KR101779391B1 - A composition comprising compounds isolated from Agrimonia pilosa Ledeb. for preventing or treating metabolic disorder - Google Patents
A composition comprising compounds isolated from Agrimonia pilosa Ledeb. for preventing or treating metabolic disorder Download PDFInfo
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- KR101779391B1 KR101779391B1 KR1020150018426A KR20150018426A KR101779391B1 KR 101779391 B1 KR101779391 B1 KR 101779391B1 KR 1020150018426 A KR1020150018426 A KR 1020150018426A KR 20150018426 A KR20150018426 A KR 20150018426A KR 101779391 B1 KR101779391 B1 KR 101779391B1
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Abstract
본 발명은 짚신나물로부터 분리된 화합물을 포함하는 대사성 질환의 예방 또는 치료용 조성물에 관한 것이다. 상기 짚신나물로부터 분리된 화합물은 단백질 타이로신 탈인산화효소 1B 또는 알파-글루코시다아제의 저해 활성이 우수하여 당뇨병 또는 비만의 예방 또는 치료용 조성물로 유용하게 사용될 수 있다. The present invention relates to a composition for preventing or treating a metabolic disease comprising a compound isolated from a strawberry herb. The compound isolated from the strawberry herb has excellent inhibitory activity of protein tyrosine dephosphorylase 1B or alpha-glucosidase, and thus can be effectively used as a composition for preventing or treating diabetes or obesity.
Description
본 발명은 짚신나물(Agrimonia pilosa Ledeb.)로부터 분리된 화합물을 포함하는 대사성 질환의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating a metabolic disease comprising a compound isolated from a sandalwood ( Agrimonia pilosa Ledeb.).
최근 경제 발전에 따른 식생활 습관의 변화와 인구의 고령화 및 각종 스트레스와 관련하여 현대 생명과학의 큰 발전에도 불구하고 암을 비롯한 심혈관 질환, 대사성 질환의 발병도 증가하고 있는 추세이다. 특히, 상기 대사성 질환 중에서 당뇨병은 인슐린의 절대적 결핍 또는 저항성으로 인한 당대사 기능이상을 특징으로 하는 만성 소모성 질환으로 전신적인 무기력과 저항성 저하, 혈관장애, 뇌경색, 심근경색 등 기타 다양한 합병증을 유발하는 질병이다. 또한, 세계보건기구(WHO)에 따르면 3억 5천만 명의 사람들이 당뇨병을 겪고 있으며 2030년에는 그 숫자가 2배 더 증가할 것이라고 예상하였다(Danaei, G. et al., 2011).Recent developments in modern life science related to changes in dietary habits and population aging and various stresses due to recent economic developments are leading to an increase in the incidence of cardiovascular and metabolic diseases including cancer. Among the metabolic diseases, diabetes mellitus is a chronic wasting disease characterized by an abnormal glucose metabolism due to an absolute deficiency or resistance of insulin. It is a disease which causes various complications such as systemic insensitivity and resistance decrease, vascular disorder, cerebral infarction, myocardial infarction to be. In addition, the World Health Organization (WHO) estimated that 350 million people are suffering from diabetes and that by 2030 the number will increase by a factor of two (Danaei, G. et al., 2011).
당뇨병은 발병원인과 병태양상에 따라 크게 2가지 유형으로 구분되는데, 특정한 인간 림프구 항원(HLA)과 바이러스 감염 등으로 랑게르한스섬의 베타세포가 파괴되어 인슐린의 분비가 정상적으로 진행되지 않아 발병하는 인슐린 의존형인 제1형 당뇨병이 있으며, 운동부족과 비만, 과식, 스트레스 등으로 인하여 근육, 간, 지방조직 등 말초조직에서 인슐린에 대한 저항성 증가로 유발되는 인슐린 비의존성인 제2형 당뇨병이 이에 해당한다. 특히, 현대 사회의 노령화와 생활습관의 변화로 제2형 당뇨병이 당뇨병 전체 환자의 90% 이상을 차지하고 있고 그 수도 꾸준히 증가하는 추세이다. 제2형 당뇨병 발병의 주요 원인으로는 인슐린 저항성이며, 이는 일정량의 인슐린 농도에 대한 반응이 정상보다 감소되어 있는 상태를 말하며 일반적으로 유전적, 환경적인 요인으로 발생한다(Hossain, P. et al., 2007).Diabetes mellitus is divided into two types according to the cause and the pathogenesis of the disease. The insulin-dependent insulin-dependent diabetes mellitus is caused by the fact that the beta cells of Langerhans is destroyed by specific human lymphocyte antigen (HLA) Type 1 diabetes mellitus is an insulin-independent type 2 diabetes mellitus induced by increased resistance to insulin in peripheral tissues such as muscle, liver, and adipose tissue due to lack of exercise, obesity, overeating, and stress. In particular, with the aging of modern society and changes in lifestyle, type 2 diabetes accounts for more than 90% of all diabetics and the number is steadily increasing. The main cause of type 2 diabetes is insulin resistance, a condition in which the response to a given amount of insulin is less than normal, and is generally caused by genetic and environmental factors (Hossain, P. et al. , 2007).
비만은 단순히 과체중으로 인한 미용적인 영향 및 삶의 질이 낮아진다는 문제만이 아니라 주요 사망 원인이 되며, 대사성 질환에서 큰 비중을 차지하는 질환이라는 것으로 인식이 바뀌고 있다. 세계보건기구(WHO)의 통계에 따르면 비만은 발병률이 증가하여 2008년 기준으로 세계 인구의 약 6%인 4억 명 정도가 비만으로 조사되었고, 2015년에는 7억 명 이상이 될 것으로 예측하고 있다. 특히 OECD 국가의 경우, 성인 비만인구는 해마다 증가하는 추세이며, 미국의 경우 3명 중 1명은 비만인 것으로 조사되었다. 우리나라도 생활환경의 변화로 비만인구가 급증하고 있으며 체질량 지수(body mass index, BMI)가 25 이상인 한국 성인 비만인구는 매년 40여만 명씩 늘어 2005년 기준으로 10명 중 3명은 비만인 것으로 조사되었다. 또한, 질병관리본부의 자료에 따르면 1995년 비만인구는 전체 인구의 26.3%이었으나 2001년에는 전체 인구의 30.6%, 2005년에는 전체 인구의 31.5%로 급증하였고, 지속적인 증가 추세를 나타내고 있다.Obesity is not only a cosmetic effect due to overweight, and a lower quality of life, but also a major cause of death and a major contributor to metabolic diseases. According to statistics from the World Health Organization (WHO), the incidence of obesity is estimated to be around 4 billion, or about 6% of the world's population, estimated to be obesity by 2008, and by 2015 to more than 700 million . Especially in OECD countries, the adult obesity population is increasing year by year, and in the United States, one in three is obese. In Korea, the obesity population is increasing rapidly due to changes in the living environment, and the Korean adult obesity population with a body mass index (BMI) of 25 or more is increased by 40 million every year. As of 2005, 3 out of 10 were obese. According to data from the CDC, the obesity population in 1995 was 26.3% of the total population, but in 2001 it increased to 30.6% of the total population and to 31.5% of the total population in 2005, showing a steady increase trend.
