KR20200008429A - Composition for tumor immunomodulation comprising a glyceride compound derived from Malva verticillata - Google Patents
Composition for tumor immunomodulation comprising a glyceride compound derived from Malva verticillata Download PDFInfo
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- KR20200008429A KR20200008429A KR1020180082522A KR20180082522A KR20200008429A KR 20200008429 A KR20200008429 A KR 20200008429A KR 1020180082522 A KR1020180082522 A KR 1020180082522A KR 20180082522 A KR20180082522 A KR 20180082522A KR 20200008429 A KR20200008429 A KR 20200008429A
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- glyceride
- formula
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- cells
- cancer
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Abstract
Description
본 발명은 아욱으로부터 유래된 글리세라이드 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 항암용 약학적 조성물; 암 예방 또는 개선용 식품 조성물; 및 상기 화합물의 제조방법에 관한 것이다.The present invention comprises a glyceride compound derived from mallow or a pharmaceutically acceptable salt thereof as an active ingredient, an anticancer pharmaceutical composition; Food composition for preventing or improving cancer; And to a method for preparing the compound.
약초 요법(herbal therapy) 또는 식물의약(phytomedicine)으로 알려진 바와 같이, 식물, 식물 부분 또는 식물-유래 물질의 치료적 용도는 일반적으로 보완 대체 의학의 형태로 간주되어 왔다. 현재 약초 요법은 부작용 등으로 인해 새로운 치료법 개발을 필요로 함에도 불구하고, 약초의 낮은 독성 및 이러한 약초의 면역 자극제로서의 용도를 지지하는 경험적인 역사로 인해, 통합 의약으로서 치료학적으로 적용될 수 있을 것으로 기대된다. 또한, 한의학에서 많이 사용되는 본초 중 하나로서, 황기(Astragalus membranaceus) 분획 추출물에 대한 연구에서는 자연적인 면역 메커니즘을 조절하여 특정한 감염 질환 및 종양 질환의 발명 및 진행을 방해할 수 있음을 입증한 바 있다.As known as herbal therapy or phytomedicine, the therapeutic use of plants, plant parts or plant-derived materials has generally been considered a form of complementary alternative medicine. Although herbal remedies currently require development of new therapies due to side effects, etc., the low toxicity of the herbs and the empirical history of supporting their use as immune stimulants are expected to be therapeutically applicable as integrative medicines. do. In addition, as one of the herbs widely used in oriental medicine, Astragalus membranaceus ) fractional extracts have demonstrated that natural immune mechanisms can be modulated to hinder the invention and progression of certain infectious and tumor diseases.
화학적 암 예방(Chemoprevention)이란 식물 영양소나 약초를 이용하여 암을 예방하거나 치료하는 행위를 말하고, 이 분야는 면역학, 분자생물학, 후성유전학, 약학 등 여러 생명과학을 기반으로 서양 의학과 동양 의학을 아우르는 융합 의학으로 미래의 암 정복에 대한 기대를 모으고 있다. 화학적 암 예방은 식품을 포함한 다양한 천연 물질의 사용을 통해 질병 과정을 지연, 차단 또는 역전시킬 수 있고, 이전의 연구에서 커큐민(Curcumin)과 같은 다양한 식품 물질이 잠재적인 치료제로 연구되어 왔다.Chemoprevention refers to the act of preventing or treating cancer using plant nutrients or herbs, and this field is a convergence between Western medicine and Oriental medicine based on various life sciences such as immunology, molecular biology, epigenetics, and pharmacy. Medicine is raising hopes for conquering the future of cancer. Chemical cancer prevention can delay, block or reverse the disease process through the use of a variety of natural substances, including foods, and various food substances, such as curcumin, have been studied as potential therapeutics in previous studies.
이와 관련하여, 아욱(Malva verticillata)의 안전성이 한국의 식품의약품안전처(KMFDS) 및 국제 식품 규격위원회(CAC)에 의해 입증되었다. 아욱(Chinese mallow)은 동아시아에서 허브티 및 약초로서 대중적으로 사용된 다엽성 식물이다. 지난 수십년 동안, 식품으로서의 아욱의 용도는 동 아시아에 널리 알려져 있고, 세계적으로 소비자들은 아욱을 쉽게 식품으로서 찾을 수 있다. 아욱 씨앗은 또한 이뇨제, 완화제, 최유제로서 전통적인 중국 약용 제제로서 사용되어 왔다. 이러한 의약적 용도에도 불구하고, 아욱의 지상부의 화학적 구성성분 및 생물학적 활성에 대해서는 잘 알려져 있지 않았다. In this regard, Malva verticillata ) has been proven by the Korea Food and Drug Administration (KMFDS) and the International Food Standards Commission (CAC). Chinese mallow is a multi-leafed plant popularly used as herbal tea and herb in East Asia. In the past decades, the use of mallow as a food is widely known in East Asia, and consumers around the world can easily find mallow as a food. Mallow seeds have also been used as traditional Chinese medicinal preparations as diuretics, laxatives, and lactose. Despite these medicinal uses, little is known about the chemical constituents and biological activity of the above-mentioned mallow.
