KR20130104103A - Composition comprising extract of myristica fragrans or lignan compounds isolated therefrom for treating or preventing vascular diseases - Google Patents
Composition comprising extract of myristica fragrans or lignan compounds isolated therefrom for treating or preventing vascular diseases Download PDFInfo
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- KR20130104103A KR20130104103A KR1020120025291A KR20120025291A KR20130104103A KR 20130104103 A KR20130104103 A KR 20130104103A KR 1020120025291 A KR1020120025291 A KR 1020120025291A KR 20120025291 A KR20120025291 A KR 20120025291A KR 20130104103 A KR20130104103 A KR 20130104103A
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- KR
- South Korea
- Prior art keywords
- nectandrin
- vascular
- extract
- nutmeg
- pharmaceutical composition
- Prior art date
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Abstract
Description
본 발명은 육두구(Myristica fragrans) 추출물 또는 이로부터 분리된 리그난계 화합물을 함유하는 혈관 질환의 예방 또는 치료용 조성물에 관한 것으로서, 더욱 자세하게는, 육두구 10~30% 에탄올 수용액 추출물 또는 이로부터 분리된 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물(2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compounds)을 유효성분으로 함유하는 혈관 질환의 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a nutritional supplement ( Myristica fragrans ) extract or a composition for the prevention or treatment of vascular diseases containing a lignan-based compound isolated therefrom, and more specifically, 10-30% aqueous ethanol extract or 2,5-bis-aryl separated therefrom It relates to a composition for the prevention or treatment of vascular diseases containing -3,4-dimethyltetrahydrofuran lignan compounds (2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compounds) as an active ingredient.
현대 사회에서 혈관 질환은 심각한 사회적 문제로 대두되고 있다. 상기 혈관 질환으로는 동맥경화증, 고혈압, 협심증, 심근경색, 허혈성 심장질환, 심부전, 경혈관 동맥 성형술 후 발생하는 합병증, 뇌경색, 뇌출혈, 및, 뇌졸중 등이 있다. 2010년 통계청에서 발표한 사망원인 통계를 보면, 고혈압성 질환, 허혈성 심장 질환, 뇌혈관 질환을 포함한 혈관 질환은 우리나라 사망원인의 2위로서, 악성 종양 다음으로 높은 순위를 차지하고 있으며, 남성은 55세 이상, 여성은 65세 이상에서 혈관 질환의 사망률이 크게 증가한다. 특히 동맥경화증과 관련된 위험인자는 연령, 성별, 고혈압, 고지혈증, 당뇨병, 흡연, 운동 부족과 비만이다. 혈관 질환 환자들은 이를 치료하기 위해 지속적인 약물을 투여받지만 현대 의학에서 완치가 되기는 쉽지 않다. 또 약물을 오래 투여하다가 보면 그에 대한 부작용도 크다. In modern society, vascular disease is becoming a serious social problem. Examples of the vascular diseases include arteriosclerosis, hypertension, angina pectoris, myocardial infarction, ischemic heart disease, heart failure, complications arising after pericardial artery arteriography, cerebral infarction, cerebral hemorrhage, and stroke. According to the statistics released by the National Statistical Office in 2010, vascular diseases including hypertensive diseases, ischemic heart diseases and cerebrovascular diseases are the second leading cause of death in Korea, followed by malignant tumors, Or more, the mortality rate of vascular disease is greatly increased in women over 65 years of age. In particular, risk factors associated with atherosclerosis are age, sex, hypertension, hyperlipidemia, diabetes, smoking, lack of exercise and obesity. Patients with vascular disease receive continuous medication to treat it, but it is not easy to cure it in modern medicine. If you take the medicine for a long time, the side effect is big.
상기 혈관 질환 중에서도, 동맥경화증(atherosclerosis)은 주로 유전적 변이, 고콜레스테롤혈증, 호모시스틴뇨증(homocystinemia), 당뇨 등의 대사성 손상, 와류, 고혈압 등의 물리적 손상, 또는 심장, 신장 이식 후의 면역학적 손상 등의 지속 또는 반복되는 스트레스에 의하여 혈관 내피 세포가 정상적인 항상성을 유지하지 못하는 기능 이상 상태에서 기인되는 것으로 알려져 있다. 또한 혈관 내피 세포의 부착 물질(adhesion molecule)의 발현이 현저히 증가하고, 세포 투과성이 증가되어 단핵구 등의 혈중 면역 세포, 혈소판, 지방질 등의 부착성 및 조직으로의 투과성이 증가되며, 이들 면역 세포들에 의한 염증매개인자 및 성장인자의 분비 등의 염증반응으로 동맥경화성 병변이 발생하는 것으로 알려져 있다. 예를 들어, 혈중 저밀도지단백(low density lipoprotein, LDL)이 내피를 통하여 산화 및 당결합 등을 거쳐 변형-LDL으로 변화하게 되고, 이들은 혈관 내피 세포 및 평활근을 자극하고 손상을 유발하게 된다. 게다가 VCAM-1, ICAM-1을 포함하는 부착물질 발현으로 인해 LDL의 내피 세포 내 유입/축적이 촉진되고, 산화 LDL이 대식세포 등의 유입 및 거품 세포(foam cell)로의 활성화를 유발하는 과정을 되풀이하여 염증반응을 촉진하게 된다.Among the vascular diseases, atherosclerosis is mainly due to genetic variation, hypercholesterolemia, homocystinemia, metabolic damage such as diabetes, physical damage such as vortex, hypertension, or immunological damage after heart and kidney transplantation. It is known that vascular endothelial cells are caused by dysfunctional states that do not maintain normal homeostasis due to constant or repeated stress. In addition, the expression of adhesion molecules of vascular endothelial cells is significantly increased, and cell permeability is increased to increase adhesion of blood immune cells such as monocytes, platelets and lipids, and permeability to tissues. Atherosclerotic lesions are known to occur due to inflammatory reactions such as secretion of inflammation mediators and growth factors. For example, low density lipoprotein (LDL) in the blood is transformed into modified-LDL through oxidation and glycosylation through the endothelium, which stimulates and damages vascular endothelial cells and smooth muscle. In addition, the expression of adherents including VCAM-1 and ICAM-1 promotes the influx / accumulation of LDL into endothelial cells, and the process of oxidative LDL inducing macrophages and the like and activation of foam cells. Repeatedly promotes the inflammatory response.
또한, 상기 혈관 질환 중의 하나인, 혈관 내벽 비후화(intimal hyperplasia, neointima) 현상은 스텐트 시술 및 풍선조형술 후 발생하는 혈관 재협착의 1차 원인으로 알려져 있다. 이는 내벽(intima) 부위의 혈관 평활근 세포의 과다증식 및 중벽(media) 부위의 평활근 세포 이동능의 증가로 인해 발생한다고 한다. 혈관 내벽 비후화는 혈액의 이동경로를 좁히는 효과가 있으므로 혈액순환의 장애가 될 수 있으며, 동맥경화증의 병인으로도 알려져 있다. In addition, one of the vascular diseases, the vascular wall thickening (intimal hyperplasia, neointima) phenomenon is known as the primary cause of vascular restenosis occurring after stent surgery and balloon surgery. This is due to overproliferation of vascular smooth muscle cells in the inner wall and increased smooth muscle cell migration in the medial wall. Vascular wall thickening may be a disorder of blood circulation because it has an effect of narrowing the flow path of blood, and is also known as the cause of atherosclerosis.
한편, 혈관 내피 세포 내에 존재하는 eNOS(endothelial nitric oxide synthase)는 L-아르기닌(L-arginine)을 기질로 하여 NO(nitric oxide)를 생성시키며, 이로 인해 혈관의 이완 촉진 및 LDL 산화과정을 억제하여 동맥경화의 진행과정을 억제하는 역할을 한다. 따라서, eNOS의 활성 저하는 혈관 내피의 기능 이상의 원인 또는 대표적 병리표지인자로 작동하게 된다. 반대로, eNOS 활성을 촉진시키는 물질은 만성혈관 질환을 개선시킬 수 있는 후보약물로 이용할 수 있는데, 실제 3세대 베타 차단제(beta-blocker)인 네비볼롤(nebivolol)은 eNOS 활성화를 통하여 혈관 이완효과를 강화시키는 것으로 알려져 있다. Meanwhile, endothelial nitric oxide synthase (eNOS) present in vascular endothelial cells produces NO (nitric oxide) based on L-arginine (L-arginine), thereby promoting vascular relaxation and inhibiting LDL oxidation. It inhibits the progression of atherosclerosis. Thus, deactivation of eNOS acts as a cause or representative pathologic marker of vascular endothelial dysfunction. Conversely, a substance that promotes eNOS activity can be used as a candidate drug to improve chronic vascular disease. Nebivolol, a third-generation beta-blocker, enhances vascular relaxation through eNOS activation. It is known to make.
혈관 내피의 기능 이상은 동맥경화증을 포함하는 대부분의 혈관 질환의 핵심병인으로 작용하고 있으나, 전술한 바와 같이 다양한 병리과정이 관여하므로 이를 개선하는 치료제 개발이 미흡한 실정이다. 따라서, 혈관 내피의 기능 이상을 제어하는 후보물질의 발굴은 혈관 질환의 치료제 개발에 중요한 단서를 제시할 수 있을 것이다. Dysfunction of the vascular endothelium acts as a key cause of most vascular diseases including atherosclerosis, but as described above, various pathologies are involved and development of a therapeutic agent for improving this is insufficient. Therefore, the discovery of candidate substances that control the vascular endothelial dysfunction may suggest important clues in the development of therapeutic agents for vascular diseases.
