KR20020036981A - Manufacturing of low molecular weight angiotensin converting converting enzyme inhibitor from hot water extracts of the flowers of Chrysanthemum boreale Makino - Google Patents
Manufacturing of low molecular weight angiotensin converting converting enzyme inhibitor from hot water extracts of the flowers of Chrysanthemum boreale Makino Download PDFInfo
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- KR20020036981A KR20020036981A KR1020020014640A KR20020014640A KR20020036981A KR 20020036981 A KR20020036981 A KR 20020036981A KR 1020020014640 A KR1020020014640 A KR 1020020014640A KR 20020014640 A KR20020014640 A KR 20020014640A KR 20020036981 A KR20020036981 A KR 20020036981A
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- molecular weight
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Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/38—Other non-alcoholic beverages
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/70—Clarifying or fining of non-alcoholic beverages; Removing unwanted matter
- A23L2/72—Clarifying or fining of non-alcoholic beverages; Removing unwanted matter by filtration
- A23L2/74—Clarifying or fining of non-alcoholic beverages; Removing unwanted matter by filtration using membranes, e.g. osmosis, ultrafiltration
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/20—Natural extracts
- A23V2250/21—Plant extracts
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2300/00—Processes
- A23V2300/14—Extraction
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Chemical & Material Sciences (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Water Supply & Treatment (AREA)
- Botany (AREA)
- Mycology (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
고혈압은 순환기 계통의 만성퇴행성 질환으로서 혈압조절 및 전해질 균형의 조절에 중요한 역할을 하는 레닌-안지오텐신 시스템 (renin-angiotensin)의 생리화학적 기전으로 설명된다. 특히 엔지오텐신 전환효소 (angiotensin converting enzyme, ACE)는 데카펩타이드 (decapeptide)인 엔지오텐신 I 으로부터 다이펩타이드 (dipeptide, His-Leu)를 절단함으로서 혈관 수축 작용을 갖는 엔지오텐신 II 로 전환시키는 역할을 하는 효소이다. 엔지오텐신 II의 증가는 강한 혈압 상승작용과 항이뇨 호르몬인 엘도스테론 (aldosterone)의 분비를 촉진하고 물과 나트륨의 배설을 억제하여 순환 혈액 양을 증가시킴으로서 고혈압을 일으키게 한다. 또한 ACE는 혈관 이완작용을 하는 브레디키닌 (bradykinin)을 분해하여 불활성 시킴으로써 결과적으로 혈압상승을 유발하는 역할을 한다. 그러므로 ACE 저해제는 ACE의 작용을 억제함으로써 혈관 수축을 막아 혈압 강하효과를 나타낼 수 있기에 고혈압 치료에 획기적인 전기를 마련해 준 약물이다. 대표적인 ACE 억제제로서는 화학 합성제인 캡토프릴 (captopril)이 개발되어 고혈압 치료제로서 이용되고 있으나, 마른기침, 두통, 식용부진, 미각이상, 발진, 백혈구 감소 등 부작용이 많아 최근의 연구 방향은 부작용이 없는 천연물에서의 ACE 저해제 개발에 집중되고 있다. ACE 저해작용을 나타내는 물질은 펩타이드성 물질과 폴리페놀성 물질로 대별되는데, 펩타이드성 저해물질은 뱀독으로부터 처음 분리되어 보고된 이래, 다랑어, 정어리, 고등어, 전갱이, 가다랭이, 새우, 가리비 등의 어패류의 효소 가수분해물, 우유단백질인 케이신 (casein), 달걀의 알부민 (albumin), 젤라틴 (gelatin), 동물의 혈장 등에서 분리한 펩타이드 등이 보고되었다.[G. Oshima, et al., Biochimica et Biophysica Acta, 566, 128, 1979; S. Maruyama, et al., Agric. Biol. Chem., 46(5), 1393, 1982; S. Maruyama, et al., Agric. Biol. Chem., 51(6), 1581, 1987; M. Kohmura, et al., Agric. Biol. Chem., 54(4), 1101, 1990; Yasuo Ariyoshi, Trends in Food Sci. Tech., 4, 139, 1993; Song, K. B., et al., Biotech. Tech., 10(7), 479, 1996; Song, K. B., et al., Agric. Chem. Biotech., 40(1), 39, 1997] 폴리페놀성 물질로는 감나무잎, 밀감 등의 추출물, 녹차의 탄닌, 알로에 아세틸만닌, 키토산 올리고당, 양파 조미액, 밀감 피층에서 얻은 탄닌류가 ACE 저해효과를 갖는 것으로 밝혀졌다.