또한, 천연 식물 오일은 디아실글리세롤 또는 모노아실글리세롤과 같은 부분적인 아실글리세라이드를 대량으로 함유하는 것으로 알려져 있다. 아실글리세라이드와 같은 지방 소립(LD: Lipid droplet)은 지질의 저장 및 대사회전을 조절하는 동적인 소기관이며, 이들은 막 및 지질 수송, 단백질 저장, 단백질 분해 등에 있어 중요한 역할을 한다. 또한, 아실글리세라이드는 항-신경염증 활성을 가지는 것으로 보고되었다(Wu XY et al, Chemical constituents of the rare cliff plant Oresitrophe rupifraga and their antineuroinflammatory activity. Chem. Biodivers. 13:1030-1037 (2016))Natural plant oils are also known to contain large amounts of partial acylglycerides such as diacylglycerol or monoacylglycerol. Lipid droplets, such as acylglycerides, are dynamic organelles that regulate the storage and metabolic rotation of lipids, which play an important role in membrane and lipid transport, protein storage, and protein degradation. Acylglycerides have also been reported to have anti-neuroinflammatory activity (Wu XY et al, Chemical constituents of the rare cliff plant Oresitrophe rupifraga and their antineuroinflammatory activity. Chem. Biodivers. 13: 1030-1037 (2016))
NK 세포는 바이러스에 감염된 세포나 암세포를 직접 파괴하는 면역 세포로서, 선천적인 면역을 담당하는 혈액 속 백혈구의 일종으로, 간과 골수에서 성숙한다. '자연살해세포'라고도 한다. 즉, NK 세포의 주 기능은 바이러스에 감염된 세포나 암세포를 직접 공격해 없애는 것이다. 바이러스에 감염된 세포나 암세포는 다른 세포와 달리 세포 표면에 특정 단백질(MHC Class I)이 적어지는 것 등의 이상이 생기는데, NK 세포가 이 이상을 감지해 바이러스에 감염된 세포나 암세포를 인지한다고 알려져 있다. NK 세포가 바이러스에 감염된 세포나 암세포를 공격할 때는 퍼포린(perforin)을 분비해 감염 세포나 암세포의 세포막에 구멍을 내고, 여기에 그랜자임(granzyme)을 내어 이 세포들을 사멸시키는 것이다. 이 밖에 다른 면역 세포의 증식을 유도하는 등의 역할을 하는 면역 반응을 일으키는 물질인 케모카인(chemokine) 및 사이토카인(cytokine)을 분비할 수도 있다. 최근 몇몇의 연구를 통해, NK 세포는 선천 및 후천 면역 시스템의 특성을 모두 가지는 것으로 입증되었다. 특히 NK세포가 암세포를 공격해 암세포의 발생과 증식, 전이를 막는다는 것 외에도 암이 재발하는데 가장 중요한 역할을 하는 암 줄기세포를 효과적으로 제어할 수 있다는 것이 밝혀지며, NK세포를 이용한 항암치료 연구가 진행되어 왔다.NK cells are immune cells that directly destroy virus-infected cells or cancer cells. They are a type of white blood cells in the blood that are responsible for innate immunity and mature in the liver and bone marrow. Also known as 'natural killer cells'. In other words, the main function of NK cells is to directly attack and kill cells infected with viruses or cancer cells. Unlike other cells, cancer-infected cells and cancer cells develop abnormalities such as a small amount of a specific protein (MHC Class I) on the cell surface. NK cells are known to detect this abnormality and recognize virus-infected cells or cancer cells. . When NK cells attack virus-infected cells or cancer cells, they secrete perforin, puncture the cell membranes of infected cells or cancer cells, and kill them by giving granzymes to them. In addition, chemokines (cytokine) and cytokines (cytokine), which are substances which cause an immune response, such as inducing proliferation of other immune cells, may be secreted. Recent studies have demonstrated that NK cells have both innate and acquired immune system characteristics. In particular, NK cells attack cancer cells to prevent the development, proliferation, and metastasis of cancer cells. In addition, it has been found that cancer stem cells, which play an important role in cancer recurrence, can be effectively controlled. It has been going on.
상기와 같은 배경 하에, 본 발명자들은 NK 세포 활성을 향상시키고, 궁극적으로 종양 면역 조절을 통한 항암 효과를 가진 천연물 유래의 화합물을 찾고자 예의 노력한 결과, 아욱 지상부 분획물 및 이로부터 유래된 글리세라이드 화합물을 분리 및 동정하였고, 비장세포 증식 분석(splenocyte proliferation assay)을 통해 안정성을 확인하였으며, 아욱 분획물 및 상기 화합물을 종양세포인 YAC-1 세포에 처리하였을 때 세포 독성 효과를 가지며, NK 세포의 활성을 향상시키는 것을 확인하여 본 발명을 완성하였다. Based on the above background, the present inventors have diligently separated compounds from mallow territories and glyceride compounds derived therefrom as a result of intensive efforts to improve natural NK cell activity and ultimately have anticancer effects through tumor immune regulation. And it was confirmed, the stability was confirmed through the splenocyte proliferation assay, malignant fraction and the compound have a cytotoxic effect when treated with tumor cells YAC-1 cells, which improves the activity of NK cells It was confirmed that the present invention was completed.
본 발명의 하나의 목적은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 항암용 약학적 조성물로서,One object of the present invention is a pharmaceutical composition for anticancer comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient,
[화학식 1][Formula 1]
상기 화학식에서 R1이 팔미토일(palmitoyl), 스테아로일(stearoyl), 리노레노일(linolenoyl) 및 리노레오일(linoleoyl)로 이루어진 군으로부터 선택되는 것이고, R2가 수소(H) 및 리노레오일로 이루어진 군으로부터 선택되는 것인, 항암용 약학적 조성물을 제공하는 것이다.In the above formula, R 1 is selected from the group consisting of palmitoyl, stearoyl, linolenoyl and linoleoyl, and R 2 is hydrogen (H) and linoleo It is to provide a pharmaceutical composition for anticancer, which is selected from the group consisting of one.
본 발명의 다른 목적은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving cancer comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은 아욱 추출물 또는 이의 분획물로부터 상기 화학식 1로 표시되는 화합물을 분리하는 단계를 포함하는, 상기 화합물의 제조 방법을 제공하는 것이다.Still another object of the present invention is to provide a method for preparing the compound, which comprises the step of separating the compound represented by Chemical Formula 1 from the mallow extract or its fraction.
상기 목적을 달성하기 위한 하나의 양태로서, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 항암용 약학적 조성물을 제공한다. As one embodiment for achieving the above object, the present invention provides a pharmaceutical composition for anticancer comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
상기 화학식 1로 표시되는 화합물은 R1은 팔미토일(palmitoyl), 스테아로일(stearoyl), 리노레노일(linolenoyl) 및 리노레오일(linoleoyl)로 이루어진 군으로부터 선택되는 것이고, R2는 수소(H)일 수소(H) 및 리노레오일로 이루어진 군으로부터 선택되는 화합물일 수 있다.The compound represented by Formula 1 is R 1 is selected from the group consisting of palmitoyl, stearoyl, linolenoyl and linoleoyl, R 2 is hydrogen ( H) yl hydrogen (H) and linoleoyl may be a compound selected from the group consisting of.