한편, 단백질 타이로신 탈인산화효소 1B(protein tyrosine phosphatase 1B, PTP1B)는 하기 참고도 1에서와 같이, 인슐린 수용체(insulin receptor) 및 인슐린 수용체 기질(insulin receptor substrates)의 탈인산화를 일으켜 인슐린의 신호전달 기전을 방해함으로써 인슐린 저항성을 야기시키는 효소로 알려져 있다. 또한, 상기 단백질 타이로신 탈인산화 효소는 렙틴의 신호전달 과정에서도 렙틴 수용체 및 Jak에서 일어나는 인산화를 저해하고 렙틴 신호전달 기전을 억제함으로써 비만을 일으키는 원인으로도 알려져 있다(Malamas, M. S. et al., 2000).On the other hand, protein tyrosine phosphatase 1B (PTP1B) induces dephosphorylation of insulin receptors and insulin receptor substrates, as shown in the following Reference 1, Is known to be an enzyme that causes insulin resistance by interfering with insulin resistance. In addition, the protein tyrosine dephosphorylase is also known to cause obesity by inhibiting the leptin signal transduction mechanism and inhibiting phosphorylation induced by leptin receptor and Jak in the signal transduction of leptin (Malamas, MS et al., 2000) .
[참고도 1][Reference Figure 1]
비록, 현재까지의 단백질 타이로신 탈인산화효소 1B에 관한 연구는 상대적으로 초기 단계에 머물러 있지만, 최근 단백질 타이로신 탈인산화효소 1B의 생물학적 기능 및 질환 유발 기전이 밝혀짐에 따라 새로운 약물 개발의 타겟이 되고 있다(Thareja, S. et al., 2012). 특히, 당뇨, 비만, 암 등 난치성 질환에 있어서 단백질 타이로신 탈인산화효소 1B의 역할이 규명됨에 따라 이 효소의 저해를 타겟으로 하는 신약 개발에 많은 투자가 이루어지고 있다. 이에 대한 예로서, 단백질 타이로신 탈인산화효소 1B(protein tyrosine phosphatase 1B, PTP1B) 유전자를 제거한 쥐에서는 인슐린 내성이 제거되어 제2형 당뇨병이 유발되지 않았으며, 비만이 저해되는 현상이 보고되었으며(Elchebly, M. et al., 1999), 단백질 타이로신 탈인산화효소 1B(protein tyrosine phosphatase 1B, PTP1B)를 저해하는 물질들이 항당뇨 효과를 보이는 현상이 관찰되고 있다(Klaman, L. D. et al., 2000).Although studies on protein tyrosine dephosphorylase 1B to date have remained at a relatively early stage, recently, the biological function and pathogenesis mechanism of protein tyrosine dephosphorylase 1B has been clarified and it has become a target of new drug development (Thareja, S. et al., 2012). Particularly, as the role of protein tyrosine dephosphorylase 1B in the intractable diseases such as diabetes, obesity and cancer is clarified, much investment has been made in the development of new drugs targeting the inhibition of this enzyme. As an example of this, in rats in which protein tyrosine phosphatase 1B (PTP1B) gene was removed, insulin resistance was eliminated and type 2 diabetes was not induced, and obesity was inhibited (Elchebly, M. et al., 1999), and substances that inhibit protein tyrosine phosphatase 1B (PTP1B) have been shown to exhibit antidiabetic effects (Klaman, LD et al., 2000).
현재까지 임상에 들어간 단백질 타이로신 탈인산화효소 1B를 비롯한 각종 타이로신 탈인산화효소의 저해제는 하기 참고도 2와 같은데, 대부분 합성 화합물로서 낮은 생체이용률, 독성 및 부작용으로 인해 임상시험에서 탈락된 경우가 많다. 따라서 안전성이 높은 천연물 유래의 저해제 개발이 요구되고 있다(Johnson, T. O. et al., 2002).The inhibitor of various tyrosine dephosphorylases including the protein tyrosine dephosphorylase 1B that has entered into clinical practice to date is shown in Reference 2 in the following reference. Most of the compounds are eliminated in clinical trials because of low bioavailability, toxicity and side effects. Therefore, it is required to develop an inhibitor derived from a highly safe natural product (Johnson, T. O. et al., 2002).
[참고도 2][Reference Figure 2]
알파-글루코시다아제(α-glucosidase)는 소장의 융모에 존재하는 소화 효소로 이당류나 소당류를 탄수화물의 소화흡수 상태인 단당류로 가수분해하는 역할을 한다. 따라서 알파-글루코시다아제 저해물질은 십이지장을 비롯한 공장 상부에서 탄수화물의 가수분해를 저해(소화 흡수율을 저하)시켜 혈당치의 상승을 억제할 수 있으므로 당뇨병, 비만증, 과당증 등 성인병의 치료 목적으로 이용될 수 있다. 또한, 혈당 강하 조절에 대한 이용목적으로, 탄수화물 대사에 필수적인 알파-글루코시다아제 저해에 대한 많은 연구가 이루어져 왔다(Tewari, N. et al., 2003).Α-glucosidase is a digestive enzyme present in the villi of the small intestine and serves to hydrolyze disaccharides and small sugars into monosaccharides which are digestion and absorption state of carbohydrates. Therefore, the alpha-glucosidase inhibitor can inhibit hydrolysis of carbohydrates (lower digestion and absorption rate) at the upper part of the plant including the duodenum, thereby suppressing the increase of blood glucose level, and thus is used for the treatment of adult diseases such as diabetes, obesity, . In addition, for use in controlling blood glucose lowering, many studies have been conducted on alpha-glucosidase inhibition essential for carbohydrate metabolism (Tewari, N. et al., 2003).
짚신나물은 다년생 숙근초로 장미과에 속하며 한국, 중국, 일본 등에서 서식한다. 우리나라의 경우에는 야산의 길가, 들판 등에 흔히 자라며, 선학초, 용아, 용아초, 황아초, 황용초, 지선초 등으로 부르기도 한다. 전통적으로 민간요법, 녹즙 등으로 널리 이용되어 왔고, 폐암, 간암, 식도암, 종양, 통증제거, 지형, 지사, 토혈, 혈토, 자궁출혈, 열기 등의 약용으로 널리 이용되어 왔다. 그 성분으로는 아그리모닌(agrimonin), 아그리모노라이드(agrimonolide), 탄닌(tannin), 스테롤(sterol), 유기산, 사포닌 등이 포함되어 있으며, 수렴지혈(收斂止血), 익기강심(益氣强心), 지사, 지혈(止血), 건위(健胃) 등의 효능이 있는 것으로 알려져 있다(정보섭 et al., 1998; Jung, M. et al., 2007; Miyamoto, K. et al., 1987; Jung, C. H. et al., 2010; Shin, W. J. et al., 2010).It is a perennial herbaceous perennial plant belonging to Rosaceae and it lives in Korea, China, Japan and others. In Korea, it grows frequently in the roadside of the mountains and fields, and it is also called Seonghakcho, Yonga, Yongaeko, Hwanghaeko, Hwangyongjang, Gijunseok. Traditionally, it has been widely used for folk medicine, green juice, etc. and has been widely used for medicines such as lung cancer, liver cancer, esophageal cancer, tumor, pain relief, topography, branching, blood, hematoma, uterine bleeding and fever. Its components include agrimonin, agrimonolide, tannin, sterol, organic acid, saponin, etc., and it can be used for the treatment of constipation hemostasis, Jung, M. et al., 2007; Miyamoto, K. et al., 1998). In the present study, 1987; Jung, CH et al., 2010; Shin, WJ et al., 2010).
짚신나물을 이용한 다양한 연구(한국특허 제726364호; 한국특허 제1121514호; 한국특허 제1223662호)가 이루어지고 있는 가운데 짚신나물의 추출물을 사용하여 당뇨 및 당뇨 합병증 또는 인슐린 저항성 증후군의 예방 및 치료에 관한 연구는 보고되었으나(Liu, X. et al., 2014; 한국특허 제2014-0084928호; 한국특허 제2014-0077237호), 짚신나물로부터 분리된 화합물이 당뇨병이나 비만과 같은 대사성 질환에 대한 치료 효과가 있음을 확인한 이전 보고는 아직 없다.A variety of studies using strawberry herbs (Korean Patent No. 726364; Korean Patent No. 1121514; Korean Patent No. 1223662) have been conducted, and the use of the extract of strawberry herb has been used to prevent and treat diabetic and diabetic complications or insulin resistance syndrome (Liu, X. et al., 2014; Korean Patent No. 2014-0084928; Korean Patent No. 2014-0077237), a compound isolated from a strawberry herb has been used for treatment of metabolic diseases such as diabetes and obesity There is no previous report confirming the effectiveness.
