KR101014004B1 - Compositions and functional food for prevention and treatment of obesity - Google Patents
Compositions and functional food for prevention and treatment of obesity Download PDFInfo
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- KR101014004B1 KR101014004B1 KR1020080062600A KR20080062600A KR101014004B1 KR 101014004 B1 KR101014004 B1 KR 101014004B1 KR 1020080062600 A KR1020080062600 A KR 1020080062600A KR 20080062600 A KR20080062600 A KR 20080062600A KR 101014004 B1 KR101014004 B1 KR 101014004B1
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- obesity
- ethyl acetate
- compound
- coumaroyl
- trans
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
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Abstract
본 발명은 다래 뿌리 추출물의 에틸아세테이트 층과 여기에서 분리된 신규 화합물인 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p-coumaroyl actinidic acid]이 비만 유발 원인 중의 하나인 췌장 지방분해효소(pancreatic lipase)의 효능을 효과적으로 억제함을 확인하였다.
따라서, 본 발명의 다래뿌리 추출물의 에틸아세테이트 층과 여기에서 분리된 신규 화합물인 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p- coumaroyl actinidic acid]은 비만 예방, 치료 또는 개선용 약학 조성물, 건강기능성 식품에 유용하게 이용될 수 있을 것이다.
다래, 췌장, 지방분해효소, 비만,
The present invention relates to the ethyl acetate layer of the extract of T. aeruginosa and 3 β ( trans - p- coumaroyl) oxy-2 a , 23-dihydroxyurs-12: 20 (30) -dien-28-oic acid [ It was confirmed that 3- O - trans - p- coumaroyl actinidic acid] effectively inhibited the efficacy of pancreatic lipase, one of the causes of obesity.
Thus, the ethyl acetate layer of the Tara root extract of the present invention and 3 β ( trans - p- coumaroyl) oxy-2 a , 23-dihydroxyurs-12: 20 (30) -dien-28-oic, which is a novel compound separated therefrom Acid [3- O - trans - p -coumaroyl actinidic acid] may be useful in pharmaceutical composition for preventing, treating or ameliorating obesity, and in dietary supplements.
Sputum, pancreas, lipase, obesity,
Description
본 발명은 다래에서 분리한 신규화합물인 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p-coumaroyl actinidic acid] 및 이를 이용한 비만 예방, 치료 또는 개선용 약학 조성물, 건강기능성 식품에 관한 것이다.The present invention is a novel compound isolated from the future 3 β ( trans - p -coumaroyl) oxy-2 a , 23-dihydroxyurs-12: 20 (30) -dien-28-oic acid [3- O - trans - p- coumaroyl actinidic acid] and a pharmaceutical composition for preventing, treating or improving obesity using the same, and a health functional food.
비만은 에너지 흡수와 소비의 불균형에 의해 발생한다. 여분의 에너지는 지방세포에 저장되어 지방세포의 수나 크기를 증가시킨다. 또한 고혈압(hypertension), 고지혈증(hyperlipidemia), 동매경화증(arteriosclerosis), 당뇨병(diabetes)을 비롯한 다양한 질병의 강력한 위험인자 중 하나이다(Borgstrom, B., Exocrine Pancreas, Pathology and Diseases. Raven Press, New York, pp. 361-401, 1981). 이처럼 만병의 근원인 비만을 치료하기 위해 많은 연구들이 진행 되고 있다. 비만을 치료하기 위해 많은 연구들이 진행되고 있다. 비만을 예방·치료하기 위한 요법 중 하나로 소화기관에서 lipase 효능을 저해함으로써 지방산의 흡수를 저하시키는 방법이다(Ballinger, A., et al., Eur . J. Pharm . Sci., 440, 109-117, 2002; Yanovski, S. J., et al., New Engl . J. Med., 346, 591-602, 2002). 췌장 지방분해효소는 위장관에서 triacylglycerol를 2-monoacylglycerol과 fatty acid로 가수분해하는 반응을 촉매하여 지방흡수를 증진시키는 핵심적인 효소이다(Bitou, N., et al., Lipids , 34, 441-445, 1999). 따라서 이 효소를 효과적이고 특이적으로 저해할 때, 비만을 예방, 치료 또는 개선하는 효과가 있음이 보고되었다(Gargouri, Y., et al., Biochim . Biophys . Acta, 1344, 6-37, 1997).Obesity is caused by an imbalance in energy absorption and consumption. The extra energy is stored in fat cells, increasing the number or size of fat cells. It is also one of the strongest risk factors for various diseases, including hypertension, hyperlipidemia, arteriosclerosis, and diabetes (Borgstrom, B., Exocrine Pancreas, Pathology and Diseases.Raven Press, New York, pp. 361-401, 1981). As such, many studies are being conducted to treat obesity, which is the source of all diseases. Many studies are underway to treat obesity. One of the therapies to prevent and treat obesity is to reduce the absorption of fatty acids by inhibiting the effect of lipase in the digestive tract (Ballinger, A., et al., Eur . J. Pharm . Sci ., 440, 109-117). , 2002; Yanovski, SJ, et al., New Engl . J. Med ., 346, 591-602, 2002). Pancreatic lipase is a key enzyme that enhances fat absorption by catalyzing the hydrolysis of triacylglycerol into 2-monoacylglycerol and fatty acids in the gastrointestinal tract (Bitou, N., et al., Lipids , 34, 441-445, 1999). Therefore, effective and specific inhibition of this enzyme has been reported to have the effect of preventing, treating or ameliorating obesity (Gargouri, Y., et al., Biochim . Biophys . Acta , 1344, 6-37, 1997). ).