구체적으로는 상기 화학식 2 내지 5로 표시되는 (2S)-1-O-팔미토일 글리세라이드((2S)-1-O-palmitoyl glyceride), (2S)-1-O-스테아로일 글리세라이드((2S)-1-O-stearoyl glyceride), (2S)-1-O-리노레노일 글리세라이드((2S)-1-O-linolenoyl glyceride) 및 (2S)-1,2―디-O-리노레오일 글리세라이드((2S)-1,2―di-O-linoleoyl glyceride)로 이루어진 군으로부터 선택되는 것일 수 있으나, 이에 제한되는 것은 아니다. 상기 글리세라이드 화합물의 항암 효과는 기존에 알려진 바 없고 본 발명에서 최초로 확인하였다.Specifically, (2S) -1-O-palmitoyl glyceride ((2S) -1-O-palmitoyl glyceride), (2S) -1-O-stearoyl glyceride represented by
본 발명은 아욱 분획물 및 상기 화학식 1로 표시되는 화합물이 항암 효과를 가지고, 구체적으로는 NK 세포의 항-종양 활성을 향상시키는 종양 면역 조절 효과를 갖는다는 기술사상에 기초하며, 이는 본 발명자들에 의하여 최초로 규명된 것이다. The present invention is based on the technical idea that the mallow fraction and the compound represented by Chemical Formula 1 have an anticancer effect, specifically, have a tumor immunomodulatory effect of enhancing anti-tumor activity of NK cells. Was first identified.
본 발명에서 상기 화학식 1로 표시되는 화합물은 아욱 추출물 또는 이의 분획물로부터 분리하여 동정한 것일 수 있다. 이 때, '아욱 (Malva verticillata)'은 상업적으로 판매되는 것을 구입하거나, 자연에서 채취 또는 재배된 것을 사용할 수 있다. 상기 아욱 추출물은 천연, 잡종, 변종 식물의 다양한 기관으로부터 추출될 수 있고, 예를 들어, 지상부, 뿌리, 줄기, 잎 뿐만 아니라 아욱 조직 배양물로부터 추출하여 생산할 수 있고, 특히 아욱 지상부를 사용한 것일 수 있으나, 이에 제한되는 것은 아니다. In the present invention, the compound represented by Chemical Formula 1 may be identified by separating from mallow extract or a fraction thereof. At this time, ' Malva verticillata ) 'can be purchased commercially, or may be harvested or grown in nature. The mallow extract may be extracted from various organs of natural, hybrid, and variegated plants, and may be extracted and produced from, for example, mallow tissue culture, as well as above ground parts, roots, stems, and leaves. However, it is not limited thereto.
본 발명에서 '아욱 추출물'은 아욱 지상부를 대상으로 물, 탄소수 1 내지 4의 저급 알코올, 에틸아세테이트, 부탄올, 및 이들의 혼합용매로 이루어진 군으로부터 선택되는 용매, 보다 구체적으로, 메탄올을 용매로 하여 추출한 결과물일 수 있다. 또한, 추출 온도는 20 내지 100℃, 20 내지 80℃, 30 내지 60℃, 40 내지 50℃일 수 있고, 추출 기간은 약 1시간 내지 4일 동안 열수 추출, 냉침 추출, 환류 냉각 추출 또는 초음파 추출 등의 추출방법을 사용하여 추출할 수 있으나, 이에 제한되는 것은 아니다. 항암 효과를 가지는 상기 화학식 1로 표시되는 화합물을 분리하기 위해 아욱 추출물을 생산하는 방법이라면 제한되지 않고 이용할 수 있다. In the present invention, 'mallow extract' is a solvent selected from the group consisting of water, a lower alcohol having 1 to 4 carbon atoms, ethyl acetate, butanol, and a mixed solvent thereof, more specifically, methanol as a solvent It may be an extracted result. In addition, the extraction temperature may be 20 to 100 ℃, 20 to 80 ℃, 30 to 60 ℃, 40 to 50 ℃, the extraction period is about 1 hour to 4 days hydrothermal extraction, cold extraction, reflux cooling extraction or ultrasonic extraction Extraction may be performed using an extraction method such as, but is not limited thereto. If the method of producing mallow extract to separate the compound represented by the formula (1) having an anticancer effect can be used without limitation.
본 발명에서 '분획물'은 다양한 구성성분을 포함하는 혼합물로부터 특정성분 또는 특정 그룹을 분리하는 분획방법에 의하여 얻어진 결과물을 의미한다. 구체적으로, 본 발명에서는 아욱 추출물을 용매 분획법, 한외여과 분획법, 크로마토그래피 분획법 등의 다양한 방법으로 분획한 결과물 등을 포함한다. In the present invention, 'fraction' means a result obtained by the fractionation method of separating a specific component or a specific group from a mixture containing various components. Specifically, in the present invention, mallow extract is obtained by fractionation by various methods such as solvent fractionation, ultrafiltration fractionation, chromatography fractionation, and the like.
이외에도, 본 발명의 화합물은 아욱을 제외한 다른 천연 공급원으로부터 분리된 것일 수 있고, 당업계에 공지된 방법을 통해 화학적으로 합성하거나 시판되는 물질일 수 있으며, 이를 포함하여 입수 경로에 관계없이 본 발명에서 사용할 수 있다.In addition, the compounds of the present invention may be isolated from other natural sources except mallow, and may be chemically synthesized or commercially available through methods known in the art, and in this invention regardless of the access route, including Can be used
구체적으로 본 발명의 일 실시예에서는 아욱 분획물을 처리할 경우 종양 세포에 대응하는 NK 세포의 세포 독성 활성을 유의적으로 증가시켜 항암 효과를 나타냄을 확인하였다. 또한, 비장세포 증식 분석에서 유의적인 독성을 나타내지 않음을 확인하여 아욱 분획물의 안정성을 확인하였다.Specifically, in the embodiment of the present invention, when treated with mallow fractions, it was confirmed that the cytotoxic activity of NK cells corresponding to tumor cells was significantly increased to show anticancer effects. In addition, the stability of the mallow fraction was confirmed by confirming no significant toxicity in the splenocyte proliferation assay.
