KR102050063B1 - COMPOSITION CONTAINING Spraciss crispa EXTRACT FOR PREVENTING OR TREATING DYSLIPIDEMIA-ASSOCIATED DISEASES - Google Patents
COMPOSITION CONTAINING Spraciss crispa EXTRACT FOR PREVENTING OR TREATING DYSLIPIDEMIA-ASSOCIATED DISEASES Download PDFInfo
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- KR102050063B1 KR102050063B1 KR1020190020227A KR20190020227A KR102050063B1 KR 102050063 B1 KR102050063 B1 KR 102050063B1 KR 1020190020227 A KR1020190020227 A KR 1020190020227A KR 20190020227 A KR20190020227 A KR 20190020227A KR 102050063 B1 KR102050063 B1 KR 102050063B1
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- 229960002675 xylitol Drugs 0.000 description 1
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Abstract
본 발명의 일 실시예는 꽃송이버섯 추출물을 포함하며, PCSK9 유전자의 발현을 억제하는, 이상지질혈증 관련 질환 예방 또는 치료용 조성물을 제공한다. One embodiment of the present invention includes a flower mushroom extract, and provides a composition for preventing or treating dyslipidemia-related diseases that inhibit the expression of the PCSK9 gene.
Description
본 발명은 꽃송이버섯 추출물을 포함하는 이상지질혈증 관련 질환 예방 또는 치료용 조성물에 대한 것으로, 보다 상세하게는, 꽃송이버섯 추출물을 포함하여 이상지질혈증 및 염증 관련 질환을 예방 또는 치료할 수 있는 약학적 조성물 및 꽃송이버섯 추출물에서 유래된 신규 화합물에 대한 것이다.The present invention relates to a composition for the prevention or treatment of dyslipidemia-related diseases comprising a zinnia mushroom extract, and more specifically, a pharmaceutical composition capable of preventing or treating dyslipidemia and inflammatory diseases, including a zinnia mushroom extract. And to a novel compound derived from the blossom mushroom extract.
최근, 생활습관의 서구화 등 건강 환경의 변화로 고지혈증, 동맥경화 등의 심혈관계 질환의 발병률이 높아지고 있다. 이러한 심혈관계 질환은 지질대사 이상으로 일어나는 경우가 대부분인 것으로 알려져 있다. 특히, 혈중 콜레스테롤이나 중성지방 농도를 결정하는 지단백(lipoprotein) 대사의 이상으로 발생되는 이상지질혈증은 심혈관계 질환을 유발하는 주요 원인으로 지적되고 있다.Recently, the incidence of cardiovascular diseases such as hyperlipidemia and arteriosclerosis is increasing due to changes in the health environment such as westernization of lifestyle. It is known that such cardiovascular diseases are caused by abnormal lipid metabolism. In particular, dyslipidemia caused by abnormal lipoprotein metabolism, which determines blood cholesterol or triglyceride levels, has been pointed out as a major cause of cardiovascular disease.
이상지질혈증(dyslipidemia)이란 혈장 내 총 콜레스테롤, 저밀도지단백-콜레스테롤(LDL-Cholesterol), 중성지방(triglyceride)이 증가되거나 고밀도지단백-콜레스테롤(HDL-Cholesterol)의 감소로 유발되는 혈관질환을 통칭하는 것으로, 동맥내벽에 콜레스테롤 등이 침착돼 동맥의 내면이 좁아짐에 따라 여러 장기와 사지말단에 혈액공급이 원활치 않은 혈액순환장애 등의 증상을 의미한다.Dyslipidemia is a collective term for vascular diseases caused by a decrease in plasma total cholesterol, low density lipoprotein-cholesterol (LDL-Cholesterol), triglyceride, or a decrease in high density lipoprotein-cholesterol (HDL-Cholesterol). In addition, as cholesterol is deposited on the inner wall of the artery, the inner surface of the artery is narrowed, which means symptoms such as poor blood circulation in the blood supply to various organs and extremities.
이상지질혈증은 혈중 내 지질 농도 변화에 따른 다양한 질환을 유발시키기도 하는데, 특히, 동맥경화의 발생은 동맥내벽세포의 이상적인 분화에 의한 것으로 혈중 콜레스테롤 농도와 높은 상관관계를 가진다고 보고되었다[Casteli, W. P. et al., JAMA., 256, 2835-2845(1986)]. 동맥경화는 동맥이 비후되고 경화되어 탄력을 잃고 약해진 것으로서, 노화와 더불어 발생하는 주요 질환 중의 하나이다. 동맥경화는 뇌동맥 또는 관상동맥에서 일어나기 쉬운데, 뇌동맥경화증의 경우에는 두통, 현기증, 정신장애를 나타내고 뇌연화증의 원인이 되며 관상동맥 경화증의 경우에는 심장부에 동통과 부정맥을 일으켜 협심증, 심근경색 등의 원인이 되는 것으로 알려져 있다. Dyslipidemia also causes various diseases due to changes in lipid concentrations in the blood. In particular, the occurrence of atherosclerosis is due to the ideal differentiation of arterial wall cells and has been reported to have a high correlation with blood cholesterol levels [Casteli, WP et. al., JAMA., 256, 2835-2845 (1986). Atherosclerosis is an artery that thickens and hardens, loses its elasticity and weakens, and is one of the major diseases that occur with aging. Atherosclerosis is more likely to occur in the cerebral artery or coronary arteries. In the case of cerebral arteriosclerosis, headache, dizziness, and mental disorders are indicated, and cerebral atherosclerosis is caused. It is known to become.
혈중 콜레스테롤 농도가 높으면 이러한 심혈관계 질환이 유발되기 쉽다. 예를 들어, 고콜레스테롤혈증(hypercholesterolemia)은 혈장 중의 콜레스테롤 농도가 220~250 mg/L이상인 상태를 의미하며, 이 경우 저밀도 지질단백질(LDL, low-density lipoprotein) 속의 콜레스테롤이 170mg/dL이상인 경우가 많고, 동맥경화증이 발생하기 쉽다.High blood cholesterol levels are likely to cause these cardiovascular diseases. For example, hypercholesterolemia refers to a condition in which the cholesterol level in plasma is 220-250 mg / L or more, in which case the cholesterol in low-density lipoprotein (LDL) is 170 mg / dL or more. Many are likely to develop atherosclerosis.
이러한, 심혈관계 질환을 예방 또는 치료하기 위해 혈중 콜레스테롤 농도를 줄이는 것이 필요하다. 혈중 콜레스테롤의 농도를 감소시키기 위한 방법은 크게 두 가지가 알려져 있다. 첫째, 간장에서 생성되는 콜레스테롤의 양을 줄이는 것이며, 둘째, LDL-R(low-density lipoprotein receptor, LDL-수용체)의 양을 증가시키는 것이다.In order to prevent or treat such cardiovascular diseases, it is necessary to reduce blood cholesterol levels. There are two known methods for reducing the concentration of cholesterol in the blood. First, it reduces the amount of cholesterol produced in the liver, and second, increases the amount of low-density lipoprotein receptor (LDL-receptor).
간장에서의 콜레스테롤 생성을 억제하는 약물로, 현재 고지혈증 치료제로 흔히 사용되는 스타틴(statin) 계열의 약물이 있다(Goldstein, J. L. and Brown, M. S. 2009. "The LDL Receptor." Arterioscler Thromb Vasc Biol 29: 431-438). 스타틴 계열의 약물은 세포내 콜레스테롤 합성 과정의 율속 효소(rate-limiting enzyme)인 HMG-CoA reductase의 활성을 억제하여 세포 내 콜레스테롤의 양을 감소시켜 혈중으로 분비되는 콜레스테롤의 양을 감소시킴으로써 혈중 콜레스테롤의 농도를 낮춘다. 스타틴 계열의 약물에 의하여 세포 내 콜레스테롤 양이 감소됨에 따라 2차적으로 세포막의 LDL-R 발현을 증가되는 결과가 나타난다.A drug that inhibits the production of cholesterol in the liver is a statin family of drugs commonly used as a drug for hyperlipidemia (Goldstein, JL and Brown, MS 2009. "The LDL Receptor." Arterioscler Thromb Vasc Biol 29: 431 -438). Statin drugs inhibit the activity of HMG-CoA reductase, a rate-limiting enzyme in intracellular cholesterol synthesis, which reduces the amount of cholesterol in the blood and reduces the amount of cholesterol released into the blood. Lower the concentration As the amount of cholesterol in the cell decreases due to statin drugs, LDL-R expression of the cell membrane is increased secondly.
보다 구체적으로, 통상적으로 사용되는 고콜레스테롤혈증 치료제로 심바스타틴(simvastatin), 로바스사틴(lovastatin), 메바스타틴(mevastatin) 등과 같은 스타틴 계열의 약물이 있으며, 이들은 콜레스테롤 합성에 관여하는 효소인 HMG-CoA reductase를 저해함으로써 혈중 콜레스테롤 수치를 낮추는 것으로 알려져 있다. More specifically, conventionally used drugs for treating hypercholesterolemia include statin-based drugs such as simvastatin, lovastatin, and mevastatin, and these are HMG-CoA, an enzyme involved in cholesterol synthesis. It is known to lower blood cholesterol levels by inhibiting reductase.
그러나, 일부 환자들의 경우, 이러한 약물의 사용에도 불구하고, LDL-콜레스테롤 감소에 충분한 효과가 나타나지 않아 최근 새로운 기전에 의한 새로운 고콜레스테롤혈증 치료제가 개발되고 있다.However, in some patients, despite the use of these drugs, there is no sufficient effect on the reduction of LDL-cholesterol, and new therapeutic agents for hypercholesterolemia due to new mechanisms have recently been developed.
한편, 간세포막에 발현되는 LDL-R(LDL수용체)은 혈중의 LDL-콜레스테롤(LDL-cholesterol)을 간세포로 가져와 대사시켜 제거하는 기능을 한다. 그런데, PCSK9(proprotein convertase subtilisin-kexin type 9)가 이러한 LDL-R을 불활성시켜 LDL-콜레스테롤 간세포 내로 유입되는 것을 막아, 혈중 콜레스테롤 수치를 높이는 것으로 알려져 있다. 따라서, PCSK9 저해제를 개발하여 LDL-R을 활성화시켜 고지혈증을 치료하고자 하는 연구가 전세계적으로 이루어지고 있다. On the other hand, LDL-R (LDL receptor) expressed in the hepatocyte membrane serves to remove and metabolize LDL-cholesterol in the blood into hepatocytes. However, it is known that PCSK9 (proprotein convertase subtilisin-kexin type 9) inactivates such LDL-Rs and prevents them from entering LDL-cholesterol stem cells, thereby raising blood cholesterol levels. Therefore, studies to treat hyperlipidemia by developing PCSK9 inhibitors and activating LDL-R have been conducted worldwide.
