KR20050047208A - Composition containing the compound isolated from an extract of zingiber cassumunar for preventing and treating cancer disease - Google Patents
Composition containing the compound isolated from an extract of zingiber cassumunar for preventing and treating cancer disease Download PDFInfo
- Publication number
- KR20050047208A KR20050047208A KR1020030081000A KR20030081000A KR20050047208A KR 20050047208 A KR20050047208 A KR 20050047208A KR 1020030081000 A KR1020030081000 A KR 1020030081000A KR 20030081000 A KR20030081000 A KR 20030081000A KR 20050047208 A KR20050047208 A KR 20050047208A
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- South Korea
- Prior art keywords
- cancer
- compound
- carcinoma
- lower alkyl
- formula
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- 239000011787 zinc oxide Substances 0.000 description 1
- 239000001841 zingiber officinale Substances 0.000 description 1
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Abstract
본 발명은 천연 물질로부터 분리된 신규한 항암제에 관한 것으로서, 상세하게는 본 발명의 생강(Zingiber cassumunar Roxb.) 추출물로부터 분리된 화합물을 포함하는 조성물은 여러 사람 암세포에 대하여 세포 독성을 나타내므로 암 질환의 예방 및 치료를 위한 의약품 및 건강기능식품으로 이용될 수 있다.The present invention relates to a novel anticancer agent isolated from a natural substance, and in particular, a composition comprising a compound isolated from the extract of ginger ( Zingiber cassumunar Roxb.) Of the present invention exhibits cytotoxicity against various human cancer cells. It can be used as a medicine and health functional food for the prevention and treatment of.
Description
본 발명은 생강 추출물로부터 분리된 화합물을 포함하는 암 질환의 예방 및 치료를 위한 조성물에 관한 것이다.The present invention relates to a composition for the prevention and treatment of cancer diseases comprising a compound isolated from ginger extract.
암은 인류가 해결해야 할 난치병 중의 하나로, 전 세계적으로 이를 치유하기 위한 개발에 막대한 자본이 투자되고 있는 실정이며, 우리나라의 경우, 질병 사망원인 중 제 1위의 질병으로서 연간 약 10 만 명 이상이 진단되고, 약 6 만 명 이상이 사망하고 있다. 이러한 암의 유발 인자인 발암물질로는 흡연, 자외선, 화학물질, 음식물, 기타 환경인자들이 있으나, 그 유발 원인이 다양하여 치료제의 개발이 어려울 뿐만 아니라 발생하는 부위에 따라 치료제의 효과 또한 각기 다르다. 현재 치료제로 사용되는 물질들은 상당한 독성을 지니고 있으며, 암 세포만을 선택적으로 제거하지 못하므로, 암의 발생 후 이의 치료뿐 아니라, 암의 발생을 예방하기 위한 독성이 적고 효과적인 항암제의 개발이 절실히 필요하다.Cancer is one of the incurable diseases that humanity has to solve, and huge capital is invested in the development to cure it all over the world.In Korea, it is the number one disease death cause and more than 100,000 people a year It is diagnosed, and about 60,000 or more die. Carcinogens, which cause cancer, are smoking, ultraviolet rays, chemicals, foods, and other environmental factors. However, various causes are not only difficult to develop a therapeutic agent, but also effective effects vary depending on the site of occurrence. Currently, the substances used as therapeutic agents are extremely toxic and cannot selectively remove only cancer cells. Therefore, there is an urgent need for the development of low-toxic and effective anti-cancer agents to prevent cancer after treatment. .
암이란 "제어되지 않은 세포성장"으로 특징지어지며, 이러한 비정상적인 세포성장에 의해 종양(tumor)이라고 불리는 세포 덩어리가 형성되어 주위의 조직으로 침투하고 심한 경우에는 신체의 다른 기관으로 전이되기도 한다. 학문적으로는 신생물(neoplasia)이라고도 불린다. 암은 수술, 방사선 및 화학요법으로 치료를 하더라도 많은 경우에 근본적인 치유가 되지 못하고 환자에게 고통을 주며 궁극적으로는 죽음에 이르게 하는 난치성 만성질환이다. 암의 발생요인으로는 여러 가지가 있으나, 내적 요인과 외적 요인으로 구분하기도 한다. 정상세포가 어떠한 기전을 거쳐 암세포로 형질전환이 되는지에 대해서는 정확하게 규명되지는 않았으나, 적어도 80~90%가 환경요인 등 외적인자에 의해 영향을 받아 발생하는 것으로 알려져 있다. 내적 요인으로는 유전 인자, 면역학적 요인 등이 있으며, 외적 요인으로는 화학물질, 방사선, 바이러스 등이 있다. 암의 발생에 관련되는 유전자에는 종양형성유전자(oncogenes)와 종양억제유전자(tumor suppressor genes)가 있는데, 이들 사이의 균형이 위에서 설명한 내적 혹은 외적 요인들에 의해 무너질 때 암이 발생하게 된다.Cancer is characterized by "uncontrolled cell growth," which results in the formation of cell masses called tumors that infiltrate surrounding tissues and, in severe cases, metastasize to other organs of the body. Academia is also called neoplasia. Cancer is an intractable chronic disease that, even if treated with surgery, radiation, and chemotherapy, in many cases does not heal fundamentally, suffers the patient, and ultimately leads to death. There are many factors that cause cancer, but they can be divided into internal and external factors. It is not known exactly how normal cells are transformed into cancer cells, but at least 80-90% are known to be influenced by external factors such as environmental factors. Internal factors include genetic factors, immunological factors, and external factors include chemicals, radiation, and viruses. Genes involved in the development of cancer include oncogenes and tumor suppressor genes, which occur when the balance between them is broken down by internal or external factors described above.
