이 화합물은 하기 화학식 1과 같은 구조의 화합물임을 확인할 수 있었고, 이는 자연계에서 처음으로 분리된 화합물로서 카욥테로사이드 A(Caryopteroside A)로 명명하였다. Based on the above analysis results, it was confirmed that this compound was a compound having a structure shown in the following
[화학식 1][Chemical Formula 1]
제조예 3-2 : 화합물 2의 구조분석Production Example 3-2: Analysis of Structure of
[α]19 D -244°(c 0.60, MeOH) [α] 19 D -244 ° ( c 0.60, MeOH)
HRESMS(positive-ion mode):m/z = 945.2660(Calcd. for C44H49O23: 949.2665)HRESMS (positive-ion mode): m / z = 945.2660 ( Calcd . For C 44 H 49 O 23 : 949.2665)
1H-NMR (600 MHz, CD3OD): δ 1.06(3H, d, J=6.1 Hz, H-r6), 3.08(2H, t, J=9.4 Hz, H-g′4), 3.16(1H, t, J=8.5 Hz, H-g2), 3.23(1H, t, J=8.2 Hz, H-g′2), 3.32(1H, m, overlapped with solvent, H-g′4), 3.35(1H, m, H-g5), 3.38(1H, m, H-g′5), 3.51(1H, dd, J=6.6, 11.8 Hz, H-g6a), 3.55(1H, m, H-r5), 3.58-3.62(3H, m, H-r3, r4, g6b), 3.73(1H, brt, J=11.2 Hz, H-g′6a), 3.79(1H, t, J=9.3 Hz, H-g3), 3.96(1H, t, J=2.1 Hz, H-r2), 4.47(1H, d, J=7.8 Hz, H-g′1), 4.82(1H, t, J=9.6 Hz, H-g4), 4.89(1H, overlapped with solvent, H-g1), 5.04(1H, d, J=1.6 Hz, H-r1), 5.16(1H, dd, J=1.9, 11.6 Hz, H-g′6b), 5.24(1H, s, H-7), 5.64(1H, s, H-8), 6.28(1H, d, J=15.9 Hz, H-8′), 6.35(1H, d, J=15.8 Hz, H-8″), 6.73(1H, dd, J=1.3, 8.4 Hz, H-6), 6.76(1H, d, J=8.9 Hz, H-5), 6.78(1H, d, J=8.3 Hz, H-5′), 6.86(1H, d, J=1.3 Hz, H-2), 6.91(1H, d, J=8.3 Hz, H-5″), 6.95(1H, dd, J=1.9, 8.3 Hz, H-6′), 7.07(1H, d, J=1.3 Hz, H-2′), 7.06(1H, dd, J=1.7, 8.3 Hz, H-6″), 7.40(1H, d, J=1.9 Hz, H-2″), 7.59(1H, d, J=15.9 Hz, H-7′), 7.61(1H, d, J=15.8 Hz, H-7″).
1 H-NMR (600 MHz, CD 3 OD): δ 1.06 (3H, d, J = 6.1 Hz, H-r6), 3.08 (2H, t, J = 9.4 Hz, Hg'4), 3.16 (1H, t, J = 8.5 Hz, H -g2), 3.23 (1H, t, J = 8.2 Hz, Hg'2), 3.32 (1H, m, overlapped with solvent, Hg'4), 3.35 (1H, m, H (1H, d, J = 6.6, 11.8 Hz, H-g6a), 3.55 (1H, m, H-r5), 3.58-3.62 m, H-r3, r4, g6b), 3.73 (1H, brt, J = 11.2 Hz, Hg'6a), 3.79 (1H, t, J = 9.3 Hz, H-g3), 3.96 (1H, t, J = 2.1 Hz, H-r2), 4.47 (1H, d, J = 7.8 Hz, Hg'1), 4.82 (1H, t, J = 9.6 Hz, H- -g1), 5.04 (1H, d , J = 1.6 Hz, H-r1), 5.16 (1H, dd, J = 1.9, 11.6 Hz, Hg'6b), 5.24 (1H, s, H-7), 5.64 (1H, s, H-8 ), 6.28 (1H, d, J = 15.9 Hz, H-8 '), 6.35 (1H, d, J = 15.8 Hz, H-8 "), 6.73 (1H, dd, J = 1.3, 8.4 Hz, H -6), 6.76 (1H, d, J = 8.9 Hz, H-5), 6.78 (1H, d, J = 8.3 Hz, H-5 '), 6.86 (1H, d , J = 1.3 Hz, H- 2), 6.91 (1H, d, J = 8.3 Hz, H-5 "), 6.95 (1H, dd, J = 1.9, 8.3 Hz, H-6 '), 7.07 (1H , d, J = 1.3 Hz, H-2 '), 7.06 (1H, dd, J = 1.7, 8.3 Hz, H-6 "), 7.40 (1H, d, J = 1.9 Hz, H-2"), 7 .59 (1H, d, J = 15.9 Hz, H-7 '), 7.61 (1H, d, J = 15.8 Hz, H-7'').