보다 구체적으로, 간장세포막에 존재하는 LDL-R은 혈중 콜레스테롤을 세포 내로 유입시켜 콜레스테롤이 간장에서 대사되어 배설되게 함으로써 혈중 콜레스테롤의 농도를 감소시키는 단백질이다.More specifically, LDL-R present in the hepatic cell membrane is a protein that reduces the concentration of cholesterol in the blood by introducing cholesterol into the cells to cause the cholesterol is metabolized and excreted in the liver.
또한, PCSK9은 세포막에 존재하는 LDL-R의 EGF-A 도메인과 결합하여 세포 내로 이동한 후 세포 내에서 LDL-R이 라이소좀(lysosome)에서 분해될 수 있도록 하는 단백질이다 (Horton, J. et al. 2007. "Molecular biology of PCSK9: its role in LDL metabolism." Trends in Biochemical Sciences 32: 71-77). PCSK9의 발현이 증가될 경우 LDL-R이 감소되어 혈중 콜레스테롤의 농도가 급격히 증가한다. 반면, PCSK9의 발현이 억제되는 경우 LDL-R의 양이 증가되어, 혈중 콜레스테롤 농도가 감소되며, 그에 따라 관상동맥질환의 발병률을 현저히 낮아질 수 있다.In addition, PCSK9 is a protein that binds to the EGF-A domain of LDL-R in the cell membrane and migrates into cells, thereby allowing LDL-R to be degraded in lysosomes in cells (Horton, J. et. 2007. "Molecular biology of PCSK9: its role in LDL metabolism." Trends in Biochemical Sciences 32: 71-77). Increased expression of PCSK9 decreases LDL-R, leading to a sharp increase in blood cholesterol levels. On the other hand, when the expression of PCSK9 is inhibited, the amount of LDL-R is increased, thereby reducing the blood cholesterol level, thereby significantly lowering the incidence of coronary artery disease.
현재까지 PCSK9의 조절을 통하여 혈중 콜레스테롤 농도의 감소를 유도하는 방법으로는 siRNA(small interfering RNA)를 이용하여 PCSK9의 합성을 억제하는 방법, PCSK9에 대한 항체를 이용하여 PCSK9의 양을 감소시키는 방법, PCSK9과 LDL-R간의 결합을 방해하는 펩타이드를 이용하여 PCSK9의 활성을 억제하는 방법 및 저분자 화합물(small compound)을 이용하여 PCSK9의 활성을 억제하거나 발현 양의 감소를 유도하는 방법이 있다.Until now, the method of inducing the reduction of blood cholesterol level through the regulation of PCSK9 is a method of inhibiting the synthesis of PCSK9 using siRNA (small interfering RNA), a method of reducing the amount of PCSK9 using an antibody to PCSK9, There is a method of inhibiting the activity of PCSK9 using a peptide that interferes with the binding between PCSK9 and LDL-R, and a method of inhibiting the activity of PCSK9 or reducing the amount of expression using a small compound.
저분자 화합물을 이용한 방법으로 베르베린(berberine)(Kong, W., et al. 2004 Nature Medicine 10: 1344-1351), 케노데옥시콜린산(chenodeoxycholic acid), FXR (farnesoid X receptor)를 이용하는 방법이 있다.Methods using low molecular weight compounds include berberine (Kong, W., et al. 2004 Nature Medicine 10: 1344-1351), chenodeoxycholic acid, and FXR (farnesoid X receptor). .
꽃송이버섯(Sparassis crispa)은 씹는 맛이 좋고 송이버섯과 같은 은은한 향을 갖는 버섯으로, 항암효과를 가진 적응소(adaptogen)로 알려져 있다. 구체적으로, 꽃송이버섯은 부작용이 없고, 약효가 특정한 장기나 기관에 한정하지 않으며, 정상화 작용을 가지는 버섯으로, 한의학 분야에서는 사용되어 왔다. Sparassis crispa is a mushroom that has good chewing taste and has a subtle scent like pine mushroom. It is known as an adaptogen with anticancer effect. Specifically, the mushroom mushroom has no side effects, the drug is not limited to a specific organ or organ, and has a normalizing action, has been used in the field of Oriental medicine.
이러한 꽃송이버섯의 효능, 특히 항암작용은 복합다당체에 기인하는 것으로 알려져 있다. 또한, 꽃송이버섯은 항암, 면역기능 향상에 탁월한 효과가 있는 것으로 알려진 베타 글루칸 성분을 다량 함유하는 것으로 알려져 있다.It is known that the potency of the zinnia mushroom, particularly the anticancer action, is due to the complex polysaccharide. In addition, blossom mushroom is known to contain a large amount of beta glucan component known to have an excellent effect on anti-cancer, immune function enhancement.
본 발명의 일 실시예는, 꽃송이버섯 추출물을 포함하는 이상지질혈증 관련 질환 예방 또는 치료용 조성물을 제공하고자 한다.One embodiment of the present invention, to provide a composition for the prevention or treatment of dyslipidemia-related diseases comprising the flower extract.
본 발명의 다른 일 실시예는, 꽃송이버섯에서 추출된 화합물을 포함하는 이상지질혈증 관련 질환 예방 또는 치료용 조성물을 제공하고자 한다.Another embodiment of the present invention, to provide a composition for preventing or treating dyslipidemia-related diseases comprising a compound extracted from the mushroom.
본 발명의 또 다른 일 실시예는, 꽃송이버섯 추출물을 포함하는 건강 보조 식품을 제공하고자 한다.Another embodiment of the present invention, to provide a dietary supplement comprising the mushroom extract.
본 발명의 또 다른 일 실시예는, 꽃송이버섯 추출물로부터 유래된 신규 화합물을 제공하고자 한다.Another embodiment of the present invention, to provide a novel compound derived from the mushroom extract.
이러한 과제를 해결하기 위해, 본 발명의 일 실시예는, 꽃송이버섯 추출물을 포함하며, PCSK9 유전자의 발현을 억제하는, 이상지질혈증 관련 질환 예방 또는 치료용 조성물을 제공한다.In order to solve this problem, an embodiment of the present invention, including the mushroom extract, and provides a composition for preventing or treating dyslipidemia-related diseases, which suppresses the expression of the PCSK9 gene.
상기 꽃송이버섯 추출물은 LDL-수용체(LDL-R)의 발현을 증가시킨다.The mushroom extract increases the expression of LDL-receptor (LDL-R).
상기 꽃송이버섯 추출물은 꽃송이버섯의 용매 추출물이며, 상기 용매는 물(H2O) 및 탄소수 1 내지 4의 저급 알코올 중 적어도 하나를 포함한다.The flower mushroom extract is a solvent extract of the flower mushroom, and the solvent includes at least one of water (H 2 O) and a lower alcohol having 1 to 4 carbon atoms.
상기 꽃송이버섯 추출물은, 하기 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside), 하기 화학식 8로 표현되는 하나비라타켈리드 A(hanabiratakelide A), 하기 화학식 11로 표현되는 아데노신(adenosine) 및 하기 화학식 14로 표현되는 5α,6α-에폭시-(22E,24R)-에르고스타-8(14),22-디엔-3β,7β-diol[5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7β-diol] 중 적어도 하나를 포함한다.The mushroom extract, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by the following formula (1) (2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside), hanabiratakelide A represented by
[화학식 1][Formula 1]
상기 화학식 1에서 R은 리보스(ribose)이다.In Formula 1, R is ribose.
[화학식 8] [Formula 8]
[화학식 11][Formula 11]
[화학식 14][Formula 14]
본 발명의 다른 일 실시예는, 하기 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside)를 제공한다.Another embodiment of the present invention, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by the following formula (1) (2-hydroxy-3-methoxy- 6-methyl benzoic acid methyl ester 4-O-α-D-riboside.
[화학식 1][Formula 1]
여기서, R은 리보스(ribose)이다.Where R is ribose.
본 발명의 또 다른 일 실시예는, 하기 화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드(5-methoxy-phthalide 7-O-α-D-riboside)를 제공한다.Another embodiment of the present invention, 5-methoxy-phthalide 7-O-α-D-riboside represented by the following formula 3 (5-methoxy-phthalide 7-O-α-D-riboside) to provide.
[화학식 3][Formula 3]
여기서, R1과 R3는 수소(H)이고, R2는 메틸기(CH3)이고, R4는 O-리보스(O-ribose)이다.Wherein R 1 and R 3 are hydrogen (H), R 2 is a methyl group (CH 3), and R 4 is O-ribose.
본 발명의 또 다른 일 실시예는, 하기 화학식 4로 표현되는 6-메톡시-4,5,7-트리히드록시 프탈라이드(6-methoxy-4,5,7-trihydroxy phthalide)를 제공한다.Another embodiment of the present invention provides 6-methoxy-4,5,7-trihydroxy phthalide represented by the following Chemical Formula 4 (6-methoxy-4,5,7-trihydroxy phthalide).
[화학식 4][Formula 4]
본 발명의 또 다른 일 실시예는, 하기 화학식 5로 표현되는 5,6-디하이드록시-7-메톡시프탈라이드(5,6-dihydroxy-7-methoxy phthalide)를 제공한다.Another embodiment of the present invention provides 5,6-dihydroxy-7-methoxy phthalide represented by the following Chemical Formula 5.
[화학식 5] [Formula 5]
본 발명의 또 다른 일 실시예는, 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside); 화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드(5-methoxy-phthalide 7-O-α-D-riboside); 화학식 4로 표현되는 6-메톡시-4,5,7-트리히드록시 프탈라이드(6-methoxy-4,5,7-trihydroxy phthalide); 및 화학식 5로 표현되는 5,6-디하이드록시-7-메톡시프탈라이드(5,6-dihydroxy-7-methoxy phthalide); 중에서 선택된 적어도 하나를 포함하는, 이상지질혈증 관련 질환 예방 또는 치료용 조성물을 제공한다.Another embodiment of the present invention, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester represented by
상기 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드, 상기 5-메톡시-프탈라이드 7-O-α-D-리보시드, 상기 6-메톡시-4,5,7-트리히드록시 프탈라이드 및 상기 5,6-디하이드록시-7-메톡시프탈라이드는 꽃송이버섯에서 추출된다.The 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside, the 5-methoxy-phthalide 7-O-α-D-riboside, the 6- Methoxy-4,5,7-trihydroxy phthalide and the 5,6-dihydroxy-7-methoxyphthalide are extracted from the blossom mushroom.