암은 혈액암과 고형암으로 크게 분류되며, 폐암, 위암, 유방암, 구강암, 간암, 자궁암, 식도암, 피부암 등 신체의 거의 모든 부위에서 발생한다. 이들 악성종양을 치료하기 위해 사용하는 방법들 중 수술이나 방사선 요법을 제외한 화학요법제를 총칭하여 항암제라고 하며, 주로 핵산의 합성을 저해하여 항암활성을 나타내는 물질이 대부분이다. 화학요법제는 크게 대사길항제(antimetabolites), 알킬화제(alkylating agents), 유사분열억제제(antimitotic drugs), 호르몬제 (hormones) 등으로 분류되며, 암세포의 증식에 필요한 대사과정을 저해하는 대사길항제로는 엽산유도체(methotrexate), 퓨린유도체(6-mercaptopurine, 6-thioguanine), 피리미딘유도체(5-fluorouracil, Cytarabine) 등이 있으며, DNA의 구아닌 등에 알킬기를 도입하여 DNA의 구조를 변형시키고 사슬절단을 시켜 항암효과를 발휘하는 알킬화제로는 니트로겐 머스타드계 화합물(chlorambucil, cyclophosphamide), 에틸렌이민계 화합물(thiotepa), 알킬설포네이트계 화합물 (busulfan), 니트로소우레아계 화합물(carmustine), 트리아젠계 화합물 (dacarbazine)이 있다. 분열시기 특이성 약물로서 유사분열을 차단하여 세포분열을 억제하는 유사분열억제제에는 악티노마이신 D(actinomycin D), 독소루비신, 블레오마이신, 미토마이신과 같은 항암성항암제, 빈크리스틴, 빈블라스틴과 같은 식물알칼로이드, 탁산환을 포함하는 유사분열 저해제인 탁소이드 등이 포함된다. 이외에 부신피질호르몬이나 프로게스테론과 같은 호르몬제와 시스플라틴 같은 백금함유 화합물이 항암제로서 사용되고 있다. Cancer is classified into blood cancer and solid cancer, and it occurs in almost every part of the body such as lung cancer, stomach cancer, breast cancer, oral cancer, liver cancer, uterine cancer, esophageal cancer, and skin cancer. Among the methods used to treat these malignancies, chemotherapy agents, except surgery or radiation therapy, are collectively called anticancer agents, and most of them show anticancer activity by inhibiting the synthesis of nucleic acids. Chemotherapeutic agents are broadly classified into antimetabolites, alkylating agents, antimitotic drugs, and hormones, and folates that inhibit metabolic processes necessary for the proliferation of cancer cells. Derivatives (methotrexate), purine derivatives (6-mercaptopurine, 6-thioguanine), pyrimidine derivatives (5-fluorouracil, Cytarabine), etc.Introducing alkyl groups to guanine of DNA to modify the structure of DNA and chain-cutting Alkylating agents that exert the effect include nitrogen mustard compounds (chlorambucil, cyclophosphamide), ethyleneimine compounds (thiotepa), alkylsulfonate compounds (busulfan), nitrosourea compounds (carmustine), triazene compounds (dacarbazine) There is. Mitosis inhibitors that inhibit mitosis by blocking mitosis as anti-mitotic drugs include plant drugs such as actinomycin D, doxorubicin, bleomycin, and anticancer drugs such as mitomycin, vincristine, and vinblastine. Alkaloids, taxoids including mitosis inhibitors including taxane rings, and the like. In addition, hormones such as corticosteroids and progesterone and platinum-containing compounds such as cisplatin are used as anticancer agents.
화학요법제의 가장 큰 문제는 약제 내성으로써, 항암제에 의한 초기의 성공적인 반응에도 불구하고 결국에는 치료가 실패하게 되는 주요 요인이다. 이러한 부작용을 극복하는 문제와 관련지어 최근에는 민간에서 사용되어지는 천연물에서 그 활성 성분을 찾으려는 노력이 진행되고 있다. The biggest problem with chemotherapeutic agents is drug resistance, which, despite the initial successful response by anticancer agents, is a major factor that eventually causes treatment to fail. In connection with the problem of overcoming these side effects, efforts have recently been made to find the active ingredient in natural products that are used in the private sector.
본 발명의 생강(Zingiber cassumunar Roxb.)은 생강과(Zingiberaceae) 식물에 속하는 진지버(Zingiber) 속 식물로서, 동남아시아 등지에 광범위하게 분포되어 있으며 민간요법으로 이용되어 왔다. 진지버속 식물이 민간요법으로 사용되는 예로는, 말레이시아에서 여러 진지버속 식물의 뿌리가 위통, 멀미, 구토, 간질, 인후통, 기침, 타박상, 상처, 해산, 안질환, 간장병, 류머티즘, 근육통, 백선(버짐), 천식, 발열, 악성종양 및 종기 등의 치료제로 사용된다. 또한, 진지버속 식물의 성분으로는 여러 진지버속 식물 뿌리의 주성분으로 커큐미노이드(curcuminoid)(Ruby et al., Cancer Lett., 94, pp79-83, 1995; Ishida et al., Bioorg. Med. Chem., 10, pp3481-3487, 2002; Vimala et al., Br. J. Cancer, 80, pp110-116, 1999), 플라보노이드 글리코사이드(flavonoid glycoside)(Nakatani et al., Agric. Biol. Chem., 55, pp455-460, 1991; Murakami et al., Phytochemistry, 31 , pp2689-2693, 1992), 세스퀴터페노이드(sesquiterpenoid)(Murakami et al., Carcino genesis, 23, pp795-802, 2002) 및 폴리페놀(polyphenol) (Murakami et al., Phytochemistry, 31, pp2689-2693, 1992) 등이 보고되고 있다.Ginger ( Zingiber cassumunar Roxb.) Of the present invention is a genus Zingiber (Zingiber) belonging to the plant (Zingiberaceae), widely distributed in Southeast Asia, and has been used as a folk remedy. Examples of the use of creeper plants as a folk remedy include the fact that the roots of various creeper plants in Malaysia include stomach pain, motion sickness, vomiting, epilepsy, sore throat, cough, bruises, wounds, dissolution, eye disease, liver disease, rheumatism, myalgia, ringworm ( Ringworm), asthma, fever, malignancy and boils. In addition, the components of the genus Citrus plants are curcuminoids (Ruby et al., Cancer Lett., 94 , pp79-83, 1995; Ishida et al., Bioorg. Med. Chem., 10 , pp3481-3487, 2002; Vimala et al., Br. J. Cancer, 80 , pp110-116, 1999), flavonoid glycosides (Nakatani et al., Agric. Biol. Chem. , 55 , pp455-460, 1991; Murakami et al., Phytochemistry, 31 , pp2689-2693, 1992), sesquiterpenoids (Murakami et al., Carcino genesis, 23 , pp795-802, 2002) and Polyphenols (Murakami et al., Phytochemistry, 31 , pp2689-2693, 1992) and the like have been reported.
생강의 뿌리는 인도네시아에서는 복통, 설사, 구충, 통증, 류마티즘, 자궁질환을 치료하는 전통 약재로 사용되어 왔다(Ozaki et al., Chem. Pharm. Bull., 39, pp2353-2356, 1991). 또한, 활성에 관한 연구로서는 항산화 작용(Masuda et al., Chem. Lett., 1, pp189-192, 1993; Jitoe et al., Tetrahedron Lett., 35, pp981-984, 1994), 항염증 작용(Ozaki et al., Chem. Pharm. Bull., 39, pp2353-2356, 1991; Jeenapongsa et al., J. Ethnopharmacol., 87, pp143-148, 2003), 살충 작용(Nugroho et al., Phytochemistry, 41, pp129-132, 1996) 및 자궁 이완 작용(Kanjanapothi et al., Planta Med., 53, pp329-332, 1987)이 보고되었으며, 생강의 뿌리의 성분에 관한 연구에서는 페닐부테노이드(phenylbutenoid) 및 커큐미노이드(curcuminoid)가 보고되었다(Masuda and Jitoe, Phytochemistry, 39, pp459-461, 1995; Tuntiwachwuttikul et al., Phytochemistry, 20, 1164-1165, 1981; Masuda et al., Chem. Lett., 1, pp189-192, 1993; Jitoe et al., Tetrahedron Lett., 35, pp981-984, 1994).Ginger root has been used in Indonesia as a traditional medicine for treating abdominal pain, diarrhea, hookworm, pain, rheumatism and uterine disease (Ozaki et al., Chem. Pharm. Bull., 39 , pp2353-2356, 1991). In addition, studies on activity include antioxidant activity (Masuda et al., Chem. Lett., 1 , pp 189-192, 1993; Jitoe et al., Tetrahedron Lett., 35 , pp981-984, 1994), anti-inflammatory action ( Ozaki et al., Chem. Pharm. Bull., 39 , pp2353-2356, 1991; Jeenapongsa et al., J. Ethnopharmacol. , 87 , pp143-148, 2003), insecticidal action (Nugroho et al., Phytochemistry , 41 , pp129-132, 1996) and uterine relaxation (Kanjanapothi et al., Planta Med. , 53 , pp329-332, 1987), and studies on the components of the roots of ginger have been reported in Curcuminoids have been reported (Masuda and Jitoe, Phytochemistry, 39 , pp459-461, 1995; Tuntiwachwuttikul et al., Phytochemistry, 20 , 1164-1165, 1981; Masuda et al., Chem. Lett., 1 , pp 189-192, 1993; Jitoe et al., Tetrahedron Lett., 35 , pp981-984, 1994).
