KR20020081003A - Compositions Comprising ar-Turmerone And The Use Thereof - Google Patents
Compositions Comprising ar-Turmerone And The Use Thereof Download PDFInfo
- Publication number
- KR20020081003A KR20020081003A KR1020010020955A KR20010020955A KR20020081003A KR 20020081003 A KR20020081003 A KR 20020081003A KR 1020010020955 A KR1020010020955 A KR 1020010020955A KR 20010020955 A KR20010020955 A KR 20010020955A KR 20020081003 A KR20020081003 A KR 20020081003A
- Authority
- KR
- South Korea
- Prior art keywords
- cox
- tumeron
- cancer
- composition
- turmerone
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 27
- NAAJVHHFAXWBOK-ZDUSSCGKSA-N (+)-(S)-ar-turmerone Chemical compound CC(C)=CC(=O)C[C@H](C)C1=CC=C(C)C=C1 NAAJVHHFAXWBOK-ZDUSSCGKSA-N 0.000 title claims abstract description 9
- XOCANRBEOZQNAQ-KGLIPLIRSA-N ar-turmerone Natural products C[C@H](CC(=O)C=C(C)C)[C@@H]1CC=C(C)C=C1 XOCANRBEOZQNAQ-KGLIPLIRSA-N 0.000 title abstract description 5
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- NAAJVHHFAXWBOK-UHFFFAOYSA-N (+)-ar-Turmerone Chemical compound CC(C)=CC(=O)CC(C)C1=CC=C(C)C=C1 NAAJVHHFAXWBOK-UHFFFAOYSA-N 0.000 claims 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- 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
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Abstract
Description
본 발명은 새로운 항염증제 및 암예방제에 관한 것이다. 보다 상세히는 천연물 생약 아출 추출물에서 유래된 것으로, 시클로옥시게나제-2 (cyclooxygenase-2: COX-2) 및 유도 니트릭 옥사이드 신타제(inducible nitric oxide synthase: iNOS)를 저해하는 하기 화학식 (Ⅰ)로 표현되는 화합물 및 그 유도체에 관한 것이다.The present invention relates to novel anti-inflammatory and cancer prevention agents. More specifically, it is derived from the natural herbal herbal extract extract, which inhibits cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). It relates to a compound and derivatives thereof represented by.
아스피린, 이부프로펜, 아세트아미노펜 등으로 대표되는 비-스테로이드성 소염진통제(nonsteroidal antiinflammatory drugs: NSAIDs)의 항염증 효과는 COX 효소 활성을 억제하는 것에 의해 매개된다 (Vane 등, Annu. Rev. Pharmacol.Toxicol.,38, 97, 1998). COX는 생체 내에 존재하는 프로스타그란딘(prostaglandin)의 생합성에 관련하는 주 효소이다(Smith 등, J. Biol. Chem.,271, 33157, 1996).The anti-inflammatory effects of nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin, ibuprofen, acetaminophen, etc. are mediated by inhibiting COX enzyme activity (Vane et al., Annu. Rev. Pharmacol. Toxicol. , 38 , 97, 1998). COX is a major enzyme involved in the biosynthesis of prostaglandin present in vivo (Smith et al., J. Biol. Chem., 271 , 33157, 1996).
COX는 생체 내에 두 종류의 이성 효소, COX-1과 COX-2가 존재한다. COX-1은 정상 상태에서 발현하여 위장관을 보호하거나 신장 기능을 조절하는데 관여한다. COX-2는 염증이나 기타 면역 반응시 세포분열인자(mitogen)나 시토킨 (cytokines)류에 의해 세포 내에서 일시적이고 빠르게 발현된다. NSAIDs가 부작용을 나타내는 것은 COX-2 효소에 대한 선택성이 결여되어 COX-1을 불필요하게 억제하는 데서 기인하는 것으로 알려져 있다 (Masferrer 등, Proc. Natl. Acad. Sci. USA,91, 3228, 1994; Seibert 등, Proc. Natl. Acad. Sci. USA,91, 12013, 1994). 따라서 현재의 연구는 기존의 비-스테로이드성 소염진통제의 부작용을 감소시키기 위하여 보다 선택적으로 COX-2를 억제하는 물질을 찾는데 집중되어 있다.COX has two kinds of isomers, COX-1 and COX-2, in vivo. COX-1 is expressed in steady state and is involved in protecting the gastrointestinal tract or regulating kidney function. COX-2 is transiently and rapidly expressed in cells by mitogens and cytokines during inflammation and other immune responses. NSAIDs exhibit side effects due to the lack of selectivity for COX-2 enzymes and unnecessary inhibition of COX-1 (Masferrer et al., Proc. Natl. Acad. Sci. USA, 91 , 3228, 1994; Seibert et al., Proc. Natl. Acad. Sci. USA, 91 , 12013, 1994). Therefore, the current research is focused on finding substances that inhibit COX-2 more selectively in order to reduce the side effects of existing non-steroidal anti-inflammatory drugs.
제 1세대 COX-2 저해제는 니메슬리드(nimesulide), 에토돌락(etodolac), 멜록시캄(meloxicam) 등의 약물로서 실험 동물모델에서 강한 항염증 효과를 내는 동시에 위장에 최소한의 부작용을 나타내는 약물 중심으로 개발되었다 (Bennett 등, Drugs,46, 1, 1993). 제 2세대 COX-2 저해제는 효소의 구조 분석을 통하여 개발된 것으로 쎌렉콕시브(celecoxib, celebrex), L-745,337 등이 이에 속한다. 이들 제 2세대 저해제는 제 1세대 약물들에 비하여 COX-2에 대한 선택성이 훨씬 증가한 것으로 COX-1에 비해 100 배 이상의 선택성을 지니고 있다 (Griswold 등, Med. Res. Rev.,16, 181, 1996).First-generation COX-2 inhibitors are drugs such as nimesulide, etodolac, and meloxicam, which have strong anti-inflammatory effects in experimental animal models and at the same time have minimal side effects on the stomach. Centrally developed (Bennett et al, Drugs, 46 , 1, 1993) Second generation COX-2 inhibitors have been developed through structural analysis of enzymes, such as celecoxib (celebecox), L-745,337 and the like. These second generation inhibitors have a much higher selectivity for COX-2 compared to first generation drugs, and are 100 times more selective than COX-1 (Griswold et al., Med. Res. Rev., 16 , 181, 1996).