현재 알려진 대표적인 췌장 지방분해효소 저해물질로는 Streptomyces toxitricini로부터 유래된 lipstatin의 유도체인 tetrahydrolipstatin(Orlistat)으로 미국 FDA에서 장기투여용 약물로 승인되어 제니칼이란 상품명으로 제품화되었다. 이것은 세계에서 가장 많이 판매되고 있다. 제니칼은 섭취된 지방의 약 30%를 저해할 정도로 효능이 가장 우수한 것으로 알려져 있다(Drent, M. L.,et al., Int . J. Obes ., 19, 221 -226, 1995). Triglyceride를 분해하는 lipase에 비가역적인 결합을 하여 불활성화 시킴으로써 triglyceride의 흡수, 더 나아가 cholesterol의 흡수를 감소시킨다. 분해되지 못한 triglyceride, cholesterol은 미변환체로 대변으로 배설된다. A representative pancreatic lipase inhibitor currently known is tetrahydrolipstatin (Orlistat), a derivative of lipstatin derived from Streptomyces toxitricini , which was approved by the US FDA as a drug for long-term administration and commercialized under the trade name Genical. This is the most sold in the world. Xenical is known to be the most potent to inhibit about 30% of the fat consumed (Drent, ML, et al., Int . J. Obes ., 19, 221-226 , 1995). By inactivating an irreversible bond to the lipase that degrades triglycerides, it reduces triglyceride absorption and further cholesterol absorption. Triglycerides and cholesterol that are not degraded are unconverted and excreted in feces.
그러나 임상에서 장기투여할지라도(2년) 다이어트만 실시한 경우와 비교할 때, 월등하게 뛰어나지 못함이 보고되고 있다. 뿐만 아니라 안면마비, 위장 장애, 과민증, 담즙분비장애, 지용성 비타민 흡수억제 등과 같은 부작용도 있는 것으로 알려져 있다(Drent, M. L., et al., Int . J. Obes., 17, 241-244, 1993; Peter, C., et al., Br . J. Clin . Pharmacol., 51, 135-141, 2001). However, even long-term administration (two years) in clinical practice has not been reported to be superior to the diet alone. In addition, there are known side effects such as facial paralysis, gastrointestinal disorders, hypersensitivity, bile secretion disorders, and fat-soluble vitamin absorption inhibition (Drent, ML, et al., Int . J. Obes ., 17, 241-244, 1993; Peter, C., et al., Br . J. Clin . Pharmacol ., 51, 135-141, 2001).
국내에서도 재심사를 위하여 793명을 대상으로 실시한 시판 후 사용 성적 조사 결과 이상반응은 30.4%(241명/793명)가 보고됐다. 특히 이상반응 중 제니칼과 인과관계가 있는 것으로 조사된 것은 29.9%(237명)로 나타났다. 흔히 관찰되는 이상반응은 위장관계 증상으로 29%(230명)이었으며, 이중 시판 전 임상에서 나타나지 않았던 새로운 이상반응으로 피부감각이상, 변비, 소화불량 및 속쓰림 등이 보고됐다. 특히 식약청은 허가변경을 통해 과도한 체중 감소는 담석증의 위험을 증가시킬 수 있다고 경고했다. 2형 당뇨병의 예방에 대한 임상시험에서 담석증 발생율은 이 약 투여군에서 2.9%(47/1649), 위약군에서 1.8%(30/1655)로 나타났다고 보고하였다(데일리팜, 2007. 10. 02.). 또한 실제적으로 예측할 수 없는 설사로 복용하는 동안 생활에 많은 불편을 주고 있음이 보고되고 있다.In Korea, 30.4% (241/793) of adverse reactions were reported as a result of post-marketing results survey of 793 people for review. In particular, 29.9% (237 persons) were causally related to Jennal among the adverse reactions. The most common adverse reactions were gastrointestinal symptoms (29%, 230 patients). Among them, new adverse reactions that did not occur in pre-clinical studies were skin sensation, constipation, indigestion, and heartburn. In particular, the FDA warned that excessive weight loss could increase the risk of cholelithiasis through a change in permit. In clinical trials for the prevention of
상기와 같은 문제점을 해결하기 위하여 소화억제제 중 지방분해효소 억제 효능이 우수한 다래뿌리 추출물의 에틸아세테이트층 분획물과 상기 에틸아세테이트층분획물에서 분리된 신규 화합물인 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p-coumaroyl actinidic acid]를 제공하여 비만의 예방, 치료 또는 개선용 약학적 조성물, 건강 기능성 식품을 제공하는데 그 목적이 있다.In order to solve the above problems, 3 β ( trans - p- coumaroyl) oxy-2, which is a novel compound separated from the ethyl acetate layer fraction and the ethyl acetate layer fraction, has been shown to be effective in inhibiting lipase in digestion inhibitors. a , 23-dihydroxyurs-12: 20 (30) -dien-28-oic acid [3- O - trans - p- coumaroyl actinidic acid] to provide a pharmaceutical composition, health functional food for the prevention, treatment or improvement of obesity The purpose is to provide.