그러나 생강에서 분리된 물질들에 대한 지속적인 연구에도 불구하고, 이 식물로부터 세포독성에 대한 효능 물질의 분리에 대한 어떠한 교시나 시사된 바 없다.However, despite continuing research on isolated substances from ginger, no teaching or suggestion has been made of the separation of potent substances for cytotoxicity from this plant.
이에 본 발명자들은 민간에서 많이 사용되는 생약제 기원의 암질환 치료제를 연구한 결과, 생강으로부터 분리된 본 발명의 화합물들이 우수한 항암 효과를 나타냄을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors have completed the present invention by confirming that the compounds of the present invention isolated from ginger have excellent anticancer effects as a result of studying cancer drug treatment agents of herbal origin, which are widely used in folk medicine.
본 발명의 목적은 항암 활성을 갖는 생강 추출물로부터 분리된 본 발명의 화합물들을 유효성분으로 포함하는 암 질환의 예방 및 치료를 위한 약학조성물 및 건강기능식품을 제공하는 것이다. An object of the present invention is to provide a pharmaceutical composition and health functional food for the prevention and treatment of cancer diseases comprising the compounds of the present invention isolated from ginger extract having anticancer activity as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 생강으로부터 분리된 하기 일반식 (Ⅰ)의 화합물 또는 이의 약리학적으로 허용 가능한 염을 유효성분으로 포함하는 암 질환 예방 및 치료를 위한 약학조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention and treatment of cancer diseases comprising the compound of formula (I) or a pharmacologically acceptable salt thereof isolated from ginger as an active ingredient.
상기 식에서,Where
R1, R2, R3는 각각 독립적으로 -H, -OR5, -SR5 또는 -NR5이고,R 1 , R 2 , R 3 are each independently -H, -OR 5 , -SR 5 or -NR 5 ,
R5는 수소 또는 탄소수 1 내지 5의 저급 알킬기이고,R 5 is hydrogen or a lower alkyl group having 1 to 5 carbon atoms,
R4는 -OR6로 치환되거나 비치환된 탄소수 1 내지 5의 저급 알킬기 또는 알킬렌기이고,R 4 is a C1-5 lower alkyl or alkylene group unsubstituted or substituted with -OR 6 ,
R6는 수소, 탄소수 1 내지 3의 저급 알킬기 또는 알킬케톤기이다.R 6 is hydrogen, a lower alkyl group having 1 to 3 carbon atoms, or an alkyl ketone group.
상기 일반식 (I)의 화합물 중에서 바람직한 화합물은 일반식 (I)의 정의에서 R1 내지 R3가 각각 독립적으로 -H 또는 -OR5로서 R5가 탄소수 1 내지 5의 저급 알킬기이고, R4는 알킬렌기 또는 -OR6로 치환된 저급알킬기로서 R6가 수소, 저급 알킬기인 화합물이고, 보다 바람직하기로는 하기 구조식 (Ia)의 (E)-4-(3,4-디메톡시페닐)부트 -1,3-디엔, 구조식 (Ib)의 (E)-4-(2,4,5-트리메톡시페닐)부트-1,3-디엔, 구조식 (Ic)의 (E)-4-(3,4-디메톡시페닐)부트-3-엔-1-일 아세테이트 및 구조식 (Id)의 (E)-4-(3,4-디메톡시페닐)부트-3-엔-1-올이다.Preferred compounds among the compounds of the formula (I) is that R 1 to R 3 in the definition of formula (I) each independently -H, or R 5 -OR 5 as A lower alkyl group having 1 to 5 carbon atoms, R 4 is an alkylene group or a lower alkyl group substituted with -OR 6 , wherein R 6 is hydrogen or a lower alkyl group, and more preferably, ( E ) -4 of Structural Formula (Ia) -(3,4-dimethoxyphenyl) but-1,3-diene, ( E ) -4- (2,4,5-trimethoxyphenyl) but-1,3-diene of structural formula (Ib), structural formula (Ic) (E) -4- ( 3,4- dimethoxyphenyl) (E) -4- (3,4- dimethoxyphenyl) of the boot-3-en-1-yl acetate and formula (Id) of But-3-ene-1-ol.
(Ia) (Ia)
또한, 상기 화합물들은 초두구(Alpinia katsumadai Hayata), 고량강(Alpinia officinarum Hance), 익지(Alpinia oxyphylla Miq), 백두구(Amomum cardamomum Linn.), 양춘사(Amomum villosum Lour.), 울금(Curcuma aromatica Salisb.), 강황(Curcuma longa Linn.), 아출(Curcuma zedoaria Rosc.), 양하(Zingiber mioga (Thunb.) Rosc.) 및 생강(Zingiber cassumunar Roxb.) 식물, 바람직하게는 생강으로부터 분리되어 수득될 수 있다.In addition, the compounds include Alpinia katsumadai Hayata, Alpinia officinarum Hance, Alpinia oxyphylla Miq, Amomum cardamomum Linn., Amomum villosum Lour., Curcuma aromatica Salisb .), Curcuma longa Linn., Curcuma zedoaria Rosc., Zingiber mioga (Thunb. Rosc.) And Ginger ( Zingiber cassumunar Roxb.) Plants, preferably obtained separately from ginger have.
상기 암질환은 일반적인 암질환을 포함하며, 바람직하게는 위암, 결장암, 유방암, 폐암, 비소세포성폐암, 골암, 췌장암, 피부암, 두부 또는 경부암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 항문부근암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 호지킨병(Hodgkin's disease), 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직 육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, 중추신경계(CNS; central nervous system) 종양, 1차 CNS 림프종, 척수 종양, 뇌간 신경교종, 뇌하수체 선종 등으로부터 선택된 하나 이상의 질환을 포함한다.The cancer diseases include general cancer diseases, preferably gastric cancer, colon cancer, breast cancer, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer , Anal leiomyoma, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma Cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal or ureter cancer, renal cell carcinoma, renal pelvic carcinoma, central nervous system (CNS) tumor, primary CNS lymphoma, spinal cord tumor, One or more diseases selected from brain stem glioma, pituitary adenoma, and the like.
이하 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 생강(Zingiber cassumunar Roxb.) 극성용매 추출물 및 비극성용매 추출물은 하기와 같이 수득될 수 있다.Ginger ( Zingiber cassumunar Roxb.) Polar solvent extract and non-polar solvent extract of the present invention can be obtained as follows.