한편, eNOS의 조절은 내피 세포 내 칼슘 축적, 조효소인 테트라하이드로바이오프테린(tetrahydrobiopterin)의 조절 등의 다양한 경로가 보고되어 있으나, 최근 가장 중요한 조절 기전으로 알려져 있는 것은 eNOS의 인산화이다. eNOS는 다양한 인산화 부위를 갖고 있으나, 이중 Ser-1177의 인산화는 에스트로겐 수용체(Circulation, 2002, 105(11), 1368~1373), PI3-kinase/Akt(Nature, 1999, 399, 601~605), MAP kinase(J. Biol. Chem., 2001, 276(50), 47642~47649) 및 AMP kinase(J. Biol. Chem., 2003, 278(34), 31629~31639) 등의 다양한 신호전달체계에 의하여 조절되며, 이는 eNOS의 활성변화에 중요한 역할을 담당하게 된다. 실제로, 여성호르몬인 에스트로겐 분비가 약화되는 폐경기 여성의 경우, 심혈관계 질환 발병 비율이 월등히 높아지는데, eNOS의 활성 저하가 주 원인이라고 할 수 있다. 따라서, eNOS 인산화에 의한 효소활성을 높이는 천연물질의 발굴은 혈관 내피의 기능 이상 및 혈액순환 개선을 위한 중요한 전략이 될 수 있다.On the other hand, the regulation of eNOS has been reported various pathways such as calcium accumulation in endothelial cells, the regulation of the coenzyme tetrahydrobiopterin (tetrahydrobiopterin), the phosphorylation of eNOS is known to be the most important regulatory mechanism recently. eNOS has various phosphorylation sites, but the phosphorylation of Ser-1177 is estrogen receptor (Circulation, 2002, 105 (11), 1368 ~ 1373), PI3-kinase / Akt (Nature, 1999, 399, 601 ~ 605), MAP kinase (J. Biol. Chem., 2001, 276 (50), 47642 ~ 47649) and AMP kinase (J. Biol. Chem., 2003, 278 (34), 31629 ~ 31639) Is regulated, and plays an important role in changing the activity of eNOS. In fact, in postmenopausal women whose female hormone estrogen secretion is weakened, the incidence of cardiovascular disease is significantly increased, which can be attributed to the decreased activity of eNOS. Therefore, the discovery of natural substances that enhance enzymatic activity by eNOS phosphorylation may be an important strategy for dysfunction of blood vessels and improvement of blood circulation.
본 발명의 대상 천연물인 육두구(Myristica fragrans)는 육두구과에 속하는 상록교목으로 수마트라나 자바에서 재배되는 자웅이주 식물이다. 과실은 난구형 육질로서 가운데에 홍색의 가종피에 둘러싸여진 종자를 포함한다. 육두구는 예로부터 소스 등 식품의 향미료로서 광범위하게 이용되어 왔고, 한방에서는 설사, 복부팽만, 구토, 식욕감퇴 등의 방향성 건위제로 사용되었다.Nutmeg ( Myristica fragrans ), a natural product of the present invention, is an evergreen tree belonging to the nutmeg family and is a herbaceous plant grown in Sumatra or Java. Fruits are egg-shaped flesh, and include seeds surrounded by a red scarlet seed coat in the center. Nutmeg has been widely used as a flavoring agent for foods such as sauces, and has been used in herbal medicine as an aromatic nutrient for diarrhea, bloating, vomiting, and loss of appetite.
그러나, 이러한 육두구의 유용성과 더불어, 많은 문헌에서 육두구를 다량 복용하게 되면 급성독성이 일어난다고 보고하고 있는데, 육두구 추출물에는 인체에 독성을 나타내는 대표적인 물질로서 아래 그림에 개시되어 있는 알킬벤젠 유도체인 미리스티신(myristicin), 엘레미신(elemicin), 샤프롤(safrole) 등이 함께 추출되는 것으로 알려져 있다. However, in addition to the usefulness of these nutmeg, many literatures report that acute toxicity occurs when a large amount of nutmeg is used. The nutmeg extract is a representative substance which is toxic to humans, and is an alkylbenzene derivative, myristi, which is disclosed in the following figure. It is known that myristicin, elemicin, safrole and the like are extracted together.
상기 화합물들은 사람이 섭취하면 체내에서 암페타민 유도체로 변화되어 항정신성 약물과 비슷한 독성작용을 나타내는 것으로 잘 알려져 있으며, 전통적으로도 육두구의 독성을 제거하기 위해, 육두구를 석회수에 하루 정도 담가두었다가 불로 건조하여 약재에 사용하기도 했다. 육두구의 독성물질로서 가장 많이 존재하는 것이 미리시트신(Yagaku Zasshi, 128(1), 2008, 129~133)이며, 육두구 메탄올 추출물은 평균 2.1%의 미리스티신을 함유하고 있는 것으로 보고된 바 있다(Natural Toxins, 5(5), 1997, 186~192). These compounds are known to exhibit toxic effects similar to those of antipsychotic drugs when they are ingested by humans and are converted into amphetamine derivatives in the body. Traditionally, to remove the toxicity of nutmeg, the nutmeg is soaked in lime for one day, It was also used in medicinal materials. The most common toxic substance in nutmeg is myricitin (Yagaku Zasshi, 128 (1), 2008, 129 ~ 133), and the nutmeg extract has been reported to contain 2.1% of mysticin on average. Natural Toxins, 5 (5), 1997, 186-192).
육두구 추출물과 관련된 선행 특허로는 "생약 추출물을 포함하는 콜레스테롤 에스터레이즈 저해용 조성물(한국등록특허 제399529호)" 및 "한약재 추출물을 유효성분으로 함유하는 관상동맥성 심장 질환 또는 동맥경화증의 예방 또는 치료용 약학 조성물(한국등록특허 제793204호)" 등이 있으나 이들은 단지 활성성분이 규명되지 않은 육두구 추출물 자체를 사용한 것으로서 육두구 추출물 중에 함유된 화합물의 활성을 확인한 본 발명과는 관련성이 적다.Prior patents related to nutmeg extract include "composition for inhibiting cholesterol esterase containing herbal extract (Korean Patent No. 399529)" and "prevention or treatment of coronary heart disease or arteriosclerosis containing herbal extract as an active ingredient. Pharmaceutical composition (Korean Patent No. 793204) ”and the like, but they are only used as the nutmeg extract itself, whose active ingredient is not identified, and is less relevant to the present invention confirming the activity of the compound contained in the nutmeg extract.
육두구 추출물에서 분리된 화합물과 관련된 선행 특허로는 "항암제로 유발되는 독성의 억제제 및 이를 함유하는 항암제 조성물(한국등록특허 제646574호)", "리그난계 화합물을 유효성분으로 함유하는 여드름 치료 또는 예방용 조성물(한국등록특허 제567431호)", "간보호 및 간장질환 치료용 의약 조성물(한국등록특허 제619498호)", "리그난계 화합물을 함유하는 염증성 질환의 치료 또는 예방용 약학적 조성물(한국등록특허 제579752호)", "제2형 당뇨병 치료 또는 예방용 약제학적 조성물(한국등록특허 제627643호)", "메이스리그난 화합물 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 함유하는 PPARα에 의해 매개되는 질환의 예방 또는 치료용 조성물(한국등록특허 제830192호)", "리그난계 화합물을 함유하는 뇌신경질환의 치료 또는 예방용 약학적 조성물(한국등록특허 제679306호)" 등이 있으나, 이들은 메이스리그난(macelignan) 화합물을 이용한 다양한 활성이 개시된 것으로서, 상기 메이스리그난 화합물은 본 발명의 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물과는 그 구조와 특성이 다르며, 적용 용도 또한 다르다.The prior patents related to the compounds isolated from the extract of nutmeg include "inhibitor of toxicity caused by anticancer agent and anticancer composition containing it (Korean Patent No. 646574)", "treatment or prevention of acne containing lignan compound as active ingredient , A pharmaceutical composition for the treatment or prevention of an inflammatory disease containing a lignan compound (Korean Patent Registration No. 567431), a medicinal composition for treating liver diseases and liver diseases (Korean Patent No. 619498) Korean Patent No. 579752), "" Pharmaceutical composition for the treatment or prevention of
본 발명의 목적은 육두구(Myristica fragrans) 추출물 또는 이로부터 분리된 리그난계 화합물을 함유하는 혈관 질환의 예방 또는 치료용 조성물을 제공하는 데에 있다. 본 발명의 또 다른 목적은, 육두구 10~30% 에탄올 수용액 추출물 또는 이로부터 분리된 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물(2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compounds)을 유효성분으로 함유하는 혈관 질환의 예방 또는 치료용 조성물을 제공하는 데에 있다. An object of the present invention is nutmeg ( Myristica fragrans ) extract or a composition for the prevention or treatment of vascular diseases containing a lignan compound isolated therefrom. Still another object of the present invention is a 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan-based compound (2,5-bis-aryl-3) extracted from 10-30% ethanol aqueous solution of nutmeg or separated therefrom It is to provide a composition for the prevention or treatment of vascular diseases containing, 4-dimethyltetrahydrofuran lignan compounds) as an active ingredient.
본 발명은 육두구(Myristica fragrans) 추출물 또는 이로부터 분리된 리그난계 화합물을 함유하는 혈관 질환의 예방 또는 치료용 조성물에 관한 것이다. 상기 혈관 질환은 동맥경화증, 고혈압, 협심증, 심근경색, 허혈성 심장질환, 심부전, 경혈관 동맥 성형술 후 발생하는 합병증, 뇌경색, 뇌출혈, 및, 뇌졸중 등으로 이루어진 군으로부터 선택된 질환일 수 있다.The present invention relates to a nutritional supplement ( Myristica fragrans ) extract or a composition for the prevention or treatment of vascular diseases containing a lignan compound isolated therefrom. The vascular disease may be a disease selected from the group consisting of atherosclerosis, hypertension, angina pectoris, myocardial infarction, ischemic heart disease, heart failure, complications occurring after carotid angioplasty, cerebral infarction, cerebral hemorrhage, and stroke.
상기 육두구 추출물은 육두구를 10~30% 에탄올 수용액 추출물로 추출하여 미리스티신 등의 독성물질이 제거된 상태로 제조되어 안정성이 높다.The nutmeg extract is prepared in a state in which toxic substances such as myristicin are removed by extracting nutmeg with 10-30% ethanol aqueous solution extract and having high stability.