상기 본 발명의 목적을 달성하기 위한 본 발명에 따른 다래의 뿌리를 세절하여 알콜 또는 알콜 수용액으로 추출한 후, 계통분리하여 계통분획 층인 에틸아세테이트 층 분획물 과 상기 다래의 뿌리 추출물의 에틸아세테이트 층에서 분리된 신규 화합물인 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p-coumaroyl actinidic acid]을 유효성분으로 함유하는 비만의 예방, 치료용 또는 개선용 약학적 조성물, 건강기능식품을 특징으로 한다.In order to achieve the object of the present invention, the root of the stalk according to the present invention is chopped and extracted with an alcohol or an aqueous alcohol solution, and then separated into a system fractionation layer, an ethyl acetate layer fraction, and an ethyl acetate layer of the root extract. A new compound, 3 β ( trans - p -coumaroyl) oxy-2 a , 23-dihydroxyurs-12: 20 (30) -dien-28-oic acid [3- O - trans - p -coumaroyl actinidic acid] It is characterized by the prevention, treatment or improvement of the pharmaceutical composition, health functional food containing.
본 발명의 다래의 뿌리 추출물의 에틸아세테이트층 분획물과 상기 다래의 뿌리 추출물의 에틸아세테이트 층에서 분리된 신규화합물인 3β(trans-p- coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p-coumaroyl actinidic acid]은 비만 유발 원인 중의 하나인 췌장 지방분해효소(pancreatic lipase)의 효능을 효과적으로 억제함을 확인하였다. Ethyl acetate layer fraction of the root extract of the present invention and 3 β ( trans - p -coumaroyl) oxy-2 a , 23-dihydroxyurs-12: 20 (a new compound isolated from the ethyl acetate layer of the root extract of 30) -dien-28-oic acid [3- O - trans - p- coumaroyl actinidic acid] was found to effectively inhibit the efficacy of pancreatic lipase, one of the causes of obesity.
대표적인 비만 치료제인 제니칼은 효능미비와 예상할 수 없는 설사현상 등으로 일상생활에 치명적인 불편을 주고 있기 때문에, 새로운 소재 개발과 뿐만 아니라 FTA를 대응할 수 있는 국내제품의 개발로 수입대체효과 또는 수출 효과가 불가피함을 고려할 때 본 발명의 다래의 뿌리 추출물의 에틸아세테이트층 분획물과 상기 신규화합물은 비만이나 관련 질병의 예방, 치료 또는 개선을 위한 물질로 사용될 수 있을 것이다.As a representative obesity treatment agent, Zenical is causing fatal inconveniences in daily life due to poor efficacy and unpredictable diarrhea, it has not only a new material development but also a domestic product that can cope with FTA. Considering the inevitable, the ethyl acetate layer fraction of the root extract of the present invention and the novel compound may be used as a material for the prevention, treatment or improvement of obesity or related diseases.
본 발명은 다래에서 분리된 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p-coumaroyl actinidic acid]의 분자식을 가지는 신규화합물 및 다래의 뿌리를 알콜 또는 알콜 수용액으로 추출한 후, 헥산, 에틸아세테이트, 부탄올과 물로 계통분리하여 계통분획 층인 에틸아세테이트층 분획물에 관한 것이다.The present invention relates to 3 β ( trans - p- coumaroyl) oxy-2 a , 23-dihydroxyurs-12: 20 (30) -dien-28-oic acid isolated from the above [3- O - trans - p- coumaroyl actinidic acid It is related with ethyl acetate layer fraction which is a phylogenetic layer by extracting a novel compound having a molecular formula of] and the root of the stalk with an alcohol or an aqueous alcohol solution, and then systematically separating it with hexane, ethyl acetate, butanol and water.
다래[(Actinidia arguta Planchon; Actinidiaceae(다래과)]는 부드러운 껍질을 가진 포도알 크기의 키위의 일종으로 한국, 중국, 일본, 시베리아가 원산지이다(Ferguson, R., New Zealand Kiwifruit, 81, 23-24, 1991). 다래는 오랜 세월동 안 식용으로 뿐만 아니라 일반건강의 개선을 위한 전통약재로서 이용하여 왔다(Kim, J.-G., et al., Traditional Drugs of the East Color Edition. Young-Rim Publishing Co., Seoul, p. 207, 1995). 다래의 성분에 대한 연구로는 flavonoid(Webby, R. F., et al., Phytochemistry, 29, 289-292, 1990), phenolic compound(Lim, H. -W., et al., Nat . Prod . Sci., 12, 221-225, 2006), triterpene 그리고 lignan(Whang, J. I., et al., Kor . J. Pharmacogn., 31, 357-363, 2000)들에 대한 분리·보고들이 있다. 그러나 비만 관련 보고는 없다. [[ Actinidia arguta Planchon; Actinidiaceae] is a type of kiwifruit with a soft shell and is native to Korea, China, Japan and Siberia (Ferguson, R., New). Zealand Kiwifruit , 81, 23-24, 1991). Darae has been used not only as a food for a long time, but also as a traditional medicine for improving general health (Kim, J.-G., et al., Traditional Drugs of the East Color Edition.Young-Rim Publishing Co., Seoul, p. 207, 1995). Studies on the constituents of the fungus include flavonoids (Webby, RF, et al., Phytochemistry , 29, 289-292, 1990), phenolic compounds (Lim, H.-W., et al., Nat . Prod . Sci . , 12, 221-225, 2006), triterpene and lignan (Whang, JI, et al., Kor . J. Pharmacogn ., 31, 357-363, 2000). But there are no reports of obesity.