본 발명에서 '약학적으로 허용 가능한 염'은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 약제학적으로 사용될 수 있는 형태의 염을 의미하는데, 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 상기 화학식 1로 표시되는 화합물, 구체적으로는 상기 화학식 2 내지 5로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기부가염을 의미한다. 이러한 염으로는 약학적으로 허용되는 유리산 (free acid)에 의해 형성되는 산부가염 또는 염기에 의해 형성되는 금속염이 있다.In the present invention, 'pharmaceutically acceptable salt' refers to a salt that can be used pharmaceutically even among salts in which cations and anions are bound by electrostatic attraction, and are relatively nontoxic and harmless to a patient. As a concentration having a side effect attributable to this salt does not reduce any beneficial organic or inorganic addition salt of the compound represented by the formula (1), specifically, the compound represented by the formula (2) to (5) it means. Such salts include acid addition salts formed by pharmaceutically acceptable free acids or metal salts formed by bases.
유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레산 (maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산 (fumaric acid), 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, 아스코르브산, 카본산, 바닐릭산, 요오드화수소산 (hydroiodic acid) 등을 사용할 수 있으나, 이에 제한되지 않는다.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, maleic 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, etc. This is not restrictive.
또한, 염기를 사용하여 약학적 또는 식품학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속 염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상, 또는 식품상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염 (예, 질산은)과 반응시켜 얻을 수 있다.Bases can also be used to make pharmaceutically or food acceptable metal salts. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium, or calcium salt in a pharmaceutical or food form, but is not limited thereto. Corresponding silver salts can also be obtained by reacting an alkali or alkaline earth metal salt with a suitable silver salt (eg silver nitrate).
본 발명의 화합물의 약학적으로 허용 가능한 염은 달리 명시되지 않는 한, 상기 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적 또는 식품학적으로 허용 가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용 가능한 염으로는 히드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트 (메실레이트) 및 p-톨루엔술포네이트 (토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the compounds of this invention include salts of acidic or basic groups which may be present in such compounds, unless otherwise specified. For example, pharmaceutically or food acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate , Hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts, and the like. It may be prepared through a known method for preparing a salt.
본 발명에서 용어 '암'은 세포의 사멸 조절과 관련된 질병으로서, 정상적인 세포 사멸 균형이 깨지는 경우 세포가 과다하게 증식하게 됨으로써 생기는 질병을 일컫는다. 이러한 비정상적 과다 증식 세포들은 경우에 따라 주위 조직 및 장기에 침입하여 종괴를 형성하고, 체내의 정상적인 구조를 파괴하거나 변형시키게 되는데, 이러한 상태를 암이라고 한다. 일반적으로 종양(tumor)이라 하면 신체 조직의 자율적인 과잉 성장에 의해 비정상적으로 자란 덩어리를 의미하며, 양성 종양에 비해 성장속도가 매우 빠르고, 주변 조직에 침윤하면서 전이(metasis)가 일어나 생명을 위협하는 악성 종양을 통상적으로 '암(cancer)'이라 한다. 암의 종류로는 뇌척수종양, 두경부암, 폐암, 유방암, 흉선종, 중프종, 식도암, 취암, 대장암, 간암, 위암, 췌장암, 담도암, 신장암, 방광암, 전립선암, 고환암, 생식세포종, 난소암, 자궁 경부암, 자궁 내막암, 대장암, 림프종, 급성 백혈병, 만성 백혈병, 다발성 골수종, 육종, 악성 흑생종 및 피부암을 포함하나, 상기 예들에 의해 본 발명의 암의 종류가 본 발명의 암의 종류가 한정되는 것은 아니다. 상기 암은 이에 제한되지는 않으나, 구체적으로는 종양 면역 조절에 의해 항암 효과를 나타내는 암일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the term 'cancer' refers to a disease related to cell death control, and refers to a disease caused by excessive proliferation of cells when a normal cell death balance is broken. These abnormally over-proliferating cells sometimes invade surrounding tissues and organs to form masses and destroy or modify the normal structure of the body, which is called cancer. In general, the term "tumor" refers to agglomerates grown abnormally by autonomous overgrowth of body tissues, and is much faster than benign tumors, and metastasis occurs while invading surrounding tissues. Malignant tumors are commonly referred to as 'cancer'. Types of cancer include cerebral spinal cord tumor, head and neck cancer, lung cancer, breast cancer, thymoma, mesothelioma, esophageal cancer, cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, biliary tract cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, germ cell tumor, ovary Cancer, cervical cancer, endometrial cancer, colorectal cancer, lymphoma, acute leukemia, chronic leukemia, multiple myeloma, sarcoma, malignant melanoma and skin cancer. Is not limited. The cancer is not limited thereto, but may be a cancer that exhibits anticancer effect by tumor immune regulation, but is not limited thereto.
또한, 본 발명에서 '종양 면역'은 암 면역이라고도 하며, 종양 세포를 대상으로 하는 면역을 의미한다. 또한, 본 발명에서 '면역 조절'는 아욱 분획물, 및 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 조성물의 투여로 종양 세포를 대상으로 하는 면역을 조절하는 모든 행위를 의미한다. In addition, in the present invention, 'tumor immunity' is also referred to as cancer immunity, and means immunity targeting tumor cells. In addition, in the present invention, 'immunomodulation' refers to all the factors that control the immunity to tumor cells by administration of a composition containing the mallow fraction and the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. It means an act.