따라서, 바람직하게는, 본 발명은 미리스티신 함량이 0.5 중량% 이하이고, 하기 화학식 1의 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물(2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compounds)인, 넥탄드린 B(Nectandrin B), 넥탄드린 A(Nectandrin A), 프라그란신 C1(Fragransin C1), 베루코신(Verrucosin), 사우서네틴디올(Saucernetindiol) 및 테트라하이드로푸로구아이아신(Tetrahydrofuroguaiacin)으로 이루어진 군 중에서 선택되는 1종 이상의 화합물이 포함된 육두구 10~30% 에탄올 수용액 추출물을 함유하는 것을 특징으로 하는 혈관 질환의 예방 또는 치료용 약학 조성물에 관한 것이다. Therefore, preferably, the present invention has a myristicin content of 0.5% by weight or less, and the 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compound (2,5-bis-) of
[화학식 1][Formula 1]
또한, 본 발명은 상기 육두구 10~30% 에탄올 수용액 추출물로부터 분리된 상기 화학식 1의 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물(2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compounds)인, 넥탄드린 B(Nectandrin B), 넥탄드린 A(Nectandrin A), 프라그란신 C1(Fragransin C1), 베루코신(Verrucosin), 사우서네틴디올(Saucernetindiol) 및 테트라하이드로푸로구아이아신(Tetrahydrofuroguaiacin)으로 이루어진 군 중에서 선택되는 1종 이상의 화합물을 함유하는 것을 특징으로 하는 혈관 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.In addition, the present invention is a 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compound (2,5-bis-aryl-3) of
상기 2,5-비스아릴 테트라하이드로퓨란 리그난계 화합물은 육두구를 마쇄한 후 에탄올 10~30% 수용액으로 추출하는 단계; 및, 크로마토그래피를 이용하여 2,5-비스아릴 테트라하이드로퓨란 리그난계 화합물을 순수하게 분리 정제하는 단계;를 통해 얻을 수 있다.The 2,5-bisaryltetrahydrofuran lignan compound is obtained by grinding nutmeg and extracting it with 10 to 30% aqueous solution of ethanol; And purely separating and purifying the 2,5-bisaryl tetrahydrofuran lignan compound using chromatography.
상기 육두구 10~30% 에탄올 수용액 추출물은 추가로 이온교환수지를 사용하여 남아있는 미량의 미리스티신을 제거함과 동시에 2,5-비스아릴 테트라하이드로퓨란 리그난계 화합물을 농축시킬 수 있다. 따라서, 상기 이온교환수지 용출물은 육두구 10~30% 에탄올 수용액 추출물처럼 상기 화학식 1의 2,5-비스아릴 테트라하이드로퓨란 리그난계 화합물인, 넥탄드린 B(Nectandrin B), 넥탄드린 A(Nectandrin A), 프라그란신 C1(Fragransin C1), 베루코신(Verrucosin), 사우서네틴디올(Saucernetindiol) 및 테트라하이드로푸로구아이다신(Tetrahydrofuroguaiacin)로 이루어진 군 중에서 선택되는 1종 이상의 화합물을 유효성분으로 포함하는 것을 특징으로 한다. 또한, 상기 육두구의 이온교환수지 용출물의 미리스티신 함량은 0.1 중량% 이하일 수 있다. 상기 이온교환수지는 더욱 상세하게는 합성흡착제로서 방향족계 무치환 수지(디아이온 HP-20류, SP825류, AXT204류, XAD1600T류, MN200류) 중의 하나일 수 있다. The 10 to 30% ethanol aqueous solution extract of the nutmeg may further be used to remove the remaining trace amount of myristidine and concentrate the 2,5-bisaryltetrahydrofuran lignan compound using an ion exchange resin. Thus, the ion exchange resin eluate is a 2,5-bisaryl tetrahydrofuran lignan compound of
본 발명의 2,5-비스아릴 테트라하이드로퓨란 리그난계 화합물인 넥탄드린 B(Nectandrin B), 넥탄드린 A(Nectandrin A), 프라그란신 C1(Fragransin C1), 베루코신(Verrucosin), 사우서네틴디올(Saucernetindiol) 및 테트라하이드로푸로구아이다신(Tetrahydrofuroguaiacin)은 육두구로부터 유기용매(알코올, 에테르, 아세톤 등)에 의한 추출, 헥산과 물의 분배, 칼럼크로마토그래피에 의한 방법 등, 식물체 성분의 분리 추출에 이용되는 공지의 방법을 단독 또는 적합하게 조합하여 용이하게 얻을 수가 있다. 조추출물은 필요에 따라서 상법에 따라서 더욱 정제할 수 있다.Nectandrin B, Nectandrin A, Fragransin C1, Verrucosin, and Suchenetin, which are 2,5-bisaryltetrahydrofuran lignan compounds of the present invention, Saucernetindiol and Tetrahydrofuroguaiacin can be separated and extracted from nutmeg by extraction with an organic solvent (alcohol, ether, acetone, etc.), hexane and water, and column chromatography. Known methods used can be easily obtained by using alone or in suitable combination. The crude extract can be further purified according to the conventional method, if necessary.
본 발명에서 사용하는 크로마토그래피에는 실리카겔 칼럼 크로마토그래피(silica gel column chromatography), 엘에이취-20 칼럼 크로마토그래피(LH-20 column chromatography), 이온교환수지 크로마토그래피(ion exchange resin chromatography), 박층크로마토그래피(TLC; thin layer chromatography) 및 고성능 액체 크로마토그래피(high performance liquid chromatography) 등이 이용될 수 있다.The chromatography used in the present invention includes silica gel column chromatography, LH-20 column chromatography, ion exchange resin chromatography, thin layer chromatography Thin layer chromatography (TLC) and high performance liquid chromatography may be used.
또한, 본 발명의 육두구 10~30% 에탄올 수용액 추출물 또는 이로부터 분리된 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물은 육두구로부터 쉽게 분리할 수 있을 뿐만 아니라 안정도도 높으므로 식품, 의약품의 첨가제로 이용할 수 있다.In addition, the 10 to 30% ethanol aqueous solution extract of the nutmeg of the present invention or the 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compound isolated therefrom not only can be easily separated from nutmeg, Therefore, it can be used as an additive for foods and medicines.
상기 육두구 10~30% 에탄올 수용액 추출물 또는 이로부터 분리된 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물을 포함하는 약학 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. 상기 약학 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 육두구 10~30% 에탄올 수용액 추출물 또는 이로부터 분리된 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토오스, 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, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. The pharmaceutical composition comprising the aqueous solution of 10 to 30% ethanol in nutmeg or the 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compound isolated therefrom may be formulated into powders, granules, And may be formulated in the form of tablets, capsules, suspensions, emulsions, oral preparations such as syrups and aerosols, external preparations, suppositories, and sterilized injection solutions. Examples of carriers, excipients and diluents that can be contained in the pharmaceutical composition 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 formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may be prepared by mixing the aqueous solution of 10 to 30% ethanol in the nutmeg of the present invention or the 2,5-bis- Dimethyltetrahydrofuran lignan compound is prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. 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. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 육두구 10~30% 에탄올 수용액 추출물 또는 이로부터 분리된 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물을 함유하는 약학 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중과, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 2000㎎/㎏/일의 범위이다. 더 바람직한 투여량은 1㎎/㎏/일 내지 500㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. The dosage of the pharmaceutical composition containing the 10 to 30% ethanol aqueous solution extract of the nutmeg or the 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compound isolated therefrom of the present invention may vary depending on the age, Sex, weight and the particular disease or condition being treated, the severity of the disease or condition, the route of administration, and the judgment of the prescriber. Dosage determinations based on these factors are within the level of ordinary skill in the art and generally the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferable dosage is 1 mg / kg / day to 500 mg / kg / day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
본 발명의 육두구 10~30% 에탄올 수용액 추출물 또는 이로부터 분리된 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물을 함유하는 약학 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사에 의해 투여될 수 있다. 본 발명의 추출물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있는 약제이다. The pharmaceutical composition containing the extract of aqueous solution of 10 to 30% ethanol in nutmeg or the 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compound isolated therefrom of the present invention can be administered to mammals such as rats, ≪ / RTI > by various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection. Since the extract of the present invention has little toxicity and side effects, it can be safely used even for long-term administration for the purpose of prevention.
또한, 본 발명은 육두구 10~30% 에탄올 수용액 추출물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 건강기능식품을 제공한다. 본 발명의 건강기능식품은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 추출물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강기능성식품류 등이 있다. 상세하게는, 본 발명은 육두구 10~30% 에탄올 수용액 추출물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 혈관 질환의 예방 또는 개선용 건강기능식품을 제공한다. The present invention also provides a health functional food comprising 10 to 30% ethanol aqueous solution extract of nutmeg and a food acceptable food supplementary additive. The health functional food of the present invention includes forms such as tablets, capsules, pills, and liquids. Examples of the foods to which the extract of the present invention can be added include various foods, beverages, gums, tea, vitamins , And health functional foods. Specifically, the present invention provides a health functional food for the prevention or improvement of vascular diseases, including nutmeg 10-30% ethanol aqueous solution extract and food acceptable food supplement additives.
본 발명에 따른 육두구 10~30% 에탄올 수용액 추출물은 독성물질인 미리스티신 함량이 낮으면서 2,5-비스아릴 테트라하이드로퓨란 리그난계 화합물의 농도가 높아 기존의 육두구 추출물보다도 독성에 대한 안전성 및 생리활성효과가 높다. 또한, 상기 육두구 10~30% 에탄올 수용액 추출물 또는 이로부터 분리된 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물은 혈관 내피 세포의 eNOS 인산화를 매개로 하는 NO 생성 활성화 효과와 혈관 평활근 세포 증식 억제를 통한 혈관 내벽 비후 억제효과가 있어, 동맥경화증, 고혈압, 협심증, 심근경색, 허혈성 심장질환, 심부전, 경혈관 동맥 성형술 후 발생하는 합병증, 뇌경색, 뇌출혈, 및, 뇌졸중 등을 비롯한 혈관 질환을 효과적으로 예방 또는 억제할 수 있는 조성물로 유용하게 사용될 수 있다.
도 1은 육두구를 30% 에탄올로 추출한 추출물에서 분리한 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물을 HPLC로 분석한 스펙트럼 결과를 나타내는 그림이다.
도 2a는 넥탄드린 B(Nectandrin B)를 ECV 304 세포(presumptive endothelial cell line)에 처리한 후, eNOS 인산화가 증가하는 것을 웨스턴 블롯을 이용하여 확인한 결과를 나타내며, 도 2b는 넥탄드린 B를 24시간 처리한 배지에서 NO 생성 정도가 증가하는 것을 그리에스 반응액을 이용하여 확인한 결과를 나타낸다.
도 3은 육두구의 30% 에탄올 수용액 추출물, 테트라하이드로푸로구아이아신 B(Tetrahydrofuroguaiacin B), 베루코신(Verucosin), 프라그란신(Fragransin C1), 사우서네틴디올(Saucernetindiol)이 eNOS 인산화를 증가시키는 것을 확인하는 웨스턴 블롯 분석 결과이다.