본 발명의 생강(Zingiber cassumunar Roxb.)을 건조하여, 뿌리를 세절한 다음, 시료 무게(g)의 약 1배 내지 20배, 바람직하게는 약 3배 내지 10배의 물, C1 내지 C4의 저급 알콜 또는 이들의 혼합용매, 바람직하게는 메탄올로, 20℃ 내지 100℃ , 바람직하게는 50℃ 내지 70℃의 추출온도에서 약 1시간 내지 10일, 바람직하게는 약 2시간 내지 5시간동안 냉침, 열수추출, 초음파 추출, 환류 냉각 추출, 더욱 바람직하게는 환류 냉각 추출방법을 이용하여 상층액을 회수한 다음, 상기의 과정을 2 내지 7회 반복 수행하여 상층액을 모으고 감압 농축하여 생강 극성용매 가용추출물을 수득할 수 있다.Ginger ( Zingiber cassumunar Roxb.) Of the present invention is dried, chopped roots, and then water of about 1 to 20 times, preferably about 3 to 10 times the water (C 1 to C 4) Lower alcohols or a mixed solvent thereof, preferably methanol, at an extraction temperature of 20 ° C. to 100 ° C., preferably 50 ° C. to 70 ° C. for about 1 to 10 days, preferably about 2 to 5 hours. After recovering the supernatant using cold needle, hot water extraction, ultrasonic extraction, reflux cooling extraction, more preferably reflux cooling extraction method, repeat the above procedure 2 to 7 times to collect the supernatant and concentrated under reduced pressure to ginger ginger Solvent soluble extracts can be obtained.
또한 본 발명의 비극성용매 가용추출물은 상기 극성용매 가용추출물을 증류수에 현탁한 후, 이를 현탁액이 약 1 내지 100배, 바람직하게는 약 1 내지 5배 부피의 헥산, 에틸아세테이트, 메틸렌클로라이드, 클로로포름과 같은 비극성 용매를 가하여 1회 내지 10회, 바람직하게는 2회 내지 5회 비극성용매 가용층을 추출, 분리하여 수득할 수 있다. 또한 추가로 통상의 분획 공정을 수행할 수도 있다(Harborne J.B. Phytochemical methods: A guide to modern techniques of plant analysis., 3rd Ed., pp 6-7, 1998).In addition, the non-polar solvent soluble extract of the present invention, after suspending the polar solvent soluble extract in distilled water, the suspension is about 1 to 100 times, preferably about 1 to 5 times the volume of hexane, ethyl acetate, methylene chloride, chloroform and The same nonpolar solvent can be added to obtain a non-polar solvent soluble layer 1 to 10 times, preferably 2 to 5 times, to be obtained by extraction and separation. It is also possible to further carry out conventional fractionation processes (Harborne JB Phytochemical methods: A guide to modern techniques of plant analysis., 3rd Ed. , Pp 6-7, 1998).
더욱 구체적으로는 상기 공정으로 수득된 생강 비극성용매 가용추출물 중 활성이 높은 분획들을 취하여 TLC 상에서 비슷한 R f 수치를 갖는 분획들을 모아 단일 분획을 만들고 건조하여 정제된 형태의 정제 분획물을 얻은 다음, 용출용매로 메틸렌클로라이드, 클로로포름, 헥산, 에틸아세테이트, 메탄올, 증류수 또는 이들의 혼합용매를 사용하여, 바람직하게는 메틸렌클로라이드:메탄올 혼합용매를 사용하여 실리카겔 컬럼크로마토그래피를 수행하여 5 내지 13개의 분획으로 분리할 수 있다. 분리된 분획물들을 다시 분획하여 상기 구조식 (Ia)의 (E)-4-(3,4-디메톡시페닐)부트-1,3-디엔, 구조식 (Ib)의 (E)-4-(2,4,5-트리메톡시페닐)부트-1,3-디엔, 구조식 (Ic)의 (E)-4-(3,4-디메톡시페닐)부트-3-엔-1-일 아세테이트 및 구조식 (Id)의 (E)-4-(3,4-디메톡시페닐)부트-3-엔-1-올 화합물을 수득할 수 있다.More specifically, the fractions having high activity in the ginger non-polar solvent soluble extract obtained by the above process are taken, the fractions having similar R f values are collected on TLC to form a single fraction, and dried to obtain a purified fraction of purified form. With methylene chloride, chloroform, hexane, ethyl acetate, methanol, distilled water or a mixed solvent thereof, silica gel column chromatography is preferably carried out using a methylene chloride: methanol mixed solvent to separate into 5 to 13 fractions. Can be. The separated fractions were fractionated again to give ( E ) -4- (3,4-dimethoxyphenyl) but-1,3-diene of formula (Ia), ( E ) -4- (2, 4,5-trimethoxyphenyl) but-1,3-diene, ( E ) -4- (3,4-dimethoxyphenyl) but-3-en-1-yl acetate of formula (Ic) and structural formula ( ( E ) -4- (3,4-dimethoxyphenyl) but-3-en-1-ol compound of Id) can be obtained.
본 발명의 암 질환의 예방 및 치료효과를 갖는 화합물들은 통상의 치환기들의 합성 및 분획 방법을 통하여 합성될 수 있다(Herbert O. House: Modern Synthetic Reactions, 2nd Ed., The Benjamin/Cummings Publishing Co., 1972).Compounds having a prophylactic and therapeutic effect of cancer diseases of the present invention can be synthesized through the synthesis and fractionation method of conventional substituents (Herbert O. House: Modern Synthetic Reactions , 2nd Ed ., The Benjamin / Cummings Publishing Co., 1972).
상기 일반식 (Ⅰ)으로 표기되는 본 발명의 화합물들은 당해 기술 분야에서 통상적인 방법에 따라 약학적으로 허용 가능한 염 및 용매화물로 제조될 수 있다. The compounds of the present invention represented by the general formula (I) may be prepared with pharmaceutically acceptable salts and solvates according to conventional methods in the art.
약학적으로 허용 가능한 염으로는 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 산부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 메탄올, 에탄올, 아세톤 또는 아세토니트릴과 같은 수혼화성 유기 용매를 사용하여 침전시켜서 제조한다. 동몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.As the pharmaceutically acceptable salt, acid addition salts formed by free acid are useful. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.
이 때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산 (propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르빈산, 카본산, 바닐릭산, 히드로 아이오딕산 등을 사용할 수 있다.In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, and the like.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리토 금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
상기의 일반식 (Ⅰ)의 약학적으로 허용 가능한 염은, 달리 지시되지 않는 한, 일반식 (Ⅰ)의 화합물에 존재할 수 있는 산성 또는 염기성기의 염을 포함한다. 예를 들면, 약학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염이 포함되며, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄설포네이트(메실레이트) 및 p-톨루엔설포네이트(토실레이트) 염이 있으며, 당업계에서 알려진 염의 제조방법이나 제조과정을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the above general formula (I) include salts of acidic or basic groups which may be present in compounds of general formula (I) unless otherwise indicated. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and methods or processes for preparing salts known in the art It can be prepared through.