본 발명에서 항암 효과는 NK 세포의 항-종양 활성을 향상시킴으로써 달성되는 것일 수 있다. 구체적으로 본 발명의 일 실시예에서는 본 발명의 아욱 분획물 및 상기 화학식 2 내지 5로 표시되는 화합물을 처리할 경우, NK-sensitive 종양 세포인 YAC-1에 대응하는 NK 세포의 활성을 증가시킴으로써 항암 효과를 나타냄을 확인하였다. 또한, 아욱 분획물 및 상기 화학식 2 내지 5로 표시되는 화합물의 비장세포 증식 분석을 통해 이들의 안정성을 확인하였다.The anticancer effect in the present invention can be achieved by enhancing the anti-tumor activity of NK cells. Specifically, in the embodiment of the present invention, the anti-cancer effect by increasing the activity of NK cells corresponding to YAC-1, a NK-sensitive tumor cell, when treating the mallow fraction of the present invention and the compounds represented by
나아가, 본 발명의 일 실시예에서는 면역 조절 활성에 있어, 모노아실 글리세라이드 화합물(화합물 1 내지 3)이 디아실 글리세라이드 화합물(화합물 4)에 비해 NK 세포 매개된 종양 세포의 생존능을 더욱 감소시키고, 모노아실 글리세라이드 화합물의 지방산의 탄소수가 길고 불포화 지방산을 포함할수록(화합물 3), 지방산의 탄소수가 짧고 포화 지방산을 포함한 모노아실 글리세라이드 화합물(화합물 1 또는 2)에 비해 NK 세포 활성을 더욱 증가시킴을 확인하였다. 즉, 본 발명의 아욱 분획물 및 상기 화학식 1로 표시되는 화합물은 종양 세포에 대응하는 면역 세포 기능의 활성화를 통해, 항암용 약학적 조성물의 유효성분으로 사용할 수 있을 것이다. Furthermore, in one embodiment of the present invention, in the immunomodulatory activity, monoacyl glyceride compounds (
본 발명에서 '약학적 조성물'은 질병의 예방 또는 치료를 목적으로 제조된 것을 의미하며, 실제 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.In the present invention, the 'pharmaceutical composition' means prepared for the purpose of preventing or treating a disease, and can be administered in various oral and parenteral dosage forms during actual clinical administration, and when formulated, commonly used fillers, Diluents or excipients such as extenders, binders, wetting agents, disintegrants, surfactants and the like can be prepared.
또한, 각각의 제형에 따라 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. In addition, each formulation may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate , Lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, oppadry, sodium starch glycolate, carnauba lead, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, sucrose, dextrose, sorbitol, talc and the like can be used.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 혼합 추출물에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘카보네이트 (Calcium carbonate), 수크로스 (Sucrose), 락토오스 (Lactose) 또는 젤라틴 등을 섞어 조제할 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 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, water, or the like in the mixed extract of the present invention. Sucrose, lactose or gelatin can be mixed and prepared. In addition to the simple excipients, lubricants such as magnesium styrate talc may also be used. Liquid preparations for oral administration include suspensions, solvents, emulsions and syrups, and include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함될 수 있다. 비수성용제, 현탁용제로는 프로필렌글리콜 (Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, 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 조성물은 목적하는 방법에 따라 경구투여하거나 비경구투여할 수 있으며, 비경구투여시 피부 외용 또는 복강 내 주사, 직장 내 주사, 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사 주입방식을 선택할 수 있다. 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양할 수 있다.The composition of the present invention can be administered orally or parenterally according to the desired method, and during parenteral administration, external skin or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection Can be selected. The dosage may vary depending on the weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion and severity of the patient.
본 발명의 조성물은 약학적으로 유효한 양으로 투여할 수 있다. 상기 약학적으로 유효한 양은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 건강상태, 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 또한, 본 발명의 약학적 조성물은 단독으로 또는 암 예방, 치료, 또는 개선 효과를 나타내는 기타 약학적 활성 화합물과 결합하여 또는 적당한 집합을 이루어 사용될 수 있다.The composition of the present invention may be administered in a pharmaceutically effective amount. The pharmaceutically effective amount refers to an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to the medical treatment and not causing side effects, and the effective dose level refers to the patient's state of health, type of disease, severity, The activity of the drug, the sensitivity to the drug, the method of administration, the time of administration, the route of administration and the rate of excretion, the duration of treatment, the factors including the drug used in combination or co-administration, and other factors well known in the medical art. In addition, the pharmaceutical compositions of the present invention may be used alone or in combination with other pharmaceutically active compounds which have a cancer prevention, treatment, or ameliorating effect or in a suitable collection.
본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여할 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용을 유발하지 않으면서 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. Taking all of these factors into consideration it is important to administer an amount that can achieve the maximum effect in a minimum amount without causing side effects and can be readily determined by one skilled in the art.
본 발명의 다른 양태로서, 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 암 예방 또는 개선용 식품 조성물로서, As another embodiment of the present invention, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, cancer prevention or improvement food composition,
[화학식 1][Formula 1]
상기 화학식에서 R1이 팔미토일(palmitoyl), 스테아로일(stearoyl), 리노레노일(linolenoyl) 및 리노레오일(linoleoyl)로 이루어진 군으로부터 선택되는 것이고, R2가 수소(H) 및 리노레오일로 이루어진 군으로부터 선택되는 것인, 암 예방 또는 개선용 식품 조성물을 제공한다.In the above formula, R 1 is selected from the group consisting of palmitoyl, stearoyl, linolenoyl and linoleoyl, and R 2 is hydrogen (H) and linoleo It provides a food composition for preventing or improving cancer, which is selected from the group consisting of one.
화합물, 약학적으로 허용 가능한 염, 암 예방 또는 개선에 대한 설명은 전술한 바와 같다. 또한, 본 발명의 아욱 분획물 및 상기 화학식 1로 표시되는 화합물의 항암 효과에 대해서는 전술한 바와 같다. The description of the compounds, pharmaceutically acceptable salts, cancer prevention or amelioration is as described above. In addition, the anticancer effect of the mallow fraction of the present invention and the compound represented by the formula (1) is as described above.
본 발명에서 '예방'은 아욱 분획물 및 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 상기 조성물의 섭취로 상기 암의 발병을 억제 또는 지연시키는 모든 행위를 의미한다. In the present invention, the 'prevention' refers to all actions of inhibiting or delaying the onset of the cancer by the ingestion of the composition containing the mallow fraction and the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. .