본 발명의 또 다른 일 실시예는, 꽃송이버섯 추출물을 포함하며, PCSK9 유전자의 발현을 억제하는, 이상지질혈증 관련 질환 예방 또는 치료용 건강 기능 식품을 제공한다.Another embodiment of the present invention, including the mushroom extract, and provides a dietary supplement for the prevention or treatment of dyslipidemia-related diseases, which suppresses the expression of the PCSK9 gene.
본 발명의 일 실시예에 따른 이상지질혈증 관련 질환 예방 또는 치료용 조성물은 천연물인 꽃송이버섯 추출물을 포함하며, PCSK9(proprotein convertase subtilisin-kexin type 9) 유전자의 발현을 억제하여 이상지질혈증 관련 질환을 예방 또는 치료한다. 본 발명의 일 실시예에 따르면, 꽃송이버섯 추출물은 PCSK9 유전자의 과발현에 의하여 발생하는 고콜레스테롤 혈증을 예방, 개선 또는 치료할 수 있다.A composition for preventing or treating dyslipidemia-related diseases according to an embodiment of the present invention includes an extract of a pine mushroom, which is a natural product, to suppress dyslipidemia-related diseases by inhibiting the expression of the PCSK9 gene (proprotein convertase subtilisin-kexin type 9). Prevent or treat. According to one embodiment of the present invention, the blossom mushroom extract may prevent, improve or treat hypercholesterolemia caused by overexpression of the PCSK9 gene.
본 발명의 일 실시예에 따른 이상지질혈증 관련 질환 예방 또는 치료용 조성물은 PSCK9의 발현을 억제하여 LDL-R(low-density lipoprotein receptor, LDL-수용체)의 발현을 증가시킴으로써, 콜레스테롤 조절에 우수한 효과를 나타낸다.Composition for preventing or treating dyslipidemia related diseases according to an embodiment of the present invention by inhibiting the expression of PSCK9 to increase the expression of LDL-R (low-density lipoprotein receptor, LDL-receptor), excellent effect on cholesterol control Indicates.
도 1은 꽃송이버섯의 메탄올 추출물(실시예 1)의 처리 및 메탄올 추출물의 분획물(실시예 2-5)의 처리에 의한 PCSK9 mRNA의 상대적인 발현량을 나타내는 그래프이다.
도 2는 화합물 1 내지 14 및 대조군 처리에 의한 PCSK9 mRNA의 상대적인 발현량을 나타내는 그래프이다.
도 3 내지 33은 화합물 1 내지 14에 대한 분광분석 그래프이다.1 is a graph showing the relative expression level of PCSK9 mRNA by the treatment of the methanol extract of the mushroom (Example 1) and the treatment of the fraction of the methanol extract (Example 2-5).
Figure 2 is a graph showing the relative expression of PCSK9 mRNA by
3 to 33 are spectroscopic graphs for Compounds 1-14.
이하, 실시예를 참조하여 본 발명을 보다 구체적으로 설명한다.Hereinafter, the present invention will be described in more detail with reference to Examples.
본 발명의 일 실시예는 꽃송이버섯(Sprassis crispa) 추출물을 포함하는 이상지질혈증 관련 질환 예방 또는 치료용 조성물을 제공한다.One embodiment of the present invention provides a composition for the prevention or treatment of dyslipidemia-related diseases, including the extract of the mushroom ( Sprassis crispa ).
꽃송이버섯(Sparassis crispa)은 민주름버섯목 꽃송이과에 속하는 식용버섯으로, 풍부한 식이섬유를 가지며, 베타-1,3-결합으로 연결된 주쇄에 베타-1,6-결합의 측쇄를 가진 베타-글루칸(β-glucan)을 포함한다. 또한, 꽃송이버섯은 항암 효과를 갖는 것으로 알려져 있다. Sparassis crispa is an edible mushroom belonging to the Democratic Mushroom family, with abundant dietary fiber and a beta-glucan having a beta-1,6-linked side chain in the beta-1,3-linked backbone. β-glucan). In addition, blossom mushrooms are known to have anticancer effects.
본 발명의 일 실시예는 이러한 꽃송이버섯으로부터 추출된 추출물을 이상지질혈증 관련 질환의 예방 또는 치료용 조성물에 적용한 것이다.One embodiment of the present invention is applied to the composition for the prevention or treatment of dyslipidemia-related diseases, the extract extracted from the flower mushroom.
본 발명의 일 실시예에 따르면, 상기 꽃송이버섯 추출물은 PCSK9 유전자의 발현을 억제하여 이상지질혈증 관련 질환을 예방 또는 치료한다. 또한, 본 발명의 일 실시예에 따르면, 꽃송이버섯 추출물은 LDL-수용체(LDL-R)의 발현을 증가시킴으로써, 이상지질혈증 관련 질환을 예방 또는 치료할 수 있다.According to one embodiment of the invention, the blossom mushroom extract inhibits the expression of the PCSK9 gene to prevent or treat dyslipidemia related diseases. In addition, according to an embodiment of the present invention, the flower mushroom extract may increase or decrease the expression of LDL-receptor (LDL-R), thereby preventing or treating dyslipidemia related diseases.
본 발명의 일 실시예에 있어서, 이상지질혈증은 PCSK9 유전자의 과발현에 의해 유발된 것일 수 있다.In one embodiment of the present invention, dyslipidemia may be caused by overexpression of the PCSK9 gene.
구체적으로, 간세포막에 발현되는 LDL-R(LDL 수용체)는 혈중의 LDL-콜레스테롤(LDL-cholesterol)을 간세포로 가져와 대사시켜 제거하는 기능을 하는데, PCSK9 (proprotein convertase subtilisin-kexin type 9)는 이러한 LDL-R을 불활성화시킨다. 즉, PCSK9은 LDL-R을 불활성화시켜 LDL-콜레스테롤이 간세포 내로 유입되는 것을 막아, 혈중 콜레스테롤 수치를 높인다. Specifically, LDL-R (LDL receptor) expressed in the hepatocyte membrane functions to remove and metabolize LDL-cholesterol (LDL-cholesterol) in the blood to hepatocytes. PCSK9 (proprotein convertase subtilisin-kexin type 9) Inactivate LDL-R. In other words, PCSK9 inactivates LDL-R and prevents LDL-cholesterol from entering the hepatocytes, thereby raising blood cholesterol levels.
본 발명의 일 실시예에 따른 꽃송이버섯 추출물은 PCSK9 유전자의 발현을 억제하여 PCSK9가 LDL-R을 불활성화시키는 것을 방지함으로써, LDL- 콜레스테롤이 간세포 내로 유입되어 제거되도록 한다.Blossom mushroom extract according to an embodiment of the present invention inhibits the expression of the PCSK9 gene to prevent PCSK9 from inactivating LDL-R, so that LDL-cholesterol is introduced into and removed from hepatocytes.
본 발명의 일 실시예에 따르면 꽃송이버섯 추출물은 꽃송이버섯의 용매 추출물이다. According to an embodiment of the present invention, the blossom mushroom extract is a solvent extract of the blossom mushroom.
구체적으로, 꽃송이버섯 추출물을 획득하기 위해 다양한 추출용매가 이용될 수 있다. 용매로, 극성 용매 또는 비극성 용매를 이용할 수 있다. Specifically, various extracting solvents may be used to obtain the flower mushroom extract. As the solvent, a polar solvent or a nonpolar solvent can be used.
극성 용매로, 물(H2O), 알코올, 아세트산, DMFO(dimethyl-formamide) 및 DMSO(dimethyl sulfoxide) 중 적어도 하나가 사용될 수 있다. 여기서, 알코올은, 메탄올, 에탄올, 프로판올, 부탄올, 노말-프로판올, 이소-프로판올, 노말-부탄올, 1-펜탄올, 2-부톡시에탄올, 에틸렌글리콜 및 부틸렌글리콜을 포함한다.As the polar solvent, at least one of water (H 2 O), alcohol, acetic acid, dimethyl-formamide (DMFO) and dimethyl sulfoxide (DMSO) may be used. Here, alcohol includes methanol, ethanol, propanol, butanol, normal-propanol, iso-propanol, normal-butanol, 1-pentanol, 2-butoxyethanol, ethylene glycol and butylene glycol.
비극성 용매로, 아세톤, 아세토나이트릴, 에틸 아세테이트, 메틸 아세테이트, 플루오로알칸, 펜탄, 헥산, 2,2,4-트리메틸펜탄, 데칸, 사이클로헥산, 사이클로펜탄, 디이소부틸렌, 1-펜텐, 1-클로로부탄, 1-클로로펜탄, o-자일렌, 디이소프로필 에테르, 2-클로로프로판, 톨루엔, 1-클로로프로판, 클로로벤젠, 벤젠, 디에틸 에테르, 디에틸 설파이드, 클로로포름, 디클로로메탄, 1,2-디클로로에탄, 어닐린, 디에틸아민, 에테르, 사염화탄소, THF 등이 사용될 수 있다.As a nonpolar solvent, acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, 1-pentene, 1-chlorobutane, 1-chloropentane, o-xylene, diisopropyl ether, 2-chloropropane, toluene, 1-chloropropane, chlorobenzene, benzene, diethyl ether, diethyl sulfide, chloroform, dichloromethane, 1,2-dichloroethane, anneal, diethylamine, ether, carbon tetrachloride, THF and the like can be used.
예를 들어, 용매는 물(H2O) 및 탄소수 1 내지 4의 저급 알코올 중 적어도 하나를 포함할 수 있다. 즉, 꽃송이버섯이 용매인 물(H2O) 및 탄소수 1 내지 4의 저급 알코올 중 어느 하나 또는 이들의 혼합물에 의해 추출되어 꽃송이버섯 추출물이 만들어질 수 있다.For example, the solvent may include at least one of water (H 2 O) and lower alcohols having 1 to 4 carbon atoms. That is, the blossom mushroom is extracted by any one or a mixture of water (H 2 O) and a lower alcohol having 1 to 4 carbon atoms as a solvent may be a mushroom mushroom extract.