쎌렉콕시브(Celecoxib)의 경우 1999년 하반기에 시장에 출시된 후 현재까지 약 5억달러 이상의 매출액을 나타낼 정도로 제약업계에서 두각을 나타내었으며 부작용이나 효능면에서 우수성이 입증되고 있다. 최근에는 COX-2 단백질의 정확한 3차 구조 분석을 토대로 결합부위(binding site)에 친화력이 강한 분자 모형이 설계되고 있다. 차후 제 3세대 COX-2 저해제는 산화적 스트레스, 염증반응, 허혈 등에 의한 COX-2 유전자 발현 자체를 억제하는 물질이 될 것으로 기대하고 있다.Celcoxib, which was introduced to the market in the second half of 1999, has been outstanding in the pharmaceutical industry with sales of more than about $ 500 million so far, and has proven to be excellent in terms of side effects and efficacy. Recently, molecular models with strong affinity for binding sites have been designed based on accurate three-dimensional structural analysis of COX-2 proteins. The third generation COX-2 inhibitor is expected to be a substance that inhibits COX-2 gene expression itself by oxidative stress, inflammatory response, ischemia and the like.
한편, COX-2 저해제는 염증의 치료 뿐 아니라, 암 예방의 측면에서도 중요한 역할을 할 것으로 기대된다. 보고에 의하면 암세포 및 악성 종양 조직에서는 COX-2의 유도가 증대되어 정상 세포에 비해 훨씬 많은 양의 프로스타글란딘(prostaglandin)이 생성되며 종양조직내의 프로스타글란딘(prostaglandin)량의 증가는 대부분이 COX-2 발현의 증가로 인한 것이라고 한다 (Kargman 등 Cancer Res.,55, 2556, 1995; Ristimaki 등 Cancer Res.,57, 1276, 1997). 프로스타그란딘 E2(prostaglandin E2: PGE2)와 같은 프로스타글란딘(prostaglandin)류는 혈관 생성을 촉진하고 세포의 증식을 촉진할 뿐 아니라 면역 능력을 억제하므로 이들의 과잉 생성은 암세포의 성장에 좋은 환경을 형성하여 준다. 더욱이 COX-2의 과도한 발현은 세포사멸(apoptosis)을 억제하고 암세포의 전이 능력을 증대시킨다.COX-2 inhibitors, on the other hand, are expected to play an important role in the prevention of cancer as well as in the treatment of inflammation. Reportedly, the induction of COX-2 in cancer cells and malignant tumor tissues resulted in much higher levels of prostaglandin compared to normal cells, and the increase in the amount of prostaglandin in tumor tissues is largely due to COX-2 expression. This is due to the increase (Kargman et al. Cancer Res., 55 , 2556, 1995; Ristimaki et al. Cancer Res., 57 , 1276, 1997). Prostaglandins, such as prostaglandin E2 (PGE2), not only promote blood vessel formation, promote cell proliferation, but also inhibit immune capacity, so their overproduction creates a good environment for cancer cell growth. Moreover, excessive expression of COX-2 inhibits apoptosis and increases the metastatic capacity of cancer cells.
이와 관련하여, 최근 NSAIDs를 장기간 사용해온 사람들에서 결장암이 일어날 확률이 40-50% 감소된다는 연구가 있었으며, 가족성대장선종(familial adenomatous polyposis, FAP)를 가진 환자들에 있어 결장선종(colorectal polyposis)이 결장암으로 발전되는 단계가 NSAIDs계 약물에 의해 방지되는 것이 관찰되었다 (Peleg 등, Arch. Intern. Med.,154, 394, 1994). 또한 결장암 실험모델인 Apc mouse에서도 결장암의 발생 단계인 APC 유전자의 변형 및 소실 단계에 있어 항상 COX-2 발현 및 활성의 증가가 선행되었다 (Prescott 등, Cell,87, 783, 1996). 이외에도 다양한 연구 결과에서 COX-2가 결장암의 발생단계에 큰 영향을 미치는 것이 밝혀졌으며 또, 사람의 위암 및 유방암 조직에서도 COX-2 단백질이 정상 조직에 비해 훨씬 많이 발현되고, COX 저해제가 사람 유방암 세포의 성장을 억제하였으며, 동물모델에서도 유도시킨 암의 발생이 COX-2 저해제에 의해 크게 감소되었다 (Noguchi 등, Fatty Acids,53, 325, 1995; Thompson 등, Cancer Res.,57, 267, 1997). 그러므로 결장암 뿐 만 아니라 위암과 유방암에서도 COX-2에 대한 선택적 저해제로서 암의 예방이 가능할 것으로 기대된다. 따라서 COX-2 선택적 저해제는 새로운 항염증제 개발의 주요 목표가 될 뿐 아니라 암예방제로의 개발 가능성이 높다고 할 수 있다.In this regard, recent studies have shown a 40-50% reduction in the risk of colon cancer in people who have used NSAIDs for a long time, and colorectal polyposis in patients with familial adenomatous polyposis (FAP). It has been observed that the stage of development of this colon cancer is prevented by NSAIDs-based drugs (Peleg et al., Arch. Intern. Med., 154 , 394, 1994). In addition, in Apc mice, a colon cancer experimental model, COX-2 expression and activity were always increased in the stage of modification and loss of APC gene, which is a stage of colon cancer (Prescott et al., Cell, 87 , 783, 1996). In addition, various studies have shown that COX-2 significantly affects the developmental stage of colon cancer. COX-2 protein is expressed more in human stomach and breast cancer tissues than in normal tissues, and COX inhibitors are expressed in human breast cancer cells. Growth was inhibited, and the incidence of cancer induced in animal models was greatly reduced by COX-2 inhibitors (Noguchi et al., Fatty Acids, 53 , 325, 1995; Thompson et al., Cancer Res., 57 , 267, 1997). . Therefore, it is expected that cancer can be prevented as a selective inhibitor of COX-2 in gastric and breast cancer as well as colon cancer. Therefore, COX-2 selective inhibitors are not only the main targets for the development of new anti-inflammatory drugs, but also the potential for cancer prevention.