본 발명에서 '개선'은 상기 조성물의 섭취로 치료되는 상태와 관련된 파라미터, 예를 들면 종양의 크기를 감소시키는 등의 모든 행위를 의미한다.In the present invention, the term 'improvement' means all actions such as reducing the size of a tumor, for example, parameters related to the condition treated with the ingestion of the composition.
본 발명에서 식품 조성물은 유효성분인 상기 화학식 1로 표시되는 화합물 이외에 식품학적으로 허용 가능한 식품보조첨가제를 포함할 수 있다.In the present invention, the food composition may include a food supplement acceptable food additive in addition to the compound represented by the formula (1) as an active ingredient.
본 발명에서 '식품보조첨가제'란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.In the present invention, "food supplement" means a component that can be added to food supplements, and can be appropriately selected and used by those skilled in the art as being added to prepare a health functional food of each formulation. Examples of food additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic and natural flavors, colorants and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners. , pH regulators, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like, but is not limited by the examples of the food supplement additive of the present invention.
본 발명의 식품 조성물에는 건강기능식품이 포함될 수 있다. 본 발명에서 '건강기능식품'이란 특정보건용 식품, 기능성 식품, 건강식품과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미하는데, 상기 식품은 탈모 관련 질환의 예방 또는 개선에 유용한 효과를 얻기 위하여 정제, 캡슐, 분말, 과립, 액상, 환 등의 다양한 형태로 제조될 수 있다. 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 암 예방 또는 개선을 위한 보조제로 섭취가 가능하다.The food composition of the present invention may include a health functional food. In the present invention, 'health functional food' is the same term as a specific health food, functional food, health food, means a food that has a high effect of medicine, medical effect processed to appear efficiently in addition to the nutritional control function, the food Silver may be prepared in various forms such as tablets, capsules, powders, granules, liquids, pills and the like in order to obtain useful effects in preventing or ameliorating hair loss-related diseases. Unlike general medicine, it has the advantage that there are no side effects that may occur when taking a long-term use of the drug as a raw material, and excellent portability, the health functional food of the present invention can be taken as an adjuvant for cancer prevention or improvement. .
본 발명의 건강기능식품이 취할 수 있는 형태에는 제한이 없으며, 통상적인 의미의 식품을 모두 포함할 수 있고, 기능성 식품 등 당업계에 알려진 용어와 혼용 가능하다. 구체적으로, 상기 식품은 본 발명의 식품 조성물을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강 기능성 식품류 등으로 사용될 수 있다. 당업자의 선택에 따라 식품에 포함될 수 있는 적절한 기타 보조성분과 공지의 첨가제를 혼합하여 제조할 수 있다. 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 본 발명에 따른 화학식 1로 표시되는 화합물을 주성분으로 하여 제조한 즙, 차, 젤리 및 주스 등에 첨가하여 제조할 수 있다. 또한 동물을 위한 사료로 이용되는 식품도 포함한다.There is no restriction on the form that the health functional food of the present invention can take, and may include all foods in a conventional meaning, and may be mixed with terms known in the art such as functional foods. Specifically, the food is a food prepared by adding the food composition of the present invention to food materials, such as beverages, teas, spices, gums, confectionery, encapsulated, powdered, suspensions, for example, various foods, beverages , Gums, teas, vitamin complexes, health functional foods and the like can be used. According to the choice of those skilled in the art, it can be prepared by mixing the known additives with other suitable auxiliary ingredients that can be included in food. Examples of foods that can be added include meat, sausages, breads, chocolates, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products, including ice cream, various soups, beverages, teas, drinks, alcoholic beverages and Vitamin complexes, and the like, can be prepared by adding the compound represented by the formula (1) according to the invention as a main ingredient juice, tea, jelly and juice. It also includes foods used as feed for animals.
본 발명의 다른 양태로서, 아욱 추출물 또는 이의 분획물로부터 하기 화학식 1로 표시되는 화합물을 분리하는 단계를 포함하는, 상기 화합물의 제조방법으로서,In another embodiment of the present invention, comprising the step of separating the compound represented by the following formula (1) from the mallow extract or fractions thereof,
[화학식 1][Formula 1]
상기 화학식에서 R1이 팔미토일(palmitoyl), 스테아로일(stearoyl), 리노레노일(linolenoyl) 및 리노레오일(linoleoyl)로 이루어진 군으로부터 선택되는 것이고, R2가 수소(H) 및 리노레오일로 이루어진 군으로부터 선택되는 것인, 화합물의 제조방법을 제공한다. In the above formula, R 1 is selected from the group consisting of palmitoyl, stearoyl, linolenoyl and linoleoyl, and R 2 is hydrogen (H) and linoleo It provides a method for producing a compound, which is selected from the group consisting of one.
구체적으로는 상기 제조방법에 의해 제조되는 화합물은 전술한 화학식 2 내지 5로 표시되는 화합물로 이루어진 군으로부터 선택되는 것일 수 있으나, 이에 제한되는 것은 아니다.Specifically, the compound prepared by the preparation method may be selected from the group consisting of the compounds represented by the
상기 아욱, 추출물, 분획물, 화합물에 대한 설명은 전술한 바와 같다.The description of the mallow, extract, fraction, compound is as described above.
본 발명에서 아욱 분획물, 아욱 유래의 글리세라이드 화합물에 의해 종양 세포에 대한 NK 세포의 활성을 향상시키고, 비장세포 증식 분석에서 안정성을 확인하였으므로, 본 발명의 조성물은 항암용 조성물 및 암 예방 또는 개선용 건강기능식품의 개발에 널리 활용될 수 있다. In the present invention, mallow fraction, glyceride compound derived from mallow improves the activity of NK cells on tumor cells, and confirmed the stability in the splenocyte proliferation assay, the composition of the present invention for anticancer composition and cancer prevention or improvement It can be widely used in the development of dietary supplements.
도 1는 아욱 분획물 및 화합물 1-4의 비장세포 증식에 대한 효과를 나타낸 것이다 (* p < 0.05, ** p < 0.001; MVE: 아욱 EtOAc 분획물, MVB: n-BuOH 분획물, MVW: 아욱 물 분획물, 1: (2S)-1-O-palmitoyl glyceride, 2: (2S)-1-O-stearoyl glyceride, 3: (2S)-1-O-linolenoyl glyceride, 4: (2S)-1,2-di-O-linoleoyl glyceride).