본 발명의 목적은 짚신나물로부터 분리된 화합물을 포함하는 대사성 질환의 예방 또는 치료용 조성물을 제공하는데 있다. 보다 자세하게는, 짚신나물로부터 분리된 아피게닌-7-O-베타-D-글루쿠로니드-6"-메틸에스터(apigenin-7-O-β-D-glucuronide-6"-methyl ester, 화합물 1), 케르세틴-7-O-베타-D-글루코시드(quercetin-7-O-β-D-glucoside, 화합물 2), 캄페롤-3-O-알파-L-람노사이드(kaempferol-3-O-α-L-rhamnoside, 화합물 3) 및 메틸 2-하이드록실 트리코사노에이트(methyl 2-hydroxyl tricosanoate, 화합물 4)로 이루어진 군 중에서 선택되는 1종 이상의 화합물을 포함하는 대사성 질환의 예방 또는 치료용 조성물을 제공하는데 있다.It is an object of the present invention to provide a composition for preventing or treating a metabolic disease comprising a compound isolated from a strawberry herb. More specifically, the apigenin-7-O-beta-D-glucuronide-6 "-methyl ester, compound O-beta-D-glucoside (Compound 2), camelol-3-O-alpha-L-rhamnoside (kaempferol- O-alpha-L-rhamnoside, compound 3) and methyl 2-hydroxyl tricosanoate (compound 4), for the prevention or treatment of a metabolic disease comprising at least one compound selected from the group consisting of Compositions.
본 발명은 짚신나물(Agrimonia pilosa Ledeb.)로부터 분리된 화합물을 포함하는 대사성 질환의 예방 또는 치료용 조성물에 관한 것이다. 보다 자세하게는, 짚신나물로부터 분리된 하기 화학식 1의 아피게닌-7-O-베타-D-글루쿠로니드-6"-메틸에스터(apigenin-7-O-β-D-glucuronide-6"-methyl ester, 화합물 1), 케르세틴-7-O-베타-D-글루코시드(quercetin-7-O-β-D-glucoside, 화합물 2), 캄페롤-3-O-알파-L-람노사이드(kaempferol-3-O-α-L-rhamnoside, 화합물 3) 및 메틸 2-하이드록실 트리코사노에이트(methyl 2-hydroxyl tricosanoate, 화합물 4)로 이루어진 군 중에서 선택되는 1종 이상의 화합물을 포함하는 대사성 질환의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a method for producing the < RTI ID = pilosa Ledeb. ≪ / RTI > The present invention also relates to a composition for preventing or treating metabolic diseases. More specifically, the apigenin-7-O-beta-D-glucuronide-6 "-methyl ester of the formula (1) methyl ester, compound 1), quercetin-7-O-β-D-glucoside (compound 2), camperol-3-O-alpha-L-lumoside a metabolic disease comprising at least one compound selected from the group consisting of kaempferol-3-O- alpha -L-rhamnoside, compound 3) and methyl 2-hydroxyl tricosanoate (compound 4) Prevention or treatment of cancer.
[화학식 1][Chemical Formula 1]
상기 대사성 질환은 비만 또는 당뇨병 중에서 선택되는 질환일 수 있다.The metabolic disease may be a disease selected from obesity or diabetes.
또한, 상기 화합물은 단백질 타이로신 탈인산화효소 1B(protein tyrosine phosphatase 1B, PTP1B) 또는 알파-글루코시다아제(α-glucosidase)의 활성을 저해하는 것을 특징으로 하는 대사성 질환의 예방 또는 치료용 조성물에 관한 것이다.Also, the present invention relates to a composition for preventing or treating metabolic diseases, which inhibits the activity of protein tyrosine phosphatase 1B (PTP1B) or alpha-glucosidase .
상기 조성물은 약제학적으로 허용되는 담체, 부형제 또는 희석제를 추가하여 약제학적 투여형으로 제형화되는 것을 특징으로 하는 대사성 질환의 예방 또는 치료용 조성물에 관한 것이다.Wherein the composition is formulated into a pharmaceutical dosage form by addition of a pharmaceutically acceptable carrier, excipient or diluent, to a composition for the prevention or treatment of metabolic diseases.
또 다른 일면에 있어서, 본 발명은 짚신나물로부터 분리된 아피게닌-7-O-베타-D-글루쿠로니드-6"-메틸에스터(apigenin-7-O-β-D-glucuronide-6"-methyl ester, 화합물 1), 케르세틴-7-O-베타-D-글루코시드(quercetin-7-O-β-D-glucoside, 화합물 2), 캄페롤-3-O-알파-L-람노사이드(kaempferol-3-O-α-L-rhamnoside, 화합물 3) 및 메틸 2-하이드록실 트리코사노에이트(methyl 2-hydroxyl tricosanoate, 화합물 4)로 이루어진 군 중에서 선택되는 1종 이상의 화합물을 포함하는 대사성 질환의 예방 또는 개선용 건강기능식품에 관한 것이다.In yet another aspect, the present invention provides a pharmaceutical composition comprising an apigenin-7-O-beta-D-glucuronide-6 " -methyl ester, compound 1), quercetin-7-O-beta-D-glucoside (compound 2), camperol-3-O-alpha-L- a metabolic disease comprising at least one compound selected from the group consisting of kaempferol-3-O- alpha -L-rhamnoside (compound 3) and methyl 2-hydroxyl tricosanoate (compound 4) The present invention relates to a health functional food for preventing or ameliorating osteoporosis.
또한, 본 발명은 짚신나물을 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매로 짚신나물 추출물을 제조하는 단계; 상기 짚신나물 추출물을 메틸렌클로라이드, 에틸아세테이트, n-부탄올을 이용하여 순차적으로 분획하는 단계; 및 상기 각 분획물을 크로마토그래피를 이용하여 아피게닌-7-O-베타-D-글루쿠로니드-6"-메틸에스터(apigenin-7-O-β-D-glucuronide-6"-methyl ester, 화합물 1), 케르세틴-7-O-베타-D-글루코시드(quercetin-7-O-β-D-glucoside, 화합물 2), 캄페롤-3-O-알파-L-람노사이드(kaempferol-3-O-α-L-rhamnoside, 화합물 3) 및 메틸 2-하이드록실 트리코사노에이트(methyl 2-hydroxyl tricosanoate, 화합물 4) 화합물을 분리하는 방법에 관한 것이다.Also, the present invention provides a method for producing a strawberry herb, comprising the steps of: preparing a strawberry herb extract by using water, a lower alcohol of C1 to C4 or a mixed solvent thereof; Sequentially fractionating the strawberry seed extract using methylene chloride, ethyl acetate and n-butanol; And each of the above fractions was subjected to apigenin-7-O-beta-D-glucuronide-6 "-methyl ester, Compound 1), quercetin-7-O-beta-D-glucoside (Compound 2), camperol-3-O-alpha-L-rhamnoside kaempferol- -O-alpha-L-rhamnoside, compound 3) and methyl 2-hydroxyl tricosanoate (compound 4) compound.