13C-NMR (150 MHz, CD3OD): δ 18.9(C-r6), 62.6(C-g6), 64.8(C-g′6), 70.8(C-r5), 70.9(C-g4), 72.6(C-g′4), 72.7(C-r3), 74.7(C-g2), 74.8(C-g5), 76.2(C-g′5), 76.3(C-g′2), 76.9(C-r4), 78.1(C-g′3), 79.6(C-7), 83.1(C-r2), 84.9(C-g3), 97.2(C-8), 101.4(C-g1), 103.6(C-r1), 106.4(C-g′1), 114.6(C-2), 114.9(C-8′), 115.3(C-2′), 116.5(C-5), 116.7(C-5′), 116.9(C-5″), 119.1(C-8″), 119.3(C-6), 119.9(C-2″), 123.4(C-6′), 126.5(C-6″), 127.1(C-1′), 129.9(C-1″), 130.9(C-1), 141.7(C-3″), 146.2(C-7″), 146.7(C-3), 146.9(C-4), 147.0(C-3′), 148.3(C-7′), 148.5(C-4″), 150.0(C-4′), 168.2(C-9″), 168.6(C-9′).
13 C-NMR (150 MHz,
무정형의 분말인 상기 화합물은 1H-NMR 스펙트럼에서 δ 7.59(1H, d, J=15.9 Hz, H-7′)에서의 피크와 δ 6.28(1H, d, J=15.9 Hz, H-8′)에서의 피크, 그리고 δ 7.61(1H, d, J=15.8 Hz, H-7″)의 피크와 6.35(1H, d, J=15.8 Hz, H-8″) 피크가 각각 doublet으로 나타나며, 그들의 커플링 상수로서 trans 비닐(vinyl)기가 2개 존재하는 것을 알 수 있었다. Powder of the compound of the amorphous 1 H-NMR spectrum at δ 7.59 (1H, d, J = 15.9 Hz, H-7 ') with the peak δ 6.28 in (1H, d, J = 15.9 Hz, H-8' ) peaks, and δ 7.61 (1H, d, J = 15.8 Hz, H-7 ") peak and 6.35 (1H, d, J = 15.8 Hz, H-8 of"), each peak appears as a doublet, in their It can be seen that there are two trans vinyl groups as a coupling constant.
δ 7.06(1H, dd, J=1.7, 8.3 Hz, H-6″)에서의 doublet of doublet 피크는 6.91(1H, d, J=8.3 Hz, H-5″) 피크와 ortho 커플링을 하고, δ 7.40(1H, d, J=1.9 Hz, H-2″) 피크와 meta 커플링을 하고 있어, 방향족 고리가 ABX system으로 치환되었음을 알 수 있었으며, δ 6.95(1H, dd, J=1.9, 8.3 Hz, H-6′)피크가 δ 6.78 (1H, d, J=8.3 Hz, H-5′) 피크와 ortho 커플링을 하고, δ 7.07(1H, d, J=1.3 Hz, H-2′) peak와 meta 커플링을 하고 있어 이 방향적 고리 역시 ABX system으로 치환된 화합물임을 알 수 있었다. 한편, δ 6.73(1H, dd, J=1.3, 8.4 Hz, H-6) 피크가 δ 6.76(1H, d, J=8.9 Hz, H-5) 피크와 ortho 커플링을, 6.86(1H, d, J=1.3 Hz, H-2) 피크와 meta 커플링을 하고 있어, 이 방향족 고리 역시 ABX system으로 치환되어 있음을 알 수 있었다. δ 5.24(1H, s, H-7)와 5.64(1H, s, H-8)에서의 피크는 각각 하나의 수소에 해당하는 피크이며, 화학적 이동을 통하여 산소와 결합하고 있는 형태임을 예상하였다. δ 5.16(1H, dd, J=1.9, 11.6 Hz, H-g′6b)에서의 피크는 당의 6번에서 기인한 것으로 작용기가 존재함을 알 수 있었으며, δ 5.04(1H, d, J=1.6 Hz, H-r1)에서의 넓은 doublet 피크와 δ 1.06(3H, d, J=6.1 Hz, H-r6)에서의 3개의 수소에 해당하는 단일 피크는 람노오스(rhamnose)의 전형적인 피크로 각각 아노머 수소와 6번 수소에서 기인한 피크임을 알 수 있었다. δ 3-4 사이의 복잡한 피크로 당의 존재를 추정하였고, δ 4.47(1H, d, J=7.8 Hz, H-g′1)에서의 doublet 피크는 당의 아노머 수소에 기인한 것으로 그 커플링 상수로서 β-form임을 알 수 있었다. 따라서 이 화합물은 3개의 방향족 고리. 2개의 trans 비닐기 및 3개의 당이 존재하며 하나의 당은 람노오스임을 알 수 있었다. a δ 7.06 (1H, dd, J = 1.7, 8.3 Hz, H-6 "), doublet of doublet peak, 6.91 (1H, d, J = 8.3 Hz, H-5 in") peak and ortho coupling, and δ 7.40 (1H, d, J = 1.9 Hz, H-2 ") there is a peak and a meta coupling, there was a ring can be seen that replacing a ABX system, δ 6.95 (1H, dd, J = 1.9, 8.3 (1H, d, J = 1.3 Hz, H-2 ') was subjected to an ortho coupling with a peak of δ 6.78 (1H, d, J = 8.3 Hz, H- ) peak and meta coupling, indicating that this aromatic ring was also substituted by the ABX system. On the other hand, δ 6.73 (1H, dd, J = 1.3, 8.4 Hz, H-6) peak at δ 6.76 (1H, d, J = 8.9 Hz, H-5) the peak and ortho coupling, 6.86 (1H, d , J = 1.3 Hz, H-2) peak and meta coupling, indicating that this aromatic ring was also replaced by the ABX system. The peaks at δ 5.24 (1H, s, H-7) and 5.64 (1H, s, H-8) are peaks corresponding to one hydrogen, respectively. 5.16 δ peak at (1H, dd, J = 1.9 , 11.6 Hz, Hg'6b) is was found to be the one that a functional group resulting from the
13C-NMR 스펙트럼에서 δ 168.2(C-9″)와 168.6(C-9′)에서의 피크로부터 카보닐기를 예상할 수 있었으며, δ 60-80사이의 피크들은 3개의 당에서 기인한 피크이며, 그 화학 이동으로부터 2개의 글루코오스와 1개의 람노오스임을 알 수 있었다(Steaven et al., 1990, Leroy et al., 1972). DEPT(135°) 스펙트럼에서는 두 개의 글루코오스에서 기인하는 6번 탄소 피크 이외에는 어떠한 피크도 나타나지 않아 전형적인 페닐프로파노이드(phenylpropanoid)와는 조금 다른 형태임을 예상할 수 있었다. Carbonyl groups could be expected from the peaks at δ 168.2 (C-9 ") and 168.6 (C-9 ') in the 13 C-NMR spectrum, with peaks between δ 60-80 being the peaks due to the three sugars , And it was found from the chemical shift that it is two glucose and one rhamnose (Steaven et al., 1990, Leroy et al., 1972). In the DEPT (135 °) spectrum, no peak was observed except for the 6th carbon peak originating from the two glucose, so it could be expected that it was slightly different from the typical phenylpropanoid.