COX와 함께 염증뿐만 아니라 암예방 효과로 주목받고 있는 것이 유도 니트릭 옥사이드 씬타제(inducible nitric oxide synthase: iNOS)의 억제제이다. NOS 역시 지속적으로 발현되는 (constitute form) 것과 유도성 (inducible form)이 존재하는데, iNOS에 의한 니트릭 옥사이드 (nitric oxide: NO)의 과잉 생성은 병리적 혈관확장, 세포독성, 조직손상 등 생체에 유해한 작용을 나타낸다. 최근에는 NO가 혈관투과성 증가, 부종 등의 염증 반응을 야기하거나 COX의 활성을 촉진시켜 프로스타그란딘 등 염증 매개체의 생합성을 촉진하여 염증 반응을 심화시키고, 각종 암조직에서 iNOS가 크게 증가한다는 사실들이 확인되었다 (Aeberhard 등, Biochem. Biophys. Res. Commun,,208, 1053, 1995; Barnes 등, Immunology Today,16, 128, 1995; McCartney 등, J. Exp. Med.,178, 749, 1993).Along with COX, attention has been paid not only to inflammation but also to cancer prevention effects, as well as inhibitors of inducible nitric oxide synthase (iNOS). NOS also has a continuous form (institute form) and inducible form, and the overproduction of nitric oxide (NO) by iNOS may cause pathological vasodilation, cytotoxicity, and tissue damage. Exhibits harmful effects. Recently, NO has been shown to cause inflammatory reactions such as increased vascular permeability, edema, or promote COX activity to promote biosynthesis of inflammatory mediators such as prostaglandins, which intensify the inflammatory response, and significantly increase iNOS in various cancer tissues. (Aeberhard et al., Biochem. Biophys. Res. Commun ,, 208 , 1053, 1995; Barnes et al., Immunology Today, 16 , 128, 1995; McCartney et al., J. Exp. Med., 178 , 749, 1993).
이에 본 발명자들은 한방에서 많이 사용되는 생약제 기원의 항염증 및 암예방제를 연구한 결과, 생약 성분에서 분리된 ar-투메론이 우수한 염증억제 및 암예방 효과를 나타내는 것을 확인하고 본 발명을 완성하기에 이르렀다.Therefore, the present inventors have studied the anti-inflammatory and cancer preventive agents of herbal origins that are widely used in herbal medicine, and confirmed that ar-tumeron separated from the herbal components showed excellent anti-inflammatory and cancer prevention effects and completed the present invention. Reached.
본 발명은 유효량의 ar-투메론을 포함하는 염증 치료용 약학 조성물 및 상기 조성물을 사용하여 염증을 치료하는 방법을 제공한다.The present invention provides a pharmaceutical composition for treating inflammation comprising an effective amount of ar-tumerones and a method for treating inflammation using the composition.
본 발명은 유효량의 ar-투메론을 포함하는 암생성 억제용 또는 암예방용 약학 조성물 및 상기 약학 조성물을 환자에게 투여하여 암을 예방 내지 치료하는 방법을 제공한다.The present invention provides a pharmaceutical composition for inhibiting or preventing cancer, comprising an effective amount of ar-tumeron, and a method for preventing or treating cancer by administering the pharmaceutical composition to a patient.
본 발명은 COX-2 유도활성 저해능 및/또는 iNOS 저해능을 측정하므로서 ar-투메론이 고농도 함유된 분획을 스크리닝하는 방법을 제공한다.The present invention provides a method for screening a fraction containing a high concentration of ar-tumerones by measuring COX-2 inducing activity inhibitory activity and / or iNOS inhibitory activity.
본 발명은 생강과 식물로부터 ar-투메론을 분리하는 방법을 제공한다.The present invention provides a method for separating ar-tumerones from the ginger family.
도 1은 ar-투메론의 시클로옥시게나제-2(COX-2) 저해능을 나태낸 그래프이다.1 is a graph showing the cyclooxygenase-2 (COX-2) inhibitory ability of ar-tumeron.
도 2는 ar-투메론의 유도 니트릭 옥사이드 씬타제 (inducible nitric oxide synthase: iNOS) 저해능을 나타낸 그래프이다.FIG. 2 is a graph showing the inducible nitric oxide synthase (iNOS) inhibition ability of ar-tumeron.
본 발명은 암의 예방 치료 및 염증 관련 질병의 치료에 관한 것이다. 구체적으로 본 발명은 유효량의 ar-투메론을 포함하는 염증 치료용 약학 조성물 및 상기 조성물을 사용하여 염증을 치료하는 방법을 제공한다. ar-투메론은 하기 화학식 (1)로 표시되는 천연 물질이다.The present invention relates to the prophylactic treatment of cancer and the treatment of inflammation related diseases. Specifically, the present invention provides a pharmaceutical composition for treating inflammation comprising an effective amount of ar-tumeron and a method for treating inflammation using the composition. ar-tumeron is a natural substance represented by following General formula (1).