이하 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 화합물은 짚신나물을 물, 저급 알코올 또는 이들의 혼합용매로 추출하여 분리될 수 있다. 바람직하게는, 짚신나물을 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매 추출물을 크로마토그래피로 분획하여 얻을 수 있다. 보다 바람직하게는, 짚신나물 지상부를 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매로 짚신나물 추출물을 제조하는 단계; 상기 짚신나물 추출물을 메틸렌클로라이드, 에틸아세테이트, n-부탄올을 이용하여 순차적으로 분획하는 단계; 및 상기 각 분획물을 크로마토그래피를 이용하여 화합물을 분리하는 단계를 포함하여 얻을 수 있다.The compound of the present invention can be isolated by extracting the strawberry herb with water, a lower alcohol or a mixed solvent thereof. Preferably, the strawberry herb can be obtained by fractionation of water, C1 to C4 lower alcohols or a mixed solvent extract thereof by chromatography. More preferably, the step of preparing the strawberry herb extract by using water, a lower alcohol of C1 to C4 or a mixed solvent thereof is used as the root portion of the strawberry herb; Sequentially fractionating the strawberry seed extract using methylene chloride, ethyl acetate and n-butanol; And separating the compounds by chromatography on each of the fractions.
상기 크로마토그래피는 실리카겔 컬럼 크로마토그래피(silica gel column chromatography), RP-18 컬럼 크로마토그래피(RP-18 column chromatography), 박층 크로마토그래피(thin layer chromatography, TLC), 이온교환수지 크로마토그래피(ion exchange resin chromatography), 중압 액체 크로마토그래피(medium pressure liquid chromatography), 실리카겔 진공 액체 크로마토그래피(silica gel vacuum liquid chromatography) 및 고성능 액체 크로마토그래피(high performance liquid chromatography, HPLC) 중에서 선택될 수 있다. The chromatography can be carried out by silica gel column chromatography, RP-18 column chromatography, thin layer chromatography (TLC), ion exchange resin chromatography ), Medium pressure liquid chromatography, silica gel vacuum liquid chromatography and high performance liquid chromatography (HPLC).
한편, 본 발명의 화합물은 당해 기술 분야에서 통상적인 방법에 따라 합성될 수 있으며, 약학적으로 허용 가능한 염으로 제조될 수도 있다. Meanwhile, the compound of the present invention can be synthesized according to a conventional method in the art, and can also be prepared as a pharmaceutically acceptable salt.
또한, 본 발명은 짚신나물로부터 분리된 아피게닌-7-O-베타-D-글루쿠로니드-6"-메틸에스터(apigenin-7-O-β-D-glucuronide-6"-methyl ester, 화합물 1), 케르세틴-7-O-베타-D-글루코시드(quercetin-7-O-β-D-glucoside, 화합물 2), 캄페롤-3-O-알파-L-람노사이드(kaempferol-3-O-α-L-rhamnoside, 화합물 3) 및 메틸 2-하이드록실 트리코사노에이트(methyl 2-hydroxyl tricosanoate, 화합물 4)로 이루어진 군 중에서 선택되는 1종 이상의 화합물을 포함하는 대사성 질환의 예방 또는 치료용 약학 조성물을 제공한다. 상기 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 상기 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 present invention also relates to apigenin-7-O-β-D-glucuronide-6 "-methyl ester, apigenin-7-O- Compound 1), quercetin-7-O-beta-D-glucoside (Compound 2), camperol-3-O-alpha-L-rhamnoside kaempferol- A compound of formula (I), a compound of formula (I), a compound of formula (I), a compound of formula (I), a compound of formula A pharmaceutical composition is provided. The pharmaceutical composition containing the compound can be formulated in the form of oral, granule, tablet, capsule, suspension, emulsion, syrup, aerosol or the like oral preparation, external preparation, suppository and sterilized injection solution according to a conventional method Can be used. 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 contain at least one excipient, such as 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. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.
본 발명의 화합물을 포함하는 약학 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중, 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 comprising the compound of the present invention will vary depending on the age, sex, body weight, the specific disease or condition to be 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 화합물을 포함하는 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 화합물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있는 약제이다.The pharmaceutical compositions comprising the compounds of the present invention may be administered to mammals such as rats, livestock, humans, and the like in a variety of 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 compound of the present invention has little toxicity and side effects, it can be safely used even for long-term administration for preventive purposes.
또한, 본 발명은 짚신나물로부터 분리된 아피게닌-7-O-베타-D-글루쿠로니드-6"-메틸에스터(apigenin-7-O-β-D-glucuronide-6"-methyl ester, 화합물 1), 케르세틴-7-O-베타-D-글루코시드(quercetin-7-O-β-D-glucoside, 화합물 2), 캄페롤-3-O-알파-L-람노사이드(kaempferol-3-O-α-L-rhamnoside, 화합물 3) 및 메틸 2-하이드록실 트리코사노에이트(methyl 2-hydroxyl tricosanoate, 화합물 4)로 이루어진 군 중에서 선택되는 1종 이상의 화합물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 당뇨 또는 비만과 같은 대사성 질환의 예방 또는 개선용 건강기능식품을 제공한다. 상기 화합물은 본 발명의 건강기능식품에 0.001~100 중량%로 하여 첨가될 수 있다. 본 발명의 건강기능식품은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제 등이 있다.The present invention also relates to apigenin-7-O-β-D-glucuronide-6 "-methyl ester, apigenin-7-O- Compound 1), quercetin-7-O-beta-D-glucoside (Compound 2), camperol-3-O-alpha-L-rhamnoside kaempferol- At least one compound selected from the group consisting of -O-α-L-rhamnoside, compound 3, and methyl 2-hydroxyl tricosanoate (compound 4) And a metabolic disease such as diabetes or obesity. The compound may be added in an amount of 0.001 to 100% by weight to the health functional food of the present invention. The health functional food of the present invention includes forms such as tablets, capsules, pills, and liquids, and examples of foods to which the compound of the present invention can be added include various foods, beverages, gums, tea, vitamins .
본 발명은 짚신나물로부터 분리된 화합물을 포함하는 대사성 질환의 예방 또는 치료용 조성물에 관한 것이다. 상기 짚신나물로부터 분리된 화합물은 단백질 타이로신 탈인산화효소 1B 또는 알파-글루코시다아제에 대한 저해 활성이 우수하여 대사성 질환의 예방 또는 치료용 조성물로 유용하게 사용될 수 있다.The present invention relates to a composition for preventing or treating a metabolic disease comprising a compound isolated from a strawberry herb. The compound isolated from the strawberry herb has excellent inhibitory activity against protein tyrosine dephosphorylase 1B or alpha-glucosidase, and thus can be effectively used as a composition for preventing or treating metabolic diseases.
도 1은 짚신나물 에탄올 추출물, 에틸아세테이트 분획물, 짚신나물로부터 분리된 화합물 1~4, 양성대조 물질인 RK-682(3-hexadecanoyl-5-hydroxymethyl-tetronic acid)의 단백질 타이로신 탈인산화효소 1B 저해 효과(IC50)를 나타내는 그래프이다.
도 2는 짚신나물 에탄올 추출물, 에틸아세테이트 분획물, 짚신나물로부터 분리된 화합물 1~4, 양성대조 물질인 아카보즈(acarbose)의 알파-글루코시다아제 저해 효과(IC50)를 나타내는 그래프이다.1 shows the inhibition effect of protein tyrosine dephosphorylase 1B on 3-hexadecanoyl-5-hydroxymethyl-tetronic acid (RK-682), a positive control substance, compounds 1 to 4 isolated from strawberry seed oil ethanol extract, ethyl acetate fraction, (IC 50 ).
FIG. 2 is a graph showing the alpha-glucosidase inhibitory effect (IC 50 ) of the positive control substance acarbose, Compounds 1 to 4 isolated from strawberry seed oil ethanol extract, ethyl acetate fraction, and straw sandwich.