도 2은 아욱 분획물 및 화합물 1-4의 NK 세포 활성에 대한 효과를 나타낸 것이다 (* p < 0.05, ** p < 0.01, *** p < 0.001)Figure 1 shows the effect on the splenocyte proliferation of mallow fraction and compound 1-4 ( * p <0.05, ** p <0.001; MVE: mallow EtOAc fraction, MVB: n -BuOH fraction, MVW: mallow water fraction , 1: (2S) -1- O -palmitoyl glyceride, 2: (2S) -1- O -stearoyl glyceride, 3: (2S) -1- O -linolenoyl glyceride, 4: (2S) -1,2- di- O -linoleoyl glyceride).
Figure 2 shows the effect on the NK cell activity of mallow fractions and compounds 1-4 ( * p <0.05, ** p <0.01, *** p <0.001)
이하, 본 발명을 하기 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited only to these examples.
<< 실시예Example 1> 일반적인 실험 과정 및 식물 재료 1> General experimental process and plant material
1-1. 일반적인 실험 과정1-1. General Experiment Process
GC-MS 스펙트럼은 Shimadzu GC-MS-QP2010 Plus spectrometer(Kyoto, Japan) 상에서 기록하였다. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) 시약은 Dutchefa Bichemie B.V.(Haarlem, The Netherlands)에서 구입하였다. Dimethyl sulfoxide(DMSO)는 대정 화학(경기도, 한국)에서 구입하였다. Dulbecco's Modified Eagle's Medium(DMEM), RPMI 1640 배지, 소 태아 혈청(FBS), 인산 완충 생리식염수(PBS), L-글루타민 및 페니실린-스트렙토마이신은 Invitrogen Life Technologies Inc.(Carlsbad, CA, USA)에서 수득하였다. 별도로 명시되지 않는 한, 모든 시약을 분석용 품위(analytical grade)로 사용하였다.GC-MS spectra were recorded on a Shimadzu GC-MS-QP2010 Plus spectrometer (Kyoto, Japan). 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) reagent was purchased from Dutchefa Bichemie B.V. (Haarlem, The Netherlands). Dimethyl sulfoxide (DMSO) was purchased from Daejeong Chemical (Gyeonggi-do, Korea). Dulbecco's Modified Eagle's Medium (DMEM), RPMI 1640 medium, fetal bovine serum (FBS), phosphate buffered saline (PBS), L-glutamine and penicillin-streptomycin are obtained from Invitrogen Life Technologies Inc. (Carlsbad, CA, USA) It was. Unless otherwise specified, all reagents were used in analytical grade.
1-2. 식물 재료1-2. Plant material
본 실시예에서 사용한 아욱 (Malva verticillata) 지상부는 2016년 4월에 한국 남양주시의 상업 농장에서 수집하였고, 표본 시료 (KHU20160419)를 경희대학교 천연물 화학 (Natural Product Chemistry) 실험실에 보관하였다. Malva used in this example verticillata ) The ground section was collected at a commercial farm in Namyangju, South Korea in April 2016, and the specimen sample (KHU20160419) was stored in the Natural Product Chemistry laboratory at Kyunghee University.
1-3. 통계 분석1-3. Statistical analysis
데이터는 Prism 5 Statistical Software package (GraphPad, San Diego, CA, USA)를 사용하여 수행하였다. 모든 데이터는 평균 ± 평균의 표준 오차 (standard error of the mean; SEM)로 표현하였다. 그룹 간의 통계학적 비교는 반복적인 일원 분산 분석 (one-way ANOVA)과 Tukey test를 사용하여 수행하였다. p < 0.05, 0.01 및 0.001은 통계적으로 유의한 것으로 간주하였다.Data was performed using
<< 실시예Example 2> 아욱 2> mallow 분획물의Fraction 제조 Produce
건조한 아욱의 지상부 (3.1 kg)를 80% 메탄올 (MeOH, 54.0 L Х 5)로 실온에서 24시간 동안 추출하였다. 추출물을 여과지(6 ㎛, 70 mm)를 통해 여과하고 43 ℃에서 감압 하에 증발시켜 794g의 추출물을 수득하였다. 수득한 메탄올 추출물을 물 (2 L)에 현탁시키고, 에틸아세테이트 (EtOAc, 2 L Х 4) 및 n-부탄올 (n-BuOH, 2 L Х 4)로 연속하여 추출하였다. 각 층을 농축시켜 에틸아세테이트 분획물 (MVE, 80g), n-부탄올 분획물 (MVB, 77g) 및 물 분획물 (MVW, 637g)을 수득하였다. The dry mallow ground portion (3.1 kg) was extracted with 80% methanol (MeOH, 54.0 L Х 5) at room temperature for 24 hours. The extract was filtered through filter paper (6 μm, 70 mm) and evaporated at 43 ° C. under reduced pressure to yield 794 g of extract. The resulting methanol extract was suspended in water (2 L) and extracted successively with ethyl acetate (EtOAc, 2 L Х 4) and n -butanol ( n- BuOH, 2 L Х 4). Each layer was concentrated to give an ethyl acetate fraction (MVE, 80 g), n -butanol fraction (MVB, 77 g) and water fraction (MVW, 637 g).