[Matsubara, Y., et al., Agric. Biol. Chem., 49(4), 909, 1985; Cho, Y., et al., Korean J. Food Sci. Tech., 25(3), 238, 1993; Ryu, I. W., et al., Korean J. Food Sci. Tech., 29(1), 1269, 1997; Hong, S. P., et al., Korean J. Food Sci. Tech., 30(6), 1476, 1998; Park, E. J., et al., Food Sci. Biotech., 9(3), 163, 2000] 국내에서도 된장, 쌀, 오징어, 도축혈액의 혈장, 해초류, 버섯 등에서 유래하는 ACE 저해 펩타이드에 관한 연구가 있는데[Yang, H. C., et al., Agric. Chem. Biotech., 37(6), 441, 1994; Shin, J. I., et al., J. Food Sci. Tech., 27(2), 230, 1995; Ko, Y. S., et al., J. Korean Fish. Soc., 32(4), 427,1999; Song, K. B., et al., 대한민국특허, 등록번호 10-215090; Song, K. B., et al., 대한민국특허, 등록번호 10-215091; Suh, H. J., et al., Food Res. Int., 34, 177, 2001] 산국 꽃잎으로부터의 ACE 저해효과를 갖는 물질의 제조에 대한 연구는 없다.Hypertension is a chronic degenerative disease of the circulatory system and is explained by the physiochemical mechanism of the renin-angiotensin system, which plays an important role in the regulation of blood pressure and electrolyte balance. In particular, angiotensin converting enzyme (ACE) is an enzyme that converts dipeptide (His-Leu) from decapeptide (decapeptide) to engiotensin II having vasoconstrictive action. to be. An increase in engiotensin II causes hypertension by promoting strong blood pressure synergism and the secretion of the antidiuretic hormone aldosterone and inhibiting the excretion of water and sodium, increasing the amount of circulating blood. In addition, ACE decomposes and inactivates bradykinin, which acts as a vasorelaxant, and as a result, increases blood pressure. Therefore, ACE inhibitor is a drug that provides a breakthrough in the treatment of hypertension because it can suppress blood vessel constriction by inhibiting the action of ACE. As a representative ACE inhibitor, captopril, a chemical synthesis agent, has been developed and used as an antihypertensive agent, but there are many side effects such as dry cough, headache, edible weakness, taste disorder, rash, and white blood cell reduction. Is focusing on developing ACE inhibitors in Substances exhibiting ACE inhibitory activity are broadly classified into peptide and polyphenolic substances. Since peptide inhibitors have been reported from snake venom for the first time, it has been reported that tuna, sardine, mackerel, horse mackerel, bonito, shrimp, scallops, etc. Enzyme hydrolysates, milk protein casein, egg albumin (geal), gelatin (gelatin), and peptides isolated from animal plasma have been reported. [G. Oshima, et al., Biochimica et Biophysica Acta, 566, 128, 1979; S. Maruyama, et al., Agric. Biol. Chem., 46 (5), 1393, 1982; S. Maruyama, et al., Agric. Biol. Chem., 51 (6), 1581, 1987; M. Kohmura, et al., Agric. Biol. Chem., 54 (4), 1101, 1990; Yasuo Ariyoshi, Trends in Food Sci. Tech., 4, 139, 1993; Song, K. B., et al., Biotech. Tech., 10 (7), 479, 1996; Song, K. B., et al., Agric. Chem. Biotech., 40 (1), 39, 1997] Examples of polyphenolic substances include extracts from persimmon leaves and mandarin, tannins from green tea, aloe acetylmannin, chitosan oligosaccharides, onion seasonings, and tannins from mandarin skins. It has been found to have an effect. Matsubara, Y., et al., Agric. Biol. Chem., 49 (4), 909, 1985; Cho, Y., et al., Korean J. Food Sci. Tech., 25 (3), 238, 1993; Ryu, I. W., et al., Korean J. Food Sci. Tech., 29 (1), 1269, 1997; Hong, S. P., et al., Korean J. Food Sci. Tech., 30 (6), 1476, 1998; Park, E. J., et al., Food Sci. Biotech., 9 (3), 163, 2000] In Korea, there are studies on ACE inhibitory peptides derived from doenjang, rice, squid, slaughter blood plasma, seaweeds and mushrooms [Yang, H. C., et al., Agric. Chem. Biotech., 37 (6), 441, 1994; Shin, J. I., et al., J. Food Sci. Tech., 27 (2), 230, 1995; Ko, Y. S., et al., J. Korean Fish. Soc., 32 (4), 427, 1999; Song, K. B., et al., Korean Patent No. 10-215090; Song, K. B., et al., Korean Patent No. 10-215091; Suh, H. J., et al., Food Res. Int., 34, 177, 2001] There is no study on the preparation of substances with ACE inhibitory effects from the petals of the country.