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나, 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the intention is to provide an exhaustive, complete, and complete disclosure of the principles of the invention to those skilled in the art.
<실시예 1. 짚신나물 유래 화합물의 분리>≪ Example 1: Isolation of a compound derived from strawberry seeds >
본 발명에서 사용된 짚신나물(Agrimonia pilosa Ledeb.) 지상부는 2011년에 한국 대구가톨릭대학교에 있는 재배농장에서 구입하였다. 상기 짚신나물 지상부 32kg을 80%[v/v] 에탄올 40ℓ로 실온에서 3회 추출한 후 여과하였고, 여과된 에탄올 추출액을 농축하여 2.52kg의 에탄올 추출물을 얻었다. 상기 에탄올 추출물(2.52kg)을 2ℓ의 물에 현탁하여, 메틸렌클로라이드(2ℓ×5), 에틸아세테이트(2ℓ×5), n-부탄올(2ℓ×5)을 순차적으로 가해 메틸렌클로라이드, 에틸아세테이트, n-부탄올 분획물(각각 1.13kg, 165g, 500g)을 얻었고, 마지막으로 물층 잔사를 포함하는 분획물(700g)을 얻었다. 이 후 상기 4가지 분획물에서 단백질 타이로신 탈인산화효소 1B에 대해 상대적으로 강한 저해 활성을 갖는 에틸아세테이트 분획물에서 본 발명의 화합물을 분리하였다.The top portion of the sandworm ( Agrimonia pilosa Ledeb.) Used in the present invention was purchased at a cultivation farm in Catholic University, Daegu, Korea in 2011. 32 kg of the above ground straw portion was extracted three times at room temperature with 40 L of 80% [v / v] ethanol and filtered. The filtered ethanol extract was concentrated to obtain 2.52 kg of ethanol extract. The ethanol extract (2.52 kg) was suspended in 2 L of water and methylene chloride (2 L × 5), ethyl acetate (2 L × 5) and n-butanol (2 L × 5) -Butanol fractions (1.13 kg, 165 g, and 500 g, respectively) were obtained. Finally, a fraction (700 g) containing the water layer residue was obtained. The compounds of the present invention were then isolated from the ethyl acetate fraction having a relatively strong inhibitory activity against protein tyrosine dephosphorylase 1B in the four fractions.
상기 에틸아세테이트 분획물(165g)은 실리카겔 컬럼 및 n-헥산-에틸아세테이트를 이용하여 6개의 소분획물(Fr. EA1-EA6)을 얻었다. 이 중 Fr. EA2 소분획물(3.3g)에 실리카겔 컬럼 및 헥산-아세톤을 이용하여 4개의 소분획물 Fr. EA2.1-EA2.4를 얻었다. Fr. EA2.1 소분획물은 다시 실리카겔 컬럼 및 헥산-아세톤(95:5[v:v])을 이용하여 화합물 4(20.8mg)를 분리하였다.The ethyl acetate fraction (165 g) obtained six small fractions (Fr. EA1-EA6) using a silica gel column and n-hexane-ethyl acetate. Of these, Fr. A small fraction of EA2 (3.3 g) was fractionated by silica gel column and hexane-acetone into four small fractions Fr. EA2.1-EA2.4 was obtained. Fr. The EA2.1 fraction was further purified by silica gel column and hexane-acetone (95: 5 [v: v]) to separate Compound 4 (20.8 mg).
또한, Fr. EA3(6.4g) 소분획물은 RP-18 컬럼 및 50%[v/v] 메탄올 조건으로 분리하여 4개의 소분획물 Fr. EA3.1-EA3.4를 얻었다. Fr. EA3.3 소분획물은 다시 실리카겔 컬럼 및 메틸렌클로라이드-메탄올-물(7:1:0.1[v:v:v])을 이용하여 화합물 1(68.2mg)을 분리하였다.Also, Fr. The EA3 (6.4 g) fraction was separated into RP-18 column and 50% [v / v] methanol, and four small fractions Fr. EA3.1-EA3.4 was obtained. Fr. The EA3.3 fractions were again separated on silica gel column and methylene chloride-methanol-water (7: 1: 0.1 [v: v: v]) to give Compound 1 (68.2 mg).
또한, Fr. EA4(5.7g) 소분획물은 RP-18 컬럼 및 40%[v/v] 메탄올 조건으로 분리하여 5개의 소분획물 Fr. EA4.1-EA4.5를 얻었다. 그 중 Fr. EA4.3, Fr. EA4.4 소분획물들은 각각 다시 실리카겔 컬럼 및 메틸렌클로라이드-메탄올-물(7:1:0.1[v:v:v])을 이용하여 Fr. EA4.3에서 화합물 3(38.0mg)을, Fr. EA4.4에서 화합물 2(2.5mg)를 각각 분리하였다.Also, Fr. The EA4 (5.7 g) subfractions were separated by RP-18 column and 40% [v / v] methanol conditions to give five small fractions Fr. EA4.1-EA4.5 was obtained. Among them, Fr. EA4.3, Fr. The EA4.4 sub-fractions were further purified using silica gel column and methylene chloride-methanol-water (7: 1: 0.1 [v: v: v]). Compound 3 (38.0 mg) was obtained in EA4.3 from Fr. Compound 2 (2.5 mg) was isolated from EA4.4.
<실시예 2. 짚신나물 유래 화합물의 물리화학적 구조 확인><Example 2> Identification of the physicochemical structure of the compound derived from the sandalwood herbarium>
실시예 2-1. 아피게닌-7-O-베타-D-글루쿠로니드-6"-메틸에스터 (화합물 1)Example 2-1. Apigenin-7-O-beta-D-glucuronide-6 "-methyl ester (Compound 1)
apigenin-7-O-β-D-glucuronide-6"-methyl ester;apigenin-7-O- [beta] -D-glucuronide-6 "-methyl ester;
pale yellow amorphous powder;pale yellow amorphous powder;
IR (KBr) ν max cm-1: 3364, 1750, 1670, 1620, 1600, 1565, 1510, 1180, 1190, 1090, 1050, 840;IR (KBr) ? Max cm -1 : 3364, 1750, 1670, 1620, 1600, 1565, 1510, 1180, 1190, 1090, 1050, 840;
1H NMR (C5D5N) δ: 4.44-4.62 (3H, m, H-2"-4"), 3.66 (3H, s, OCH3), 4.95 (1H, d, J = 9.5 Hz, H-5"), 6.05 (1H, d, J = 6.0 Hz, H-1"), 6.90 (1H, d, J = 2.0 Hz, H-6), 6.91 (1H, s, H-3), 7.16 (1H, J = 2.0 Hz, H-8), 7.21 (2H, d, J = 8.5 Hz, H-3', 5'), 7.85 (2H, d, J = 8.5 Hz, H-2', 6'), 13.63 (1H, br s, 5-OH); 1 H NMR (C 5 D 5 N) δ: 4.44-4.62 (3H, m, H-2 "-4"), 3.66 (3H, s, OCH 3), 4.95 (1H, d, J = 9.5 Hz, H-5 "), 6.05 (1H, d, J = 6.0 Hz, H-1"), 6.90 (1H, d, J = 2.0 Hz, H- 7.16 (1H, J = 2.0 Hz , H-8), 7.21 (2H, d, J = 8.5 Hz, H-3 ', 5'), 7.85 (2H, d, J = 8.5 Hz, H-2 ', 6 '), 13.63 (1H, br s, 5-OH);
13C NMR (C5D5N) δ: 51.0 (OCH3), 71.7 (C-4"), 73.3 (C-2"), 76.1 (C-5"), 76.4 (C-3"), 94.2 (C-8), 99.5 (C-1"), 100.6 (C-6), 102.9 (C-3), 105.7 (C-10), 115.7 (C-3', 5'), 120.9 (C-1'), 127.9 (C-2', 6'), 156.8 (C-9), 161.6 (C-4'), 161.7 (C-5), 162.5 (C-7), 163.9 (C-2), 169.1 (C-6"), 181.7 (C-4); 13 C NMR (C 5 D 5 N) δ: 51.0 (OCH 3), 71.7 (C-4 "), 73.3 (C-2"), 76.1 (C-5 "), 76.4 (C-3"), (C-8), 99.5 (C-1), 100.6 (C-6), 102.9 (C-3), 105.7 -1 '), 127.9 (C-2', 6 '), 156.8 (C-9), 161.6 ), 169.1 (C-6 "), 181.7 (C-4);
FAB-MS m/z 461 [M+H]+ (C22H20O11).FAB-MS m / z 461 [ M + H] + (C 22 H 20 O 11).