1H-1HCOSY에서 3개의 sugar들의 정확한 위치를 알 수 있었으며, vinyl기와 aromatic ring의 연결 관계도 확실히 알 수 있었다. 또한, 이 화합물에 결합하고 있는 치환기들의 정확한 결합 위치를 파악하기 위하여 HMBC와 HMQC 실험을 하였다. HMQC에서는 탄소와 수소 간의 정확한 피크들을 동정할 수 있었으며, 용매의 물 피크에 중첩되어 있던 글루코오스의 아노머 수소인 δ 4.89에서의 피크와 δ 101.4에서의 아노머 탄소의 상관관계가 나타나 글루코오스의 정확한 위치도 파악할 수 있었다. HMBC에서는 4차 탄소의 정확한 위치를 알 수 있었다. 즉, δ 5.64(1H, s)에서의 펜에틸(phenethyl)의 8번에 해당하는 메틴 수소(methine proton)는 δ 101.4에서의 글루코오스 1번 탄소와 δ 79.6에서의 7번 메틴 탄소와 각각 상관관계가 나타나고, 7번 탄소는 δ 6.73(1H, dd, J=1.3, 8.4 Hz)에서의 6번 수소, 6.86(1H, d, J=1.3 Hz)에서의 2번 수소와 상관관계가 나타나 펜에틸기가 글루코오스 1번에 위치하고 있음을 알 수 있었다. δ 5.04(1H, d, J=1.6 Hz)에서의 람노오스 아노머 수소는 δ 84.9에서의 글루코오스 3번 탄소와 상관관계가 나타나고, 또 다른 글루코오tm의 아노머 수소인 δ 4.47(1H, d, J=7.8 Hz)에서의 피크는 δ 83.1에서의 람노오스 2번 탄소와 상관관계가 나타나 이 화합물은 글루코오스의 3번에 람노오스가 위치하고, 람노오스 2번에 다른 글루코오스가 결합한 형태임을 알 수 있었다. 한편, 글루코오스 4번 수소에서 기인하는 δ 4.82(1H, t, J=9.6 Hz)에서의 피크는 δ 168.6(C-9′)에서의 카페오일기에서 기인한 카보닐 탄소와 상관관계를 보이고, 다른 글루코오스의 6번에서 기인하는 δ 3.73(1H, brt, J=11.2 Hz, H-g′6a)의 피크와 5.16(1H, dd, J=1.9, 11.6 Hz, H-g′6b)에서의 피크는 δ 168.2(C-9″)에서의 피크와 상관관계가 나타나므로 2개의 카페오일기는 각각 글루코오스 4번과 다른 글루코오스의 6번에 결합하고 있음을 알 수 있었다. 또한, δ 5.64(1H, s)에서의 펜에틸기의 8번 수소는 δ 130.9에서의 1번 탄소와 δ 141.7에서의 3″번 탄소와 상관관계가 나타나고, δ 5.24에서의 7번 수소는 δ 130.9에서의 1번 탄소, δ 148.5에서의 4″번 탄소와 상관관계가 나타나 글루코오스의 6″에 결합된 카페오일기 3번과 4번, 펜에틸기의 7번과 8번 위치에서 고리를 형성하고 있음을 알 수 있었다. The exact positions of the three sugars in 1 H- 1 HCOSY were found, and the connection between the vinyl group and the aromatic ring was also evident. In addition, HMBC and HMQC experiments were carried out to determine the exact binding position of the substituents bonded to this compound. HMQC was able to identify the exact peaks between carbon and hydrogen, and the correlation between the peak at δ 4.89, anomeric hydrogen of glucose superimposed on the water peak of the solvent, and the anomeric carbon at δ 101.4, showed the exact position of glucose . In HMBC, the exact position of the fourth carbon was found. That is, the methine proton corresponding to the 8th phenethyl at .delta. 5.64 (1H, s) has a correlation with the 1st carbon of glucose at .delta. 101.4 and the 7th methine carbon at .delta.79.6, respectively And
상기 분석 결과를 종합하여 이 화합물은 하기 화학식 2과 같은 구조의 화합물임을 확인할 수 있었고, 이는 자연계에서 처음으로 분리된 화합물로서 카욥테로사이드 B(Caryopteroside B)로 명명하였다. From the results of the above analysis, it was confirmed that this compound was a compound having a structure represented by the following formula (2), which was named Caryopteroside B as the first compound isolated in nature.