본 발명의 일 실시예에 있어서, "추출물"은 용매를 이용한 추출물인 조추출물(crude extract) 뿐만 아니라, 조추출물이 추가적으로 분획(fractionation)되어 얻어진 분획물 또는 조추출물이 정제되어 얻어진 정제물을 포함한다. In one embodiment of the present invention, the "extract" includes not only crude extract, which is an extract using a solvent, but also a fraction obtained by further fractionation of the crude extract or a purified product obtained by purifying the crude extract. .
즉, 본 발명의 일 실시예에 따른 꽃송이버섯 추출물은 추출용매를 이용하여 얻어진 용매 추출물(조추출물)뿐만 아니라, 조추출물을 정제 또는 여과하여 얻어진 정제물 또는 분획물을 포함한다. 예를 들어, 용매 추출물을 일정한 분자량 컷-오프 값을 갖는 한외 여과막을 통과시켜 얻은 분획, 다양한 크로마토그래피에 의한 분리, 기타 다양한 정제 방법을 통해 얻어진 분획물도 본 발명의 일 실시예에 따른 꽃송이버섯 추출물에 포함된다.That is, the flower mushroom extract according to one embodiment of the present invention includes not only a solvent extract (crude extract) obtained by using an extraction solvent, but also a purified or fraction obtained by purifying or filtering the crude extract. For example, fractions obtained by passing the solvent extract through an ultrafiltration membrane having a constant molecular weight cut-off value, separation by various chromatography, and fractions obtained through various purification methods are also obtained from the mushroom extract according to one embodiment of the present invention. Included in
또한, 본 발명의 일 실시예에 따른 꽃송이버섯 추출물은, 예를 들어, 꽃송이버섯을 용매로 처리하여 수득한 꽃송이버섯의 용매 추출물을 감압 증류 및 동결 건조하거나 분무 건조하여 수득된 분말도 포함하는 의미이다.In addition, the blossom mushroom extract according to an embodiment of the present invention, for example, means that the solvent extract of the blossom mushroom obtained by treating the blossom mushroom with a solvent, also obtained by distillation under reduced pressure and freeze drying or spray drying to be.
본 발명의 일 실시예에 따르면, 꽃송이버섯 추출물은, 하기 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside)(화합물 1), 하기 화학식 2로 표현되는 2,4-디하이드록시-3-메톡시-6-메틸벤조에이트 (2,4-dihydroxy-3-methoxy-6-methylbenzoate)(화합물 2), 하기 화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드(5-methoxy-phthalide 7-O-α-D-riboside)(화합물 3), 하기 화학식 4로 표현되는 6-메톡시-4,5,7-트리히드록시 프탈라이드(6-methoxy-4,5,7-trihydroxy phthalide)(화합물 4), 하기 화학식 5로 표현되는 5,6-디히드록시-7-메톡시프탈라이드(5,6-dihydroxy-7-methoxy phthalide) (화합물 5), 하기 화학식 6으로 표현되는 5-히드록시-7-메톡시프탈라이드(5-hydroxy-7-methoxyphthalide)(화합물 6), 하기 화학식 7로 표현되는 5-메톡시-7-히드록시프탈라이드(5-methoxy-7-hydroxyphthalide)(화합물 7), 하기 화학식 8로 표현되는 하나비라타켈리드 A(hanabiratakelide A)(화합물 8), 하기 화학식 9로 표현되는 니코틴아미드(nicotinamide)(화합물 9), 하기 화학식 10으로 표현되는 5′-디옥시-5′-메틸티오아데노신(5′-deoxy-5′-methylthioadenosine)(화합물 10), 하기 화학식 11로 표현되는 아데노신(adenosine)(화합물 11), 하기 화학식 12로 표현되는 에르고스테롤(ergosterol)(화합물 12), 하기 화학식 13으로 표현되는 에르고스테롤 퍼옥사이드(ergosterol peroxide)(화합물 13) 및 하기 화학식 14로 표현되는 5α,6α-에폭시-(22E,24R)-에르고스타-8(14),22-디엔-3β,7β-diol[5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7β-diol](화합물 14) 중 적어도 하나를 포함한다.According to one embodiment of the present invention, the flower mushroom extract, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside (2-hydroxy -3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside) (Compound 1), 2,4-dihydroxy-3-methoxy-6-methylbenzo represented by the following formula (2) 8 (2,4-dihydroxy-3-methoxy-6-methylbenzoate) (Compound 2), 5-methoxy-phthalide 7-O-α-D-riboside represented by the following formula (3): 5-methoxy-phthalide 7-O-α-D-riboside) (Compound 3), 6-methoxy-4,5,7-trihydroxy phthalide represented by the following general formula (4): 6-methoxy-4,5,7-trihydroxy phthalide ) (Compound 4), 5,6-dihydroxy-7-methoxy phthalide represented by the formula (5) (Compound 5), 5 represented by the formula (6) -Hydroxy-7-methoxyphthalide (compound 6), represented by the following formula (7) Is 5-methoxy-7-hydroxyphthalide (compound 7), hanabiratakelide A (compound 8) represented by the following formula (8), formula (9) Nicotinamide (Compound 9) represented by, 5'-deoxy-5'-methylthio adenosine (5'-deoxy-5'-methylthioadenosine) represented by the formula (10) (compound 10), formula 11 Adenosine (compound 11) represented by the following, ergosterol (compound 12) represented by the following formula (12), ergosterol peroxide (compound 13) represented by the following formula (13) and the following formula 14 5α, 6α-epoxy- (22E, 24R) -ergosta-8 (14), 22-diene-3β, 7β-diol [5α, 6α-epoxy- (22E, 24R) -ergosta-8 (14) ), 22-diene-3β, 7β-diol] (compound 14).
[화학식 1][Formula 1]
여기서, R은 리보스(ribose)이다.Where R is ribose.
[화학식 2][Formula 2]
[화학식 3][Formula 3]
R1과 R3는 수소(H)이고, R2는 메틸기(CH3)이고, R4는 O-리보스(O-ribose)이다. O-리보스의 "O"는 산소(oxygen)이다. R 1 and R 3 are hydrogen (H), R 2 is methyl group (CH3), and R 4 is O-ribose. "O" in O-ribose is oxygen.
[화학식 4][Formula 4]
[화학식 5][Formula 5]
[화학식 6][Formula 6]
[화학식 7][Formula 7]
[화학식 8][Formula 8]
[화학식 9][Formula 9]
[화학식 10][Formula 10]
[화학식 11][Formula 11]
[화학식 12][Formula 12]
[화학식 13][Formula 13]
[화학식 14][Formula 14]
한편, 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드는, 예를 들어 하기 화학식 1a로 표현되는 구조식을 가질 수 있다.Meanwhile, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by
[화학식 1a][Formula 1a]
또한, 화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드는, 예를 들어 하기 화학식 3a로 표현되는 구조식을 가질 수 있다.In addition, 5-methoxy-phthalide 7-O-α-D-riboside represented by the formula (3), for example, may have a structural formula represented by the formula (3a).
[화학식 3a][Formula 3a]
본 발명의 일 실시예에 따른 이상지질혈증 관련 질환 예방 또는 치료용 조성물은 약학적으로 유효한 양의 꽃송이버섯 추출물에 더하여, 약학적으로 허용되는 담체, 부형제 및 희석제 중 적어도 하나를 추가로 포함할 수 있다.The composition for preventing or treating dyslipidemia related diseases according to an embodiment of the present invention may further include at least one of a pharmaceutically acceptable carrier, excipient, and diluent, in addition to the pharmaceutically effective amount of the extract of the matsutake mushroom. have.
여기서, "약학적으로 허용되는" 이란 생리학적으로 허용되고 인간에게 투여될 때, 활성성분의 작용을 저해하지 않으며 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 비독성이라는 것을 의미한다.Herein, "pharmaceutically acceptable" means that when physiologically acceptable and administered to humans, it is non-toxic that does not inhibit the action of the active ingredient and does not usually cause an allergic reaction such as gastrointestinal disorders, dizziness or the like. it means.
이러한 약학적으로 허용되는 담체, 부형제 및 희석제의 예로, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유 등이 있다. Examples of such pharmaceutically acceptable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like.
또한, 본 발명의 일 실시예에 따른 이상지질혈증 관련 질환 예방 또는 치료용 조성물은 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.In addition, the composition for preventing or treating dyslipidemia-related diseases according to an embodiment of the present invention may further include a filler, an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, a preservative, and the like.
"약학적으로 유효한 양"이란 음성 대조군에 비해 그 이상의 반응을 나타내는 양을 말하며 바람직하게는 이상지질혈증 관련 질환을 예방 또는 치료하는 효과를 나타내기에 충분한 양을 말한다. 본 발명의 일 실시예에 있어서, 꽃송이버섯 추출물의 약학적으로 유효한 양은 0.01 내지 100 mg/day/kg 체중이다. 그러나, 본 발명의 일 실시예가 이에 한정되는 것은 아니며, 약학적으로 유효한 양은 질환의 종류 및 이의 중증정도, 환자의 연령, 체중, 건강상태, 성별, 투여 경로 및 치료기간 등과 같은 여러 인자에 따라 적절히 조정될 수 있다."Pharmaceutically effective amount" refers to an amount which has a higher response than a negative control, and preferably an amount sufficient to have an effect of preventing or treating a dyslipidemia related disease. In one embodiment of the present invention, the pharmaceutically effective amount of the mushroom extract is 0.01 to 100 mg / day / kg body weight. However, one embodiment of the present invention is not limited thereto, and the pharmaceutically effective amount may be appropriately determined according to various factors such as the type of disease and its severity, the age, weight, health condition, sex, route of administration and duration of treatment. Can be adjusted.
또한, 본 발명의 일 실시예에 따른 이상지질혈증 관련 질환 예방 또는 치료용 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출이 가능하도록 당업계에 공지된 방법에 따라 제형화 될 수 있다. 제형의 예로, 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캡슐, 멸균 주사용액, 멸균 분말 등이 있다.In addition, a composition for preventing or treating dyslipidemia-related diseases according to an embodiment of the present invention may be formulated according to methods known in the art to enable rapid, sustained or delayed release of the active ingredient after administration to a mammal. Can be. Examples of formulations include powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders and the like.