이하, 본 발명을 실시 예를 들어 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail with reference to Examples.
본 발명에 따른 신규화합물인 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p- coumaroyl actinidic acid]은 하기의 화학식을 갖는다.3 β ( trans - p- coumaroyl) oxy-2 a , 23-dihydroxyurs-12: 20 (30) -dien-28-oic acid [3- O - trans - p -coumaroyl actinidic acid, a novel compound according to the present invention ] Has the following formula.
화학식 1의 신규화합물: 무색결정(MeOH). mp 265-267℃ [a]D 25 +84.6°(c 0.20, pyridine); New compound of formula 1: colorless crystals (MeOH). mp 265-267 ° C. [a] D 25 + 84.6 ° ( c 0.20, pyridine);
UV (MeOH) λmax (log ε): 312 (4.37) nm; IR max (NaCl) 3490-3380, 3086-2850, 1712, 1667, 1631, 1600, 1515, 1450, 1331, 1291, 1192, 1167, 1023, 959, 828, 656 cm-1; UV (MeOH) λ max (log ε): 312 (4.37) nm; IR max (NaCl) 3490-3380, 3086-2850, 1712, 1667, 1631, 1600, 1515, 1450, 1331, 1291, 1192, 1167, 1023, 959, 828, 656 cm −1 ;
1H NMR (300 MHz, pyridine-d 6) δ 7.97 (1H, d, J = 16.0, H-7'), 7.56 (1H, d, J = 9.0, H-2'/6'), 7.17 (1H, d, J = 8.5, H-3'/5'), 6.65 (1H, d, J = 16.0, H-8'), 5.92 (1H, d, J = 9.5, H-3), 5.47 (1H, br t, H-12), 4.82 (1H, br s, H-30a), 4.77 (1H, br s, H-30b), 4.46 (1H, ddd, J = 11.0, 9.5, 4.5, H-2), 3.64 (1H, d, J = 11.5, H-23a), 3.50 (1H, d, J = 11.5, H-23b), 2.75 (1H, d, J = 11.5, H-18), 2.36 (1H, dt, J = 12.5, 4.5, H-1a), 1.85 (1H, dd, J = 10.0, 7.0, H-7'), 1.44 (1H, br t, J = 12.0, H-1b), 1.17 (3H, s, H-27), 1.10 (3H, d, J = 6.5, H-29), 1.08 (3H, s, H-25), 1.07 (3H, s, H-26), 0.96 (3H, s, H-24); 1 H NMR (300 MHz, pyridine- d 6 ) δ 7.97 (1H, d, J = 16.0, H-7 '), 7.56 (1H, d, J = 9.0, H-2' / 6 '), 7.17 ( 1H, d, J = 8.5, H-3 '/ 5'), 6.65 (1H, d, J = 16.0, H-8 '), 5.92 (1H, d, J = 9.5, H-3), 5.47 ( 1H, br t, H-12), 4.82 (1H, br s, H-30a), 4.77 (1H, br s, H-30b), 4.46 (1H, ddd, J = 11.0, 9.5, 4.5, H- 2), 3.64 (1H, d, J = 11.5, H-23a), 3.50 (1H, d, J = 11.5, H-23b), 2.75 (1H, d, J = 11.5, H-18), 2.36 ( 1H, dt, J = 12.5, 4.5, H-1a), 1.85 (1H, dd, J = 10.0, 7.0, H-7 '), 1.44 (1H, brt, J = 12.0, H-1b), 1.17 (3H, s, H-27), 1.10 (3H, d, J = 6.5, H-29), 1.08 (3H, s, H-25), 1.07 (3H, s, H-26), 0.96 (3H , s, H-24);
13C-NMR (75 MHz, pyridine-d 6) δ 179.6 (C-28), 168.8 (C-9'), 161.8 (C-4'), 154.1 (C-20), 145.4 (C-8'), 139.4 (C-13), 131.0 (C-2'/6'), 126.6 (C-1'), 126.2 (C-12), 117.2 (C-3'/5'), 116.2 (C-7'), 105.5 (C-30), 80.3 (C-3), 67.0 (C-2), 65.2 (C-23), 56.0 (C-18), 48.9 (C-1), 48.6 (C-17), 48.3 (C-5), 47.6 (C-9), 44.2 (C-4), 43.0 (C-14), 40.4 (C-8), 40.0 (C-22), 38.4 (C-10), 38.1 (C-19), 33.4 (C-7), 33.1 (C-21), 29.0 (C-15), 25.2 (C-16), 24.12 (C-11), 24.07 (C-27), 18.6 (C-6), 17.83 (C-25), 17.80 (C-26), 16.9 (C-29), 15.2 (C-24); EIMS m/z (rel. int.) 632 ([M]+, 3), 485(2), 387 (10), 246 (33), 201 (56), 187 (17), 147 (100), 119 (39); 13 C-NMR (75 MHz, pyridine- d 6 ) δ 179.6 (C-28), 168.8 (C-9 '), 161.8 (C-4'), 154.1 (C-20), 145.4 (C-8 ' ), 139.4 (C-13), 131.0 (C-2 '/ 6'), 126.6 (C-1 '), 126.2 (C-12), 117.2 (C-3' / 5 '), 116.2 (C- 7 '), 105.5 (C-30), 80.3 (C-3), 67.0 (C-2), 65.2 (C-23), 56.0 (C-18), 48.9 (C-1), 48.6 (C- 17), 48.3 (C-5), 47.6 (C-9), 44.2 (C-4), 43.0 (C-14), 40.4 (C-8), 40.0 (C-22), 38.4 (C-10 ), 38.1 (C-19), 33.4 (C-7), 33.1 (C-21), 29.0 (C-15), 25.2 (C-16), 24.12 (C-11), 24.07 (C-27) , 18.6 (C-6), 17.83 (C-25), 17.80 (C-26), 16.9 (C-29), 15.2 (C-24); EIMS m / z (rel. Int.) 632 ([M] + , 3), 485 (2), 387 (10), 246 (33), 201 (56), 187 (17), 147 (100), 119 (39);
HREIMS m/z: 632.3710 ([M]+, Calcd for C39H52O7: 632.3713).HREIMS m / z : 632.3710 ([M] + , Calcd for C 39 H 52 O 7 : 632.3713).