상기와 같은 방법으로 얻어진 본 발명의 일반식 (I)의 화합물, 바람직하게는 (E)-4-(3,4-디메톡시페닐)부트-1,3-디엔, (E)-4-(2,4,5-트리메톡시페닐)부트-1,3-디엔, (E)-4-(3,4-디메톡시페닐)부트-3-엔-1-일 아세테이트 및 (E)-4-(3,4-디메톡시페닐)부트-3-엔-1-올 화합물의 항암 효과를 알아보기 위하여, 시험관 내(in vitro)에서 A549(사람 폐암 세포), Col2(사람 결장암 세포), SNU-638(사람 위암 세포) 및 HT-1080(사람 섬유종양 세포)의 세포독성을 실험한 결과, 본 발명의 화합물들은 암세포주에 대하여 탁월한 세포 독성 효과를 나타냄을 확인하였다.Compound of the general formula (I) of the present invention obtained by the above method, preferably ( E ) -4- (3,4-dimethoxyphenyl) but-1,3-diene, ( E ) -4- ( 2,4,5-trimethoxyphenyl) but-1,3-diene, ( E ) -4- (3,4-dimethoxyphenyl) but-3-en-1-yl acetate and ( E ) -4 To investigate the anticancer effects of-(3,4-dimethoxyphenyl) but-3-en-1-ol compound, in vitro A549 (human lung cancer cells), Col2 (human colon cancer cells), SNU The cytotoxicity of -638 (human gastric cancer cells) and HT-1080 (human fibrous tumor cells) was tested and found that the compounds of the present invention showed excellent cytotoxic effects against cancer cell lines.
본 발명의 암 질환의 예방 및 치료용 약학조성물은, 조성물 총 중량에 대하여 상기 추출물 또는 화합물을 0.1 내지 50 중량%로 포함한다. The pharmaceutical composition for preventing and treating cancer diseases of the present invention comprises 0.1 to 50% by weight of the extract or compound based on the total weight of the composition.
본 발명의 화합물을 포함하는 약학조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.Pharmaceutical compositions comprising the compounds of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
본 발명의 화합물의 약학적 투여 형태는 이들의 약학적 허용 가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. Pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.
본 발명에 따른 화합물을 포함하는 약학조성물은, 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. 화합물을 포함하는 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 상기 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 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(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골(macrogol), 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical compositions comprising the compounds according to the present invention may be prepared in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. Can be formulated and used. Carriers, excipients and diluents that may be included in the composition comprising the compound include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, or the like. ) Or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 화합물은 1일 0.0001 내지 100mg/kg으로, 바람직하게는 0.001 내지 10mg/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위을 한정하는 것은 아니다.Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably at 0.001 to 10 mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
본 발명의 화합물은 쥐, 생쥐, 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(intracerebroventricular) 주사에 의해 투여될 수 있다. The compounds of the present invention can be administered to mammals such as mice, mice, livestock, humans, and the like by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명은 암에 의해 유발되는 질환의 예방 효과를 나타내는 상기 화합물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 건강기능식품을 제공한다. 본 발명의 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강 기능성 식품류 등이 있다.The present invention provides a dietary supplement comprising the compound and a food acceptable acceptable food supplement additive that exhibit a prophylactic effect of a disease caused by cancer. Examples of the food to which the compound of the present invention can be added include various foods, beverages, gums, teas, vitamin complexes, and health functional foods.
또한, 암에 의해 유발되는 질환의 예방 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 화합물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 5 g, 바람직하게는 0.3 내지 1g의 비율로 가할 수 있다. It may also be added to foods or beverages for the purpose of preventing the disease caused by cancer. At this time, the amount of the compound in the food or beverage may be added at 0.01 to 15% by weight of the total food weight, the health beverage composition may be added in a ratio of 0.02 to 5 g, preferably 0.3 to 1g based on 100 ml. have.
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다.The health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the compound as an essential ingredient in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 화합물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 화합물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 화합물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the compounds of the present invention include various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and its Salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the compounds of the present invention may contain flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is usually selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the compound of the present invention.
본 발명은 다음의 실시예 및 실험예에 의거하여 더욱 상세히 설명되나, 본 발명이 이에 의해 제한되지는 않는다.The present invention is described in more detail based on the following examples and experimental examples, but the present invention is not limited thereto.
실시예 1. 생강(Example 1 Ginger Zingiber cassumunarZingiber cassumunar Roxb.) 극성용매 가용추출물의 제조 Roxb.) Preparation of Polar Solvent Soluble Extracts
인도네시아(Indonesia)의 수라바야(Surabaya) 지역에서 생강(Zingiber cassumunar Roxb.)를 채집하여 건조시키고 뿌리를 세절하여 얻은 시료 500 g을 100% 메탄올 10ℓ에 넣고, 환류냉각 장치를 이용하여 수욕조 상에서 3시간 동안 추출하였다. 이 과정을 2회 반복하여 상층액을 모은 후, 감압 농축하여 생강 조추출물 50 g을 수득하였다.Ginger ( Zingiber cassumunar Roxb.) From Surabaya, Indonesia, was collected and dried, and the roots were chopped, and 500 g of the sample was placed in 10 l of 100% methanol and heated in a water bath using a reflux condenser. Extraction for 3 hours. This process was repeated twice to collect the supernatant, and then concentrated under reduced pressure to obtain 50 g of crude ginger extract.
실시예 2. 생강 비극성용매 분획물의 제조Example 2 Preparation of Ginger Nonpolar Solvent Fractions
상기 실시예 1에서 얻은 생강 조추출물 50 g을 증류수 1ℓ에 현탁시킨 후, 헥산 1ℓ를 첨가하여 용해한 다음 이를 분획여두에서 헥산층에 용해되는 성분만 분리하여 진공 건조하였다. 이 과정을 5회 반복 수행하여 헥산 분획물 14.3g을 수득하였다. 남은 수층에 클로로포름 1ℓ를 첨가하여 분획여두에서 클로로포름층에 용해되는 성분만 분리해서 진공건조하였다. 이 과정을 5회 반복 수행하여 클로로포름 분획물 12.9g을 수득하였다. 상기와 동일한 과정으로 수행하여 n-부탄올 분획물 3.3g 및 수층 11.4g을 수득하였다.50 g of the crude crude extract obtained in Example 1 was suspended in 1 L of distilled water, and then dissolved by adding 1 L of hexane, and then vacuum dried by separating only the components dissolved in the hexane layer in the fractionated filter. This process was repeated five times to give 14.3 g of hexane fraction. 1 L of chloroform was added to the remaining aqueous layer, and only the components dissolved in the chloroform layer were separated and dried under vacuum. This process was repeated five times to give 12.9 g of chloroform fraction. The same procedure as described above gave 3.3 g of n-butanol fraction and 11.4 g of aqueous layer.
실시예 3. (Example 3. EE )-4-(3,4-디메톡시페닐)부트-1,3-디엔의 분리 정제Separation and Purification of 4- (3,4-dimethoxyphenyl) but-1,3-diene
상기 실시예 2에서 얻은 용매 분획 중 가장 활성이 높은 클로로포름 분획 13.0g을 메틸렌클로라이드:메탄올 혼합용매(100:1 →10:1)를 사용하여 실리카겔 컬럼크로마토그래피(실리카 겔 60, 230 내지 400 메쉬, Merck사)를 실시하여 13개의 분획으로 분리하고, 이들 분획 중 1번 분획 1.8 g을 다시 헥산:에틸아세테이트 혼합용매(100:0 →0:100)를 사용하여 실리카겔 컬럼크로마토그래피(실리카겔 60, 230 내지 400 메쉬, Merck사)를 실시하였다. 이로부터 나온 1번에서 활성 성분인 (E)-4-(3,4-디메톡시페닐)부트-1,3-디엔(화합물 1이라 명명) 143㎎을 분리하였다.13.0 g of the chloroform fraction having the highest activity among the solvent fractions obtained in Example 2 was subjected to silica gel column chromatography (silica gel 60, 230 to 400 mesh, using methylene chloride: methanol mixed solvent (100: 1 → 10: 1)). Merck), and separated into 13 fractions, and 1.8 g of fraction 1 of these fractions was again subjected to silica gel column chromatography (silica gel 60, 230) using a hexane: ethyl acetate mixed solvent (100: 0 → 0: 100). To 400 mesh, Merck). From this No. 1, 143 mg of ( E ) -4- (3,4-dimethoxyphenyl) but-1,3-diene (named Compound 1) as an active ingredient was isolated.