본 발명의 일 실시예에 따른 이상지질혈증 관련 질환 예방 또는 치료용 조성물은 경구적 또는 비경구적으로 투여 될 수 있다. 비경구적 투여 경로로, 예를 들어, 경피, 비강, 복강, 근육, 피하, 정맥 등의 경로가 있다.Composition for preventing or treating dyslipidemia related disease according to an embodiment of the present invention may be administered orally or parenterally. Parenteral routes of administration include, for example, transdermal, nasal, abdominal, muscle, subcutaneous, and intravenous routes.
본 발명의 일 실시예에 따른 이상지질혈증 관련 질환 예방 또는 치료용 조성물은 이상지질혈증 관련 질환을 예방 또는 치료할 수 있는 공지의 화합물과 병행하여 투여될 수 있다.The composition for preventing or treating dyslipidemia related diseases according to an embodiment of the present invention may be administered in parallel with a known compound capable of preventing or treating dyslipidemia related diseases.
본 발명의 일 실시예에 따른 이상지질혈증 관련 질환 예방 또는 치료용 조성물은 이상지질혈증 관련 질환을 예방 또는 치료하기 위한 식품 및 의약품 등에 유용하게 적용될 수 있다.The composition for preventing or treating dyslipidemia related diseases according to an embodiment of the present invention may be usefully applied to foods and pharmaceuticals for preventing or treating dyslipidemia related diseases.
식품으로, 음식물, 기능성 식품(functional food), 영양보조제(nutritional supplement), 건강식품(health food), 식품 첨가제(food additives) 등이 있다. 식품은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다.Foods include foods, functional foods, nutritional supplements, health foods, food additives and the like. The food may be prepared in various forms according to conventional methods known in the art.
예를 들어, 건강식품으로 차, 주스, 드링크, 과립제, 캡슐제, 분말제 등이 있다. 또한, 음식물 제조를 위한 분말 또는 농축액 역시 식품에 포함된다.For example, health foods include tea, juice, drinks, granules, capsules, powders, and the like. In addition, powders or concentrates for food preparation are also included in the food.
이하, 실시예 및 시험예를 참조하여 본 발명을 더욱 상세하게 설명한다. 이러한 실시예와 시험예는 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되지 않는다는 것은 당해 기술분야에서 통상의 지식을 가진 자에게 있어 자명한 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. These examples and test examples are intended to illustrate the present invention more specifically, it is obvious to those skilled in the art that the scope of the present invention is not limited by these.
<실시예 1> 꽃송이버섯 추출물의 제조Example 1 Preparation of Blossom Mushroom Extract
자실체 전체가 건조된 꽃송이버섯 1 kg에 100% 메탄올(MeOH)을 가하고 80℃에서 3시간동안 환류추출 하였다. 추출액을 여과하여 취한 후, 잔사에 다시 100% 메탄올을 가하고 다시 환류추출하는 과정을 2회 반복하여 메탄올 추출액을 얻었고, 이를 감압농축하여 총 153g의 메탄올 추출물(실시예 1)을 얻었다. 100% methanol (MeOH) was added to 1 kg of the dried mushrooms, and the whole fruiting body was refluxed at 80 ° C. for 3 hours. After extracting the extract by filtration, 100% methanol was added to the residue again and reflux extraction was repeated twice to obtain a methanol extract, concentrated under reduced pressure to obtain a total of 153g of methanol extract (Example 1).
<실시예 2-5> 꽃송이버섯 추출물로부터 유기 용매 분획물 제조Example 2-5 Preparation of Organic Solvent Fraction from Blossom Mushroom Extracts
실시예 1에서 제조된 꽃송이버섯의 메탄올 추출물 153g을 증류수(H2O)에 현탁시킨 후 헥산 (n-hexane), 메틸렌클로라이드 (CH2Cl2), 에틸아세테이트 (EtOAc) 및 부탄올 (n-BuOH)순으로 분획 과정을 3회 반복하여, 각각 헥산 분획물 (17.6g)(실시예 2), 메틸렌클로라이드 분획물(2.7g)(실시예 3), 에틸아세테이트 분획물 (9.8g)(실시예 4), 부탄올 분획물 (15.0g)(실시예 5)을 제조하였다. 이와 같이 제조된 분획물을 각각 실시예 2 내지 5라고 하였다.153 g of the methanol extract of the flower mushroom prepared in Example 1 was suspended in distilled water (H 2 O), followed by hexane (n-hexane), methylene chloride (CH 2 Cl 2 ), ethyl acetate (EtOAc) and butanol (n-BuOH The fractionation process was repeated three times, followed by hexane fraction (17.6 g) (Example 2), methylene chloride fraction (2.7 g) (Example 3), ethyl acetate fraction (9.8 g) (Example 4), Butanol fraction (15.0 g) (Example 5) was prepared. The fractions thus prepared were referred to as Examples 2 to 5, respectively.
<화합물 1 내지 14> 에틸아세데이트 분획물로부터 단일 화합물 분리
실시예 4에서 제조된 에틸아세데이트 분획물 (9.8g)을 헥산:에틸아세테이드:메탄올 (10:1:0 → 2.5:1:0 →1.5:1:0 → 1:1:0.2)과 메틸렌클로라이드:메탄올:증류수 (10:1:0 → 5:1:0.1)의 용매 조성으로 실리카겔 컬럼 크로마토그피를 수행하여 7개의 소분획 (E1, E2, E3, E4, E5, E6, E7)을 얻었다. The ethyl acetate fraction (9.8 g) prepared in Example 4 was mixed with hexane: ethyl acetate: methanol (10: 1: 0 → 2.5: 1: 0 → 1.5: 1: 0 → 1: 1: 0.2) and methylene. Silica gel column chromatography was carried out with a solvent composition of chloride: methanol: distilled water (10: 1: 0 → 5: 1: 0.1) to obtain 7 small fractions (E1, E2, E3, E4, E5, E6, E7). .
이 중, E2 분획을 헥산:아세톤 (20:1 → 15:1)의 용매 조성으로 실리카겔 컬럼 크로마토그래피를 수행하여 화합물 2 (8.6 mg)(화학식 2)를 얻었다. Of these, the E2 fraction was subjected to silica gel column chromatography with a solvent composition of hexane: acetone (20: 1 to 15: 1) to obtain compound 2 (8.6 mg) (Formula 2).
E4 분획을 클로로포름:아세톤 (65:1 → 20:1 → 10:1 → 7:1)의 용매 조성으로 실리카겔 컬럼 크로마토그래피를 수행하여 6개의 소분획 (E4-1, E4-2, E4-3, E4-4, E4-5, E4-6)을 얻었으며, 이들 중 E4-1 분획을 증류수:아세토나이트릴 (60:40 → 45:55, v/v)의 용매 조성으로 역상 HPLC를 수행하여 화합물 12 (15 mg)(화학식 12), 화합물 13 (18.5 mg)(화학식 13), 화합물 14 (1.5 mg)(화학식 14)를 얻었다. The E4 fraction was subjected to silica gel column chromatography with a solvent composition of chloroform: acetone (65: 1 → 20: 1 → 10: 1 → 7: 1) to give 6 small fractions (E4-1, E4-2, E4-3). , E4-4, E4-5, E4-6), of which the E4-1 fraction was subjected to reverse phase HPLC with a solvent composition of distilled water: acetonitrile (60:40 → 45:55, v / v) Compound 12 (15 mg) (Formula 12), Compound 13 (18.5 mg) (Formula 13), and Compound 14 (1.5 mg) (Formula 14) were obtained.
E5 분획을 증류수:메탄올 (80:20 → 0:100, v/v)의 용매 조성으로 역상 HPLC을 수행하여 화합물 1 (2.4 mg)(화학식 1), 화합물 5 (2.9 mg)(화학식 5), 화합물 6 (1.7 mg)(화학식 6), 화합물 7 (1.8 mg)(화학식 7), 화합물 8 (5.6 mg)(화학식 8), 화합물 9 (7.3 mg)(화학식 9), 화합물 10 (4.1 mg)(화학식 10)을 얻었다.The E5 fraction was subjected to reverse phase HPLC with a solvent composition of distilled water: methanol (80:20 → 0: 100, v / v) to give Compound 1 (2.4 mg) (Formula 1), Compound 5 (2.9 mg) (Formula 5), Compound 6 (1.7 mg) (Formula 6), Compound 7 (1.8 mg) (Formula 7), Compound 8 (5.6 mg) (Formula 8), Compound 9 (7.3 mg) (Formula 9), Compound 10 (4.1 mg) (Formula 10) was obtained.
E6 분획을 증류수:메탄올 (95:5 → 50:50, v/v)의 용매 조성으로 역상 HPLC를 수행하여 화합물 3 (13 mg)(화학식 3), 화합물 4 (6.5 mg)(화학식 4), 화합물 11 (2.9 mg)(화학식 11)을 얻었다.The E6 fraction was subjected to reverse phase HPLC with a solvent composition of distilled water: methanol (95: 5 to 50:50, v / v) to give Compound 3 (13 mg) (Formula 3), Compound 4 (6.5 mg) (Formula 4), Compound 11 (2.9 mg) was obtained.
화합물 1 내지 14를 확인하기 위해 분광분석을 실시하였다. 구체적으로, 1H NMR 스페트럼(spectrum) 분석, 13C NMR 스펙트럼(spectrum) 분석 및 HR-ESI-MS 스펙트럼(spectrum)을 분석을 하였다. 도 3 내지 33은 화합물 1 내지 14에 대한 분광분석 그래프이다.Spectroscopic analysis was performed to identify
구체적으로, 도 3은 화합물 1에 대한 1H NMR 스페트럼(spectrum)이고, 도 4는 화합물 1에 대한 13C NMR 스펙트럼(spectrum)이고, 도 5는 화합물 1에 대한 HR-ESI-MS 스펙트럼(spectrum)이다.Specifically, FIG. 3 is a 1 H NMR spectrum for
도 6은 화합물 2에 대한 1H NMR 스페트럼(spectrum)이고, 도 7은 화합물 2에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 6 is the 1 H NMR spectrum for
도 8은 화합물 3에 대한 1H NMR 스페트럼(spectrum)이고, 도 9는 화합물 3에 대한 13C NMR 스펙트럼(spectrum)이고, 도 10은 화합물 3에 대한 HR-ESI-MS 스펙트럼(spectrum)이다.FIG. 8 is the 1 H NMR spectrum for Compound 3, FIG. 9 is the 13 C NMR spectrum for Compound 3, FIG. 10 is the HR-ESI-MS spectrum for Compound 3 .