실시예 2-2. 케르세틴-7-O-베타-D-글루코시드 (화합물 2)Example 2-2. Quercetin-7-O-beta-D-glucoside (Compound 2)
quercetin-7-O-β-D-glucoside;quercetin-7-O- [beta] -D-glucoside;
yellow powder;yellow powder;
mp. 254-256℃;mp. 254-256 占 폚;
1H NMR (CD3OD) δ: 7.75 (1H, d, J = 2.0 Hz, H-2'), 7.65 (1H, dd, J = 2.0, 8.4 Hz, H-6'), 6.87 (1H, d, J = 8.4 Hz, H-5'), 6.74 (1H, d, J = 2.4 Hz, H-8), 6.45 (1H, d, J = 2.0 Hz, H-6), 5.04 (1H, d, J = 7.2 Hz, H-1"), 3.30-3.92 (6H, m, H-2", H-3", H-4", H-5", H-6a", and H-6b"); 1 H NMR (CD 3 OD) δ: 7.75 (1H, d, J = 2.0 Hz, H-2 '), 7.65 (1H, dd, J = 2.0, 8.4 Hz, H-6'), 6.87 (1H, d, J = 8.4 Hz, H -5 '), 6.74 (1H, d, J = 2.4 Hz, H-8), 6.45 (1H, d, J = 2.0 Hz, H-6), 5.04 (1H, d H-6b "," J = 7.2 Hz, H-1"), 3.30-3.92 (6H, m, H-2 ", H- );
13C NMR (CD3OD) δ: 146.4 (C-2), 137.8 (C-3), 177.6 (C-4), 162.3 (C-5), 100.3 (C-6), 164.6 (C-7), 95.7 (C-8), 157.9 (C-9), 106.4 (C-10), 124.1 (C-1'), 116.3 (C-2'), 149.1 (C-3'), 148.9 (C-4'), 116.4 (C-5'), 122.0 (C-6'), 101.8 (C-1"), 74.9 (C-2"), 78.0 (C-3"), 71.5(C-4"), 78.5 (C-5"), 62.6 (C-6"); 13 C NMR (CD 3 OD) ?: 146.4 (C-2), 137.8 (C-3), 177.6 (C-4), 162.3 ), 95.7 (C-8), 157.9 (C-9), 106.4 (C-10), 124.1 4 '), 116.4 (C-5'), 122.0 (C-6 '), 101.8 "), 78.5 (C-5"), 62.6 (C-6 ");
FAB-MS m/z 465.10 [M+H]+ (C21H20O12).FAB-MS m / z 465.10 [ M + H] + (C 21 H 20 O 12).
실시예 2-3. 캄페롤-3-O-알파-L-람노사이드 (화합물 3)Examples 2-3. 3-O-alpha-L-lambsoside (Compound 3)
kaempferol-3-O-α-L-rhamnoside;kaempferol-3-O- [alpha] -L-rhamnoside;
yellow powder; yellow powder;
IR (KBr) ν max cm-1: 3299, 1659, 1615, 1507, 1372, 1315, 1240, 1169, 882;IR (KBr) ? Max cm -1 : 3299, 1659, 1615, 1507, 1372, 1315, 1240, 1169, 882;
1H NMR (CD3OD) δ: 1.65 (3H, d, J = 6.1 Hz, H-6"), 8.55 (2H, d, J = 8.9 Hz, H-2', 6'), 7.38 (2H, d, J = 8.9 Hz, H-3', 5'), 7.07 (1H, d, J = 2.1 Hz, H-8), 6.83 (1H, d, J = 2.1 Hz, H-6), 7.07 (1H, d, J = 2.1 Hz, H-8), 6.29 (1H, d, J = 1.5 Hz, H-1"); 1 H NMR (CD 3 OD) δ: 1.65 (3H, d, J = 6.1 Hz, H-6 "), 8.55 (2H, d, J = 8.9 Hz, H-2 ', 6'), 7.38 (2H , d, J = 8.9 Hz, H-3 ', 5'), 7.07 (1H, d, J = 2.1 Hz, H-8), 6.83 (1H, d, J = 2.1 Hz, H-6), 7.07 (1H, d, J = 2.1 Hz, H-8), 6.29 (1H, d, J = 1.5 Hz, H-1 ");
13C NMR (CD3OD) δ: 178.0 (C-4), 163.1 (C-7), 162.5 (C-5), 161.5 (C-8a), 157.4 (C-4'), 148.8 (C-2), 138.8 (C-3), 131.3 (C-3', 5'), 117.0 (C-2', 6'), 106.6 (C-1"'), 100.6 (4a), 100.3 (C-6), 95.3 (C-8), 74.2, 73.0, 72.3, 72.0 (C-2"'-5"'), 19.2 (C-6"'); 13 C NMR (CD 3 OD) δ: 178.0 (C-4), 163.1 (C-7), 162.5 (C-5), 161.5 (C-8a), 157.4 (C-4 '), 148.8 (C- 2), 138.8 (C-3), 131.3 (C-3 ', 5'), 117.0 (C-2 ', 6'), 106.6 6), 95.3 (C-8), 74.2, 73.0, 72.3, 72.0 (C-2 '' - 5 ''), 19.2 (C-6 '');
ESI-MS m/z 433 [M+H]+ (C21H20O11).ESI-MS m / z 433 [ M + H] + (C 21 H 20 O 11).
실시예 2-4. 메틸 2-하이드록실 트리코사노에이트 (화합물 4)Examples 2-4. Methyl 2-hydroxyl tricosanoate (Compound 4)
methyl 2-hydroxyl tricosanoate;methyl 2-hydroxyl tricosanoate;
white powder;white powder;
IR (KBr) ν max cm-1: 1739, 1250;IR (KBr) ? Max cm -1 : 1739, 1250;
1H NMR (CDCl3) δ: 4.17 (1H, t, J = 6.25, H-2), 3.77 (3H, s, OCH3), 1.60 (2H, q, H-3), 1.20-1.31 (38H, m, H-4-H-22), 0.85 (3H, t, H-23); 1 H NMR (CDCl 3) δ : 4.17 (1H, t, J = 6.25, H-2), 3.77 (3H, s, OCH 3), 1.60 (2H, q, H-3), 1.20-1.31 (38H , m, H-4-H-22), 0.85 (3H, t, H-23);
13C NMR (CDCl3) δ: 176.1 (C-1), 70.7 (C-2), 25.0 (C-3), 29.9-29.5 (C-4-C-20), 32.1 (C-21), 22.9 (C-22), 14.3 (C-23), 52.7 (OCH3); 13 C NMR (CDCl 3) δ : 176.1 (C-1), 70.7 (C-2), 25.0 (C-3), 29.9-29.5 (C-4-C-20), 32.1 (C-21), 22.9 (C-22), 14.3 (C-23), 52.7 (OCH 3);
EI-MS m/z 384 [M]+ (C24H48O3).EI-MS m / z 384 [M] + (C 24 H 48 O 3 ).