본 발명에 따른 신규화합물은 무색결정으로 얻어졌으며 HREIMS에 의해 분자이온 m/z 632.3710 [M]+을 얻을 수 있었으며 이는 분자식(elemental formula) C39H52O7과 일치하는 것이다. 신규화합물의 EIMS 스펙트럼에서 m/z 246과 201(246-COOH)의 fragment ion들이 관찰되었는데, 이것은 카르복실(carboxyl) 그룹을 가지고 있는 urs-12-ene의 전형적인 retro-Diels-Alder cleavage로 설명할 수 있다(Aquino, R., De Simone, F., Vincieri, F. F., Pizza, C., Gacs-Baitz, E., New polyhydroxylated triterpenes from Uncaria tomentosa. J. Nat . Prod., 53, 559-564, 1990; Budzikiewicz, H., Wilson, J. M., Djerassi, C., Mass spectrometry in structural and stereochemical problems. XXXII. Pentacyclic triterpenes. J. Am. Chem . Soc., 85, 3688-3699, 1963). IR 스펙트럼에서는 hydroxyl(3490-3380 cm-1), conjugated ester(1712 cm-1) 및 carbonyl(1667 cm-1) 흡수가 관찰되었다. E환에서 메틸(methyl)그룹대신에 exocyclic 메틸렌(methylene)그룹이 관찰되었다는 점을 제외하고는 이전에 Actinidia polygama로부터 분리된 coumaroyl urs-12-ene인 3-O-trans-p-coumaroyl asiatic acid(Sashida, Y., Ogawa, K., Mori, N., Yamanouchi, T., Triterpenoids from the fruit galls of Actinidia polygama. Phytochemistry, 31, 2801-2904, 1992)와 신규화합물의 1H와 13C 화학적 이동값(chemical shift value)이 매우 유사하였다. trans-p-Coumaroyl 그룹의 존재는 δ H 6.65(1H, d, J = 16.0 Hz), 7.17(2H, d, J = 8.5 Hz), 7.56(2H, d, J = 9.0 Hz) 및 7.97(1H, d, J = 16.0 Hz)에서 나타나는 1H-NMR 공명과 EIMS 스펙트럼에서 m/z 147이 주요한 fragment ion peak으로 나타남을 통해 예상할 수 있었다. The novel compounds according to the present invention were obtained as colorless crystals and obtained by molecular ionization by HREIMS.m / z 632.3710 [M]+Was obtained, which is the elemental formula C39H52O7To match. In the EIMS spectrum of the new compoundmOfz Fragment ions of 246 and 201 (246-COOH) were observed, which can be explained by the retro-Diels-Alder cleavage typical of urs-12-ene with carboxyl groups (Aquino, R., De Simone, F., Vincieri, FF, Pizza, C., Gacs-Baitz, E., New polyhydroxylated triterpenes fromUncaria tomentosa.J. Nat . Prod53, 559-564, 1990; Budzikiewicz, H., Wilson, J. M., Djerassi, C., Mass spectrometry in structural and stereochemical problems. XXXII. Pentacyclic triterpenes.J. Am. Chem . Soc, 85, 3688-3699, 1963). In the IR spectrum, hydroxyl (3490-3380 cm)-One), conjugated ester (1712 cm-One) And carbonyl (1667 cm-One) Absorption was observed. Previously except that an exocyclic methylene group was observed instead of a methyl group in the E ring.Actinidia polygama3-, coumaroyl urs-12-ene isolated fromO-trans-p-coumaroyl asiatic acid (Sashida, Y., Ogawa, K., Mori, N., Yamanouchi, T., Triterpenoids from the fruit galls ofActinidia polygama.Phytochemistry, 31, 2801-2904, 1992) and the novel compoundsOneH and13C chemical shift values were very similar.trans-pThe presence of -Coumaroyl groupδ H 6.65 (1 H, d,J = 16.0 Hz), 7.17 (2H, d,J = 8.5 Hz), 7.56 (2H, d,J = 9.0 Hz) and 7.97 (1 H, d,J = 16.0 Hz)OneH-NMR resonance and EIMS in the spectrummOfz 147 could be expected as the major fragment ion peak.