도 11은 화합물 4에 대한 1H NMR 스페트럼(spectrum)이고, 도 12는 화합물 4에 대한 13C NMR 스펙트럼(spectrum)이고, 도 13은 화합물 4에 대한 HR-ESI-MS 스펙트럼(spectrum)이다.FIG. 11 is the 1 H NMR spectrum for Compound 4, FIG. 12 is the 13 C NMR spectrum for Compound 4, FIG. 13 is the HR-ESI-MS spectrum for Compound 4 .
도 14는 화합물 5에 대한 1H NMR 스페트럼(spectrum)이고, 도 15는 화합물 5에 대한 13C NMR 스펙트럼(spectrum)이고, 도 16은 화합물 5에 대한 HR-ESI-MS 스펙트럼(spectrum)이다.FIG. 14 is the 1 H NMR spectrum for Compound 5, FIG. 15 is the 13 C NMR spectrum for Compound 5, FIG. 16 is the HR-ESI-MS spectrum for Compound 5 .
도 17은 화합물 6에 대한 1H NMR 스페트럼(spectrum)이고, 도 18은 화합물 6에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 17 is the 1 H NMR spectrum for Compound 6, and FIG. 18 is the 13 C NMR spectrum for Compound 6. FIG.
도 19는 화합물 7에 대한 1H NMR 스페트럼(spectrum)이고, 도 20은 화합물 7에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 19 is the 1 H NMR spectrum for Compound 7, FIG. 20 is the 13 C NMR spectrum for Compound 7. FIG.
도 21은 화합물 8에 대한 1H NMR 스페트럼(spectrum)이고, 도 22는 화합물 8에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 21 is the 1 H NMR spectrum for
도 23은 화합물 9에 대한 1H NMR 스페트럼(spectrum)이고, 도 24는 화합물 9에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 23 is the 1 H NMR spectrum for
도 25은 화합물 10에 대한 1H NMR 스페트럼(spectrum)이고, 도 26은 화합물 10에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 25 is the 1 H NMR spectrum for
도 27은 화합물 11에 대한 1H NMR 스페트럼(spectrum)이고, 도 28는 화합물 11에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 27 is the 1 H NMR spectrum for
도 29는 화합물 12에 대한 1H NMR 스페트럼(spectrum)이다.FIG. 29 is a 1 H NMR spectrum for Compound 12.
도 30은 화합물 13에 대한 1H NMR 스페트럼(spectrum)이고, 도 31은 화합물 13에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 30 is the 1 H NMR spectrum for Compound 13, and FIG. 31 is the 13 C NMR spectrum for Compound 13.
도 32는 화합물 14에 대한 1H NMR 스페트럼(spectrum)이고, 도 33은 화합물 14에 대한 13C NMR 스펙트럼(spectrum)이다.FIG. 32 is the 1 H NMR spectrum for Compound 14, and FIG. 33 is the 13 C NMR spectrum for Compound 14.
분광분석 결과, 화합물 1 내지 14는 각각 상기 설명한 화학식 1 내지 14로 표현되는 화합물임을 확인하였다.즉, 화합물 1은 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside)이다.As a result of spectroscopy, it was confirmed that
[화학식 1][Formula 1]
여기서 R은 리보스(ribose)이다.Where R is ribose.
화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드는, 구체적으로, 하기 화학식 1a로 표현되는 구조식을 가질 수 있다.2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by
[화학식 1a][Formula 1a]
화합물 2는 하기 화학식 2로 표현되는 2,4-디하이드록시-3-메톡시-6-메틸벤조에이트 (2,4-dihydroxy-3-methoxy-6-methylbenzoate)이다
[화학식 2][Formula 2]
화합물 3은 하기 화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드(5-methoxy-phthalide 7-O-α-D-riboside)이다.Compound 3 is 5-methoxy-phthalide 7-O-α-D-riboside represented by the following Chemical Formula 3 (5-methoxy-phthalide 7-O-α-D-riboside).
[화학식 3][Formula 3]
화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드는, 구체적으로 하기 화학식 3a로 표현되는 구조식을 가질 수 있다.5-methoxy-phthalide 7-O-α-D-riboside represented by Formula 3 may specifically have a structural formula represented by Formula 3a.
[화학식 3a][Formula 3a]
화합물 4는 하기 화학식 4로 표현되는 6-메톡시-4,5,7-트리히드록시 프탈라이드(6-methoxy-4,5,7-trihydroxy phthalide)이다.Compound 4 is 6-methoxy-4,5,7-trihydroxy phthalide represented by Formula 4 below.
[화학식 4][Formula 4]
화합물 5는 하기 화학식 5로 표현되는 5,6-디히드록시-7-메톡시프탈라이드(5,6-dihydroxy-7-methoxy phthalide)이다.Compound 5 is 5,6-dihydroxy-7-methoxy phthalide represented by the following formula (5).
[화학식 5][Formula 5]
화합물 6은 하기 화학식 6으로 표현되는 5-히드록시-7-메톡시프탈라이드(5-hydroxy-7-methoxyphthalide)이다.Compound 6 is 5-hydroxy-7-methoxyphthalide represented by Chemical Formula 6.
[화학식 6][Formula 6]
화합물 7은 하기 화학식 7로 표현되는 5-메톡시-7-히드록시프탈라이드(5-methoxy-7-hydroxyphthalide)이다.Compound 7 is 5-methoxy-7-hydroxyphthalide represented by Chemical Formula 7 below.
[화학식 7][Formula 7]
화합물 8은 하기 화학식 8로 표현되는 하나비라타켈리드 A(hanabiratakelide A)이다
[화학식 8][Formula 8]
화합물 9는 하기 화학식 9로 표현되는 니코틴아미드(nicotinamide)이다.
[화학식 9][Formula 9]
화합물 10은 하기 화학식 10으로 표현되는 5′-디옥시-5′-메틸티오아데노신(5′-deoxy-5′-methylthioadenosine)이다.
[화학식 10][Formula 10]
화합물 11은 하기 화학식 11로 표현되는 아데노신(adenosine)이다.
[화학식 11][Formula 11]
화합물 12는 하기 화학식 12로 표현되는 에르고스테롤(ergosterol)이다.Compound 12 is ergosterol represented by the following formula (12).
[화학식 12][Formula 12]
화합물 13 하기 화학식 13으로 표현되는 에르고스테롤 퍼옥사이드(ergosterol peroxide)이다.Compound 13 is ergosterol peroxide represented by the following formula (13).
[화학식 13][Formula 13]
화합물 14는 하기 화학식 14로 표현되는 5α,6α-에폭시-(22E,24R)-에르고스타-8(14),22-디엔-3β,7β-diol[5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7β-diol] 이다.Compound 14 is 5α, 6α-epoxy- (22E, 24R) -ergosta-8 (14), 22-diene-3β, 7β-diol [5α, 6α-epoxy- (22E, 24R) represented by Formula 14 ergosta-8 (14), 22-diene-3β, 7β-diol.
[화학식 14][Formula 14]
<시험예> 인간 PCSK9 mRNA 발현 평가Test Example Evaluation of Human PCSK9 mRNA Expression
(1) HepG2 세포 배양(1) HepG2 cell culture
인간 간세포주(HepG2)를 한국생명공학연구원(Korea Research Institute of Bioscience and Biotechnology)에서 입수하였으며, 10 % 우태아혈청(Fetal Bovine Serum, FBS) 및 100 U/ml 페니실린/황산 스트렙토마이신이 첨가된 Eagle's Minimum Essential Medium 배지(EMEM)에서 배양하였다. 구체적으로 세포는 37℃, 5 % CO2 조건에서 배양되었다.HepG2 was obtained from Korea Research Institute of Bioscience and Biotechnology, Eagle's with 10% Fetal Bovine Serum (FBS) and 100 U / ml penicillin / sulfate streptomycin. Incubated in Minimum Essential Medium medium (EMEM). Specifically, cells were cultured at 37 ° C., 5% CO 2 .
이와 같이 배양된 세포를 24웰(well) 플레이트에 분주하여(1×105cells/ 500 ㎕ well)를 분주하여 실험을 하였다. The cultured cells were dispensed into 24 well plates (1 × 10 5 cells / 500 μl wells) and the experiment was performed.
먼저, 분주된 세포에 실시예 1 내지 5에서 제조된 추출물을 10㎍/㎖ 농도로 처리하여 PCSK9 유전자의 발현을 평가하였다.First, the expression of PCSK9 gene was evaluated by treating the extract prepared in Examples 1 to 5 at a concentration of 10 μg / ml.
또한, 화합물 1 내지 14를 20μM의 농도로 분주된 세포에 처리하여 PCSK9 유전자의 발현을 평가하였다. In addition, compounds 1 to 14 were treated with the cells divided at a concentration of 20 μM to evaluate the expression of the PCSK9 gene.
한편, 분주된 세포에 베르베린(Berberine)를 20μM의 농도로 처리하여 양성 대조군을 제조하였다. 베르베린(Berberine)은 기존의 동물실험과 세포실험에서 HNF1α 을 매개하는 PCSK9 유전자 전사 활성활성을 억제한다고 보고되어 있다. 이러한 효과는 ubiquitin 단백질 분해효소 경로를 막음으로써, PCSK9-LDL-R 상호작용을 억제하고 LDL-R의 감소를 막는 효과를 가지게 된다고 보고되어 있다.On the other hand, the treated cells were treated with berberine (Berberine) at a concentration of 20 μM to prepare a positive control. Berberine has been reported to inhibit HSK1 gene-mediated PCSK9 gene transcriptional activity in animal and cell experiments. These effects have been reported to block the ubiquitin protease pathway, thereby inhibiting PCSK9-LDL-R interactions and preventing the reduction of LDL-R.
또한, 분주된 세포에 아무것도 투여하지 않을 것을 음성 대조군으로 하였다.In addition, nothing was administered to the divided cells as a negative control.