[화학식 2](2)
제조예 3-3 : 화합물 8의 구조분석Production Example 3-3: Analysis of Structure of
[α]18 D -46.5°(c 0.65, MeOH) [α] 18 D -46.5 ° ( c 0.65, MeOH)
HRESMS(positive-ion mode):m/z = 653.2077(Calcd. for C30H37O16: 653.2082)HRESMS (positive-ion mode): m / z = 653.2077 ( Calcd . For C 30 H 37 O 16 : 653.2082)
1H-NMR (400 MHz, CD3OD): δ 1.81(3H, s, H-10), 1.97(1H, m, H-6a), 2.45(1H, t, J=7.5 Hz, H-9), 2.65(1H, m, H-6b), 2.97(1H, q, J=78 Hz, H-5), 3.25(2H, m, H-3′, 4′), 3.45(1H, dd, J=7.7, 9.2 Hz, H-2′), 3.51(1H, m, H-5′), 3.61(1H, dd, J=5.5, 11.8 Hz, H-6′a), 3.79(1H, d, J=9.6 Hz, H-4″a), 3.81(1H, d, J=11.5 Hz, H-6′b), 3.86(1H, s, H-2″), 4.28(2H, d, J=1.2 Hz, H-5″), 4.30(1H, d, J=10.8 Hz, H-4″b), 4.76(1H, d, J=7.6 Hz, H-1′), 5.10(1H, d, J=7.5 Hz, H-1), 5.43(1H, s, H-1″), 5.44(1H, br s, H-7), 6.22(1H, d, J=15.9 Hz, H-8′″), 6.75(1H, d, J=8.2 Hz, H-5′″), 6.90(1H, dd, J=1.9, 8.2 Hz, H-6′″), 7.01(1H, d, J=1.9 Hz, H-2′″), 7.43(1H, s, H-3), 7.52(1H, d, J=15.9 Hz, H-7′″) 1 H-NMR (400 MHz, CD 3 OD): δ 1.81 (3H, s, H-10), 1.97 (1H, m, H-6a), 2.45 (1H, t, J = 7.5 Hz, H-9 M, H-3 ', 4'), 3.45 (1H, dd, J = J = 7.7,9.2 Hz, H-2 '), 3.51 (1H, m, H-5'), 3.61 (1H, dd, J = 5.5, 11.8 Hz, H- , J = 9.6 Hz, H- 4 "a), 3.81 (1H, d, J = 11.5 Hz, H-6'b), 3.86 (1H, s, H-2"), 4.28 (2H, d, J = 1.2 Hz, H-5 ''), 4.30 (1H, d, J = 10.8 Hz, H-4 ''), 4.76 (1H, d, J = 7.6 Hz, H- , J = 7.5 Hz, H- 1), 5.43 (1H, s, H-1 "), 5.44 (1H, br s, H-7), 6.22 (1H, d, J = 15.9 Hz, H-8 '"), 6.75 (1H, d , J = 8.2 Hz, H-5 '"), 6.90 (1H, dd, J = 1.9, 8.2 Hz, H-6'"), 7.01 (1H, d, J = 1.9 Hz, H-2 '") , 7.43 (1H, s, H-3), 7.52 (1H, d, J = 15.9 Hz, H-7'")
13C-NMR (100 MHz, CD3OD): δ 16.6(C-10), 36.7(C-5), 39.8(C-6), 50.2(C-9), 62.7(C-6′), 69.2(C-5″), 71.7(C-4′), 75.7(C-4″), 77.1(C-2′), 78.3(C-3′, 2″), 78.9(C-5′), 79.3(C-3″), 97.8(C-1), 98.2(C-1′), 109.7(C-1″), 112.8(C-4), 114.7(C-8′″), 115.1(C-2′″), 116.5(C-5′″), 123.1(C-6′″), 127.7(C-1′″), 128.0(C-7), 140.4(C-8), 146.7(C-3′″), 147.3(C-7′″), 149.6(C-4′″), 153.5(C-3), 169.0(C-9′″), 171.0(C-11)
13 C-NMR (100 MHz,
무정형의 분말인 상기 화합물은 1H-NMR 스펙트럼에서 δ 6.22(1H, d, J=15.9 Hz, H-8′″)에서의 피크와 δ 7.52(1H, d, J=15.9 Hz, H-7′″)에서의 피크로부터 한 그룹의 trans 비닐기를 알 수 있었으며, δ 6.75(1H, d, J=8.2 Hz, H-5′″), 6.90(1H, dd, J=1.9, 8.2 Hz, H-6′″), 7.01(1H, d, J=1.9 Hz, H-2′″)의 피크 형태는 방향족 고리가 ABX system으로 치환되어 있어 카페오일 기가 있음을 알 수 있었다. δ 1.5-5.5에서의 피크 형태로 이 화합물은 이리도이드(iridoid) 화합물임을 예상하였고, δ 3-4 사이의 복잡한 피크로 2개의 당을 추정하였으며, δ 4.76(1H, d, J=7.6㎐, H-1')의 커플링 상수로부터 이 화합물에 존재하는 당은 β-form임을 알 수 있었다(Steaven et al., 1990). 또한, δ 1.81에서의 3개의 수소에 해당하는 단일피크로 메틸기가 존재함을 알 수 있었다. Powder of the compound of the amorphous 1 H-NMR in the spectrum δ 6.22 (1H, d, J = 15.9 Hz, H-8 '") peak and δ 7.52 in (1H, d, J = 15.9 Hz, H-7 "" from the peak at) had found a group trans vinyl group, δ 6.75 (1H, d, J = 8.2 Hz, H-5 '"), 6.90 (1H, dd, J = 1.9, 8.2 Hz, H The peak of the H-2 ''), 7.01 (1H, d, J = 1.9 Hz, H-2 ''') was substituted with the ABX system. The compounds in the form of peaks at δ 1.5-5.5 were expected to be iridoid compounds and two sugars were estimated with complex peaks between δ 3-4 and δ 4.76 (1H, d, J = 7.6 Hz, H-1 '), the sugar present in this compound was found to be β-form (Steaven et al., 1990). It was also found that the methyl group was present at a single peak corresponding to three hydrogens at δ 1.81.