[화학식 1][Formula 1]
ar-투메론은Curcuma longa및Curcuma xanthorrhiza등에 존재하는 것으로 알려져 있다. 본 발명의 실시예에서 사용한 ar-투메론은 천연물 생약으로 많이 이용되고 있는 아출의 추출물에서 분리한 것이다. 아출(Zedoariae Rhizoma)은 생강과(Zingiberaceae) 식물인 봉출(Curcuma zedoariaRoscoe)의 뿌리 줄기를 그대로 또는 수증기로 쪄서 말린 것이다. 기원식물인 봉출은 다년생 초본으로서 인도, 히말라야 지방이 원산이며, 중국의 광서, 사천, 절강 등지에서 주로 생산되고, 가을과 겨울에 캐어 양건한 것을 쓴다. 인도에서는 옛날부터 약용으로 쓰여왔으며 우리나라에서도 방향성 건위, 구어혈, 간질환 치료제 및 통경제 등으로 사용되어 왔다.ar-tumerones are known to exist in Curcuma longa and Curcuma xanthorrhiza and the like. Ar-tumeron used in the embodiment of the present invention is isolated from the extract of Achul which is widely used as a natural product herbal. Azeol (Zedoariae Rhizoma) is a dried root of Curcuma zedoaria Roscoe, a Zingiberaceae plant, steamed as is or with steam. The plant is a perennial herb and is native to India and the Himalayas. It is mainly produced in Guangxi, Sichuan, and Zhejiang in China. It has been used for medicinal use in India since ancient times, and it has been used in Korea as a fragrance for stomach, gastrointestinal blood, liver disease, and tong economy.
봉출의 주성분으로는 쿠르쿠민(curcumin)을 포함한 수종의 쿠르쿠미노이드(curcuminoid)와 제도아롤(zedoarol), 쿠르제온(curzeone) 등 수십종의 쎄스퀴테르펜(sesquiterpene) 성분들이 분리 보고되었다. 최근에는 아출에서 분리된 쎄스퀴테르펜들이 생쥐의 간 손상을 억제함이 밝혀졌고,게르마크론(germacrone), 쿠르디온(curdione)이 간염치료에 효과가 있음이 알려지게 되었다 (Hisashi 등, Bioorg. Med. Chem. Lett.,8, 339, 1998). 문헌(Wan-Jr 등, J. Nat. Prod.,61, 1531, 1998)은 봉출 유래의 쿠르쿠미노이드가 사람 자궁암 세포에 대하여 세포 독성을 나타낸다고 보고한 바 있다.Dozens of sesquiterpene components have been reported as curcuminoids, curcuminoids including curcumin, and zedoarol and curzeone. Recently, sesquiterpenes isolated from aches have been shown to inhibit liver damage in mice, and it has been shown that germacrone and curdione are effective in treating hepatitis (Hisashi et al., Bioorg.Med). Chem. Lett., 8 , 339, 1998). (Wan-Jr et al., J. Nat. Prod., 61 , 1531, 1998) reported that curcuminoids derived from scavenging show cytotoxicity against human uterine cancer cells.
연구 결과에 의하면, 아출에서 분리된 베타-엘레멘(β-elemene) 성분은 안티트롬보틱 효과 (antithrombotic effect)가 있으며 6-케토-프로스타글란딘 F1α(6-keto-prostaglandin F1α)와 트롬복산 B2(thromboxane B2, TXB2)의 생성을 저해하고, 데하이드로쿠르디온(dehydrocurdione)은 항염증 효과를 가지고 있다 (Yoshioka 등, Inflammation Res.,47, 476, 1998). 그러나, 아출에서 분리된 물질들에 대한 지속적인 연구에도 불구하고, 이 식물로부터 COX-2 및 iNOS에 대한 효능 물질이 분리된 바는 아직 없었다.The results indicate that the β-elemene component isolated from the achul has an antithrombotic effect, and 6-keto-prostaglandin F1α and thromboxane B2 (thromboxane). B2, TXB2), and dehydrocurdione has an anti-inflammatory effect (Yoshioka et al., Inflammation Res., 47 , 476, 1998). However, despite the continued study of the substances isolated in the acupuncture, no potent substance for COX-2 and iNOS has been isolated from this plant.
염증과 종양 발생은 밀접한 관련이 있다. 종양 발생 과정의 각 단계가 진행할수록 염증 반응에 관여하는 효소인 COX-2 (cyclooxygenase-2: 시클로옥시게나제-2)와 iNOS (inducible nitric oxide synthase: 유도성 니트릭 옥사이드 신테이즈)가 증가하는 것으로 보고 되어 있다 (Kitayama 등,Carcinogenesis,20, 2305-2310, 1999; Takahashi 등,Cancer Res.,57, 1233, 1997). 따라서, COX-2 저해제는 염증의 치료 뿐 아니라, 암예방의 측면에서도 중요한 역할을 할 것으로 기대된다.Inflammation and tumor development are closely related. As each stage of the tumor development progresses, the enzymes involved in the inflammatory response, COX-2 (cyclooxygenase-2) and iNOS (inducible nitric oxide synthase) are increased. (Kitayama et al., Carcinogenesis , 20 , 2305-2310, 1999; Takahashi et al., Cancer Res ., 57 , 1233, 1997). Therefore, COX-2 inhibitors are expected to play an important role not only in the treatment of inflammation but also in terms of cancer prevention.
NOS 역시 지속적으로 발현되는 형태 (constitutive form)와 유도성 형태 (inducible form)가 존재하는데, iNOS에 의한 니트릭 옥사이드 (NO: nitric oxide)의 과잉 생성은 병리적 혈관 확장, 세포독성, 조직손상 등과 연관되어 있다. 최근 연구 결과에 의하면 NO가 혈관투과성을 증가시키고 부종 등의 염증 반응을 야기하거나, COX의 활성을 촉진시켜 프로스타그란딘 등 염증 매개체의 생합성을 촉진하여 염증 반응을 심화시킨다고 한다. 각종 암 조직에서는 iNOS 활성이 크게 증가된다. 본 발명자들은 ar-투메론이 COX-2의 활성 및 iNOS의 활성을 억제함을 증명하였다. ar-투메론은 시험관내 (in vitro) 실험에서 COX-2에 대한 저해활성 평가 결과, IC50가 5.2 ㎍/ml로서 높은 저해 활성을 나타내었으며 (도 1), iNOS에 저해 효능 평가 결과 IC50가 3.2 ㎍/ml 로서 유의성 있는 효능을 나타내었다 (도 2).NOS also has a constitutive form and an inducible form. The overproduction of nitric oxide (NO) by iNOS is associated with pathological vasodilation, cytotoxicity, tissue damage, etc. It is related. Recent studies have shown that NO can augment inflammatory responses by increasing vascular permeability and causing inflammatory reactions such as edema, or by promoting COX activity to promote biosynthesis of inflammatory mediators such as prostaglandins. INOS activity is greatly increased in various cancer tissues. We have demonstrated that ar-tumeron inhibits the activity of COX-2 and the activity of iNOS. ar--to-melons are in vitro (in vitro) inhibitory activity evaluation results for COX-2 in the experiment, the IC 50 were found to show high inhibitory activity as 5.2 ㎍ / ml (Fig. 1), the inhibitory effect on iNOS IC 50 evaluation Showed significant efficacy as 3.2 μg / ml (FIG. 2).