<실시예 3. 단백질 타이로신 탈인산화효소 1B의 저해활성 측정><Example 3> Measurement of inhibitory activity of protein tyrosine dephosphorylase 1B>
단백질 타이로신 탈인산화효소 1B에 의해 기질인 p-니트로페닐 인산염(p-nitrophenyl phosphate, p-NPP)이 p-니트로페놀(p-nitrophenol, p-NP)로 변화되면서 노란색을 나타내므로 405㎚에서 흡광도의 변화를 통해 효소활성을 측정하였다(Cui, L. et al., 16, 1426-1429, 2006).P-nitrophenyl phosphate (p-NPP) is converted to p-nitrophenol (p-NP) as a substrate by protein tyrosine dephosphorylase 1B, (Cui, L. et al., 16, 1426-1429, 2006).
단백질 타이로신 탈인산화효소 1B(PTP1B, human, recombinant)는 BIOMOL® International LP(Plymouth Meeting, PA)에서 구입하였다. 96웰 플레이트(96 wells microtiter plate)에 최종 부피 110㎕로 완충액((50mM citrate, pH 6.0), 0.1M NaCl, 1mM EDTA 및 1mM dithiothreitol(DTT))에 0.05~0.1㎍의 단백질 타이로신 탈인산화효소 1B와 2mM p-니트로페닐 인산염, 본 발명의 화합물 1~4가 포함된 혼합 처리물을 만들었으며 대조군으로는 타이로신 탈인산화효소의 저해제 중 하나인 RK-682(3-hexadecanoyl-5-hydroxymethyl-tetronic acid)를 사용하였다.Protein tyrosine dephosphorylation enzymes 1B (PTP1B, human, recombinant) was purchased from BIOMOL ® International LP (Plymouth Meeting, PA). To a 96-well 96-well microtiter plate was added 0.05 μg of protein tyrosine dehydrogenase 1B (50 mM citrate, pH 6.0), 0.1 M NaCl, 1 mM EDTA and 1 mM dithiothreitol (DTT) And 2 mM p-nitrophenyl phosphate and compounds 1 to 4 of the present invention. As a control, RK-682 (3-hexadecanoyl-5-hydroxymethyl-tetronic acid ) Was used.
상기 혼합 처리물을 20℃에 20분간 둔 후, 10M 수산화나트륨(10M NaOH) 을 처리하여 반응을 종결시켰으며, 최종 남아있는 p-니트로페닐 인산염의 양을 405㎚에서 확인하였다. 각 화합물의 활성은 하기 표 1에 IC50(the half maximal inhibitory concentration)으로 나타내었다.The mixture was allowed to stand at 20 DEG C for 20 minutes, and then the reaction was terminated by treating with 10M sodium hydroxide (10M NaOH), and the amount of the remaining p-nitrophenyl phosphate was confirmed at 405 nm. The activity of each compound is shown in Table 1 in the IC 50 (the half maximal inhibitory concentration).
상기 표 1의 결과를 참고하면, 화합물 1~4는 각각 6.6㎍/㎖, 23.3㎍/㎖, 5.3㎍/㎖, 14.0㎍/㎖의 IC50을 나타내며 상기 에탄올 추출물에 비해 8~40배 더 강한 저해활성을 가지는 것으로 확인되고, 상기 에틸아세테이트 분획물에 비해서는 4~20배 더 강한 저해활성을 가지는 것으로 확인된다. 따라서 본 발명의 짚신나물 유래 화합물이 타이로신 탈인산화효소 1B에 대해 우수한 저해 효과를 나타냄을 확인할 수 있다.Compounds 1 to 4 exhibited an IC 50 of 6.6 μg / ml, 23.3 μg / ml, 5.3 μg / ml and 14.0 μg / ml, respectively, and were 8 to 40 times more potent than the ethanol extracts Inhibitory activity, and has an inhibitory activity that is 4 to 20 times stronger than the ethyl acetate fraction. Therefore, it can be confirmed that the compound derived from the strawberry herb of the present invention shows an excellent inhibitory effect on tyrosine dephosphorylase 1B.
<실시예 4. 알파-글루코시다아제의 저해활성 측정>≪ Example 4: Measurement of inhibitory activity of alpha-glucosidase >
알파-글루코시다아제의 기질인 p-니트로페닐-알파-D-글루코시드(p-nitrophenyl-α-D-glucoside, p-NG)가 p-니트로페놀(p-nitrophenol, p-NP)로 변화되면서 노란색을 나타내므로 405㎚에서 흡광도의 변화를 통해 효소활성을 측정하였다.P-nitrophenyl-α-D-glucoside (p-NG), which is a substrate for alpha-glucosidase, is converted to p-nitrophenol And the enzyme activity was measured at 405 nm by changing the absorbance.
알파-글루코시다아제를 완충액(0.1M phosphate buffer, pH 6.9)에 1.0U/㎖가 되도록 용해시킨 뒤 100㎕ 취해서 96웰 플레이트에 넣어주었고, 본 발명의 화합물 1~4 또는 대조군인 아카보즈(acarbose)를 50㎕씩 더하였다. 이후, 상기 혼합 처리물을 25℃에서 10분 동안 항온처리 한 후, 기질인 5mM p-니트로페닐-알파-D-글루코시드 50㎕를 더하여 405㎚에서 흡광도를 측정하여 알파-글루코시다아제 활성을 측정하였다. 각 화합물의 활성은 하기 표 2에 IC50(the half maximal inhibitory concentration)으로 나타내었다.After the α-glucosidase was dissolved in a buffer solution (0.1 M phosphate buffer, pH 6.9) so as to have a concentration of 1.0 U / ml, 100 μl of the solution was added to a 96-well plate and the compounds 1 to 4 of the present invention or acarbose ) Was added to each well. After the mixture was incubated at 25 ° C for 10 minutes, 50 μl of 5 mM p-nitrophenyl-α-D-glucoside was added and the absorbance was measured at 405 nm to determine α-glucosidase activity Respectively. The activity of each compound is shown in Table 2 in the IC 50 (the half maximal inhibitory concentration).
상기 표 2의 결과를 참고하면, 화합물 1~4는 각각 47.6㎍/㎖, 5.2㎍/㎖, 12.3㎍/㎖, 43.3㎍/㎖의 IC50을 나타내며 상기 에탄올 추출물에 비해 4~40배 더 강한 저해활성을 가지는 것으로 확인되고, 상기 에틸아세테이트 분획물에 비해서는 2~20배 더 강한 저해활성을 가지는 것으로 확인된다. 따라서 본 발명의 짚신나물 유래 화합물이 알파-글루코시다아제에 대해 우수한 저해 효과를 나타냄을 확인할 수 있다. Compounds 1 to 4 exhibited an IC 50 of 47.6 μg / ml, 5.2 μg / ml, 12.3 μg / ml and 43.3 μg / ml, respectively, and were 4-40 times more potent than the ethanol extracts Inhibitory activity, and has an inhibitory activity that is 2 to 20 times stronger than the ethyl acetate fraction. Therefore, it can be confirmed that the compound derived from the strawberry herb of the present invention shows an excellent inhibitory effect on alpha-glucosidase.