13C-NMR 스펙트럼에서 δ 171.0에서의 피크는 카르복실산의 카보닐기를, δ 169.0 피크는 카페오일기에서 기인한 카보닐기임을 예상할 수 있었다. δ 112-153에서의 피크들은 카페오일기에서 기인한 피크 이외에 4개의 피크가 더 나타나 두 개의 이중결합이 더 있음을 알 수 있었다. 당에서 기인한 피크가 δ 60-80 사이에서 나타나고 있으며 그 화학 이동과 피크 수로 미루어 글루코오스와 5탄당에 해당하는 아피오스(apiose)가 존재함을 알 수 있었다(Steaven et al., 1990, Leroy et al., 1972). In the 13 C-NMR spectrum, it was predicted that the peak at δ 171.0 was the carbonyl group of the carboxylic acid, and the δ 169.0 peak was the carbonyl group due to the caffeoyl group. The peaks at < RTI ID = 0.0 >#< / RTI > 112-153 showed four more peaks in addition to the peak due to the caffeoyl group, The peak due to sugar appears between δ 60-80, and the chemical shift and the number of peaks indicate that there is an apiose corresponding to glucose and pentose (Steaven et al., 1990, Leroy et al., 1972).
HMQC에서는 탄소와 수소 간의 정확한 피크들을 동정할 수 있었으며, HMBC에서는 이 화합물에 결합하고 있는 치환기의 위치를 정확하게 알 수 있었다. 즉, δ 4.76(1H, d, J=7.6 Hz)에서 글루코오스 1번 수소는 δ 97.8에서의 1번 탄소와 상관관계가 나타나 글루코오스는 1번에 치환되어 있음을 알 수 있었으며, δ 3.45(1H, dd, J=7.7, 9.2 Hz)에서의 글루코오스의 2번 수소와 δ 109.7에서의 아피오스의 1번 탄소와 상관관계가 나타나 아피오스는 글루코오스의 2번에 결합하고 있음을 알 수 있었다. 또한, δ 4.28(2H, d, J=1.2 Hz)의 아피오스의 5번 수소에서 기인한 피크는 δ 169.0에서의 카페오일기의 카보닐기와 상관관계가 나타나 카페오일기는 아피오스 5번에 결합하고 있음을 알 수 있었다. δ 1.81에서의 메틸 피크는 δ 140.4에서의 C-8과 상관관계가 나타나 8번 탄소에 메틸기가 치환되어 있음을 알 수 있었다. HMQC was able to identify the exact peaks between carbon and hydrogen, and HMBC was able to pinpoint the position of the substituent attached to this compound. That is, in the case of δ 4.76 (1H, d, J = 7.6 Hz), it was found that
상기 분석 결과를 종합하여 이 화합물은 하기 화학식 6a와 같은 구조의 화합물임을 확인할 수 있었고, 이는 자연계에서 처음으로 분리된 화합물로서 인카노이드 A(Incanoid A)로 명명하였다. Based on the above analysis results, it was confirmed that this compound was a compound having a structure represented by the following formula (6a), which was named as Incanoid A as the first compound isolated in nature.
[화학식 6a][Chemical Formula 6a]
제조예 3-3 : 화합물 14의 구조분석Production Example 3-3: Analysis of Structure of Compound 14
[α]25 D -25.2°° 0.52, MeOH)[[alpha]] 25 D -25.2 [ 0.52, MeOH)
HRFABMS(negative-ion mode):m/z = 657.2757(Calcd. for C31H45O15: 657.2758)HRFABMS (negative-ion mode): m / z = 657.2757 ( Calcd . For C 31 H 45 O 15 : 657.2758)
1H-NMR (400 MHz, CD3OD): δ 0.83(3H, s, H-10′″), 1.27(1H, m, H-7′″), 1.36(1H, m, H-5′″), 1.51(2H, m, H-6′″,7′″), 1.70(3H, s, H-9′″), 1.74(3H, s, H-10), 1.92(1H, m, H-6a), 2.11(1H, m, H-4), 2.28(1H, t, J=7.8 Hz, H-9), 2.63(1H, m, H-6b), 3.16(2H, m, H-3′, 4′), 3.37(1H, dd, J=7.7, 9.2 Hz, H-2′), 3.42(1H, m, H-5′), 3.50(2H, m, H-8′″), 3.52(1H, m, H-6′a), 3.69 (1H, d, J=9.6 Hz, H-4″a), 3.71(1H, s, H-2″), 3.74(1H, d, J=11.6 Hz, H-6′b), 4.13 4.18(2H, d, J=11.3 Hz, H-5″), 4.26(1H, d, J=9.6 Hz, H-4″b), 4.66(1H, d, J=7.6 Hz, H-1′), 4.97(1H, d, J=7.8 Hz, H-1), 5.34(1H, s, H-1″), 5.39(1H, br s, H-7), 6.69(1H, t, J=7.6 Hz, H-3′″), 7.28(1H, s, H-3) 1 H-NMR (400 MHz, CD 3 OD):? 0.83 (3H, s, H-10 '''), 1.27 M, H-6 '', 7 ''), 1.70 (3H, s, H-9 ''), 1.74 M, H-6a), 2.11 (1H, m, H-4), 2.28 (1H, t, J = 7.8 Hz, H- M, H-5 '), 3.50 (2H, m, H-8''), 3.37 (1H, d, J = 7.7, 9.2 Hz, ), 3.52 (1H, m, H-6'a), 3.69 (1H, d, J = 9.6 Hz, H- , J = 11.6 Hz, H- 6'b), 4.13 4.18 (2H, d, J = 11.3 Hz, H-5 "), 4.26 (1H, d, J = 9.6 Hz, H-4" b), 4.66 (1H, d, J = 7.6 Hz, H-1 '), 4.97 (1H, d, J = 7.8 Hz, H-1) , H-7), 6.69 (1H, t, J = 7.6 Hz,