(2) RNA 추출 및 정량적 역전사-폴리머라제 연쇄 반응 (Quantitative Reverse Transcription-Polymerase Chain Reaction, qRT-PCR) 분석(2) RNA Extraction and Quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) Analysis
총(total) RNA 분리, cDNA 합성 및 정량적 실시간(quantitative real-time) PCR을 문헌에 기재된 방법대로 수행하였다(Chae et al., Biological and Pharmaceutical Bulletin, 39, pp.259-266, 2016).Total RNA isolation, cDNA synthesis and quantitative real-time PCR were performed as described in the literature (Chae et al., Biological and Pharmaceutical Bulletin, 39, pp. 259-266, 2016).
구체적으로, TRIzolㄾ RNA 추출 키트(미국, Invitrogen, Life Technologies)를 사용하여 매뉴얼에 따라 전체 세포 RNA를 분리하였다. 효소(M-MLV Reverse Transcriptase, M170B, Promega, WI)를 이용하여 1차 가닥(first strand) cDNA를 합성하였다. CFX384 Real-Time PCR Detection System (Bio-Rad Laboratories, Hercules, CA) 및 2 iQ SYBR Green Supermix (Bio-Rad Laboratories, Hercules, CA)를 이용하여 매뉴얼에 따라 정량적 PCR 증폭(amplification)과 분석을 수행하였다. 증폭조건은, 95 ℃에서 3 분간 변성시킨 후 첫 주기에서 30 초 추가하였고, PCSK9와 GAPDH의 annealing 조건은 55 ℃에서 30초, 40회 반복되도록 하였다. PCSK9 프라이머로 5'- GGTACTGACCCCCAACCTG-3'(센스, 서열번호 1) 및 5'- CCGAGTGTGCTGACCATACA-3'(안티센스, 서열번호 2)를 사용하였고, GAPDH 프라이머로 5'- GAAGGTGAAGGTCGGAGTCA-3'(센스, 서열번호 3) 및 5'- AATGAAGGGGTCATTGATGG-3' (안티센스, 서열번호4)를 사용하였다. PCSK9 및 GAPDH 올리고뉴클레오티드(oligonucleotide) 프라이머는 Bioneer Corp.(Deajeon, Korea)에서 구입하였다.Specifically, total cell RNA was isolated according to the manual using TRIzol® RNA extraction kit (Invitrogen, Life Technologies, USA). First strand cDNA was synthesized using an enzyme (M-MLV Reverse Transcriptase, M170B, Promega, WI). Quantitative PCR amplification and analysis were performed according to the manual using CFX384 Real-Time PCR Detection System (Bio-Rad Laboratories, Hercules, CA) and 2 iQ SYBR Green Supermix (Bio-Rad Laboratories, Hercules, CA). . The amplification conditions were denatured at 95 ° C. for 3 minutes, and then 30 seconds were added in the first cycle. 5'- GGTACTGACCCCCAACCTG-3 '(sense, SEQ ID NO: 1) and 5'- CCGAGTGTGCTGACCATACA-3' (antisense, SEQ ID NO: 2) were used as PCSK9 primers and 5'-GAAGGTGAAGGTCGGAGTCA-3 '(sense, sequence) as GAPDH primers. No. 3) and 5′-AATGAAGGGGTCATTGATGG-3 ′ (antisense, SEQ ID NO: 4) were used. PCSK9 and GAPDH oligonucleotide primers were purchased from Bioneer Corp. (Deajeon, Korea).
이와 같이 측정된 PCSK9 mRNA의 상대적인 발현량은 도 1 및 2에 도시되었다.The relative expression levels of the PCSK9 mRNA thus measured are shown in FIGS. 1 and 2.
도 1은 꽃송이버섯의 메탄올 추출물(실시예 1)의 처리 및 메탄올 추출물(실시예 1)의 분획물(실시예 2-5)의 처리에 의한 PCSK9 mRNA의 상대적인 발현량을 나타내는 그래프이다. 1 is a graph showing the relative expression level of PCSK9 mRNA by the treatment of the methanol extract (Example 1) and the fraction (Example 2-5) of the methanol extract (Example 1).
도 1을 참조하면, 꽃송이버섯(Sparassis crispa)을 메탄올로 추출하여 얻어진 조추출물(crude extract)인 메탄올 추출물(실시예 1)로 처리된 시료에서 우수한 활성이 나타났음을 확인할 수 있다. 이와 같이, 꽃송이버섯(Sparassis crispa)의 메탄올 추출물(실시예 1)은 PCSK9 mRNA 발현에 대해 우수한 억제 효과를 가진다.Referring to FIG. 1, it can be seen that excellent activity was observed in a sample treated with methanol extract (Example 1), which is a crude extract obtained by extracting the flower of Sparassis crispa with methanol. As such, the methanol extract of Sparassis crispa (Example 1) has an excellent inhibitory effect on PCSK9 mRNA expression.
또한, 도 1을 참조하면, 메탄올 추출물(실시예 1)로부터 분획된 분획물들 중 헥산 분획물(실시예 2) 및 에틸 아세테이트 분획물(실시예 4)에서 강한 활성이 나타났음을 확인할 수 있다. 즉, 헥산 분획물(실시예 2)과 에틸 아세테이트 분획물(실시예 4)이 PCSK9 mRNA 발현에 대해 우수한 억제 효과를 가짐을 확인할 수 있다.In addition, referring to Figure 1, it can be seen that the strong activity was shown in the hexane fraction (Example 2) and ethyl acetate fraction (Example 4) of the fractions fractionated from the methanol extract (Example 1). That is, it can be seen that the hexane fraction (Example 2) and ethyl acetate fraction (Example 4) have an excellent inhibitory effect on PCSK9 mRNA expression.
다른 분획물인 메틸렌클로라이드 분획물(2.7g)(실시예 3) 및 부탄올 분획물 (15.0g)(실시예 5)에서도 양호한 활성이 나타났음을 확인할 수 있다. The other fractions methylene chloride fraction (2.7 g) (Example 3) and butanol fraction (15.0 g) (Example 5) can also be seen that good activity appeared.
또한, 실시예 4인 에틸아세데이트 분획물로부터 유래된 화학식 1 내지 14로 표현되는 화합물들(화합물 1-14)의 PCSK9 mRNA 발현에 대한 영향을 평가한 결과는 도 2에 도시되어 있다. In addition, the results of evaluating the effect on the PCSK9 mRNA expression of the compounds represented by
구체적으로, 도 2는 화합물 1 내지 14 및 대조군 처리에 의한 PCSK9 mRNA의 상대적인 발현량을 나타내는 그래프이다. 도 2를 참조하면, 특히 화합물 1, 8, 11, 14이 PCSK9 mRNA 발현에 대한 우수한 억제 효과를 가짐을 확인할 수 있다.Specifically, Figure 2 is a graph showing the relative expression of PCSK9 mRNA by the
또한, 농도에 따른 PCSK9 mRNA 발현 저해 활성을 측정한 결과, 화합물 1, 8, 11 및 14의 IC50(half maximal inhibitory concentration)는 각각 8.23, 7.18, 20.07 및 18.46 μM로, 강한 저해활성을 나타냈다. 이 때 양성 대조군으로 사용된 베르베린(berberine)의 IC50는 8.04 μM로, 화합물 1과 화합물 8은 양성 대조군과 유사하거나 양성 대조군보다 더 강한 활성을 나타냄을 확인하였다.In addition, as a result of measuring the inhibitory activity of PCSK9 mRNA expression according to the concentration, the IC 50 (half maximal inhibitory concentration) of
이와 같이, 꽃송이버섯(Sparassis crispa) 추출물 및 그 분획물들은 간에서 저밀도지단백질 수용체(LDL-R)의 분해를 촉진하는 PCSK9 mRNA의 발현에 대하여 우수한 저해 활성을 가진다. 따라서, 꽃송이버섯(Sparassis crispa) 추출물과 그 분획물들은 이상지질혈증 환자의 저밀도지단백질(LDL)을 조절하는 이상지질혈증 관련 질환 예방 또는 치료용 조성물로 사용될 수 있다.As such, the extract of Sparassis crispa and its fractions have excellent inhibitory activity against the expression of PCSK9 mRNA which promotes the degradation of low density lipoprotein receptor (LDL-R) in the liver. Therefore, the extract of Sparassis crispa and its fractions can be used as a composition for preventing or treating dyslipidemia-related diseases that control low density lipoprotein (LDL) in patients with dyslipidemia.
즉, 꽃송이버섯 추출물과 그 분획물들은 PCSK9 유전자의 발현을 억제하는 이상지질혈증 관련 질환 예방 또는 치료용 조성물에 사용될 수 있다. 또한, 꽃송이버섯 추출물과 그 분획물들은 LDL-수용체(LDL-R)의 발현을 증가시키는 이상지질혈증 관련 질환 예방 또는 치료용 조성물로 사용될 수 있다.That is, the mushroom extract and its fractions may be used in a composition for preventing or treating dyslipidemia-related diseases that inhibit the expression of the PCSK9 gene. In addition, the mushroom extract and its fractions may be used as a composition for preventing or treating dyslipidemia-related diseases that increase the expression of LDL-receptor (LDL-R).
본 발명의 일 실시예에 따른 꽃송이버섯 추출물은, 특히 PCSK9 mRNA의 발현을 억제에 탁월한 효능을 갖는, 화학식 1로 표현된 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside)(화합물 1), 화학식 8로 표현되는 하나비라타켈리드 A(hanabiratakelide A)(화합물 8), 화학식 11로 표현되는 아데노신(adenosine)(화합물 11) 및 화학식 14로 표현되는 5α,6α-에폭시-(22E,24R)-에르고스타-8(14),22-디엔-3β,7β-diol[5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7β-diol](화합물 14) 중 적어도 하나를 포함할 수 있다. Blossom mushroom extract according to an embodiment of the present invention, in particular, having an excellent efficacy in inhibiting the expression of PCSK9 mRNA, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O -α-D-riboside (2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside) (Compound 1), hanaviratakelide A represented by the formula (8) hanabiratakelide A) (compound 8), adenosine (compound 11) represented by
본 발명의 다른 일 실시예는, 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside)(화합물 1), 화학식 8로 표현되는 하나비라타켈리드 A(hanabiratakelide A)(화합물 8), 화학식 11로 표현되는 아데노신(adenosine)(화합물 11) 및 화학식 14로 표현되는 5α,6α-에폭시-(22E,24R)-에르고스타-8(14),22-디엔-3β,7β-diol[5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7β-diol](화합물 14) 중 적어도 하나를 포함하는 이상지질혈증 관련 질환 예방 또는 치료용 조성물을 제공한다.Another embodiment of the present invention, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by Formula 1 (2-hydroxy-3-methoxy-6 -methyl benzoic acid methyl ester 4-O-α-D-riboside (Compound 1), Hanabiratakelide A (Compound 8) represented by
본 발명의 또 다른 일 실시예는 신규 화합물을 제공한다.Another embodiment of the present invention provides a novel compound.