따라서, 본 발명은 염증을 치료하기에 충분한 양의 ar-투메론을 포함하는 항염증 조성물 및 이를 투여하여 염증을 치료하는 방법을 제공한다. 본 발명의 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 담체는 제약 분야에서 통상 사용되는 용매, 분산 매질, 흡수 지연제 등을 포함한다. 본 발명의 약학 조성물은 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 따라서, 본 발명의 조성물은 국부, 경구, 비경구, 비내, 정맥내, 근육내, 피하, 안내, 경피 등으로 투여 될 수 있고, 용액, 현탁액, 정제, 환약, 캡슐, 서방형 제제 등으로 제형할 수 있다. 바람직한 제형은 주사제이다. 투여량은 환자의 질병 종류 및 정도, 연령, 성별 등에 따라 당업계의 기술을 고려하여 결정한다.Accordingly, the present invention provides an anti-inflammatory composition comprising an amount of ar-tumeron sufficient to treat inflammation and a method of treating inflammation by administering the same. The composition of the present invention may comprise a pharmaceutically acceptable carrier. Carriers include solvents, dispersion media, absorption retardants, and the like commonly used in the pharmaceutical art. The pharmaceutical composition of the present invention may be administered via any general route as long as it can reach the desired tissue. Thus, the compositions of the present invention can be administered topically, orally, parenterally, intranasally, intravenously, intramuscularly, subcutaneously, intraocularly, transdermally, and formulated into solutions, suspensions, tablets, pills, capsules, sustained release formulations, and the like. can do. Preferred formulations are injections. Dosage is determined in consideration of the skill of the art depending on the type and extent of the disease, age, sex, etc. of the patient.
나아가, 본 발명은 유효량의 ar-투메론을 포함하는 암예방 내지 암 치료용 조성물 및 이를 투여하여 암을 예방하는 방법을 제공한다. 본 발명의 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 담체는 제약 분야에서 통상 사용되는 용매, 분산 매질, 흡수 지연제 등을 포함한다. 본 발명의 약학 조성물은 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 따라서, 본 발명의 조성물은 국부, 경구, 비경구, 비내, 정맥내, 근육내, 피하, 안내, 경피 등으로 투여 될 수 있고, 용액, 현탁액, 정제, 환약, 캡슐, 서방형 제제 등으로 제형할 수 있다. 바람직한 제형은 주사제이다. 투여량은 환자의 질병 종류 및 정도, 연령, 성별 등에 따라 당업계의 기술을 고려하여 결정한다.Furthermore, the present invention provides a cancer prevention to cancer treatment composition comprising an effective amount of ar-tumeron and a method for preventing cancer by administering the same. The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. Carriers include solvents, dispersion media, absorption retardants, and the like commonly used in the pharmaceutical art. The pharmaceutical composition of the present invention may be administered via any general route as long as it can reach the desired tissue. Thus, the compositions of the present invention can be administered topically, orally, parenterally, intranasally, intravenously, intramuscularly, subcutaneously, intraocularly, transdermally, and formulated into solutions, suspensions, tablets, pills, capsules, sustained release formulations, and the like. can do. Preferred formulations are injections. Dosage is determined in consideration of the skill of the art depending on the type and extent of the disease, age, sex, etc. of the patient.
본 발명은 COX-2 유도활성 저해능 및/또는 iNOS 저해능을 측정하므로서 ar-투메론이 고농도 함유된 분획을 스크리닝하는 방법을 제공한다. 본 발명이 제공하는 ar-투메론의 생물활성검정법(bioassay)은 ar-투메론이 고 농도로 농축된 분획을 찾는 데 유용하게 사용될 수 있다.The present invention provides a method for screening a fraction containing a high concentration of ar-tumerones by measuring COX-2 inducing activity inhibitory activity and / or iNOS inhibitory activity. The bioassay of ar-tumerones provided by the present invention can be usefully used to find a fraction in which ar-tumerones are concentrated at a high concentration.
본 발명은 식물, 바람직하게는 생강과 식물, 아출, 강황 등으로부터, 더욱 바람직하게는 아출 (Curcuma zedoaria)로부터 ar-투메론을 분리하는 방법을 제공한다. ar-투메론은 이를 포함하는 식물에서 추출 방법에 의하여 분리될 수 있다. 본 발명의 ar-투메론 분리방법은 건조 식물 시료, 예를 들어 생강과 식물을 물 또는 알콜로 추출하는 단계; 상기 추출물을 실리카 겔 컬럼 크로마토그라피 하는 단계; 및 상기 실리카 겔 컬럼 크로마토그라피 용출액을 TLC하는 단계로 이루어지는 것을 특징으로 한다.The present invention provides a method for separating ar-tumerones from plants, preferably from the ginger family, from Achul, turmeric, and more preferably from Cucuma zedoaria. ar-tumerones can be isolated from plants containing them by extraction methods. Ar-tumeron separation method of the present invention comprises the steps of extracting a dry plant sample, for example ginger and water plants with water or alcohol; Silica gel column chromatography on the extract; And TLC the silica gel column chromatography eluate.