13C-NMR (100 MHz, CD3OD): δ 12.5(C-9′″), 16.9(C-10), 19.7(C-10′″), 36.7(C-5), 27.4(C-4′″), 30.8(C-6′″), 37.1(C-5′″), 37.3(C-5), 40.1(C-6), 40.7(C-7′″), 50.4(C-9), 61.1(C-8′″), 62.9(C-6′), 72.0(C-5″), 75.9(C-4′), 77.1(C-4″), 78.5(C-2′), 78.6(C-3′, 2″), 79.2(C-5′), 79.5(C-3″), 98.2(C-1), 98.4(C-1′), 109.8(C-1″), 113.3(C-4), 128.3(C-7), 128.6(C-2′″), 140.7(C-8), 144.8(C-3′″), 153.3(C-3), 169.5(C-1′″), 171.5(C-11)
13 C-NMR (100 MHz, CD 3 OD):? 12.5 (C-9 '''), 16.9 (C-10), 19.7 4 ''), 30.8 (C-6 ''), 37.1 (C-5 ''), 37.3 5), 75.9 (C-4), 77.1 (C-4), 78.5 (C-2 ' ), 78.6 (C-3 ', 2 "), 79.2 (C-5'), 79.5 ), 113.3 (C-4), 128.3 (C-7), 128.6 (C-2 ''), 140.7 C-1 '''), 171.5 (C-11)
무정형의 분말인 상기 화합물은 1H-NMR 스펙트럼에서 인카노이드 A(Incanoid A)와 유사한 피크형태를 보이고 있지만 카페오일기에 해당하는 피크는 보이지 않았다. 고자장 영역에서 10번에서 기인하는 메틸기 이외에 δ 0.83(3H, s, H-10′″)와 1.70(3H, s, H-9′″)에서의 두 개의 메틸에 해당하는 단일피크를 포함하여 aliphatic 피크가 나타나 다른 치환기가 있음을 알 수 있었다. 나머지 피크는 위에서 분리한 10-데옥시제니포닉산(10-deoxygeniposidic acid)과 일치하며 글루코스와 5탄당이 더 결합하고 있음을 예상하였다. 13C-NMR 스펙트럼에서 δ 171.5에서의 피크는 카르복실산의 카보닐기임을 알 수 있었으며, δ 169.5 피크는 이 화합물에 결합하고 있는 acyl기에서 기인한 에스테르(ester) 카보닐기임을 예상할 수 있었고 그 화학적 이동값으로부터 8-히드록시-2,6-디메틸-2(E)-옥테노일기(8-hydroxy-2,6-dimethyl-2(E)-octenoyl)인 6,7-디히드로포리아멘틱산(6,7-dihydrofoliamenthic acid) 임을 알 수 있었다. 또한 이들 피크 이외에 당에서 기인한 피크가 δ 60-80 사이에서 나타나고 있으며 그 화학 이동과 피크 수로 미루어 글루코오스와 5탄당에 해당하는 아피오스(apiose)가 존재함을 알 수 있었다(Steaven et al., 1990, Leroy et al., 1972). The compound, which is an amorphous powder, has a peak shape similar to incanoid A (incanoid A) in the 1 H-NMR spectrum, but does not show a peak corresponding to the cafe oil phase. (3H, s, H-10 ''') and 1.70 (3H, s, H-9''') in addition to the methyl group originating at
HMQC에서는 탄소와 수소 간의 정확한 피크들을 동정할 수 있었으며, HMBC에서는 이 화합물에 결합하고 있는 치환기의 위치를 정확하게 알 수 있었다. 즉, δ 4.66(1H, d, J=7.6 Hz)에서 글루코오스 1번 수소는 δ 98.2에서의 1번 탄소와 상관관계가 나타나 글루코오스는 1번에 치환되어 있음을 알 수 있었으며, δ 3.37(1H, dd, J=7.7, 9.2 Hz)에서의 글루코오스의 2번 수소와 δ 109.8에서의 아피오스의 1번 탄소와 상관관계가 나타나 아피오스는 글루코오스의 2번에 결합하고 있음을 알 수 있었다. 또한, δ 4.13 4.18(2H, d, J=11.3 Hz)의 아피오스의 5번 수소에서 기인한 피크는 δ 169.5에서의 카보닐기와 상관관계가 나타나 6,7-디히드로포리아멘틱산기는 아피오스 5번에 결합하고 있음을 알 수 있었다. 상기 분석 결과를 종합하여 이 화합물은 하기 화학식 6과 같은 구조의 화합물임을 확인할 수 있었고, 이는 자연계에서 처음으로 분리된 화합물로서 인카노이드 B(Incanoid B)로 명명하였다. HMQC was able to identify the exact peaks between carbon and hydrogen, and HMBC was able to pinpoint the position of the substituent attached to this compound. That is, in the case of δ 4.66 (1H, d, J = 7.6 Hz), it was found that the
[화학식 6b][Formula 6b]
이상의 분석결과, 본 발명에서 층꽃풀 추출물의 에틸아세테이트 분획물은 4종의 신규 화합물 1, 2, 8, 14를 포함하고 있음을 확인하였다.