신규화합물의 하기 화학식 2 COSY(━)와 HMBC (→) NMR 스펙트럼에서 관측된 selected correlation으로 1H-NMR(도 1)과 COSY(도 4) 스펙트럼에서 4개의 3차 메틸그룹(δ H 1.17, 1.08, 1.07 및 0.96, 각각 3H), 하나의 2차 메틸그룹(d H 1.10, J = 6.5 Hz, 3H), 하나의 3치환 올레피닉(olefinic) 이중결합(d H 5.47, br t) 그리고 하나의 exocyclic 메틸렌그룹(δ H 4.82 and 4.77, each br s)을 확인하였다.Four tertiary methyl groups ( δ H 1.17, 1 H-NMR (FIG. 1) and COSY (FIG. 4) were selected correlations of the new compounds with the selected correlations observed in COSY (━) and HMBC (→) NMR spectra. 1.08, 1.07 and 0.96, respectively 3H), one secondary methyl group ( d H 1.10, J = 6.5 Hz, 3H), one trisubstituted olefinic double bond ( d H 5.47, br t) and one The exocyclic methylene group ( δ H 4.82 and 4.77, each br s) was confirmed.
이 외에도, δ H 5.92(d, J = 9.5 Hz, 1H)와 4.46 (ddd, J = 11.0, 9.5, 4.5 Hz, 1H)에서 공명하는 두 개의 oxymethine proton과 δ H 3.64와 3.50(d, J = 11.5 Hz, 각각 1H)에서 공명하는 hydroxymethyl proton이 신규화합물의 1H-NMR 스펙트럼 에서 관찰되었다. 신규화합물의 13C-NMR(도 2)과 DEPT 135 스펙트럼(도 3)에서도 역시 δ C 105.5와 154.1에서 exocyclic 메틸렌그룹의 존재를 확인하였다. O-trans-p-Coumaroyl(C-3), exocyclic 메틸렌그룹(C-20)을 비롯한 화합물 1에 존재하는 모든 치환체의 위치는 COSY(도 4), HMQC(도 5) 및 HMBC NMR(도 6) 기법을 통해 결정하였다. 신규화합물의 1H-NMR 스펙트럼에서 관찰된 H-2α와 H-3βproton간의 coupling constant(J = 9.5 Hz)가 관련화합물인 3-O-trans-p-coumaroyl asiatic acid(J = 9.8 Hz) (Sashida et al., 1992)나 actinidic acid(J = 9.6 Hz) (Lahlou, E. H., Hirai, N., Kamo, T., Tsuda, M., Ohigashi, H.,Actinidic acid, a new triterpene phytoalexin from unripe kiwi fruit. Biosci . Biotechnol . Biochem., 65, 480-483, 2001)와 비슷하다는 사실을 통해 신규화합물에 존재하는 2개의 2차 수산기의 2α,3βconfiguration을 유추할 수 있었다. In addition, two oxymethine protons resonating at δ H 5.92 (d, J = 9.5 Hz, 1H) and 4.46 (ddd, J = 11.0, 9.5, 4.5 Hz, 1H) and δ H 3.64 and 3.50 (d, J = Hydroxymethyl protons resonating at 11.5 Hz, 1H) were observed in the 1 H-NMR spectrum of the novel compounds. 13 C-NMR (FIG. 2) and DEPT 135 spectra (FIG. 3) of the novel compounds also confirmed the presence of exocyclic methylene groups at δ C 105.5 and 154.1. The positions of all substituents present in
이 같은 예상은 신규화합물의 NOESY 스펙트럼(도 7)을 통해 확인하였다. 하기 화학식 3은 신규화합물의 NOESY (↔) NMR 스펙트럼에서 관측된 selected correlations으로 H-2와 H-25 사이에 NOE가 관찰되었으며 이는 H-2와 H-3가 각각 β와 α position에 있음을 의미한다. 또한 신규화합물의 NOESY 스펙트럼에서 H-3과 Hb-23 그리고 H-24와 H-2/H-25에서 강한 NOE correlation이 관찰되어 hydroxymethyl 그룹의 위치는 C-23으로 결정하였다. This prediction was confirmed through the NOESY spectrum of the new compound (FIG. 7). In
따라서, 신규물질인 신규화합물의 화학적 구조를 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs-12:20(30)-dien-28-oic acid [3-O-trans-p- coumaroyl actinidic acid]로 규명하였다. Actinidic acid가 미성숙 키위열매(Actinidia deliciosa)에서 분리·보고되었지만 (Lahlou, E. H., Hirai, N., Kamo, T., Tsuda, M., Ohigashi, H.,Actinidic acid, a new triterpene phytoalexin from unripe kiwi fruit. Biosci . Biotechnol. Biochem., 65, 480-483, 2001), actinidic acid의 p-coumaroyl ester는 천연자원에서 처음으로 분리·보고되는 것이다.Thus, the chemical structure of the novel compound of
Ⅰ. 다래 뿌리의 에탄올 추출물 및 유효 신규 화합물 제조방법Ⅰ. Ethanol Extracts of T. Root and Preparation of Effective Novel Compounds
실험에 사용된 다래(Actinidia arguta Planchon)의 뿌리는 2006년 4월 충청남도 서산시 팔봉면 팔봉산 일대에서 채집하였으며 대전대학교 생명과학부 김주환 교수에 의해 정확히 동정되었다. 증거표본(no. KIOM-ACAR1)은 한국한의학연구원 한약제제연구부의 식물표본실에 보관 중이다. Tara used in the experiment ( Actinidia arguta The roots of the Planchon were collected in April 2006 from Palbongsan, Palbong-myeon, Seosan-si, Chungcheongnam-do, Korea. The specimen of evidence (no. KIOM-ACAR1) is being stored in the herbarium of the Herbal Medicine Research Department of the Korean Institute of Oriental Medicine.