도 4a는 대동맥 혈관환에 넥탄드린 B(Nectandrin B)를 처리하여 아세틸콜린과 비교하여 혈관 이완효과가 있음을 확인한 그래프이며, 도4b는 같은 조건에서 넥탄드린 B(Nectandrin B)의 처리로 인해 대동맥 혈관환 내의 eNOS 인산화가 증가하였음을 확인한 웨스턴 블롯 분석 결과이다.
도 5a는 혈관 평활근 세포에 넥탄드린 B(Nectandrin B)를 처리하여, 혈소판유래성장인자(PDGF)의 유도로 증가된 혈관 평활근 세포의 증식이 억제되는 것을 MTT 어세이를 통해 확인한 결과이며, 도 5b는 같은 조건에서, 넥탄드린 B(Nectandrin B)의 처리로 인해 DNA 합성이 억제되는 것을 BrdU 삽입법을 이용해 확인한 결과이다.
도 6은 혈관 내벽에 상처를 입은 마우스에 넥탄드린 B(Nectandrin B) 투여시 혈관 내벽 비후화가 억제되는 것을 확인한 결과를 나타낸다.FIG. 1 is a graph showing the spectral results of HPLC analysis of 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compounds separated from an extract obtained by extracting nutmeg with 30% ethanol.
FIG. 2a shows the result of confirming the increase of eNOS phosphorylation using Western blot after treating Nectandrin B to ECV 304 cells (presumptive endothelial cell line). FIG. 2b shows Nectandrin B for 24 hours. The result which confirmed the increase of NO production | generation in the cultured medium using the Gries reaction liquid is shown.
Figure 3 is a 30% ethanol aqueous solution extract of nutmeg, tetrahydrofuroguaiacin B (Verucosin), Fragransin (Fragransin C1), Sauceretine diol (Saucernetindiol) to increase eNOS phosphorylation Western blot analysis to confirm that.
Figure 4a is a graph confirming the vascular relaxation effect compared to acetylcholine by treating Nectandrin B in the aortic vascular ring, Figure 4b is due to the treatment of Nectandrin B (Nectandrin B) under the same conditions Western blot analysis confirmed that the eNOS phosphorylation in the vascular ring increased.
FIG. 5A is a result of confirming through MTT assay that Nectandrin B is treated to vascular smooth muscle cells to inhibit proliferation of increased vascular smooth muscle cells by induction of platelet-derived growth factor (PDGF), FIG. 5B In the same conditions, it was confirmed by BrdU insertion method that DNA synthesis is inhibited by the treatment of Nectandrin B (Nectandrin B).
Figure 6 shows the results confirming that the vascular inner wall thickening is inhibited when Nectandrin B (Nectandrin B) administration to the wounded blood vessel wall.
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나, 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해질 수 있도록 또한 당업자에게 본 발명의 사상이 충분히 전달될 수 있도록 제공되는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
<< 실시예Example 1 : One : 미리스티신Myristicine 함량이 적은 Low in content 육두구nutmeg 에탄올 수용액 추출물의 제조> Preparation of ethanol aqueous solution extract >
분쇄된 육두구 100g을 각 용매(표1 참조) 500㎖에 넣어 2시간 동안 3회에 걸쳐 초음파 추출기를 사용하여 각 용매조건에 대한 추출물을 제조하였다. 분리된 추출물은 동일 농도로 제조하여 사용하였고, 미리스티신 표준품은 시그마사(제품번호: M9237)에서 구입하였다. 각각의 육두구 용매 추출물과 미리스티신 표준품은 MeOH-H2O(0-32min : 63% MeOH, 32-37min : 63→100% MeOH) 조건의 HPLC[Optima Pak C18 column 4.6×250㎜, 5μm 입자 크기, 유속 1㎖/min, UV detection: 260nm]를 이용하여 분석하였고, 각각의 육두구 추출물의 미리스티신 함량은 표 1에 나타내었다.100 g of crushed nutmeg was placed in 500 ml of each solvent (see Table 1), and an extract was prepared for each solvent condition using an ultrasonic wave extender three times for 2 hours. The extracted extracts were used at the same concentration and the Myristicine standard was purchased from Sigma (product number: M9237). Each nutmeg solvent extract and myristicin standard were HPLC (Optima Pak C 18 column 4.6 × 250mm, 5μm) in MeOH-H 2 O (0-32min: 63% MeOH, 32-37min: 63 → 100% MeOH) Particle size, flow rate 1ml / min, UV detection: 260nm], and the myristicin content of each nutmeg extract is shown in Table 1.
미리스티신의 함량(%)Among the extracts
Myristicin content (%)
넥탄드린 B의 함량(%)Among the extracts
Nectarine B content (%)
표 1에 나타난 바와 같이, 10~30% 에탄올 수용액 추출물의 미리스티신 함량이, 다른 조건의 추출물에서보다 평균 3배 정도 적게 추출되는 것으로 확인되었다. 또한, 각 조건의 육두구 용매 추출물을 MeOH-H2O(0-35min: 60% MeOH, 35-60min : 60→100% MeOH) 조건의 HPLC[OptimaPak_C18 column 4.6×250mm, 5μm 입자 크기, 유속 1㎖/min, UV detection : 205, 280nm]를 이용하여 넥탄드린 B의 함량을 분석한 결과(표 1 참조), 30% 에탄올 수용액 추출물에서 넥탄드린 B가 가장 많이 추출됨을 알 수 있었다. 따라서, 활성물질의 양을 최대로 하면서 독성물질의 함량을 최소로 하는 조건은, 30% 이하 에탄올 수용액으로 육두구를 추출하는 것임을 확인할 수 있었다. As shown in Table 1, it was confirmed that the myristicin content of the 10-30% ethanol aqueous solution extract was extracted on average three times less than that of the extract under other conditions. In addition, the nutmeg solvent extract under each condition was purified by HPLC [OptimaPak_C 18 ] under MeOH-H 2 O (0-35 min: 60% MeOH, 35-60 min: 60 → 100% MeOH). column 4.6 × 250mm, 5μm particle size, flow rate 1ml / min, UV detection: 205, 280nm] and analyzed the content of nectanrin B (see Table 1). It was found that the most extracted. Therefore, it was confirmed that the nutmeg extract was extracted with an ethanol aqueous solution of 30% or less while maximizing the amount of the active substance and minimizing the toxic substance content.
<< 실시예Example 2 : 2 : 육두구nutmeg 에탄올 수용액 추출물로부터 독성물질 Toxic from Ethanol Aqueous Extract 미리스티신의Myristicin 추가 제거> Add remove>
육두구 100g을 30% 에탄올 수용액 500㎖로 추출한 후 이온교환수지 중의 하나인 디아이온 HP-20 500g에 통과시켜 흡착시켰다. 이후 30~90% 에탄올 수용액, 100% 에탄올 및 100% 아세톤을 각각 500㎖씩 사용하여 상기 흡착물을 용출하였으며 상기 용출물에 포함된 미리스티신 및 넥탄드린 B의 함량을 표 2에 나타내었다. 표 2를 참고하면, 상기 흡착물을 80% 이하 에탄올 수용액을 사용하여 용출할 때, 미리스티신이 거의 검출되지 않음을 확인할 수 있었다. 또한 넥탄드린 B는 80% 에탄올 수용액을 용매로 이용했을 때가 많이 용출되는 것으로 확인되었다. 100 g of nutmeg was extracted with 500 ml of a 30% aqueous ethanol solution and then adsorbed through 500 g of Diaion HP-20, one of ion exchange resins. Thereafter, the adsorbates were eluted using 500 mL of 30-90% ethanol aqueous solution, 100% ethanol, and 100% acetone, respectively, and the contents of myristicine and nectandrin B contained in the eluate are shown in Table 2. Referring to Table 2, it was confirmed that myristicine was hardly detected when the adsorbate was eluted with an ethanol aqueous solution of 80% or less. In addition, it was confirmed that the use of 80% ethanol aqueous solution as the solvent elicited a large amount of nethandrine B.
<< 실시예Example 3 : 3: 육두구로부터From nutmeg 추출된 화합물의 확인> Identification of extracted compounds >
상기 실시예 1의 30% 에탄올 수용액 육두구 추출물에서 HPLC를 이용하여 2,5-비스-아릴-3,4-디메틸테트라하이드로퓨란 리그난계 화합물을 분리하였으며, 상기 화합물에 대해 HPLC(도 1 참조), 1H, 13C-NMR을 이용하여 그 특성을 분석하였다. 상기 화합물의 물리화학적 특성은 다음과 같다.The 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignan compound was isolated from the nutmeg extract of 30% aqueous ethanol solution of Example 1 by HPLC, and the compound was analyzed by HPLC (see FIG. 1) 1 H, and 13 C-NMR. The physicochemical properties of the compound are as follows.
3-1. 3-1. 테트라하이드로푸로구아이아신Tetrahydrofuroguanidine B( B ( TetrahydrofuroguaiacinTetrahydrofuroguaiacin B, 화합물 1) B, compound 1)
무색의 분말, 수소핵자기공명스펙트럼: ppm(500 MHz, CDCl3): δ 0.61(6H, d, J=6.0 Hz, 3- and 4-Me), 2.67(2H, m, 3- and 4-H), 3.91(6H, 3'- and 3"-OMe), 5.12(2H, d, J=6.6 Hz, 2- and 5-H), 5.59(2H, s, 4'- and 4"-OH), 6.90-6.99(6H, m, 2'-, 5'-, 6'-, 2"-, 5"- and 6"-H), 탄소핵자기공명스펙트럼 : ppm (125 MHz, CDCl3): δ 11.7(3- and 4-Me), 41.5(C-3 and C-4), 55.8(2×OMe), 82.7(C-2 and C-5), 109.0(C-2' and C-2"), 113.9(C-5' and C-5"), 119.3(C-6' and C-6"), 132.5(C-1' and C-1"), 144.3(C-4' and C-4"), 146.2(C-3' and C-3").Colorless powder, hydrogen nuclear magnetic resonance spectrum: ppm (500 MHz, CDCl 3 ): δ 0.61 (6H, d, J = 6.0 Hz, 3- and 4-Me), 2.67 (2H, m, 3- and 4- H), 3.91 (6H, 3'- and 3 "-OMe), 5.12 (2H, d, J = 6.6 Hz, 2- and 5-H), 5.59 (2H, s, 4'- and 4" -OH ), 6.90-6.99 (6H, m, 2'-, 5'-, 6'-, 2 "-, 5"-and 6 "-H), Carbon nuclear magnetic resonance spectra: ppm (125 MHz, CDCl 3 ) δ 11.7 (3- and 4-Me), 41.5 (C-3 and C-4), 55.8 (2 × OMe), 82.7 (C-2 and C-5), 109.0 (C-2 'and C- 2 "), 113.9 (C-5 'and C-5"), 119.3 (C-6' and C-6 "), 132.5 (C-1 'and C-1"), 144.3 (C-4' and C-4 ″), 146.2 (C-3 ′ and C-3 ″).