산국은 국화과에 속하는 여러해살이 풀로서 전체 길이는 1∼1.5 m, 9∼10월에 황색꽃으로 피며 우리나라, 일본, 중국, 만주 등지에서 분포하고 있으며 전국의 산과 들에서 자란다. 산국은 옛부터 청열 해독작용이 있다고 알려져 있으며 농가진, 습진의 치료에 쓰여 왔다. 특히 물에 달인 용액은 황색포도상구균, 폐렴구균에 항균작용이 있고 혈압강하 작용이 있다고 알려져 있다. 따라서 본 발명에서는 산국 꽃잎으로부터 생체 조절 물질을 함유하는 새로운 기능성 식품 소재를 개발할 목적으로 ACE 저해제를 제조하는데 있다.It is a perennial herb belonging to the Asteraceae family, and its total length is 1-1.5m, and it blooms with yellow flowers in September-October. The country is known for its detoxifying action since ancient times and has been used to treat impetigo and eczema. In particular, water-based solutions are known to have antibacterial effects on Staphylococcus aureus and pneumococci and to lower blood pressure. Therefore, the present invention is to produce an ACE inhibitor for the purpose of developing a new functional food material containing a bioregulatory substance from the petals of the country.
지금까지 ACE 저해제에 대한 연구는 주로 식품 단백질을 펩신, 트립신 등의 단백질분해효소(protease)로 가수분해하여 얻어진 가수분해물로부터 ACE 저해효과를 갖는 기능성 펩타이드를 제조하였으나 식품 단백질의 가수분해물로부터 제조된 기능성 펩타이드는 구조적, 기능적, 생리적 해석에 관한 논란 및 경제성 등의 면에서 문제점이 있다. 따라서 본 발명에서는 옛부터 차 등으로 섭취하고 있는 식물인 산국 꽃잎으로부터 천연으로 존재하는 ACE 저해제를 제조하는 것으로서 효율적이고 경제적인 소재를 이용하여 ACE 저해제를 제조한다는 측면에서 그 기술적 효용성이있다.Until now, research on ACE inhibitors has mainly produced functional peptides having an ACE inhibitory effect from hydrolysates obtained by hydrolyzing food proteins with proteases such as pepsin and trypsin, but functional products prepared from hydrolysates of food proteins. Peptides have problems in terms of structural and functional and physiological interpretations and economics. Therefore, the present invention has a technical utility in terms of producing the ACE inhibitor using an efficient and economical material as producing a naturally-occurring ACE inhibitor from the petals of the country, which has been ingested as tea, etc. since ancient times.
제 1도는 산국 꽃잎의 열수 추출물의 겔여과크로마토그램을 나타낸 것으로 주요 분획들이 표시되어 있다.Figure 1 shows the gel filtration chromatogram of hydrothermal extract of the petals of the country, the main fractions are indicated.
제 2도는 제 1도에 있어서 엔지오텐신전환효소 저해 활성 물질을 함유하는 분획 F1을 정상 고속 액체 크로마토그라피에 다시 로딩한 크로마토그램을 나타낸 것으로 주요 분획들이 표시되어 있다.FIG. 2 shows the chromatogram of the fraction F1 containing the engiotensin converting enzyme inhibitory active substance in FIG. 1 reloaded into normal high performance liquid chromatography, and the major fractions are indicated.
제 3도는 제 2도에 있어서 엔지오텐신전환효소 저해 활성 물질을 함유하는 분획 F1을 이온교환크로마토그라피에 다시 로딩한 크로마토그램을 나타낸 것으로 주요 분획들이 표시되어 있다.FIG. 3 shows a chromatogram in FIG. 2 which reloads fraction F1 containing an angiotensin converting enzyme inhibitory active substance into ion exchange chromatography, and main fractions are indicated.