본 발명자들은 아출로부터 상기 기술된 생물활성검정법을 사용하여 본 발명의 ar-투메론을 분리하였다 (실시예 1 및 실시예 2). 분리된 화합물은 각종 이화학적 성상, 기기분석 자료를 통하여 그 구조가 (6에스)-2-메틸-6-(p-토릴)헵트-2-엔-4-온(6S)-2-Methyl-6-(2-tolyl)hept-2-en-4-one 즉, ar-turmerone (Ⅰ)인 것으로 밝혀졌다. 본 발명에서 아출에서 분리된 화합물은 정유 성분으로 쎄스퀴테르페노이드(sesquiterpenoid)에 속하며 비사볼란(bisabolane)형이다. 이 계열 화합물에 대한 COX-2 및 iNOS 저해 활성은 본 발명 이전에 보고된 바 없다.We isolated ar-tumerones of the present invention from the abus using the bioactivity assay described above (Examples 1 and 2). The separated compound has a structure of (6S) -2-methyl-6- ( p -tolyl) hept-2-en-4-one (6S) -2-Methyl- through various physicochemical properties and instrumental analysis data. 6- (2-tolyl) hept-2-en-4-one, ie ar-turmerone (I). In the present invention, the compound isolated from the achul belongs to sesquiterpenoids as an essential oil component and is bisabolane type. COX-2 and iNOS inhibitory activity against this family of compounds has not been reported prior to the present invention.
본 발명은 ar-투메론을 함유하는 암예방용 또는 항염증용 식품 조성물을 제공한다. 기재로 되는 식품은 특히 한정되는 것은 아니고, 물, 청량 음료나 과실 음료등의 드링크류, 과자류, 빵류, 면류, 조미료등, 여러 가지의 식품을 기재로 할 수가 있다. 본 발명의 식품은 기재로 되는 식품의 제조공정에 상술한 본 발명의 조성물을 첨가하는 공정을 가함으로써 혹은 기재로되는 식품의 제조 후에 상술한 본 발명의 조성물을 첨가하는 공정을 가함으로써, 용이하게 얻을 수가 있다. 이때, 필요에 따라 맛과 냄새 교정제를 첨가하여도 좋다. 본 발명의 식품에 있어서의 상술한 조성물의 함유량은 목적으로 하는 식품의 종류나 기호등에 따라 다르나, ar-투메론이 원래 지닌 예방 효과 및 보건 치료 효과를 충분히 활용하는데 있어 ar-투메론을 함유하는 식물 추출물을 0.1중량% 이상으로 하는 것이 바람직하다. 이와 같이 하여 얻어지는 본 발명의 식품은, 본 발명의 조성물을 함유하고 있기 때문에 ar-투메론이 원래 지닌 보건 예방 효과 및 보건 치료 효과를 충분히 활용할 수 있는 식품이다.The present invention provides a food composition for cancer prevention or anti-inflammatory containing ar-tumeron. The food used as a base material is not specifically limited, Various foods, such as drinks, confectionery, bread, noodles, seasonings, such as water, a soft drink, or fruit drink, can be based on. The food of this invention is easily made by adding the process of adding the composition of this invention mentioned above to the manufacturing process of the base food, or by adding the process of adding the composition of this invention mentioned above after manufacture of the food of base materials. You can get At this time, you may add a taste and odor correction agent as needed. The content of the above-mentioned composition in the food of the present invention varies depending on the type and preference of the intended food. It is preferable to make plant extract 0.1 weight% or more. Since the food of this invention obtained in this way contains the composition of this invention, it is a food which can fully utilize the health prevention effect and health treatment effect which ar-tumeron originally had.
이하 실시예에 의하여 본 발명을 보다 구체적으로 설명한다. 이들 실시예는 오로지 본 발명을 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가이들 실시예에 국한되지 않는다는 것은 자명한 것이다.The present invention will be described in more detail with reference to the following Examples. These examples are only for illustrating the present invention, and it is obvious that the scope of the present invention is not limited to these examples according to the gist of the present invention.
실시예 1Example 1
ar-투메론의 분리 정제Separation and Purification of ar-Tumeron
건조된 아출 600g을 100% 메탄올로 환류냉각 장치를 이용, 수욕상에서 3시간씩 2회 추출하였다. 추출물을 여과한 다음 감압 농축하여 28.55g의 추출물을 얻었다. 메탄올 추출물을 증류수에 분산하고 메틸렌클로라이드, 에틸아세테이트, n-부탄올 순으로 추출하여 각 용매의 가용 분획과 수층을 얻고 각 분획에 대하여 10ug/ml의 농도에서 하기 실시예3및 실시예 4의 방법에 따라 COX-2 및 iNOS 저해 활성을 측정하였다.The dried advent 600 g was extracted twice with 3% water in a water bath using a reflux condenser with 100% methanol. The extract was filtered and concentrated under reduced pressure to give 28.55 g of extract. Methanol extract was dispersed in distilled water and extracted in the order of methylene chloride, ethyl acetate, n-butanol to obtain a soluble fraction and an aqueous layer of each solvent and to the method of Examples 3 and 4 below at a concentration of 10 ug / ml for each fraction. COX-2 and iNOS inhibitory activity was measured accordingly.
용매 분획중 가장 활성이 높은 메틸렌클로라이드 분획을 가지고 클로로포름/메탄올(20/1 - 1/1) 구배로 실리카겔 칼럼 크로마토그라피를 실시하여 8개의 분획으로 나누었다. 활성이 가장 높은 2번 분획을 취하여 다시 클로로포름/메탄올 (100/1 - 1/1)의 용매로 구배적으로 실리카겔 칼럼 크로마토그라피를 실시하여 5개의 분획을 얻었다. 가장 활성이 높은 3번째 분획에 대하여 프랩 티엘시 (preparative TLC) 및 프랩 HPLC (preparative HPLC, hexane:EtoAc=97:3)를 하여 활성 성분 I(13.5 mg)를 분리하였다.The methylene chloride fraction having the highest activity among the solvent fractions was subjected to silica gel column chromatography with a chloroform / methanol (20/1-1/1) gradient, and divided into eight fractions. The second fraction with the highest activity was taken and again subjected to silica gel column chromatography with a solvent of chloroform / methanol (100/1-1/1) to obtain five fractions. The active ingredient I (13.5 mg) was isolated by preparative TLC and preparative HPLC (hexane: EtoAc = 97: 3) for the third highest active fraction.