3-2. 3-2. 사우서네틴디올Sausage net dior ( ( SaucernetindiolSaucernetindiol , 화합물 2) , Compound 2)
무색의 오일, 수소핵자기공명스펙트럼: ppm(500 MHz, CDCl3): δ 0.63(3H, d, J=6.5 Hz, 4-Me), 1.01(3H, d, J=6.5 Hz, 3-Me), 2.33(2H, m, 3- and 4-H), 3.90-3.92(6H, 3'- and 3"-OMe), 4.65(1H, d, J=9.5 Hz, 2-H), 5.46(1H, d, J=4.5 Hz, 5-H), 5.58(2H, s, 4'- and 4"-OH), 6.77-6.99(6H, m, 2'-, 5'-, 6'-, 2"-, 5"- and 6"-H), 탄소핵자기공명스펙트럼 : ppm (125 MHz, CDCl3): δ 9.42(3-Me), 11.83(4-Me), 43.4(C-3), 47.6(C-4), 55.8(2×OMe), 84.8(C-2), 85.7(C-5), 108.3(C-2'), 108.7(C-2"), 113.9(C-5'), 114.0(C-5"), 118.8(C-6'), 119.3(C-6"), 132.6(C-1'), 135.0(C-1"), 144.3(C-4'), 145.0(C-4"), 146.3(C-3"), 146.6(C-3').As a colorless oil, hydrogen nuclear magnetic resonance spectrum: ppm (500 MHz, CDCl 3 ): δ 0.63 (3H, d, J = 6.5 Hz, 4-Me), 1.01 (3H, d, J = 6.5 Hz, 3-Me ), 2.33 (2H, m, 3- and 4-H), 3.90-3.92 (6H, 3'- and 3'-OMe), 4.65 (1H, d, J = 9.5 Hz, 1H, d, J = 4.5 Hz, 5-H), 5.58 (2H, s, 4'- and 4'-OH), 6.77-6.99 (6H, m, 2 "-, 5" - and 6 "-H), carbon nuclear magnetic resonance spectrum: ppm (125 MHz, CDCl 3 ): δ 9.42 (3-Me), 11.83 (4-Me), 43.4 (C-3) (C-4), 55.8 (2xMe), 84.8 (C-2), 85.7 (C-5), 108.3 ), 114.0 (C-5), 118.8 (C-6), 119.3 (C-6) , 145.0 (C-4 "), 146.3 (C-3"), 146.6 (C-3 ').
3-3. 3-3. 베루코신Berukosin ( ( VerrucosinVerrucosin , 화합물 3) , Compound 3)
무색의 오일, 수소핵자기공명스펙트럼: ppm(500 MHz, CDCl3) : δ 0.67(3H, d, J=6.5 Hz, 4-Me), 1.06(3H, d, J=6.5 Hz, 3-Me), 1.79(1H, m, 3-H), 2.25(1H, m, 4-H), 3.87-3.89(6H, 3'- and 3"-OMe), 4.36(1H, d, J=9.5 Hz, 2-H), 5.10(1H, d, J=9.0 Hz, 5-H), 6.80-6.96(6H, m, 2'-, 5'-, 6'-, 2"-, 5"- and 6"-H), 탄소핵자기공명스펙트럼: ppm(125 MHz, CDCl3) : δ 14.8(3-Me), 15.2(4-Me), 45.9(C-4), 46.8(C-3), 56.4(2×OMe), 84.6(C-2), 89.0(C-5), 111.6(C-2'), 111.9(C-2"), 115.7(C-5'), 116.1(C-5"), 120.7(C-6'), 120.9(C-6"), 133.0(C-1'), 133.8(C-1"), 147.5(C-4'), 146.8(C-4"), 148.6(C-3"), 149.0(C-3').As a colorless oil, hydrogen nuclear magnetic resonance spectrum: ppm (500 MHz, CDCl 3 ): δ 0.67 (3H, d, J = 6.5 Hz, 4-Me), 1.06 (3H, d, J = 6.5 Hz, 3-Me ), 1.79 (1H, m, 3-H), 2.25 (1H, m, 4-H), 3.87-3.89 (6H, 3'- and 3 "-OMe), 4.36 (1H, d, J = 9.5 Hz , 2'-, 5'-, 6'-, 2'-, 5''- and 2'H), 5.10 (1H, d, J = 9.0Hz, 5H), 6.80-6.96 6 "-H), Carbon Nuclear Magnetic Resonance Spectrum: ppm (125 MHz, CDCl 3 ):? 14.8 (3-Me), 15.2 (4-Me), 45.9 C-2 '), 111.6 (C-2'), 115.7 (C-5 '), 116.1 (C- C-4 '', 146.8 (C-4 ''), 120.7 (C-6 ' , 148.6 (C-3 "), 149.0 (C-3 ').
3-4. 3-4. 넥탄드린Nectandrine B ( B ( NectandrinNectandrin B, 화합물 4) B, compound 4)
무색의 오일, 수소핵자기공명스펙트럼: ppm(600 MHz, CDCl3): δ 1.05(6H, d, J=6.0 Hz, 3- and 4-Me), 2.35(2H, m, 3- and 4-H), 3.85(6H, 3'- and 3"-OMe), 4.53(2H, d, J=5.4 Hz, 2- and 5-H), 5.74(2H, brs, 4'- and 4"-OH), 6.91(2H, d, J=7.8 Hz, 5'- and 5"-H), 6.93(2H, dd, J=1.8, 7.8 Hz, 6'- and 6"-H), 6.99(2H, d, J=1.8 Hz, 2'- and 2"-H), 탄소핵자기공명스펙트럼: ppm(200 MHz, CDCl3): δ 133.9(C-1' and C-1"), 114,1(C-2' and C-2"), 146.4(C-3' and C-3"), 144.9(C-4' and C-4"), 109.2(C-5' and C-5"), 119.1(C-6' and C-6"), 87.2(C-2 and C-5), 44.1(C-3 and C-4), 12.7(3-Me and 4-Me), 55.7(-OMe × 2).(600 MHz, CDCl 3 ):? 1.05 (6H, d, J = 6.0 Hz, 3- and 4-Me), 2.35 H), 3.85 (6H, 3'- and 3 "-OMe), 4.53 (2H, d, J = 5.4 Hz, 2- and 5-H), 5.74 (2H, brs, 4'- and 4" -OH ), 6.91 (2H, d, J = 7.8Hz, 5'- and 5''H), 6.93 (2H, dd, J = 1.8, 7.8Hz, d, J = 1.8 Hz, 2'- and 2 "-H), carbon nuclear magnetic resonance spectrum: ppm (200 MHz, CDCl 3 ): δ 133.9 (C-1 'and C-1"), 114,1 ( C-2 'and C-2 "), 146.4 (C-3' and C-3"), 144.9 (C-6 and C-6), 87.2 (C-2 and C-5), 44.1 (C-3 and C-4), 12.7 × 2).
3-5. 3-5. 넥탄드린Nectandrine A ( A ( NectandrinNectandrin A, 화합물 5) A, compound 5)
흰색결정, 수소핵자기공명스펙트럼: ppm(500 MHz, CDCL3) δ: 1.00(3H, d, J=3.5 Hz, 4-Me), 1.02(3H, d, J=3.5 Hz, 3-Me), 2.27(2H, m, 3- and 4-H), 3.80 - 3.86(9H, s, 3×OMe), 4.43(1H, d, J=7.5 Hz, 2-H), 4.44(1H, d, J=7.5 Hz, 5-H), 6.81-7.09(6H, m, Ar-H); 탄소핵자기공명스펙트럼: ppm(125 MHz, CDCL3) δ: 13.1(3-Me), 13.2(4-Me), 45.6(C-4), 45.5(C-3), 56.1-56.3(3×OMe), 88.0(C-5), 88.2(C-2), 110.9(C-2'), 111.3(C-2"), 112.7(C-5'), 115.5(C-5"), 119.5(C-6'), 120.0(C-6"), 135.1(C-1'), 136.4(C-1"), 146.9(C-4'), 148.3(C-4"), 149.9(C-3"), 150.4(C-3').White crystals, hydrogen nuclear magnetic resonance spectrum: ppm (500 MHz, CDCL 3 ) δ: 1.00 (3H, d, J = 3.5 Hz, 4-Me), 1.02 (3H, d, J = 3.5 Hz, 3-Me) (1H, d, J = 7.5 Hz, 2-H), 2.27 (2H, m, 3- and 4-H), 3.80-3.86 J = 7.5 Hz, 5-H), 6.81-7.09 (6H, m, Ar-H); Carbon Nuclear Magnetic Resonance Spectrum: ppm (125 MHz, CDCl 3 )?: 13.1 (3-Me), 13.2 (4-Me), 45.6 (C-4), 45.5 OMe), 88.0 (C-5), 88.2 (C-2), 110.9 (C-2 '), 111.3 (C-6), 120.0 (C-6), 135.1 (C-1 '), 136.4 -3 "), 150.4 (C-3 ').