제 4도는 제 3도에 있어서 엔지오텐신전환효소 저해 활성 물질을 함유하는 분획 F1을 역상고속액체크로마토그라피에 다시 로딩하여 단일 분획으로 분리한 크로마토그램을 나타낸 것이다.FIG. 4 shows the chromatogram of the fraction F1 containing the engiotensin converting enzyme inhibitory active substance in FIG. 3, reloaded into reverse phase high performance liquid chromatography, and separated into a single fraction.
본 발명은 산국 꽃잎으로부터 고혈압 억제효과를 나타내는 ACE 저해제를 제조하는 데 있다. 본 발명은 기존의 ACE 저해제의 제조방법인 단백분해효소를 사용하지 않고 기능성 음료 등 식품 소재로 사용하기에 적합한 열수추출, 한외여과, 겔여과 크로마토그라피, 고속 액체 크로마토그라피, 이온교환크로마토그라피, 역상 고속액체크로마토그라피를 이용하여 ACE 저해제를 제조하는 방법에 있다.The present invention is to produce an ACE inhibitor that exhibits an antihypertensive effect from the petals of the country. The present invention is suitable for use in food materials such as functional beverages without using protease, which is a conventional method for preparing ACE inhibitors, hot water extraction, ultrafiltration, gel filtration chromatography, high-speed liquid chromatography, ion exchange chromatography, reverse phase It is a method for preparing an ACE inhibitor using high performance liquid chromatography.
본 발명을 실시예를 통해서 설명하고자 한다.The present invention will be described through examples.
실시예 1Example 1
산국 꽃잎을 깨끗이 씻어 이물질을 제거한 후 증류수를 넣고 100℃에서 2시간 환류 추출하였다. 추출 액은 여지를 이용하여 여과한 후 4℃에서 8000 rpm, 30분간 원심분리하여 상등액만을 취하였다. 상등액은 한외여과 막 (분자량한계 1000)을 이용해 한외여과하여 조추출물을 제조하였다.The petals were washed to remove foreign substances, and then distilled water was added and refluxed at 100 ° C. for 2 hours. The extract was filtered using a filter paper and centrifuged at 8000 rpm for 30 minutes at 4 ° C to obtain only the supernatant. The supernatant was ultrafiltered using an ultrafiltration membrane (molecular weight limit 1000) to prepare a crude extract.
상기 조추출물을 시료로 하여 엔지오텐신 전환효소 저해활성을 측정하였는데, Cushman과 Cheung의 방법에 따라 실시하였다.(Cushman, D. W. and Cheung, H. S.. Biochem. Pharmacol., 20, 1637. 197) ACE 저해 정도는 기질로서 히퓨릴히스티딜류신(hippuryl- L-histidyl-L-leucine, HHL)을 사용하였으며, HHL은 300mM NaCl을 포함하는 50mM 소듐보레이트 (sodium borate) 완충용액 (pH 8.3)에 녹여 5mM HHL을 만들었다. 효소는 토끼 폐로부터 분리한 엔지오텐신 Ⅰ 전환효소(ACE)를 사용하였다. 기질에 시료를 넣고 효소를 첨가한 반응액을 37℃에서 30분간 반응시킨 다음 1N 염산을 첨가하여 반응을 중지시켰다. 반응액에 에틸아세테이트를 넣어 30초 동안 혼합한 후 3000rpm에서 15분간 원심분리한 후 상등액인 에틸아세테이트 층만을 취하여 100℃에서 1시간 정도 건조시켰다. 건조 후 시험구에 남아있는 히퓨릭에시드 (hippuric acid)에 증류수를 가해 완전히 녹인 다음 228nm에서 흡광도를 측정하여 대조구와 비교하여 ACE 저해 정도를 계산하였다. 대조구는 시료 용액 대신 소듐보레이트 완충용액 50㎕를 가하였다.The crude extract was used as a sample to measure angiotensin converting enzyme inhibitory activity, which was carried out according to the method of Cushman and Cheung (Cushman, DW and Cheung, HS. Biochem. Pharmacol., 20, 1637. 197) ACE inhibition degree Hypuryl-L-histidyl-L-leucine (HHL) was used as a substrate, and HHL was dissolved in 50 mM sodium borate buffer solution containing 300 mM NaCl (pH 8.3) to dissolve 5 mM HHL. made. Enzyme was used as enzyme for ACE enzyme (ACE) isolated from rabbit lung. The sample was placed in a substrate and the reaction solution to which the enzyme was added was reacted at 37 ° C. for 30 minutes, and then the reaction was stopped by adding 1N hydrochloric acid. Ethyl acetate was added to the reaction mixture, mixed for 30 seconds, centrifuged at 3000 rpm for 15 minutes, and only the supernatant ethyl acetate layer was taken and dried at 100 ° C. for 1 hour. After drying, distilled water was completely added to the hyplic acid remaining in the test zone, and then absorbance was measured at 228 nm to calculate the degree of ACE inhibition compared with the control. For the control, 50 μl of sodium borate buffer was added instead of the sample solution.