As a result of the above analysis, it was confirmed that the ethyl acetate fraction of the extract of Lycoris spp. Contained 4
또한, 상기 분리된 화합물의 분석 결과, 6종의 페닐프로파노이드 배당체(phenylpropanoid glycoside)로서 6-O-카페오일필리노사이드 A(3)(Zhao D. P. et. al., J. Nat. Med., 2009, 63, 241), 악테오사이드(4), 루코스셉터사이드 A(5)(Miyase T. et. al., Chem. Pharm. Bull., 1982, 30, 2732), 지오노사이드 D(6)(Sasaki H. et. al., Phytochemistry 1989, 28, 875) 및 6-카페오일-D-글루코즈(7)(Shimomura H. et. al., Phytochemistry 1987, 28, 249), 마티노사이드(13)(Miyase T. et. al., Chem. Pharm. Bull., 1982, 30, 2732)임을 확인하였으며, 1종의 이리도이드 화합물로서 8-O-아세틸-6′-O-카페오일하르파지드(9)(Zhao D. P. et. al., J. Nat. Med., 2009, 63, 241), 3종의 플라보노이드 화합물로서 에리오딕티올-7-O-β-D-글루코피라노사이드(10)(Cui C.-B. et. al., Chem. Pharm. Bull., 1990, 38, 3218) 루테올린 4′-O-β-D-글루코피라노사이드(11)(Yoshizaki M. et. al., Phytochemistry 1987, 26, 2557, Markham K. R. et. al., Terahedron 1978, 34, 1389), 로이폴린(12)(Kaneko T. et. al., Phytochemistry 1995, 39, 115)로 분석되었으며, 알려진 문헌의 내용과 일치함을 확인할 수 있었다.
As a result of the analysis of the separated compounds, 6-O-caffeoylpyrinoside A ( 3 ) (Zhao DP et al ., J. Nat. Med. 2009, 63, 241), the
실시예 1 : Example 1: tt -BHP에 의한 간세포 손상 회복 효과- Recovery effect of hepatocyte injury by BHP
층꽃풀로부터 추출한 메탄올 추출물, 이의 분획물 및 상기 제조예 2에서 분리된 화합물들을 각각 DMSO(dimethyl sulfoxide)에 녹여 100 ㎍/㎖과 100 mM로 저장 용액(stock solution)을 만들었으며, 이를 배지로 희석시켜 알맞은 농도로 사용하였다. 사람 간세포인 HepG2 세포를 96-웰 플레이트에 2×104 cell/well로 분주하여 24시간동안 배양하여 안정화하였다. 배양된 세포에 층꽃풀 메탄올 추출물, 분획물 및 이로부터 분리된 화합물들을 농도별로 처리하여 2시간 동안 배양하고, 200 μM의 t-BHP를 처리하여 3시간 동안 독성을 유발하였다. 이와 같이 처리된 세포를 세포독성 및 세포 생존 정도를 알아보기 위하여 MTT 분석법(Hansen M.B. et. al., 1989, J. Immunol. Methods 119:119)을 사용하였다. The methanol extract, its fractions and the compounds isolated in Preparation Example 2 were dissolved in dimethyl sulfoxide (DMSO) to prepare stock solutions at 100 μg / ml and 100 mM, respectively. The methanol extracts were diluted with the medium It was used at an appropriate concentration. Human hepatocyte HepG2 cells were divided into 96-well plates at 2 × 10 4 cells / well and cultured for 24 hours to stabilize them. The cultured cells were treated with methanol extracts, fractions, and compounds isolated therefrom at a concentration-dependent manner for 2 hours, and treated with 200 μM t- BHP to induce toxicity for 3 hours. MTT assay (Hansen MB et al., 1989, J. Immunol. Methods 119: 119) was used to determine the cytotoxicity and cell viability of the treated cells.
MTT가 첨가된 세포를 4시간 동안 배양한 후 시약을 제거하고 각 웰에 DMSO를 첨가하여 생성된 포마잔(formazan)을 용해시켜 마이크로플레이트 리더(microplate reader)를 이용하여 570 nm에서 흡광도를 측정하였다. t-BHP 및 시료를 처리하지 않은 대조군의 세포 생존율을 100%로 하여 독성 처리군 및 시료 처리군의 세포생존율을 대조군에 대한 상대적인 백분율로 나타내었으며 3회 반복 실험한 결과를 표 1과 표 2에 각각 나타내었다.
MTT-added cells were incubated for 4 hours, the reagents were removed, DMSO was added to each well, and the resulting formazan was dissolved. The absorbance was measured at 570 nm using a microplate reader . The cell viability of the toxic treated group and the sample treated group was expressed as a relative percentage to the control group, with the cell viability of the control group without t -BHP and the sample treated as 100%, and the results of the repeated experiment were shown in Table 1 and Table 2 Respectively.