3-6. 3-6. 프라그란신Praagan Shin C1C1 ( ( FragransinFragrance C1C1 , 화합물 6), Compound 6)
무색의 오일, 수소핵자기공명스펙트럼: ppm(500 MHz, CDCl3): δ 1.04(3H, d, J=6.6 Hz, 3-Me), 1.06(3H, d, J=7.2 Hz, 4-H), 2.32(1H, m, 3-H), 2.34(1H, m, 4-H), 3.88(9H, 3'-, 5'- and 3"-OMe), 4.50(1H, d, J=7.2 Hz, 2-H), 4.52(1H, d, J=7.2 Hz, 5-H), 5.47-5.58(2H, br, s, 4'- and 4"-OH), 6.67(2H, br, s, 2'- and 6'-H), 6.91-6.97(3H, m, 2"-, 5"- and 6"-H), 탄소핵자기공명스펙트럼: ppm(125 MHz, CDCl3): δ 12.9(3-Me), 13.1(4-Me), 44.0(C-3), 44.5(C-4), 56.3-55.8(3×OMe), 87.2(C-2), 87.5(C-5), 103.1(C-2' and C-6'), 102.9(C-2"), 114.1(C-5"), 119.3(C-6"), 134.0(C-1'), 133.5(C-1"), 145.1(C-4'), 146.4(C-4"), 146.9(C-3', C-5' and C-3"). As a colorless oil, hydrogen nuclear magnetic resonance spectrum: ppm (500 MHz, CDCl 3 ): δ 1.04 (3H, d, J = 6.6 Hz, 3-Me), 1.06 (3H, d, J = 7.2 Hz, 4-H ), 2.32 (1H, m, 3-H), 2.34 (1H, m, 4-H), 3.88 (9H, 3'-, 5'- and 3 "-OMe), 4.50 (1H, d, J = 7.2 Hz, 2H), 4.52 ( 1H, d, J = 7.2 Hz, 5-H), 5.47-5.58 (2H, br, s, 4'- and 4 "-OH), 6.67 (2H, br, s, 2'- and 6'-H) , 6.91-6.97 (3H, m, 2 "-, 5" - and 6 "-H), carbon nuclear magnetic resonance spectrum: ppm (125 MHz, CDCl 3 ): δ (C-3), 44.5 (C-4), 56.3-55.8 (3xMe), 87.2 (C-2), 87.5 , 103.1 (C-2 'and C-6'), 102.9 (C-2 "), 114.1 1 "), 145.1 (C-4 '), 146.4 (C-4"), 146.9 (C-3', C-5 'and C-3 ").
<< 실시예Example 4: 혈관 내피 세포에서 4: in vascular endothelial cells eNOSeNOS 인산화 및 Phosphorylation and NONO 생성 확인> Confirm creation
혈관 내피 세포에서 eNOS 인산화 및 NO 생성 정도를 확인하기 위해, 인간 탯줄정맥 내피 세포 기원 세포주인 ECV 304 세포(presumptive endothelial cell line)를 이용하였다. 상기 세포는 10% FBS(fetal bovine serum)와 1% 항생제가 포함된 DMEM(Dulbecco's Modified Eagles Medium)에서 트립신-EDTA(trypsin-ethylenediaminetetraacetic acid)를 이용한 계대배양을 통해 배양하였다. 이를 위해, 넥탄드린 B를 FBS(fetal bovine serum) 고갈 조건의 세포에 1시간 동안 처리하여, 총 세포 용해액(total cell lysates)을 얻고, 웨스턴 블롯 분석을 이용하여 상기 세포 용해액 내의 인산화된 eNOS의 발현량을 확인하였다. 보다 상세하게는 각각의 세포에 세포용해 버퍼 100㎕[120mM NaCl, 40mM Tris(pH 8), 0.1% NP40(Nonidet P-40)]를 처리하여 수거한 뒤, 10,000×g에서 원심분리하여 총 세포 용해액을 얻었다. 이 후, 상기 세포 용해액을 이용하여 10% SDS-PAGE(sodium dodecyl sulfate poly acrylamide gel electrophoresis) 전기영동을 실시하고 트랜스퍼 키트를 이용하여 나이트로셀룰로오스 트랜스퍼 멤브레인에 단백질을 고착시켰다. 상기 멤브레인은 5% 스킴밀크(skim milk)에서 1시간 동안 상온 조건으로 블로킹(blocking)하고, 각 단백질에 대한 1차 항체 및 이에 대한 2차 항체를 반응시킨 후, 각각의 단백질의 발현량 변화를 확인하였으며, 이에 대한 결과를 도 2a에 나타내었다. 도 2a의 결과를 참고하면, 넥탄드린 B(1~10㎍/㎖)의 처리로 인해, eNOS의 인산화(p-eNOS)가 넥탄드린 무처리군보다 증가하였음을 확인할 수 있다. 대조물질로 사용한 인슐린은 혈당 강하 효능 뿐만 아니라 eNOS의 인산화를 통한 혈관이완반응이 잘 알려져 있는데, 본 발명의 화합물들이 인슐린 100nM 처리군과 유사하게 eNOS 인산화 효과가 있음이 확인되었다. In order to confirm eNOS phosphorylation and NO production in vascular endothelial cells, ECV 304 cells (presumptive endothelial cell line), a human umbilical vein endothelial cell-derived cell line, were used. The cells were cultured by passage using trypsin-ethylenediaminetetraacetic acid (trypsin-ethylenediaminetetraacetic acid) in Dulbecco's Modified Eagles Medium (DMEM) containing 10% FBS (fetal bovine serum) and 1% antibiotic. To this end, nectandrin B was treated with FBS (fetal bovine serum) depleted conditions for 1 hour to obtain total cell lysates and phosphorylated eNOS in the cell lysates using Western blot analysis. The expression level of was confirmed. More specifically, each cell was collected by treating with 100 µl of lysis buffer [120 mM NaCl, 40 mM Tris (pH 8), 0.1% NP40 (Nonidet P-40)], followed by centrifugation at 10,000 × g for total cells. A solution was obtained. Thereafter, 10% SDS-PAGE (sodium dodecyl sulfate poly acrylamide gel electrophoresis) electrophoresis was performed using the cell lysate, and the protein was fixed to the nitrocellulose transfer membrane using a transfer kit. The membrane was blocked at room temperature for 1 hour in 5% skim milk, and after reacting the primary and secondary antibodies to each protein, the change in the amount of expression of each protein was observed. It confirmed, and the result is shown in FIG. Referring to the results of Figure 2a, it can be seen that due to the treatment of nectandrin B (1 ~ 10㎍ / ㎖), phosphorylation of eNOS (p-eNOS) was increased than the nectandrin untreated group. Insulin, used as a control, is well known for its hypoglycemic effect as well as vascular relaxation through phosphorylation of eNOS. It was confirmed that the compounds of the present invention have eNOS phosphorylation effect similar to insulin 100nM treatment group.
한편, eNOS 인산화 및 활성화에 따르는 NO 형성은 실험 배지 수거 후 아질산염 환원효소(nirate reductase) 반응을 거쳐서 생성된 NO 대사체인 아질산염(nitrite)의 함량을 Assay Design사의 그리에스(Griess) 반응액과의 반응을 거쳐서 나오는 발색 정도를 540nm에서 정량하여 도 2b에 나타내었다. 결과값은 시료 처리가 없는 대조군(넥탄드린 무처리군)을 기준(1.00)으로 하여 이에 대한 폴드(fold)값으로 표시하였다. 도 2b의 결과를 참고하면, NO의 생성량이 넥탄드린 B의 처리 농도(1~10㎍/㎖)에 따라 증가하였음을 확인할 수 있다.On the other hand, NO formation by eNOS phosphorylation and activation was measured by the reaction of Assay Design's Griess with the content of nitrite, which is a NO metabolite produced through nitrite reductase reaction after collection of experimental medium. The degree of color development coming through was quantified at 540 nm and is shown in FIG. 2B. The result was expressed as a fold value for the control group without sample treatment (nextandrin treated group) as a reference (1.00). Referring to the results of Figure 2b, it can be seen that the production of NO increased with the treatment concentration (1 ~ 10㎍ / ㎖) of nectanrin B.
또한, 넥탄드린 B 이외에도, 육두구의 30% 에탄올 수용액 추출물, 테트라하이드로푸로구아이아신(Tetrahydrofuroguaiacin B), 베루코신(Verrucosin), 프라그린신 C1(Fragransin C1), 사우서네틴디올(Saucernetindiol)의 eNOS 인산화 정도도, 상기 넥탄드린 B와 동일한 조건으로 하여 확인한 바, 넥탄드린 B의 결과와 유사하게, 각 화합물의 처리농도별(1~10㎍/㎖)로 eNOS의 인산화가 증가하는 것을 확인할 수 있었으며, 육두구의 30% 에탄올 수용액 추출물(30㎍/㎖)에서도 역시 eNOS의 인산화가 나타남을 알 수 있었다(도 3 참조). 또한, 상기 결과에는 포함되지 않았지만, 넥탄드린 A도 상기 도 3의 화합물들과 유사한 결과를 나타냄이 확인되었다. In addition to nectandrin B, eNOS of 30% ethanol extract of nutmeg, tetrahydrofuroguaiacin B, verrucosin, fragransin C1, saucernetinol, and eNOS Also, the degree of phosphorylation was confirmed under the same conditions as that of nectandrin B. Similar to the result of nectandrin B, it was confirmed that the phosphorylation of eNOS increased by the treatment concentration of each compound (1 ~ 10㎍ / ㎖). , 30% ethanol aqueous solution extract of the nutmeg (30 ㎍ / ㎖) also showed that phosphorylation of eNOS also appeared (see Figure 3). In addition, although not included in the above results, it was confirmed that nectanrin A showed similar results with the compounds of FIG. 3.