실시예 4. (Example 4. EE )-4-(2,4,5-트리메톡시페닐)부트-1,3-디엔의 분리 정제Separation and Purification of) -4- (2,4,5-trimethoxyphenyl) but-1,3-diene
상기 실시예 2에서 얻은 용매 분획 중 가장 활성이 높은 클로로포름 분획 13.0g을 메틸렌클로라이드:메탄올 혼합용매(100:1 →10:1)를 사용하여 실리카겔 컬럼크로마토그래피(실리카 겔 60, 230 내지 400 메쉬, Merck사)를 실시하여 13개의 분획으로 분리하고, 이들 분획 중 1번 분획 1.8 g을 다시 헥산:에틸아세테이트 혼합용매(100:0 →0:100)를 사용하여 실리카겔 컬럼크로마토그래피(실리카겔 60, 230 내지 400 메쉬, Merck사)를 실시하였다. 이로부터 나온 2번 분획에서 활성 성분인 (E)-4-(2,4,5-트리메톡시페닐)부트-1,3-디엔(화합물 2라 명명) 60㎎을 분리하였다.13.0 g of the chloroform fraction having the highest activity among the solvent fractions obtained in Example 2 was subjected to silica gel column chromatography (silica gel 60, 230 to 400 mesh, using methylene chloride: methanol mixed solvent (100: 1 → 10: 1)). Merck), and separated into 13 fractions, and 1.8 g of fraction 1 of these fractions was again subjected to silica gel column chromatography (silica gel 60, 230) using a hexane: ethyl acetate mixed solvent (100: 0 → 0: 100). To 400 mesh, Merck). From fraction 2 therefrom, 60 mg of the active ingredient ( E ) -4- (2,4,5-trimethoxyphenyl) but-1,3-diene (named Compound 2) was isolated.
실시예 5. (Example 5. EE )-4-(3,4-디메톡시페닐)부트-3-엔-1-일 아세테이트의 분리 정제 Separation and Purification of) -4- (3,4-dimethoxyphenyl) but-3-en-1-yl acetate
상기 실시예 2에서 얻은 용매 분획 중 가장 활성이 높은 클로로포름 분획 13.0g을 메틸렌클로라이드:메탄올 혼합용매(100:1 →10:1)를 사용하여 실리카겔 컬럼크로마토그래피(실리카 겔 60, 230 내지 400 메쉬, Merck사)를 실시하여 13개의 분획으로 분리하고, 이들 분획 중 1번 분획 1.8 g을 다시 헥산:에틸아세테이트 혼합용매(100:0 →0:100)를 사용하여 실리카겔 컬럼크로마토그래피(실리카겔 60, 230 내지 400 메쉬, Merck사)를 실시하였다. 이로부터 나온 7번 분획에서 비활성 성분인 (E)-4-(3,4-디메톡시페닐)부트-3-엔-1-일 아세테이트(화합물 3라 명명) 243㎎을 분리하였다.13.0 g of the chloroform fraction having the highest activity among the solvent fractions obtained in Example 2 was subjected to silica gel column chromatography (silica gel 60, 230 to 400 mesh, using methylene chloride: methanol mixed solvent (100: 1 → 10: 1)). Merck), and separated into 13 fractions, and 1.8 g of fraction 1 of these fractions was again subjected to silica gel column chromatography (silica gel 60, 230) using a hexane: ethyl acetate mixed solvent (100: 0 → 0: 100). To 400 mesh, Merck). In fraction 7 therefrom, 243 mg of an inactive component ( E ) -4- (3,4-dimethoxyphenyl) but-3-en-1-yl acetate (named Compound 3) was isolated.
실시예 6. (Example 6. EE )-4-(3,4-디메톡시페닐)부트-3-엔-1-올의 분리 정제Separation and Purification of 4-4- (3,4-dimethoxyphenyl) but-3-en-1-ol
상기 실시예 2에서 얻은 용매 분획 중 가장 활성이 높은 클로로포름 분획 13.0g을 메틸렌클로라이드:메탄올 혼합용매(100:1 →10:1)를 사용하여 실리카겔 컬럼크로마토그래피(실리카 겔 60, 230 내지 400 메쉬, Merck사)를 실시하여 13개의 분획으로 분리하고, 이들 분획 중 3번에서 6번까지의 분획을 합친 분획 2.2 g을 다시 헥산:아세톤 혼합용매(100:0 → 0:100)를 사용하여 실리카겔 컬럼크로마토그래피(실리카겔 60, 230 내지 400 메쉬, Merck사)를 실시하였다. 이로부터 나온 3번에서 5번까지의 분획을 합친 분획 1.6g을 다시 헥산:에틸아세테이트 혼합용매(10:1 →0:100)로 실리카겔 컬럼크로마토그래피를 실시하여, 비활성 성분인 (E)-4-(3,4-디메톡시페닐)부트-3-엔-1-올(화합물 4라 명명) 550㎎을 분리하였다.13.0 g of the chloroform fraction having the highest activity among the solvent fractions obtained in Example 2 was subjected to silica gel column chromatography (silica gel 60, 230 to 400 mesh, using methylene chloride: methanol mixed solvent (100: 1 → 10: 1)). Merck), separated into 13 fractions, and 2.2 g of the fractions 3 to 6 of these fractions were added again to the silica gel column using a hexane: acetone mixed solvent (100: 0 → 0: 100). Chromatography (silica gel 60, 230-400 mesh, Merck) was performed. 1.6 g of the combined fractions from Nos. 3 to 5 were further subjected to silica gel column chromatography with a hexane: ethyl acetate mixed solvent (10: 1 to 0: 100) to obtain an inactive component ( E ) -4. 550 mg of-(3,4-dimethoxyphenyl) but-3-en-1-ol (named compound 4) was isolated.
실시예 7. 화합물의 구조 결정Example 7. Structure Determination of Compounds
상기 실시예 3 내지 6에서 분리된 화합물에 대하여 분석 TLC (analytical TLC)를 이용하여 각 성분의 순도를 평가하였다. 단일 활성 성분임이 확인된 상태에서 각종 분광학적 IR(Bio-Rad Laboratories사, USA), Mass(JEOL사, Japane), 1H-NMR(Varian사, CA), 13C-NMR, DEPT, HSQC, HMBC 등을 실시하여 하기와 같이 화합물의 구조를 결정하였다.The purity of each component was evaluated using analytical TLC for the compounds isolated in Examples 3 to 6. In the state identified as a single active ingredient, various spectroscopic IR (Bio-Rad Laboratories, USA), Mass (JEOL, Japane), 1 H-NMR (Varian, CA), 13 C-NMR, DEPT, HSQC, HMBC and the like were carried out to determine the structure of the compound as follows.