HepG2 세포에서의 t-BHP 유도 독성에 대한 층꽃풀 추출물 및 이의 분획물의 세포독성 보호 효과Cytotoxic protective effect of extracts and their fractions against T-BHP induced toxicity in HepG2 cells
상기 표 1에서 나타낸 바와 같이, 사람 간암 세포주 유래 HepG2 세포에서 200 μM t-BHP에 의한 세포독성은 층꽃풀 추출물 및 이들의 분획물에 의하여 농도 의존적으로 억제됨을 알 수 있었다. 특히 에틸아세테이트 분획에서의 세포보호 효능은 다른 용매 분획에서의 보호효능보다 탁월한 효능을 보이고 있음을 알 수 있었으며, 5 ㎍/㎖에서의 저농도에서도 61.2±1.6%의 우수한 세포보호 효능을 나타내고 있음을 알 수 있었다. As shown in Table 1, cytotoxicity by 200 μM t-BHP in human hepatoma cell line-derived HepG2 cells was inhibited in a concentration-dependent manner by the layered extract of Fusarium oxysporum and their fractions. In particular, the cytoprotective effect of the ethyl acetate fraction was superior to that of other solvent fractions, and 61.2 ± 1.6% of the cytoprotective effect was exhibited even at a low concentration of 5 μg / ml I could.
상기 결과로부터 층꽃풀로부터 추출한 추출물 및 이들의 분획물들이 독성물질에 의한 간세포 손상 보호 효과가 우수함을 알 수 있었다.
From the above results, it was found that the extracts and their fractions extracted from the layered flower buds were excellent in protecting the hepatocyte damage by toxic substances.
HepG2 세포에서의 t-BHP 유도 독성에 대한 화합물 1 ∼ 14와 대조 약물의 세포독성 보호효과 Cytotoxic Protective Effect of
상기 표 2에서 나타낸 바와 같이, HepG2 세포에서 200 μM t-BHP에 의한 세포독성은 상기 제조예 2에서 분리 정제한 화합물 1 ∼ 14에 의하여 농도 의존적으로 감소하였다. 특히 화합물 1의 보호 효과는 대조약물로 사용한 실리빈에 비하여 매우 우수하고, 항산화물질로 잘 알려진 콰르세틴의 보호 효과와 유사한 정도에 해당하며, 1 μM에서의 저농도에서는 오히려 콰르세틴의 보호 효능 보다도 우수한 것을 알 수 있었다. 따라서 층꽃풀의 메탄올 추출물로부터 분획한 에틸 아세테이트 분획으로부터 분리한 이들 화합물들은 독성에 의한 간세포 보호제로 유용함을 알 수 있었다.
As shown in Table 2, the cytotoxicity of 200 μM t-BHP in HepG2 cells was decreased in a concentration-dependent manner by the
하기에 본 발명의 간독성 질환 예방 또는 치료제를 위한 제제예를 예시한다.
Examples of formulations for the prevention or treatment of hepatotoxic diseases of the present invention are illustrated below.
제조예 1 : 정제의 제조Preparation Example 1: Preparation of tablets
유효성분(층꽃풀 추출물) 10 gActive Ingredient (layer foliar extract) 10 g
락토스 70 gLactose 70 g
결정성 셀룰로오스 15 gCrystalline cellulose 15 g
마그네슘 스테아레이트 5 gMagnesium stearate 5 g
총 량 100 gTotal amount 100 g
상기에서 나열된 성분들을 잘게 부숴 혼합한 후 직타법(direct tableting method)에 의해 정제를 제조하였다. 각 정제의 총량은 100 ㎎이고, 그 중 유효성분의 함량은 10 ㎎이다.
The components listed above were finely crushed and mixed to prepare tablets by direct tableting method. The total amount of each tablet was 100 mg, and the content of the active ingredient was 10 mg.
제조예 2 : 캡슐제의 제조Preparation Example 2: Preparation of capsules
유효성분(층꽃풀의 추출물) 10 gActive ingredient (Extract of Liliaceae) 10 g
옥수수 전분 50 gCorn starch 50 g
카르복시 셀룰로오스 40 g40 g of carboxycellulose
총 량 100 gTotal amount 100 g
상기에서 나열된 성분들을 잘게 부숴 혼합하여 분말을 제조하였다. 6 번 경질 캡슐에 분말 100 ㎎을 넣어 캡슐제를 제조하였다.The components listed above were finely crushed and mixed to prepare a powder. 100 mg of powder was added to hard capsule No. 6 to prepare a capsule preparation.
Claims (6)
[화학식 2]
[화학식 3]
A pharmaceutical composition for hepatoprotectants, which comprises one or two compounds selected from the group consisting of compounds represented by the following formulas (2) and (3).
(2)
(3)
The pharmaceutical composition according to claim 1, wherein the compound protects hepatocytes induced by toxicity with t -butyl hydroperoxide ( t- BHP).
[화학식 2]
[화학식 3]
A food composition for liver protection, which comprises at least one member selected from the group consisting of compounds represented by the following formulas (2) and (3).
(2)
(3)
4. The food composition for liver protection according to claim 3, wherein the compound protects hepatocytes induced by toxicity with t -butyl hydroperoxide ( t- BHP).
[화학식 2]
A compound represented by the following formula (2).
(2)
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Title |
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J. Gao et al. CHEMICAL AND PHARMACEUTICAL BULLETIN-TOKYO. 2000, Volume 48, No. 7, pp. 1075-1078 * |
J. J. et al. GaoBioscience, biotechnology, and biochemistry. 1999, Volume 63, No. 6, pp. 983-988 * |
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