1) 신규화함물 추출 및 분리 1) Extraction and separation of new material
음건·세절한 다래 뿌리 16 kg을 에탄올 36ℓ로 상온에서 3 반복 추출한 후 40℃에서 감압 하에 농축시켜 에탄올 추출물(553 g)을 얻었다. 이 에탄올 추출물 중 일부(300g)를 증류수(2ℓ)에 현탁시킨 후 노르말 헥산(n-hexane, 6ℓ)과 에틸아세테이트(EtOAc, 6ℓ) 그리고 부탄올(BuOH, 6ℓ)로 순차적으로 용매분획하여 노르말 헥산층 분획물(50.5 g), 에틸아세테이트층 분획물(60.4 g), 부탄올층 분획물 (73.9 g) 및 물층 분획물(115.2 g)을 각각 얻었다. 16 kg of dried and fine stalk root was extracted with 36 L of ethanol for 3 times at room temperature, and then concentrated under reduced pressure at 40 ° C. to obtain an ethanol extract (553 g). Some of the ethanol extract (300 g) was suspended in distilled water (2 L), and then the solvent was fractionated sequentially with normal hexane ( n- hexane, 6 L), ethyl acetate (EtOAc, 6 L) and butanol (BuOH, 6 L). A fraction (50.5 g), an ethyl acetate layer fraction (60.4 g), a butanol layer fraction (73.9 g) and a water layer fraction (115.2 g) were obtained, respectively.
에틸아세테이트층 분획물(50g)에 대해 실리카겔(φ6.5x47 cm, 70-230 mesh)을 고정상으로 하고 CHCl3-MeOH 혼합용매(20:1→0:1 v/v)를 이동상으로 한 칼럼 크로마토그래픽(column chromatography)를 실시하여 9개의 분획으로 나누었다(F01-F09). 분획물 F03[CHCl3-MeOH (8:1 v/v)로 용출; 6.28 g]은 실리카겔 칼럼 크로마토그래피(φ6.5x38 cm, 230-400 mesh; CHCl3-MeOH 20:1→1:1 v/v) 실시를 통해 10개의 소분획물(F0301-F0310)로 더욱 세분화하였다. 소분획물 F0301로부터 메탄올을 이용한 재결정법으로 상기 화학식 1로 표시되는 신규화합물(82 mg)을 분리하였다. Column chromatography on ethyl acetate layer fraction (50 g) with silica gel ( φ 6.5x47 cm, 70-230 mesh) as fixed phase and CHCl 3 -MeOH mixed solvent (20: 1 → 0: 1 v / v) as mobile phase Column chromatography was performed and divided into nine fractions (F01-F09). Eluted with fraction F03 [CHCl 3 -MeOH (8: 1 v / v); 6.28 g] were further subdivided into 10 subfractions (F0301-F0310) by silica gel column chromatography ( φ 6.5x38 cm, 230-400 mesh; CHCl 3 -MeOH 20: 1 → 1: 1 v / v). . A novel compound (82 mg) represented by
II. 췌장 지방분해효소(Pancreatic Lipase) 저해 효능분석 실험II. Pancreatic Lipase Inhibitory Effect Analysis
(1) 췌장 지방분해효소 저해 실험 (1) Pancreatic Lipolytic Inhibition Experiment
Enzyme buffer(10 mM MOPS (morpholinepropanesulphonic acid)와 1 mM EDTA, pH 6.8)에 혼합된 porcine pancreatic lipase(Sigma, St. Louis, MO, USA) 30㎕(10 units)와 Tris buffer(100 mM Tris-HC1과 5 mM CaCl2, pH 7.0) 850㎕를 혼합하여 준비하였다. 여기에 다양한 농도의 시험물질과 대조군인 제니칼(Orlistat; Roche, Basel, Switzerland) 100 ㎕를 혼합하여 37℃에서 15분간 배양하였다. 이후 기질(substrate) 용액[10 mM p-NPB (p-nitrophenylbutyrate) in dimethyl formamide]을 20 ㎕를 첨가한 다음 37℃에서 15분간 더 배양하였다. 효소반응에 의해 p-NPB에서 가수분해되어 생성되는 p-nitrophenol을 ELISA reader(BIO-TEK, Synergy HT, USA)를 이용하여 400 nm의 파장에서 흡광도를 측정·분석하였다. Lipase 활성억제정도는 시험물질에 의해 억제된 정도를 퍼센트 값(%)로 환산하였다.30 μl (10 units) of porcine pancreatic lipase (Sigma, St. Louis, MO, USA) mixed with Enzyme buffer (10 mM MOPS (morpholinepropanesulphonic acid) and 1 mM EDTA, pH 6.8) and Tris buffer (100 mM Tris-HC1) And 5 mM CaCl 2 , pH 7.0) 850 μl were mixed. Here, 100 μl of various concentrations of the test substance and a control group, Genical (Orlistat; Roche, Basel, Switzerland) were mixed and incubated at 37 ° C. for 15 minutes. Subsequently, 20 μl of a substrate solution [10 mM p- NPB ( p- nitrophenylbutyrate) in dimethyl formamide] was added thereto, followed by further incubation at 37 ° C. for 15 minutes. The p -nitrophenol which is hydrolyzed from p -NPB generated by the enzyme reaction using the ELISA reader (BIO-TEK, Synergy HT, USA) , were measured at the 400 nm wavelength. The degree of inhibition of lipase activity was converted into percent value (%).