상기와 같은 방법으로 추출물의 엔지오텐신 Ⅰ전환효소에 대한 저해활성을 측정해본 결과, 산국 꽃잎 열수 추출물의 저해율은 40.1%였다.As a result of measuring the inhibitory activity of angiotensin I-converting enzyme of the extract by the same method as described above, the inhibition rate of the hot water petal hot water extract was 40.1%.
실시예 2Example 2
상기 실시예 1로부터 제조한 산국 꽃잎 열수 추출물을 겔여과 크로마토그라피(Sephadex G-15, 1.5 x 100 cm)에 로딩(loading)하였다. 인산완충용액(sodium phosphate buffer, 10 mM, pH 7.0)을 22ml/h의 유속으로 흘려 분획한 결과 도 1에서 보여지는 것처럼 5개의 주요 피크로 분획 되었는데 각 분획에 대해 ACE 전환효소에 대한 저해활성 측정을 하였다. 그 결과 가장 높은 활성을 보인 분획물은 45.2%의 저해율을 보인 분획 F1 이었다.The petals of hydroponic plants prepared from Example 1 were loaded on gel filtration chromatography (Sephadex G-15, 1.5 × 100 cm). Phosphate buffer solution (sodium phosphate buffer, 10 mM, pH 7.0) was flowed at 22 ml / h and fractionated into five main peaks as shown in Fig. 1. Determination of inhibitory activity against ACE converting enzyme for each fraction Was done. As a result, the fraction with the highest activity was fraction F1 with 45.2% inhibition rate.
실시예 3Example 3
실시예 2에서 F1를 모아서 동결건조 시킨 다음 고속액체크로마토그라피를 이용하여 정제하였다. 고속액체크로마토그라피에서는 컬럼은 아미노(-NH2) 컬럼을, 용매는 용매 A(물:아세토나이트릴 (acetonitrile), 3:97, 0.1% 트리플로로아세트산 (trifluoroacetic acid, TFA))와 용매 B (물:아세토나이트릴, 70:30, 0.1% 트리플로로아세트산)를 0.5 ㎖/min의 유속으로 0 %에서 30 %까지 30분간에 걸쳐 선형구배 (linear gradient)를 걸어 ACE 저해 물질을 분리하였다. 도 2에서 보여지는 것처럼 4개의 주요 피크로 분획 되었는데 각 분획에 대해 ACE 전환효소에 대한 저해활성 측정을 하였다. 그 결과 가장 높은 활성을 보인 분획물은 52.1%의 저해율을 보였다.In Example 2, F1 was collected, lyophilized, and purified using high performance liquid chromatography. For high performance liquid chromatography, the column is an amino (-NH2) column, the solvent is solvent A (water: acetonitrile, 3:97, 0.1% trifluoroacetic acid (TFA)) and solvent B ( Water: acetonitrile, 70:30, 0.1% trifluoroacetic acid) was subjected to a linear gradient over 30 minutes from 0% to 30% at a flow rate of 0.5ml / min to separate ACE inhibitors. As shown in FIG. 2, four major peaks were fractionated, and the inhibitory activity of ACE converting enzyme was measured for each fraction. As a result, the fraction with the highest activity showed 52.1% inhibition rate.