[1] ([One] ( EE )-4-(3,4-디메톡시페닐)부트-1,3-디엔) -4- (3,4-dimethoxyphenyl) but-1,3-diene
성상: 미황색 고무질(pale yellow gum)Appearance: pale yellow gum
분자구조식 : C12H14O2 Molecular Structure: C 12 H 14 O 2
TLC 상: R f =0.5 (헥산:에틸아세테이트 = 2:1), 10% (v/v) 황산발색시약에 갈색으로 발색.TLC phase: R f = 0.5 (hexane: ethyl acetate = 2: 1), colored brown with 10% (v / v) sulfuric acid reagent.
UV (CHCl3) λmax (log ε) 293(4.3), 238.5(4.1) nmUV (CHCl 3 ) λ max (log ε) 293 (4.3), 238.5 (4.1) nm
IR (liquid film) νmax 2925, 2853, 1597, 1514, 1463, 1419, 1266, 1233, 1138, 1026 cm-1 IR (liquid film) ν max 2925, 2853, 1597, 1514, 1463, 1419, 1266, 1233, 1138, 1026 cm -1
EIMS m/z (%) [M]+ 190 (100), 159 (75), 144 (40), 115 (60),103 (20), 51 (15)EIMS m / z (%) [M] + 190 (100), 159 (75), 144 (40), 115 (60), 103 (20), 51 (15)
1H-NMR 및 13C-NMR 은 표 1 및 표 2 참조.See 1 and 2 for 1 H-NMR and 13 C-NMR.
[2] ([2] ( EE )-4-(2,4,5-트리메톡시페닐)부트-1,3-디엔) -4- (2,4,5-trimethoxyphenyl) but-1,3-diene
성상: 미황색 고체(pale yellow solid)Appearance: pale yellow solid
분자구조식 : C13H16O3 Molecular Structure: C 13 H 16 O 3
TLC 상: R f =0.4 (헥산:에틸아세테이트 = 2:1), 10% (v/v) 황산발색시약에 갈색으로 발색.TLC phase: R f = 0.4 (hexane: ethyl acetate = 2: 1), brown color with 10% (v / v) sulfate reagent.
UV (CHCl3) λmax (log ε) 281.5(4.28), 238.5(4.26) nmUV (CHCl 3 ) λ max (log ε) 281.5 (4.28), 238.5 (4.26) nm
IR (liquid film) νmax 2926, 2853, 1607, 1510, 1463, 1401, 1317, 1208, 1034 cm-1 IR (liquid film) ν max 2926, 2853, 1607, 1510, 1463, 1401, 1317, 1208, 1034 cm -1
EIMS m/z (%) [M]+ 220 (100), 189 (90), 174 (25), 145 (30), 115 (10), 91 (15)EIMS m / z (%) [M] + 220 (100), 189 (90), 174 (25), 145 (30), 115 (10), 91 (15)
1H-NMR 및 13C-NMR 은 표 1 및 표 2 참조.See 1 and 2 for 1 H-NMR and 13 C-NMR.
[3] ([3] ( EE )-4-(3,4-디메톡시페닐)부트-3-엔-1-일 아세테이트 ) -4- (3,4-dimethoxyphenyl) but-3-en-1-yl acetate
성상: 미황색 유액 (pale yellow oil)Appearance: pale yellow oil
분자구조식 : C14H18O4 Molecular Structure: C 14 H 18 O 4
TLC 상: R f =0.3 (헥산:에틸아세테이트 = 2:1), 10% (v/v) 황산발색시약에 갈색으로 발색.TLC phase: R f = 0.3 (hexane: ethyl acetate = 2: 1), colored brown with 10% (v / v) sulfuric acid reagent.
UV (CHCl3) λmax (log ε) 268.5(4.1), 239(3.8) nmUV (CHCl 3 ) λ max (log ε) 268.5 (4.1), 239 (3.8) nm
IR (liquid film) νmax 2923, 2853, 1738, 1602, 1515, 1461, 1265, 1236, 1028 cm-1 IR (liquid film) ν max 2923, 2853, 1738, 1602, 1515, 1461, 1265, 1236, 1028 cm -1
EIMS m/z (%) [M]+ 250 (20), 190 (35), 159 (25), 117 (15), 85 (100), 83 (100), 55 (10)EIMS m / z (%) [M] + 250 (20), 190 (35), 159 (25), 117 (15), 85 (100), 83 (100), 55 (10)
1H-NMR 및 13C-NMR 은 표 1 및 표 2 참조.See 1 and 2 for 1 H-NMR and 13 C-NMR.
[4] ([4] ( EE )-4-(3,4-디메톡시페닐)부트-3-엔-1-올) -4- (3,4-dimethoxyphenyl) but-3-en-1-ol
성상: 미황색 고체(pale yellow solid)Appearance: pale yellow solid
분자구조식 : C12H16O3 Molecular Structure: C 12 H 16 O 3
TLC 상: R f =0.3 (헥산:에틸아세테이트 = 1:1), 10% (v/v) 황산발색시약에 보랏빛 갈색으로 발색.TLC phase: R f = 0.3 (hexane: ethyl acetate = 1: 1), color purple to brown in 10% (v / v) sulfuric acid reagent.
UV (CHCl3) λmax (log ε) 301(3.0) nmUV (CHCl 3 ) λ max (log ε) 301 (3.0) nm
IR (liquid film) νmax 3400, 1599, 1460, 1263, 1139, 1025 cm-1IR (liquid film) ν max 3400, 1599, 1460, 1263, 1139, 1025 cm-1
FABMS m/z [M]+ 208.2478 (calcd. 208.2595 for C12H16O3)FABMS m / z [M] + 208.2478 (calcd. 208.2595 for C 12 H 16 O 3 )
1H-NMR 및 13C-NMR 은 표 1 및 표 2 참조.See 1 and 2 for 1 H-NMR and 13 C-NMR.
실험예 1. 시험관 내 세포독성(cytotoxicity) 측정Experimental Example 1. Measurement of cytotoxicity in vitro
상기 실시예 3 내지 6에서 얻은 화합물 1 내지 화합물 4의 A549(사람 폐암 세포), Col2(사람 결장암 세포), SNU-638(사람 위암 세포) 및 HT-1080(사람 섬유종양 세포)에 대한 세포독성을 문헌에 기재된 바와 같이, SRB 법(sulforhodamine B)을 이용하여 측정하였다(Lee et al., Chemico-Biol. Interact., 115, p215, 1998).Cytotoxicity against A549 (human lung cancer cells), Col2 (human colon cancer cells), SNU-638 (human gastric cancer cells) and HT-1080 (human fibroblast cells) of Compounds 1 to 4 obtained in Examples 3 to 6 Was measured using the SRB method (sulforhodamine B) as described in the literature (Lee et al., Chemico-Biol. Interact. , 115 , p215, 1998).