<< 실시예Example 5: 혈관 이완 효과> 5: vascular relaxation effect>
본 발명의 육두구 10~30% 에탄올 수용액 추출물이 유효성분으로 함유하는 넥탄드린 B가 실제 혈관조직의 이완을 일으키는 지를 확인하기 위해, 내피가 손상되지 않은 랫드 대동맥 혈관환을 이용한 조직 챔버(organ chamber) 실험법으로 평가하였다(도 4). 이를 위해, 웅성 랫드(몸무게 300g)의 대동맥을 적출하여 2~3㎜ 직경의 혈관환 표본 제작 후, 정적수축 변환기(isometric transducer)와 연결된 고리에 현수하여 수축 및 이완정도를 측정하였다. 이완 정도는 NO 생성을 유도한다고 알려져 있는 아세틸콜린(acetylcholine, 1μM)에 대한 이완 백분율(%)로 표시하였다. 아세틸콜린의 경우 증류수에 용해한 1mM 농축액을 조직챔버에 5㎕(최종농도 1μM) 가했으며, 넥탄드린 B는 10㎎/㎖이 되도록 DMSO(dimethylsulfoxide)에 용해하여 역시 조직챔버에 최종농도가 10㎍/㎖이 되도록 처리하였다.In order to confirm whether nectanrin B, which is contained as an active ingredient, in the nutmeg 10-30% ethanol aqueous solution of the present invention, causes actual vascular tissue relaxation, a tissue chamber using a rat aortic vascular ring in which the endothelial is not damaged. It was evaluated by the experimental method (Fig. 4). To this end, the aorta of a male rat (weight 300g) was extracted, and a sample of a 2 to 3 mm diameter vascular ring was produced, and then suspended on a ring connected to an isometric transducer to measure contraction and relaxation. The degree of relaxation was expressed as percent relaxation relative to acetylcholine (1 μM), which is known to induce NO production. In the case of acetylcholine, 5 μl (
또한, 실제 대동맥에서 넥탄드린 B가 eNOS의 인산화를 일으키는지 평가하기 위하여 혈관환 표본을 미세분쇄한 후, 10,000×g로 원심분리한 상등액을 이용하여 실시예 4와 동일하게 웨스턴 블롯을 수행하였고, 시간에 따른 eNOS의 인산화를 확인하였다. 상기 결과들은 도 4에 나타내었는데, 도 4를 확인하면, 넥탄드린 B(10㎍/㎖)를 처리한 혈관이 63.5%(아세틸콜린[1μM]이 일으킨 이완반응을 100%로 환산함)의 혈관 이완 효과가 있는 것을 확인할 수 있었으며, eNOS의 인산화 역시 증가하였음을 확인할 수 있었다. In addition, in order to evaluate whether nectanrin B causes phosphorylation of eNOS in the actual aorta, Western blotting was performed in the same manner as in Example 4 using the supernatant centrifuged at 10,000 × g after crushing the vascular ring specimen. Phosphorylation of eNOS over time was confirmed. The results are shown in FIG. 4. Referring to FIG. 4, 63.5% of the blood vessels treated with nectandrin B (10 μg / ml) converted to 100% of the relaxation reaction caused by acetylcholine [1 μM]. It was confirmed that there is a relaxation effect, it was confirmed that the phosphorylation of eNOS also increased.
<< 실시예Example 6: 혈관 평활근 세포 증식 및 6: vascular smooth muscle cell proliferation and DNADNA 합성 효과> Composite Effects>
넥탄드린 B 화합물이 혈관 평활근 세포 증식에 어떠한 영향을 주는지 확인하기 위해, 랫드 대동맥에서 분리한 1차 배양 혈관 평활근 세포(계대배양 횟수 4~10 이내 세포를 이용함)에 넥탄드린 B와 PDGF(platelet-drived growth factor, 혈소판유래성장인자, 혈관 내벽의 증식을 유도함)를 처리한 후의 세포 증식 정도 및 DNA 합성정도를 MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] 분석 및 BrdU 삽입법(5-bromo-2’-deoxy-uridine uptake)으로 확인하였다. 이를 위해, 상기 혈관 평활근 세포에 넥탄드린 B를 1시간 동안 처리하고, 이후 PDGF(30ng/㎖)를 24시간 동안 처리하여 배양하였다. To determine how nectanrin B compounds affect vascular smooth muscle cell proliferation, nectedrin B and PDGF (platelet-) were used in primary cultured vascular smooth muscle cells isolated from rat aorta (using cells within 4-10 passages). the degree of cell proliferation and the degree of DNA synthesis after treatment with the drived growth factor, platelet-derived growth factor, and blood vessel lining) were determined by MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl- tetrazolium bromide] and BrdU insertion (5-bromo-2'-deoxy-uridine uptake). To this end, the vascular smooth muscle cells were treated with nectanrin B for 1 hour and then incubated with PDGF (30 ng / ml) for 24 hours.
MTT 분석은 96웰 플레이트에 배양한 혈관 평활근 세포에 MTT 시약(2㎎/㎖) 200㎕을 처리하여 4시간 동안 배양한 후, 세포 배양액을 제거하고 200㎕의 DMSO(dimethyl sulfoxide)를 이용하여 세포를 용해하여 540nm에서 흡광도를 측정하여 정량하였고 이에 대한 결과는 도 5a에 나타내었다. MTT assay was performed by incubating 200 μl of MTT reagent (2 mg / ml) on vascular smooth muscle cells cultured in 96 well plate for 4 hours, then removing the cell culture medium and using 200 μl of DMSO (dimethyl sulfoxide). Was dissolved and quantified by measuring absorbance at 540 nm. The results are shown in FIG. 5A.
도 5a를 참고하면, 넥탄드린 B의 처리 농도(1~10㎍/㎖)에 따라, 혈관 평활근 세포의 증식이 억제되는 것을 확인할 수 있었다. Referring to FIG. 5A, it was confirmed that the proliferation of vascular smooth muscle cells was suppressed according to the treatment concentration of nectanrin B (1 to 10 µg / ml).
BrdU 삽입 정도는 Roche사의 키트를 이용하여 정량하였다. 혈관 평활근 세포를 10μM BrdU 염색 용액에 2시간 동안 노출 후 고정용액으로 30분간 세포를 고정시켰다. 이후 100㎕의 BrdU 항체(anti-BrdU peroxidase-labeled antibody)에 90분간 반응한 뒤 PBS로 3회 세척하였다. 이후 기질액 100㎕/㎖를 가하여 마이크로타이터 플레이트 리더(microtiter plate reader, Berthold Tech., Bad Wildbad, Germany)를 이용하여 405nm에서 발색정도를 확인하였으며 이에 대한 결과는 도 5b에 나타내였다. The degree of BrdU insertion was quantified using a Roche kit. Vascular smooth muscle cells were exposed to 10 μM BrdU staining solution for 2 hours, and then the cells were fixed with fixed solution for 30 minutes. 100 μl of BrdU antibody (anti-BrdU) peroxidase-labeled antibody) for 90 minutes and washed three times with PBS. Subsequently, 100 μl / ml of the substrate solution was added, and the color development was confirmed at 405 nm using a microtiter plate reader (Berthold Tech., Bad Wildbad, Germany). The results are shown in FIG. 5B.
도 5b를 참고하면, 넥탄드린 B의 처리 농도(1~10㎍/㎖)에 따라, 혈관 평활근 세포에서의 DNA 합성이 억제되는 것을 확인할 수 있었다. Referring to FIG. 5B, it was confirmed that DNA synthesis in vascular smooth muscle cells was suppressed according to the treated concentration of nectanrin B (1 to 10 µg / ml).
<< 실시예Example 7: 7: 대퇴부동맥Femoral Artery 손상 후 혈관 내벽 Vascular lining after injury 비후에After rain 미치는 Affection 넥탄드린Nectandrine B의 효과> Effect of B>
본 발명의 화합물이 혈관 내벽 비후에 어떠한 영향을 주는지 확인하기 위해, 7주령 웅성 ICR 마우스(30g)를 펜토바르비탈(pentobarbital)로 마취시킨 후 대퇴부 동맥을 노출 및 손상시킨 후 가이드 와이어(guide wire)를 2분 간 혈관 내에 삽입하였다. 이후 가이드 와이어를 제거한 뒤, 혈관을 재봉합하였다. 혈관 재봉합 후, 마우스에 넥탄드린 B(20㎎/kg, 30% polyethylene glycol 400, 1% 에탄올 용매에 용해시킴)를 주 2회(월, 목요일) 3주간 투여하였으며, 대조군에는 넥탄드린 B를 녹인 용매(30% polyethylene glycol 400, 1% 에탄올 용매)만을 투여하였다. 3주 후 에테르(ether)로 마취시킨 마우스에서 대퇴부 혈관을 적출하고, 상기 대퇴부 혈관을 중성 포르말린 용액에 고정하여 혈관조직 표본을 제작하였다. 혈관 내벽의 두께는 숙련된 병리학자가 확인하여 측정하였으며, 이에 대한 측정 결과를 도 6에 나타내었다.In order to determine how the compound of the present invention affects the vascular wall thickening, a 7-week-old male ICR mouse (30g) was anesthetized with pentobarbital, and then exposed and damaged the femoral artery, followed by a guide wire. Was inserted into the vessel for 2 minutes. After removing the guide wire, the vessel was sewn. After vascular seaming, mice were treated with nectanrin B (20 mg / kg, 30% polyethylene glycol 400, dissolved in 1% ethanol solvent) twice a week (Mon, Thursday) for 3 weeks, and nectanrin B was used as a control. Only dissolved solvents (30
도 6을 참고하면 대조군(Sham) 쥐의 혈관에 비해, 가드 와이어를 삽입한 쥐(Wire-injured)의 혈관 내벽이 현저하게 두꺼워져 있는 것을 확인할 수 있었으나, 가드 와이어 처리 후, 넥탄드린 B를 투여한 마우스(+Nectandrin B, 20㎎/kg)의 혈관 내벽은 대조군과 유사한 정도의 두께를 나타내는 것으로 확인되었다. Referring to FIG. 6, the inner wall of the blood vessel of the wire-injured rat was significantly thickened compared to the blood vessel of the control rat (Sham) rat. However, after the guard wire treatment, nectanrin B was administered. The vascular lining of one mouse (+ Nectandrin B, 20 mg / kg) was found to have a thickness similar to that of the control group.
<< 실험예Experimental Example 8 : 독성실험> 8: Toxicity test>
8-1. 8-1. 급성독성Acute toxicity
본 발명의 육두구 10~30% 에탄올 수용액 추출물 및 넥탄드린 B를 단기간에 과량을 섭취하였을 때 급성적(24시간 이내)으로 동물체내에 미치는 독성을 조사하고, 치사율을 결정하기 위하여 본 실험을 수행하였다. 일반적인 마우스인 ICR 마우스 계통 30마리를 대조군과 실험군에 각각 10마리씩 배정하였다. 대조군에는 PEG-400/tween-80/에탄올(8/1/1, v/v/v) 만을 투여하고, 실험군은 육두구 10~30% 에탄올 추출물 및 넥탄드린 B를 상기 PEG-400/tween-80/에탄올(8/1/1, v/v/v)에 녹여 2g/㎏/day의 농도로 각각 경구투여하였다. 투여 24시간 후에 각각의 치사율을 조사한 결과, 대조군과 2g/㎏/day 농도의 육두구 추출물 및 넥탄드린 B를 투여한 실험군에서 마우스가 모두 생존하는 것으로 확인되었다.This experiment was conducted to investigate the toxicity of a 10 to 30% aqueous ethanol solution of nutmeg and nexandrine B of the present invention to an animal body in an acute (within 24 hours) when an excessive amount of the extract was administered in a short period of time and to determine the mortality rate . Twenty mice of the general mouse ICR mouse line were assigned to each of the control and experimental groups. In the control group, only PEG-400 / tween-80 / ethanol (8/1/1, v / v / v) was administered, and the experimental group added nutmeg 10-30% ethanol extract and nectandrin B to the PEG-400 / tween-80. It was dissolved in / ethanol (8/1/1, v / v / v) and orally administered at a concentration of 2g / kg / day, respectively. After 24 hours of administration, the mice were found to survive in the control group and in the test group administered with 2 g / kg / day of nutmeg extract and nectandrin B, respectively.