실시예 4Example 4
실시예 3에서 F1을 모아서 동결건조 시킨 다음 이온교환크로마토그라피를 이용하여 정제하였다. 컬럼은 리소스큐(resource Q)를, 용매는 트리스 완충용액(Tris, 10 mM, pH 8.0) 을 사용하였으며, 0.5㎖/min의 유속으로 1M 소듐클로라이드 (NaCl)함유 완충용액으로 45분간에 걸쳐 선형구배를 걸어 용매를 공급하였다. 도 3에 나타난 것처럼 3개의 주요 피크로 분획 되었는데 각 분획에 대해 ACE 전환효소에 대한 저해활성 측정을 하였다. 그 결과 가장 높은 활성을 보인 분획물은 56.4%의 저해율을 보였다.In Example 3, F1 was collected, lyophilized, and purified using ion exchange chromatography. The column was used for resource Q and the solvent was Tris buffer (Tris, 10 mM, pH 8.0), and the mixture was linear over 45 minutes with 1M sodium chloride (NaCl) -containing buffer at a flow rate of 0.5 mL / min. Gradient was supplied to supply solvent. As shown in FIG. 3, three main peaks were fractionated, and the inhibitory activity of ACE converting enzyme was measured for each fraction. As a result, the fraction with the highest activity showed 56.4% inhibition rate.
실시예 5Example 5
실시예 4에서 F1을 모아서 동결건조 시킨 다음 역상 고속액체크로마토그라피를 이용하여 정제하였다. 컬럼은 C18을, 용매는 0.1% TFA를 함유한 증류수와 0.1% TFA 함유 아세토나이트릴을 사용하였으며, 0.3㎖/min의 유속으로 40분간에 걸쳐 20%까지 선형구배 (linear gradient)를 걸어 용매를 공급하였다. 도 4에 나타난 것처럼 63.2%의 ACE 저해율을 보인 저해 활성 물질은 아세토나이트릴 13%에서 단일 peak로 용출되었다In Example 4, F1 was collected, lyophilized, and purified using reversed phase high performance liquid chromatography. C18 was used as the column, distilled water containing 0.1% TFA and acetonitrile containing 0.1% TFA. The solvent was subjected to a linear gradient up to 20% over 40 minutes at a flow rate of 0.3 ml / min. Supplied. As shown in FIG. 4, the inhibitory active substance showing an ACE inhibition rate of 63.2% was eluted with a single peak in 13% of acetonitrile.
산국 꽃잎으로부터 열수 추출, 분자량한계 1,000 달톤의 한외여과, 겔여과 크로마토그라피, 고속 액체 크로마토그라피, 이온교환크로마토그라피, 역상 고속액체크로마토그라피를 이용하여 ACE 저해제를 제조함으로써 효율적이고 경제적인 ACE 저해제를 제조하는 공정 개발이라는 효과를 갖는다.Efficient and economical ACE inhibitors are prepared by extracting hot water from petals of plants, ultrafiltration with a molecular weight limit of 1,000 Daltons, gel filtration chromatography, high performance liquid chromatography, ion exchange chromatography, and reverse phase high performance liquid chromatography. It has the effect of process development.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03232820A (en) * | 1990-02-06 | 1991-10-16 | Tsumura & Co | Cerebral blood circulation and metabolism improver |
| JPH0549432A (en) * | 1991-08-23 | 1993-03-02 | Takano Co Ltd | Food additive |
| JPH08322526A (en) * | 1996-05-24 | 1996-12-10 | Tokiwa Kanpo Seiyaku:Kk | Chrysanthemum-containing drink agent |
| KR20010068159A (en) * | 2001-04-30 | 2001-07-13 | 송경빈 | Manufacturing of low molecular weight angiotensin converting converting enzyme inhibitor from hot water extracts of the roots of Ixeris dentat Nakai |
| KR20010083448A (en) * | 2000-02-15 | 2001-09-01 | 양민석 | Novel Process for the Preparation of Cumambrin A and the Use thereof |
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2002
- 2002-03-19 KR KR1020020014640A patent/KR20020036981A/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03232820A (en) * | 1990-02-06 | 1991-10-16 | Tsumura & Co | Cerebral blood circulation and metabolism improver |
| JPH0549432A (en) * | 1991-08-23 | 1993-03-02 | Takano Co Ltd | Food additive |
| JPH08322526A (en) * | 1996-05-24 | 1996-12-10 | Tokiwa Kanpo Seiyaku:Kk | Chrysanthemum-containing drink agent |
| KR20010083448A (en) * | 2000-02-15 | 2001-09-01 | 양민석 | Novel Process for the Preparation of Cumambrin A and the Use thereof |
| KR20010068159A (en) * | 2001-04-30 | 2001-07-13 | 송경빈 | Manufacturing of low molecular weight angiotensin converting converting enzyme inhibitor from hot water extracts of the roots of Ixeris dentat Nakai |
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