(2) 췌장 지방분해효소 저해실험 결과(2) Pancreatic Lipolytic Inhibition Test Results
표1이다래 뿌리 추출물, 헥산층, 에틸아세테이트 층, 부탄올 층, 물층 및 본 발명의 신규화합물의 췌장 지방분해효소 저해효능을 분석하였다. 에틸아세테이트 층과 신규물질은 제니칼 [IC50 값 0.16 μg/ml(0.32 μM)] 보다는 약하지만, IC50 값이 각각 74.94 μg/ml, 9.45 μg/ml(14.95 μM)로 췌장 지방분해효소 활성을 현저히 저해하였다(표 1 참고). 제니칼은 효능미비와 예상할 수 없는 설사현상 등으로 일상생활에 치명적인 불편을 주고 있기 때문에,Table 1 was analyzed pancreatic lipase inhibitory effect of the root extract, hexane layer, ethyl acetate layer, butanol layer, water layer and the novel compounds of the present invention. The ethyl acetate layer and the new material are weaker than Xenical [IC 50 value 0.16 μ g / ml (0.32 μ M)], but the IC 50 values are 74.94 μ g / ml and 9.45 μ g / ml (14.95 μ M), respectively. Lipolytic activity was significantly inhibited (see Table 1). Because Xenical causes fatal inconvenience to daily life due to lack of efficacy and unexpected diarrhea,
다래의 뿌리의 에틸아세테이트 층과 여기에서 분리된 신규 화합물인 3β(trans-p-coumaroyl)oxy-2a,23-dihydroxyurs- 12:20(30)-dien-28-oic acid [3-O-trans-p-coumaroyl actinidic acid]는 비만이나 관련 질병의 예방, 치료 또는 개선을 위한 물질로서 사용될 수 있을 것이다.Ethyl acetate layer of the root of the larvae and a new compound isolated therefrom 3 β ( trans - p- coumaroyl) oxy-2 a , 23-dihydroxyurs- 12:20 (30) -dien-28-oic acid [3- O - trans - p -coumaroyl actinidic acid] could be used as the material for the prevention, treatment or amelioration of obesity and related diseases.
Compound
a)췌장 지방 활성을 50% 저해하는데 필요한 화합물의 농도(IC50). IC50 값은 dose inhibition curve를 통해 계산하였다. 저해효과는 4반복 실험 자료의 mean ±S.D.로서 표현하였다. a) The concentration of compound required to inhibit pancreatic adipose activity by 50% (IC 50 ). IC 50 values were calculated from dose inhibition curves. Inhibitory effect was expressed as mean ± SD of 4 replicate data.
도 1는 화학식 1의 화합물에 대한 1H-NMR 스펙트럼이다.1 is a 1 H-NMR spectrum of the compound of
도 2는 화학식 1의 화합물에 대한 3C-NMR 스펙트럼이다.2 is a 3 C-NMR spectrum of the compound of
도 3은 화학식 1의 화합물에 대한 DEPT-135 NMR 스펙트럼이다.3 is a DEPT-135 NMR spectrum for the compound of
도 4는 화학식 1의 화합물에 대한 1H-1H COSY NMR 스펙트럼이다.4 is a 1 H- 1 H COSY NMR spectrum for the compound of
도 5는 화학식 1의 화합물에 대한 13C-1H HMQC NMR 스펙트럼이다.FIG. 5 is a 13 C- 1 H HMQC NMR spectrum for a compound of
도 6은 화학식 1의 화합물에 대한 13C-1H HMBC NMR 스펙트럼이다.FIG. 6 is a 13 C- 1 H HMBC NMR spectrum for a compound of
도 7은 화학식 1의 화합물에 대한 NOESY NMR 스펙트럼이다.7 is a NOESY NMR spectrum for the compound of
Claims (7)
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JPH0967249A (en) * | 1995-06-22 | 1997-03-11 | Nippon Flour Mills Co Ltd | Glycerophosphate dehydrogenase inhibitor |
US20070259059A1 (en) * | 2006-05-05 | 2007-11-08 | Thomas Eidenberger | Kiwi Extract |
JP2008120772A (en) | 2006-11-08 | 2008-05-29 | Bhn Kk | Obesity inhibitor and edible composition |
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JPH0967249A (en) * | 1995-06-22 | 1997-03-11 | Nippon Flour Mills Co Ltd | Glycerophosphate dehydrogenase inhibitor |
US20070259059A1 (en) * | 2006-05-05 | 2007-11-08 | Thomas Eidenberger | Kiwi Extract |
JP2008120772A (en) | 2006-11-08 | 2008-05-29 | Bhn Kk | Obesity inhibitor and edible composition |
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