8-2. 8-2. 실험군Experimental group 및 대조군의 장기 및 조직 독성 실험 And control organ organs and tissue toxicity experiments
장기 독성 실험은 본 발명의 본 발명의 육두구 10~30% 에탄올 수용액 추출물 및 넥탄드린 B를 최종농도를 2g/㎏/day로 하여 C57BL/6J 마우스(각 군당 10마리)에 투여하여 실험하였다. 동물의 각 장기(조직)에 미치는 영향을 조사하기 위하여 본 발명의 육두구 10~30% 에탄올 수용액 추출물 및 넥탄드린 B를 투여한 실험군과 PEG-400/tween-80/에탄올(8/1/1, v/v/v)만을 투여한 대조군의 동물들로부터 8주 후 혈액을 채취하여 GPT(glutamate-pyruvate transferase) 및 BUN(blood urea nitrogen)의 혈액 내 농도를 Select E(Vital Scientific NV, Netherland) 기기를 이용하여 측정하였다. 그 결과, 간독성과 관계있는 것으로 알려진 GPT와 신장독성과 관계있는 것으로 알려진 BUN의 경우, 대조군과 비교하여 실험군은 별다른 차이를 보이지 않았다. 또한, 각 동물로부터 간과 신장을 정취하여 통상적인 조직절편 제작과정을 거쳐 광학현미경으로 조직학적 관찰을 시행하였으며 모든 조직에서 특이한 이상이 관찰되지 않았다. Long-term toxicity experiment was conducted by administering the nutmeg 10-30% ethanol aqueous solution extract of the present invention and nectandrin B to C57BL / 6J mice (10 per group) with a final concentration of 2g / kg / day. In order to investigate the effects on the organs (tissues) of the animals, the experimental group administered with nutmeg 10-30% ethanol aqueous solution extract and nectandrin B and PEG-400 / tween-80 / ethanol (8/1/1, Blood was collected after 8 weeks from animals in the control group that received only v / v / v), and blood concentrations of glutamate-pyruvate transferase (GPT) and blood urea nitrogen (BUN) were selected from the Select E (Vital Scientific NV, Netherland) instrument. Measured using. As a result, GPT, which is known to be related to hepatotoxicity, and BUN, which is known to be related to renal toxicity, showed no significant difference compared to the control group. In addition, liver and kidney were sampled from each animal, and histological observation was performed with an optical microscope through a conventional tissue section production process. No abnormalities were observed in all tissues.
<< 제제예Formulation example 1 : 약학적 제제> 1: Pharmaceutical preparations>
1-1. 정제의 제조1-1. Manufacture of tablets
넥탄드린 B 200g을 락토오스 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활석 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다. 200 g of nectandrin B was mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. To this mixture was added a 10% gelatin solution, which was pulverized and passed through a 14-mesh sieve. This was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into tablets.
1-2. 주사액제의 제조1-2. Injection preparation
넥탄드린 B 1g, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다.1 g of nectandrin B, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20 DEG C for 30 minutes.
<< 제제예Formulation example 2 : 식품 제조> 2: Food manufacturing>
2-1. 조리용 양념의 제조2-1. Manufacture of cooking seasonings
본 발명의 육두구 30% 에탄올 수용액 추출물을 조리용 양념에 1 중량%로 첨가하여 건강 증진용 조리용 양념을 제조하였다.The spice for health promotion was prepared by adding 1% by weight of the
2-2. 밀가루 식품의 제조2-2. Manufacture of flour food products
본 발명의 육두구 30% 에탄올 수용액 추출물을 밀가루에 0.1 중량%로 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.The nutritional enhancer was prepared by adding 0.1% by weight of the
2-3. 2-3. 스프soup 및 육즙( And juicy ( graviesgravies )의 제조Manufacturing
본 발명의 육두구 30% 에탄올 수용액 추출물을 스프 및 육즙에 0.1 중량%로 첨가하여 건강 증진용 수프 및 육즙을 제조하였다.Health enhancing soup and juice were prepared by adding a 30% ethanol aqueous solution extract of nutmeg according to the present invention to soup and juice at 0.1 wt%.
2-4. 유제품(2-4. dairy product( dairydairy productsproducts )의 제조Manufacturing
본 발명의 육두구 30% 에탄올 수용액 추출물을 우유에 0.1 중량%로 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.The
2-5. 2-5. 야채주스Vegetable juice 제조 Produce
본 발명의 육두구 30% 에탄올 수용액 추출물 0.5g을 토마토 주스 또는 당근주스 1,000㎖에 가하여 건강 증진용 야채주스를 제조하였다.Healthy vegetable juice was prepared by adding 0.5 g of the
2-6. 2-6. 과일주스Fruit juice 제조 Produce
본 발명의 육두구 30% 에탄올 수용액 추출물 0.1g을 사과주스 또는 포도주스 1,000㎖에 가하여 건강 증진용 과일주스를 제조하였다.
0.1 g of
Claims (8)
[화학식 1]
Myristicin content is 0.5% by weight or less, Nectandrin B (Nectandrin B), Nectandrin A (Fragransin C1), Verrucosin (Verrucosin), Saucerinetinol (Saucernetindiol) and tetrahydrofuroguaiacin (Tetrahydrofuroguaiacin) pharmaceutical composition for the prevention or treatment of vascular diseases, characterized in that it contains an extract of 10-30% ethanol aqueous solution containing nutmeg containing one or more compounds selected from the group consisting of .
[Formula 1]
상기 육두구 10~30% 에탄올 수용액 추출물은, 추가로 이온교환수지를 사용하여 독성물질인 미리스티신 함량이 0.1 중량% 이하이고, 하기 화학식 1의 넥탄드린 B(Nectandrin B), 넥탄드린 A(Nectandrin A), 프라그란신 C1(Fragransin C1), 베루코신(Verrucosin), 사우서네틴디올(Saucernetindiol) 및 테트라하이드로푸로구아이아신(Tetrahydrofuroguaiacin)으로 이루어진 군 중에서 선택되는 1종 이상의 화합물이 포함된 것을 특징으로 하는 혈관 질환의 예방 또는 치료용 약학 조성물.
[화학식 1]
The method of claim 1,
The nutmeg 10-30% aqueous solution of ethanol extract, the content of myristicin, which is a toxic substance using an ion exchange resin, 0.1 wt% or less, Nectandrin B of Formula 1, Nectandrin A (Nectandrin) A), fragransin C1 (Fragransin C1), berucosin (Verrucosin), Sausnetinediol (Saucernetindiol) and tetrahydrofuroguaiacin (Tetrahydrofuroguaiacin) is characterized in that it contains at least one compound selected from the group consisting of Pharmaceutical composition for the prevention or treatment of vascular diseases.
[Formula 1]
상기 약학 조성물은 eNOS(endothelial nitric oxide synthase) 인산화에 의한 NO(nitric oxide) 형성 증가 및 혈관 내벽 비후화 억제 효과가 있는 것을 특징으로 하는 혈관 질환의 예방 또는 치료용 약학 조성물.3. The method according to claim 1 or 2,
The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of vascular diseases, characterized in that it has an effect of increasing the formation of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) phosphorylation and inhibiting vascular wall thickening.
상기 혈관 질환은 동맥경화증, 고혈압, 협심증, 심근경색, 허혈성 심장질환, 심부전, 경혈관 동맥 성형술 후 발생하는 합병증, 뇌경색, 뇌출혈, 및, 뇌졸중 중에서 선택되는 질환인 것을 특징으로 하는 혈관 질환의 예방 또는 치료용 조성물.3. The method according to claim 1 or 2,
The vascular disease is a disease selected from atherosclerosis, hypertension, angina pectoris, myocardial infarction, ischemic heart disease, heart failure, complications after angioplasty, cerebral infarction, cerebral hemorrhage, and stroke. Therapeutic composition.
[화학식 1]
Mysticin is a toxic substance is 0.5% by weight or less, Nectandrin B (Nectandrin B), Nectandrin A (Fragransin C1), Verrucosin (Verrucosin), Sau Prevention or improvement of vascular disease characterized by containing 10-30% ethanol aqueous solution of nutmeg containing one or more compounds selected from the group consisting of susnetinediol and tetrahydrofuroguaiacin Dietary supplements.
[Formula 1]
상기 혈관 질환은 동맥경화증, 고혈압, 협심증, 심근경색, 허혈성 심장질환, 심부전, 경혈관 동맥 성형술 후 발생하는 합병증, 뇌경색, 뇌출혈, 및, 뇌졸중 중에서 선택되는 질환인 것을 특징으로 하는 혈관 질환의 예방 또는 개선용 건강기능식품.The method of claim 5, wherein
The vascular disease is a disease selected from atherosclerosis, hypertension, angina pectoris, myocardial infarction, ischemic heart disease, heart failure, complications after angioplasty, cerebral infarction, cerebral hemorrhage, and stroke. Health functional food for improvement.
[화학식 1]
Nectandrin B, Nectandrin A, Fragransin C1, Verrucosin, Sauceretinediol and tetrahydrofuroguacin of Formula 1 Tetrahydrofuroguaiacin) pharmaceutical composition for the prevention or treatment of vascular diseases, characterized in that it contains at least one compound selected from the group consisting of as an active ingredient.
[Formula 1]
상기 약학 조성물은 eNOS(endothelial nitric oxide synthase) 인산화에 의한 NO(nitric oxide) 형성 증가 및 혈관 내벽 비후화 억제 효과가 있는 것을 특징으로 하는 혈관 질환의 예방 또는 치료용 약학 조성물.
The method of claim 7, wherein
The pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of vascular diseases, characterized in that it has an effect of increasing the formation of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) phosphorylation and inhibiting vascular wall thickening.
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