<실시예 5. 독성실험><Example 5: Toxicity test>
실시예 5-1. 급성독성 Example 5-1. Acute toxicity
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 단기간에 과량을 섭취하였을 때 급성적(24시간 이내)으로 동물 체내에 미치는 독성을 조사하고, 치사율을 결정하기 위하여 본 실험을 수행하였다. 일반적인 마우스인 ICR 마우스를 20마리를 준비하였고, 각 군별로 10마리씩 배정하였다. 대조군에는 30% PEG-400만을 투여하고, 실험군은 본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 1.0g/㎏의 농도로 각각 경구 투여하였다. 투여 24시간 후에 각각의 치사율을 조사한 결과, 대조군과 상기 화합물 1을 투여한 실험군에서는 모두 생존하였다.The toxicity of the compound 1 (apigenin-7-O- beta -D-glucuronide-6 "-methyl ester) of the present invention to the animal body in an acute (within 24 hours) 20 mice of general mouse ICR mice were assigned to each group and 10 mice were assigned to each group. In the control group, 30% PEG-400 alone was administered, and the experimental group was administered with the compound 1 of the present invention (apigenin -7-O-? -D-glucuronide-6 "-methyl ester) was orally administered at a concentration of 1.0 g / kg. After 24 hours of administration, the respective mortality rates were examined. As a result, both the control group and the test group to which Compound 1 was administered survived.
실시예 5-2. 실험군 및 대조군의 장기 및 조직 독성 실험Example 5-2. Organ organs toxicity test in experimental group and control group
장기 독성 실험은 C57BL/6J 생쥐를 대상으로 동물의 각 장기(조직)에 미치는 영향을 조사하기 위하여 본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 1.0g/㎏의 농도로 투여한 실험군과 용매만을 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 절취하여 통상적인 조직절편 제작과정을 거쳐 광학현미경으로 조직학적 관찰을 시행하였으나 특이한 이상은 관찰되지 않았다.The long-term toxicity test was carried out on C57BL / 6J mice in order to investigate the effect of compound 1 (apigenin-7-O- beta -D-glucuronide-6 "-methyl ester) The blood was collected from the experimental group administered at a concentration of 1.0 g / kg and the control group, which was administered only with the solvent, at 8 weeks, and the concentration of glutamate-pyruvate transferase (GPT) and blood urea nitrogen (BUN) In addition, GPT, known to be associated with hepatotoxicity, and BUN, which is known to be related to renal toxicity, showed no significant difference compared to the control group, The liver and kidney were excised and histological observation was performed by an optical microscope through a conventional tissue section production process, but no abnormal abnormalities were observed.
<제제예 1. 약학적 제제>≪ Formulation Example 1 >
제제예 1-1. 정제의 제조Formulation Example 1-1. Manufacture of tablets
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester) 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 the compound 1 of the present invention 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 10% gelatin solution The mixture thus obtained was dried, to which 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate were added, and the resulting mixture was made into tablets.
제제예 1-2. 주사제의 제조Formulation Example 1-2. Injection preparation
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester) 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 the compound 1 of the present invention (apigenin-7-O-? -D-glucuronide-6 "-methyl ester), 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. And sterilized by heating at 20 DEG C for 30 minutes.
<제제예 2. 식품 제조><Formulation Example 2: Food Preparation>
제제예 2-1. 조리용 양념의 제조Formulation Example 2-1. Manufacture of cooking seasonings
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 0.2~10.0 중량%로 하여 건강 증진용 조리용 양념을 제조하였다. The health-enhancing cooking seasoning was prepared by adjusting the amount of the compound 1 of the present invention (apigenin-7-O-? -D-glucuronide-6 "-methyl ester) to 0.2-10.0 wt%.
제제예 2-2. 밀가루 식품의 제조Formulation Example 2-2. Manufacture of flour food products
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 0.1~5.0 중량%로 하여 밀가루에 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.The composition of the present invention is prepared by adding 0.1 to 5.0% by weight of the compound 1 of the present invention (apigenin-7-O- beta -D-glucuronide-6 "-methyl ester) to wheat flour and using this mixture to prepare bread, cake, Noodles were prepared to produce health promotion foods.
제제예 2-3. 스프 및 육즙(gravies)의 제조Preparation Example 2-3. Manufacture of soups and gravies
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 0.1~1.0 중량%로 하여 스프 및 육즙에 첨가하여 건강 증진용 육가공 제품, 면류의 수프 및 육즙을 제조하였다.0.1 to 1.0% by weight of the compound 1 of the present invention (apigenin-7-O-? -D-glucuronide-6 "-methyl ester) is added to the soup and the juice to improve health promotion meat products, .
제제예 2-4. 유제품(dairy products)의 제조Formulation Example 2-4. Manufacture of dairy products
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 0.1~1.0 중량%로 하여 우유에 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다. D-glucuronide-6 "-methyl ester of the present invention is added to milk in an amount of 0.1 to 1.0% by weight, and the milk is used to make various dairy products such as butter and ice cream .
제제예 2-5. 야채쥬스의 제조 Formulation Example 2-5. Manufacture of vegetable juice
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 0.5g을 토마토 또는 당근 쥬스 1,000㎖에 가하여 건강 증진용 야채쥬스를 제조하였다.0.5 g of apigenin-7-O-beta-D-glucuronide-6 "-methyl ester of the present invention was added to 1,000 ml of tomato or carrot juice to prepare vegetable juice for health promotion.
제제예Formulation example 2-6. 2-6. 과일쥬스의Of fruit juice 제조 Produce
본 발명의 화합물 1(apigenin-7-O-β-D-glucuronide-6"-methyl ester)을 0.1g을 사과 또는 포도 쥬스 1,000㎖에 가하여 건강 증진용 과일쥬스를 제조하였다.Health enhancing fruit juice was prepared by adding 0.1 g of the compound 1 of the present invention (apigenin-7-O-? -D-glucuronide-6 "-methyl ester) to 1,000 ml of apple or grape juice.
Claims (10)
[화학식 1]
[Chemical Formula 1]
상기 화합물은 단백질 타이로신 탈인산화효소 1B(protein tyrosine phosphatase 1B, PTP1B)의 활성을 저해하는 것을 특징으로 하는 비만 또는 당뇨병의 예방 또는 치료용 조성물.The method according to claim 1,
Wherein said compound inhibits the activity of protein tyrosine phosphatase 1B (PTP1B). 2. A composition for preventing or treating obesity or diabetes according to claim 1, wherein said compound inhibits the activity of protein tyrosine phosphatase 1B (PTP1B).
상기 화합물은 알파-글루코시다아제(α-glucosidase)의 활성을 저해하는 것을 특징으로 하는 비만 또는 당뇨병의 예방 또는 치료용 조성물.The method according to claim 1,
A composition for preventing or treating obesity or diabetes, which is characterized by inhibiting the activity of alpha-glucosidase.
상기 조성물은 약제학적으로 허용되는 담체, 부형제 또는 희석제를 추가하여 약제학적 투여형으로 제형화되는 것을 특징으로 하는 비만 또는 당뇨병의 예방 또는 치료용 조성물.The method according to claim 1,
Wherein the composition is formulated into a pharmaceutical dosage form by addition of a pharmaceutically acceptable carrier, excipient or diluent.
[화학식 1]
[Chemical Formula 1]
상기 화합물은 단백질 타이로신 탈인산화효소 1B(protein tyrosine phosphatase 1B, PTP1B)의 활성을 저해하는 것을 특징으로 하는 비만 또는 당뇨병의 예방 또는 개선용 건강기능식품.The method according to claim 6,
Wherein said compound inhibits the activity of protein tyrosine phosphatase 1B (PTP1B). 2. A health functional food for preventing or ameliorating obesity or diabetes.
상기 화합물은 알파-글루코시다아제(α-glucosidase)의 활성을 저해하는 것을 특징으로 하는 비만 또는 당뇨병의 예방 또는 개선용 건강기능식품.The method according to claim 6,
Wherein said compound inhibits the activity of? -Glucosidase. 2. A health functional food for preventing or ameliorating obesity or diabetes according to claim 1, wherein said compound inhibits the activity of? -Glucosidase.
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