구체적으로, 본 발명의 또 다른 일 실시예는, 하기 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside)를 제공한다.Specifically, another embodiment of the present invention, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by the following formula (1) (2-hydroxy- 3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside).
[화학식 1][Formula 1]
여기서, R은 리보스(ribose)이다.Where R is ribose.
화학식 1로 표현되는, 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드는 꽃송이버섯으로부터 추출될 수 있다.2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside, represented by the formula (1), may be extracted from the flower mushroom.
또한, 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드는, 예를 들어, 하기 화학식 1a로 표현될 수도 있다.In addition, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside may be, for example, represented by the following general formula (1a).
[화학식 1a][Formula 1a]
본 발명의 또 다른 일 실시예는, 하기 화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드(5-methoxy-phthalide 7-O-α-D-riboside)를 제공한다.Another embodiment of the present invention, 5-methoxy-phthalide 7-O-α-D-riboside represented by the following formula 3 (5-methoxy-phthalide 7-O-α-D-riboside) to provide.
[화학식 3][Formula 3]
여기서, R1과 R3는 수소(H)이고, R2는 메틸기(CH3)이고, R4는 O-리보스(O-ribose)이다.Wherein R 1 and R 3 are hydrogen (H), R 2 is a methyl group (CH 3), and R 4 is O-ribose.
화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드는 꽃송이버섯으로부터 추출될 수 있다. 5-methoxy-phthalide 7-O-α-D-riboside represented by the formula (3) can be extracted from the flower mushroom.
5-메톡시-프탈라이드 7-O-α-D-리보시드는, 예를 들어 하기 화학식 3a로 표현될 수도 있다.5-methoxy-phthalide 7-O-α-D-riboside may be represented, for example, by the following formula (3a).
[화학식 3a][Formula 3a]
본 발명의 또 다른 일 실시예는, 하기 화학식 4로 표현되는 6-메톡시-4,5,7-트리히드록시 프탈라이드(6-methoxy-4,5,7-trihydroxy phthalide)를 제공한다.Another embodiment of the present invention provides 6-methoxy-4,5,7-trihydroxy phthalide represented by the following Chemical Formula 4 (6-methoxy-4,5,7-trihydroxy phthalide).
[화학식 4][Formula 4]
화학식 4로 표현되는 6-메톡시-4,5,7-트리히드록시 프탈라이드는 꽃송이버섯으로부터 추출될 수 있다.6-methoxy-4,5,7-trihydroxy phthalide represented by the formula (4) can be extracted from the flower mushroom.
본 발명의 또 다른 일 실시예는, 하기 화학식 5로 표현되는 5,6-디하이드록시-7-메톡시프탈라이드(5,6-dihydroxy-7-methoxy phthalide)를 제공한다.Another embodiment of the present invention provides 5,6-dihydroxy-7-methoxy phthalide represented by the following Chemical Formula 5.
[화학식 5] [Formula 5]
화학식 5로 표현되는 5,6-디하이드록시-7-메톡시프탈라이드는 꽃송이버섯으로부터 추출될 수 있다.5,6-dihydroxy-7-methoxyphthalide represented by Chemical Formula 5 may be extracted from the flower mushroom.
도 2를 참조하면, 화학식 1로 표현되는 화합물 뿐만 아니라 화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드(5-methoxy-phthalide 7-O-α-D-riboside), 화학식 4로 표현되는 6-메톡시-4,5,7-트리히드록시 프탈라이드(6-methoxy-4,5,7-trihydroxy phthalide) 및 화학식 5로 표현되는 5,6-디하이드록시-7-메톡시프탈라이드(5,6-dihydroxy-7-methoxy phthalide)도 역시 PCSK9 mRNA 발현에 대한 우수한 억제 효과를 가짐을 확인할 수 있다. 즉, 이들의 단독 또는 혼합물은 PCSK9 mRNA 발현에 대하여 우수한 저해 활성을 가진다.2, not only the compound represented by the formula (1) but also 5-methoxy-phthalide 7-O-α-D-riboside represented by the formula (5-methoxy-phthalide 7-O-α-D- riboside), 6-methoxy-4,5,7-trihydroxy phthalide represented by formula 4 and 5,6-dihydride represented by formula 5 Roxy-7-methoxyphthalide (5,6-dihydroxy-7-methoxy phthalide) also can be confirmed that has an excellent inhibitory effect on the expression of PCSK9 mRNA. In other words, these alone or in combination have excellent inhibitory activity on PCSK9 mRNA expression.
따라서, 각각 화학식 1, 3, 4 및 5로 표현되는 화합물들은 단독으로 또는 서로 혼합되어 이상지질혈증 환자의 저밀도지단백질(LDL)을 조절하는 이상지질혈증 관련 질환 예방 또는 치료용 조성물로 사용될 수 있다.Therefore, the compounds represented by
따라서, 발명의 또 다른 일 실시예는, 화학식 1로 표현되는 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside), 화학식 3으로 표현되는 5-메톡시-프탈라이드 7-O-α-D-리보시드(5-methoxy-phthalide 7-O-α-D-riboside), 화학식 4로 표현되는 6-메톡시-4,5,7-트리히드록시 프탈라이드(6-methoxy-4,5,7-trihydroxy phthalide) 및 화학식 5로 표현되는 5,6-디하이드록시-7-메톡시프탈라이드(5,6-dihydroxy-7-methoxy phthalide) 중에서 선택된 적어도 하나를 포함하는, 이상지질혈증 관련 질환 예방 또는 치료용 조성물을 제공한다.Thus, another embodiment of the invention, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by the formula (1) (2-hydroxy-3-methoxy -6-methyl benzoic acid methyl ester 4-O-α-D-riboside), 5-methoxy-phthalide 7-O-α-D-riboside represented by Chemical Formula 3 (5-methoxy-phthalide 7-O -α-D-riboside), 6-methoxy-4,5,7-trihydroxy phthalide represented by formula 4 and 5 represented by formula 5 It provides a composition for the prevention or treatment of dyslipidemia-related diseases comprising at least one selected from 5,6-dihydroxy-7-methoxy phthalide.
이러한, 2-히드록시-3-메톡시-6-메틸 벤조산 메틸 에스테르 4-O-α-D-리보시드(화학식 1), 5-메톡시-프탈라이드 7-O-α-D-리보시드(화학식 3), 6-메톡시-4,5,7-트리히드록시 프탈라이드(화학식 4) 및 5,6-디하이드록시-7-메톡시프탈라이드(화학식 5)는 꽃송이버섯으로부터 추출될 수 있다.Such, 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside (Formula 1), 5-methoxy-phthalide 7-O-α-D-riboside 6-methoxy-4,5,7-trihydroxy phthalide (Formula 4) and 5,6-dihydroxy-7-methoxyphthalide (Formula 5) can be extracted from the mushroom Can be.
Claims (6)
[화학식 1]
[화학식 3]
[화학식 4]
[화학식 5]
상기 화학식 1에서 R은 리보스(ribose)이고,
상기 화학식 3에서, R1과 R3는 수소(H)이고, R2는 메틸기(CH3)이고, R4는 O-리보스(O-ribose)이다.2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by the following formula (1): 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4- O-α-D-riboside); 5-methoxy-phthalide 7-O-α-D-riboside represented by Chemical Formula 3 (5-methoxy-phthalide 7-O-α-D-riboside); 6-methoxy-4,5,7-trihydroxy phthalide represented by the following formula (4): 6-methoxy-4,5,7-trihydroxy phthalide; And 5,6-dihydroxy-7-methoxy phthalide represented by Chemical Formula 5; At least one selected from, hypercholesterolemia prevention or treatment composition.
[Formula 1]
[Formula 3]
[Formula 4]
[Formula 5]
R in Formula 1 is ribose (ribose),
In Formula 3, R 1 and R 3 are hydrogen (H), R 2 is a methyl group (CH3), R 4 is O-ribose (O-ribose).
[화학식 1]
여기서, R은 리보스(ribose)이다.2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by the following formula (1): 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4- O-α-D-riboside).
[Formula 1]
Where R is ribose.
[화학식 3]
여기서, R1과 R3는 수소(H)이고, R2는 메틸기(CH3)이고, R4는 O-리보스(O-ribose)이다.5-methoxy-phthalide 7-O-α-D-riboside represented by the following formula (3): 5-methoxy-phthalide 7-O-α-D-riboside.
[Formula 3]
Wherein R 1 and R 3 are hydrogen (H), R 2 is a methyl group (CH 3), and R 4 is O-ribose.
[화학식 4]
[Formula 4]
[화학식 5]
[Formula 5]
[화학식 1]
[화학식 3]
[화학식 4]
[화학식 5]
상기 화학식 1에서 R은 리보스(ribose)이고,
상기 화학식 3에서, R1과 R3는 수소(H)이고, R2는 메틸기(CH3)이고, R4는 O-리보스(O-ribose)이다.2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4-O-α-D-riboside represented by the following formula (1): 2-hydroxy-3-methoxy-6-methyl benzoic acid methyl ester 4- O-α-D-riboside); 5-methoxy-phthalide 7-O-α-D-riboside represented by Chemical Formula 3 (5-methoxy-phthalide 7-O-α-D-riboside); 6-methoxy-4,5,7-trihydroxy phthalide represented by the following formula (4): 6-methoxy-4,5,7-trihydroxy phthalide; And 5,6-dihydroxy-7-methoxy phthalide represented by Chemical Formula 5; Dietary supplement comprising at least one selected from
[Formula 1]
[Formula 3]
[Formula 4]
[Formula 5]
R in Formula 1 is ribose (ribose),
In Formula 3, R 1 and R 3 are hydrogen (H), R 2 is a methyl group (CH3), R 4 is O-ribose (O-ribose).
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