실시예 2Example 2
화합물의 구조 결정Determine the structure of the compound
분리된 화합물에 대하여 분석 HPLC (analytical HPLC)를 이용하여 각 성분의 순도를 평가하였다. 단일 활성 성분임이 확인된 상태에서 각종 분광학적 실험들및 특히, H1-NMR, C13-NMR, DEPT, H1-H1COSY, H1-C13COSY, HMBC 등의 기기 분석 자료를 종합하여 구조를 결정하였다. 분리된 화합물은 미황색의 오일상 물질이었으며, 구조를 결정하기 위하여 우선1H,13C의 1차원(1D) spectra를 얻었고 DEPT(Distortionless Enhancement Polarization Transfer) 실험으로 multiplicity를 조사한 결과 표 1에서와 같은 값을 얻을 수 있었다. carbon의 126,9 ppm, 129.3 ppm의 peak들은 carbon spectrum을 통해 알 수 있듯이 2배의 intensity를 가진 peak들로 2개의 carbon이 정확히 overlapped 되었다고 보인다. 이로부터 화합물 I의 탄소수는 15개임을 알 수 있다. 또한 carbon의 chemical shift를 보면 120 ~ 160 ppm 사이의 aromatic group이 보이고 upfield에 4개의 메틸(methyl)기가 있으며, 35.5 ppm에 aliphatic CH가 하나 있고 특징적인 것이 52.9 ppm의 CH2가 하나 존재한다. HMQC(Heteronuclear Multiple Quantum Correlation)와 HMBC(Heteronuclear Multiple Bond Correlation) 2차원(2D) 실험들도 2k x 256 (t2 x t1)data points로 얻었다. HMQC spectrum으로부터 200.1 ppm의 peak이 carbonyl carbon으로 확신할 수 있고 aromatic region의 CH carbon 126.9, 129.3 ppm peak들은 quarternary carbon인 143.8 ppm, 135.8 ppm carbon들과 전부 correlation을 보인다. 이것으로 126.9 ppm과 129.3 ppm의 carbon이 aromatic benzene ring의 symmetry를 이루고 있음을 알 수 있다. 이러한 결과는 Itokawa등이 분리하여 확인한 구조(Chem. Pharm. Bull., 33(8), 3488, 1985)와 일치하며 이는 분리된 단일 물질이 ar-투메론임을 확인하였다.The purity of each component was evaluated using analytical HPLC for the isolated compound. Comprehensive spectroscopic experiments, in particular H 1 -NMR, C 13 -NMR, DEPT, H 1 -H 1 COZY, H 1 -C 13 COZY, HMBC, etc. The structure was determined. The separated compound was a pale yellow oily substance. To determine the structure, first , one-dimensional (1D) spectra of 1 H and 13 C were obtained, and multiplicity was examined by DEPT (Distortionless Enhancement Polarization Transfer) experiment. Could get Peaks of 126,9 ppm and 129.3 ppm of carbon appear to be exactly overlapped by two carbons with peaks of twice the intensity, as shown by the carbon spectrum. This shows that Compound I has 15 carbon atoms. In addition, the carbon chemical shift shows aromatic groups between 120 and 160 ppm, four methyl groups in the upfield, one aliphatic CH at 35.5 ppm, and one 52.9 ppm CH 2 . Heteronuclear Multiple Quantum Correlation (HMQC) and Heteronuclear Multiple Bond Correlation (HMBC) two-dimensional (2D) experiments were also obtained with 2k x 256 (t2 x t1) data points. From the HMQC spectrum, 200.1 ppm peaks can be confirmed as carbonyl carbons, and the 126.9 and 129.3 ppm peaks of CH carbons in aromatic regions all correlate with 143.8 ppm and 135.8 ppm carbons, which are quarternary carbons. This shows that 126.9 ppm and 129.3 ppm carbon form the symmetry of the aromatic benzene ring. This result is consistent with the structure identified by Itokawa et al. (Chem. Pharm. Bull., 33 (8), 3488, 1985), which confirmed that the isolated single substance was ar-tumeron.
실시예 3Example 3
시험관 내에서 COX-2 유도 저해 활성 측정Determination of COX-2 Induced Inhibitory Activity in Vitro
COX-2 유도 저해 활성은 문헌에 기재된 방법에 의하였다 (노 등, 약학회지, 42, 558, 1998). 간략하게 설명하면, 생쥐 대식 세포인 RAW264.7 세포를 10% FBS-DMEM에 현탁하여 10 x 105세포/ml로 하였다. 이 현탁액에 최종농도가 250 μM이 되도록 아스피린을 첨가하여 세포에 잔존하는 COX효소의 활성을 비가역적으로 억제하였다. 세포 현탁액을 96-웰 세포 배양판의 각 웰에 200 μl씩 가하고, 37℃, 5% CO2에서 2시간 동안 배양하여 세포를 웰 바닥에 부착시켰다. 부착된 세포를 PBS (phosphate buferred saline)로 2회 세척한 후 표면에 남아있는 세포를 실험에 사용하였다.COX-2 induction inhibitory activity was based on the method described in the literature (Noh et al., Journal of Pharmacy, 42, 558, 1998). Briefly, the mouse macrophage RAW264.7 cells were suspended in 10% FBS-DMEM to 10 x 10 5 cells / ml. Aspirin was added to the suspension to a final concentration of 250 μM to irreversibly inhibit the activity of the COX enzyme remaining in the cells. Cell suspension was added to each well of a 96-well cell culture plate and 200 μl and incubated at 37 ° C., 5% CO 2 for 2 hours to attach cells to the bottom of the well. The attached cells were washed twice with PBS (phosphate buferred saline) and the cells remaining on the surface were used for the experiment.