1-1. 세포 배양1-1. Cell culture
A549(사람 폐암 세포), Col2(사람 결장암 세포), SNU-638(사람 위암 세포) 및 HT-1080(사람 섬유종양 세포)를 한국 세포주 은행(KCLB)으로부터 분양 받아 10% FBS 및 1% PSF 등을 함유한 MEME 배지를 사용하여, 37℃, 5% 이산화탄소 항온기에서 배양하였다. 계대 배양은 3일 내지 4일에 한번씩 시행하였다.A549 (human lung cancer cells), Col2 (human colon cancer cells), SNU-638 (human gastric cancer cells), and HT-1080 (human fibroblast cells) were distributed from the Korean Cell Line Bank (KCLB), such as 10% FBS and 1% PSF. Using MEME medium containing was incubated in 37 ℃, 5% carbon dioxide incubator. Subcultures were performed once every 3 to 4 days.
1-2. 화합물 1 내지 4의 세포독성 측정1-2. Cytotoxicity Measurements of Compounds 1-4
상기 실시예 3 내지 6에서 얻은 화합물 1 내지 화합물 4의 세포성장에 미치는 영향을 SRB 법을 이용하여 측정하였다. 즉, 상기 실험예 1-1에서 배양한 여러 세포현탁액 190㎕(5×104세포/㎖)을 96-웰 플레이트에 넣고, 여기에 10% DMSO에 용해시킨 상기 실시예 3 내지 6의 시료 10㎕를 첨가하여 3일간 배양하였다. 최소 16 웰에 상기와 동일한 세포현탁액 190㎕를 넣고 30분간 배양하여 제로-데이 대조군(zero-day control)으로 하였다. 배양한 세포를 TCA(trichloroacetic acid)로 고정시킨 후, SRB 용액으로 염색하고 트리스-염기(Tris-base)로 염색액을 용해시킨 다음, 515㎚에서 흡광도를 측정하였다. 10% DMSO를 대조군으로 하여 각 시험 물질처리에 따른 세포 생존율을 하기의 수학식 1에 따라 환산하였다.The effect on the cell growth of the compounds 1 to 4 obtained in Examples 3 to 6 was measured using the SRB method. That is, sample 10 of Examples 3 to 6, in which 190 μl (5 × 10 4 cells / ml) of various cell suspensions cultured in Experimental Example 1-1 were placed in a 96-well plate and dissolved in 10% DMSO. Incubated for 3 days with the addition of. 190 μl of the same cell suspension was added to at least 16 wells, followed by incubation for 30 minutes, to provide a zero-day control. The cultured cells were fixed with trichloroacetic acid (TCA), stained with SRB solution, lysed with Tris-base, and absorbance was measured at 515 nm. Using 10% DMSO as a control, the cell viability according to each test material treatment was converted according to Equation 1 below.
시료를 처리하지 않은 대조군을 100%로 하였을 때 시료처리군의 값을 대조군에 대한 백분율로 나타내었으며, 각 시험물질처리는 이중(duplicate) 또는 삼중(triplicate) 시험의 평균값 ±SEM으로 구하였다. IC50 값은 50% 생존율에 대한 시험 물질의 농도로 환산하여 상호 비교하였다.When the control group was not treated with the sample at 100%, the value of the sample treatment group was expressed as a percentage of the control group, and each test substance treatment was calculated as an average value ± SEM of a duplicate or triple test. IC 50 values were compared with each other in terms of concentration of test substance for 50% survival.
화합물 1 및 2는 SNU-638, HT-1080에서 활성을 타내었으며, 화합물 3 및 4는 활성을 보이지 않았다. 실험결과를 하기 표 3에 나타내었다. Compounds 1 and 2 showed activity in SNU-638, HT-1080, and compounds 3 and 4 showed no activity. The experimental results are shown in Table 3 below.
본 발명의 화합물 1 내지 4를 포함하는 약학조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Examples of the pharmaceutical compositions containing the compounds 1 to 4 of the present invention will be described, but the present invention is not intended to be limited thereto but merely to explain in detail.
제제예 1. 산제의 제조Formulation Example 1 Preparation of Powder
화합물 1 20 mgCompound 1 20 mg
유당 100 mgLactose 100 mg
탈크 10 mgTalc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2 Preparation of Tablet
화합물 2 10 mgCompound 2 10 mg
옥수수전분 100 mgCorn starch 100 mg
유당 100 mgLactose 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
제제예 3. 캅셀제의 제조Formulation Example 3 Preparation of Capsule
화합물 3 10 mgCompound 3 10 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium Stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
제제예 4. 주사제의 제조Formulation Example 4 Preparation of Injection
화합물 4 10 mgCompound 4 10 mg
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO4·12H2O 26 mg Na 2 HPO 4 · 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2㎖) 상기의 성분 함량으로 제조한다.According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).
제제예 5. 액제의 제조Formulation Example 5 Preparation of Liquid
화합물 1 20 mgCompound 1 20 mg
이성화당 10 g10 g of isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.After dissolving each component in purified water according to the usual method of preparing a liquid solution, adding lemon flavor appropriately, mixing the above components, adding purified water, adjusting the whole to 100 ml by adding purified water, and then filling into a brown bottle. The solution is prepared by sterilization.
제제예 6. 건강 음료의 제조Formulation Example 6 Preparation of Healthy Drink
화합물 2 100 ㎎Compound 2 100 mg
비타민 C 15 g15 g of vitamin C
비타민 E (분말) 100 g100 g of vitamin E (powder)
젖산철 19.75 gIron lactate 19.75 g
산화아연 3.5 g3.5 g of zinc oxide
니코틴산아미드 3.5 gNicotinamide 3.5 g
비타민 A 0.2 g0.2 g of vitamin A
비타민 B1 0.25 g0.25 g of vitamin B 1
비타민 B2 0.3g0.3 g of vitamin B 2
물 정량Water quantification
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. After mixing the above components in accordance with a conventional healthy beverage production method, and stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed sterilization and then refrigerated and stored in the present invention For the preparation of healthy beverage compositions.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is mixed with a component suitable for a favorite beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
상술한 바와 같이, 본 발명의 생강 추출물로부터 분리된 일반식 (I)의 화합물들은 암세포에 대해 탁월한 세포독성을 나타내어 암의 생성을 억제한다. 그러므로 본 발명의 생강 추출물로부터 분리된 화합물을 포함하는 조성물은 암 질환의 예방 및 치료를 위한 의약품 및 건강기능식품으로 유용하게 사용될 수 있다.As described above, the compounds of formula (I) isolated from the ginger extract of the present invention exhibit excellent cytotoxicity against cancer cells, thereby inhibiting cancer production. Therefore, the composition comprising the compound isolated from the ginger extract of the present invention can be usefully used as a pharmaceutical and nutraceutical for the prevention and treatment of cancer diseases.
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Cited By (6)
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KR100668067B1 (en) * | 2005-07-26 | 2007-01-11 | 이화여자대학교 산학협력단 | Compositions containing phenylbutenoid derivatives for the prevention and treatment of inflammatory diseases |
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KR100668067B1 (en) * | 2005-07-26 | 2007-01-11 | 이화여자대학교 산학협력단 | Compositions containing phenylbutenoid derivatives for the prevention and treatment of inflammatory diseases |
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KR20190086643A (en) * | 2019-07-11 | 2019-07-23 | 경희대학교 산학협력단 | Composition for preventing and treating a cancer comprising curcuma zedoaria |
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