세포가 부착되어 있는 각 웰에 1㎍/ml의 리포폴리사카라이드 (lipopolysaccharide, LPS)를 함유한 10% FBS-DMEM 200 μl씩 넣었다. 이때, 대조군에는 LPS가 없는 배지를 넣었다. LPS가 포함된 배지로 교환한 후 곧바로 검색 시료를 처리하여, 37℃, 5% CO2에서 16시간 배양한 후 그 상층액을 회수하였다. 효소면역분석법을 이용하여 유리된 프로스타그란딘-E2의 양을 정량하였다. LPS를 처리한 군과 처리하지 않은 군에서 생성된 프로스타그란딘-E2의 차이를 100% 활성 기준으로 하여 각 시료의 %억제율을 구하였다. 그 결과를 도 1에 나타내었다.Into each well to which cells were attached, 200 μl of 10% FBS-DMEM containing 1 μg / ml lipopolysaccharide (LPS) was added. At this time, the control group was put in the medium without LPS. The sample was treated immediately after exchange with a medium containing LPS, and the supernatant was recovered after incubating for 16 hours at 37 ° C. and 5% CO 2 . Enzyme immunoassay was used to quantify the amount of free prostaglandin-E2. The percent inhibition rate of each sample was determined based on the difference between the prostaglandin-E2 produced in the LPS-treated and non-treated groups. The results are shown in FIG.
실시예 4Example 4
시험관 내에서 iNOS 저해 활성 측정Measurement of iNOS Inhibitory Activity in Vitro
생쥐 대식 세포인 RAW264.7 세포를 페놀-레드(phenol red)가 들어 있지 않은 10% FBS-DMEH에 8 x 105세포/ml로 현탁하였다. 세포 현탁액을 24-웰 배양판의 각 웰당 1ml씩 가하고 4시간 동안 배양하여 세포를 배양판에 부착시켰다. 1㎍/ml의 LPS를 함유한 배지로 교환하고 동시에 시료를 가하여 37℃, 5% CO2에서 20 시간 동안 배양하였다. 상층액을 회수하여 96-웰 배양판에 각 웰당 배양액 100 μl씩 넣고 그리에스(Griess) 시약을 150 μl씩 가해 10 분간 가볍게 흔들어 준 후 570 nm에서 흡광도를 측정하였다. NaNO2를 표준품으로하여 검량선을 작성하고 각 시료를 처리한 배양액 중의 나이트릭 옥사이드(NO) 생성량을 구하였다. LPS를 처리한 군과 처리하지 않은 군에서 생성된 나이트릭 옥사이드(NO) 생성량의 차이를 100% 활성 기준으로 하여 각 시료의 % 억제율을 구하였다. 그 결과를 도 2에 나타내었다.Mouse macrophages, RAW264.7 cells, were suspended at 8 × 10 5 cells / ml in 10% FBS-DMEH without phenol-red. Cell suspension was added 1 ml per well of 24-well culture plate and incubated for 4 hours to attach cells to the culture plate. The medium was replaced with medium containing 1 μg / ml LPS, and samples were added at the same time and incubated at 37 ° C., 5% CO 2 for 20 hours. The supernatant was collected, 100 μl of the culture solution per well was added to a 96-well culture plate, and 150 μl of Griess reagent was added thereto, and gently shaken for 10 minutes. The absorbance was measured at 570 nm. A calibration curve was prepared using NaNO2 as a standard product, and the amount of nitric oxide (NO) produced in the culture solution treated with each sample was determined. The percentage inhibition of each sample was determined based on the difference between the amount of nitric oxide (NO) produced in the LPS-treated and untreated groups, based on 100% activity. The results are shown in FIG.
본 발명의 ar-투메론은 COX-2와 iNOS 활성을 억제하므로서 염증을 경감 내지 완화시키고 암의 생성을 억제할 수 있다. 따라서 유효량의 ar-투메론을 포함하는 본 발명의 조성물은 암생성 억제용 조성물 내지 항염증 조성물로 유용하게 사용될 수 있다.Ar-tumeron of the present invention can reduce or alleviate inflammation and inhibit the production of cancer by inhibiting COX-2 and iNOS activity. Therefore, the composition of the present invention containing an effective amount of ar-tumeron may be usefully used as a composition for inhibiting cancer production or an anti-inflammatory composition.
Claims (7)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101010930B1 (en) * | 2008-03-31 | 2011-01-25 | 편두리 | Learning development method using light glasses |
| US20110217400A1 (en) * | 2007-10-17 | 2011-09-08 | Evonik Goldschmidt Gmbh | Bioactive composition for cosmetic applications |
| KR20190086643A (en) * | 2019-07-11 | 2019-07-23 | 경희대학교 산학협력단 | Composition for preventing and treating a cancer comprising curcuma zedoaria |
| CN110724044A (en) * | 2019-10-28 | 2020-01-24 | 珠海安哲生物科技有限公司 | Preparation method of arylturmerone reference substance |
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2001
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110217400A1 (en) * | 2007-10-17 | 2011-09-08 | Evonik Goldschmidt Gmbh | Bioactive composition for cosmetic applications |
| US8420137B2 (en) * | 2007-10-17 | 2013-04-16 | Evonik Goldschmidt Gmbh | Bioactive composition for cosmetic applications |
| KR101010930B1 (en) * | 2008-03-31 | 2011-01-25 | 편두리 | Learning development method using light glasses |
| KR20190086643A (en) * | 2019-07-11 | 2019-07-23 | 경희대학교 산학협력단 | Composition for preventing and treating a cancer comprising curcuma zedoaria |
| CN110724044A (en) * | 2019-10-28 | 2020-01-24 | 珠海安哲生物科技有限公司 | Preparation method of arylturmerone reference substance |
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