<< 실시예Example 3> 아욱의 3> mallow nn -- BuOHBuOH 분획물로부터From fractions 화합물의 분리 및 동정 Isolation and Identification of Compounds
3-1. 아욱의 3-1. Mallow nn -- BuOHBuOH 분획물로부터From fractions 화합물의 분리 Isolation of the compound
상기 실시예 2의 n-부탄올 분획물 (MVB, 77g)을 실리카겔 컬럼 크로마토그래피 (φ 10 Х 15cm)에 적용시키고 클로로포름(CHCl3)-메탄올(MeOH)-물(H2O) (25 : 3 : 1 → 22 : 3 : 1 →? 20 : 3 : 1 →? 18 : 3 : 1 →? 15 : 3 : 1 →? 12 : 3 : 1, 각각 18.8L)를 용리액으로 하여 분리한 결과, 14개의 분획물 (MVB-1 내지 MVB-14)을 수득하였다. N -butanol fraction (MVB, 77 g) of Example 2 was subjected to silica gel column chromatography (
분획물 MVB-9 (4.0 g, 용출 부피/총 부피(Ve/Vt) 0.384-0.557)을 ODS 컬럼 크로마토그래피 (φ 2.5 Х 6 cm) 에 적용시키고 메탄올-물 (3 : 2 → 2 : 1 → 2 : 5 : 1 → 3 : 1 → 5 : 1, 각각 3.6 L)로 용출시켜 분리한 결과 16개의 분획물 (MVB-9-1 내지 MVB-9-16)을 수득하였다. 이 중, 분획물 MVB-9-5 (383.9 mg, Ve/Vt 0.116-0.263)를 ODS 컬럼 크로마토그래피 (φ 2.5 Х 6 cm)에 적용시키고 아세톤-물 (2 : 3, 8.0 L)로 용출시켜, 14개의 분획물 (MVB-9-5-1 내지 MVB-9-5-14)과 함께 정제된 화합물 1 [MVB-9-5-4, 22.8 mg, Ve/Vt 0.038-0.053, TLC (Kie 60 F254) Rf 0.20, CHCl3-MeOH-물 (8 : 3 : 1), TLC (RP-18 F254S) Rf 0.83, 아세톤-물 (2 : 1)]을 수득하였다. 이 중, 분획물 MVB-9-2 (115.8 mg, Ve/Vt 0.004-0.009)를 실리카겔 컬럼 크로마토그래피 (φ 2.5 Х 15 cm)에 적용시키고 CHCl3-MeOH-물 (20 : 3 : 1 → 18 : 3 : 1 → 15 : 3 : 1 → 12 : 3 : 1, 각각 1.7 L)로 용출시켜, 17개의 분획물 (MVB-9-2-1 내지 MVB-9-2-17)과 함께 정제된 화합물 2 [MVB-9-2-11, 16.1 mg, Ve/Vt 0.745-0.794, TLC (Kie 60 F254) Rf 0.65, CHCl3-MeOH-물 (65 : 35 : 10), TLC (RP-18 F254S) Rf 0.71, MeOH-물 (3 : 1)]을 수득하였다.Fraction MVB-9 (4.0 g, elution volume / total volume (V e / V t ) 0.384-0.557) was subjected to ODS column chromatography (φ 2.5 Х 6 cm) and methanol-water (3: 2 → 2: 1 → 2: 5: 1 → 3: 1 → 5: 1, eluting with 3.6 L each gave 16 fractions (MVB-9-1 to MVB-9-16). Among them, fraction MVB-9-5 (383.9 mg, V e / V t 0.116-0.263) was subjected to ODS column chromatography (φ 2.5 Х 6 cm) and eluted with acetone-water (2: 3, 8.0 L) Purified with 14 fractions (MVB-9-5-1 to MVB-9-5-14) 1 [MVB-9-5-4, 22.8 mg, V e / V t 0.038-0.053, TLC (Kie 60 F 254 ) R f 0.20, CHCl 3 -MeOH-water (8: 3: 1), TLC (RP-18 F 254S ) R f 0.83, acetone-water (2: 1)] Obtained. Among them, fraction MVB-9-2 (115.8 mg, V e / V t 0.004-0.009) was applied to silica gel column chromatography (φ 2.5 Х 15 cm) and CHCl 3 -MeOH-water (20: 3: 1 →→ Eluted with 18: 3: 1 → 15: 3: 1 → 12: 3: 1, 1.7 L each and purified with 17 fractions (MVB-9-2-1 to MVB-9-2-17) Compound 2 [MVB-9-2-11, 16.1 mg, V e / V t 0.745-0.794, TLC (Kie 60 F 254 ) R f 0.65, CHCl 3 -MeOH-water (65: 35: 10), TLC (RP-18 F 254S ) R f 0.71, MeOH -water (3: 1)] Obtained.
분획물 MVB-8 (3.5 g, Ve/Vt 0.128-0.383)을 ODS 컬럼 크로마토그래피 (φ 4.5 Х 8 cm) 에 적용시키고 메탄올-물 (3 : 1 → 4 : 1 → 5 : 1 → 6 : 1, 각각 1.0 L)로 용출시켜 분리한 결과, 17개의 분획물 (MVB-8-1 내지 MVB-8-17)과 함께 정제된 화합물 3 [MVB-8-5, 71.5 mg, Ve/Vt 0.055-0.647, TLC (Kie 60 F254) Rf 0.81, CHCl3-MeOH-물 (8 : 3 : 1), TLC (RP-18 F254S) Rf 0.52, MeOH-물 (5 : 1)]을 수득하였다. Fraction MVB-8 (3.5 g, V e / V t 0.128-0.383) was subjected to ODS column chromatography (φ 4.5 Х 8 cm) and methanol-water (3: 1 1 → 4: 1 1 5: 1 1 6: 1, each separated by elution with 1.0 L) and purified with 17 fractions (MVB-8-1 to MVB-8-17). 3 [MVB-8-5, 71.5 mg, V e / V t 0.055-0.647, TLC (Kie 60 F 254 ) R f 0.81, CHCl 3 -MeOH-water (8: 3: 1), TLC (RP-18 F 254S ) R f 0.52, MeOH -water (5: 1)] Obtained.
분획물 MVB-5 (2.4 g, Ve/Vt 0.036-0.051)을 실리카겔 컬럼 크로마토그래피 (φ 3.5 Х 15 cm) 에 적용시키고 에틸아세테이트-n-부탄올-물 (30 : 3 : 1, 2.4 L)로 용출시켜 분리한 결과, 13개의 분획물 (MVB-5-1 내지 MVB-5-13)과 함께 정제된 화합물 4 [MVB-5-12, 76.4 mg, Ve/Vt 0.766-0.874, TLC (Kie 60 F254) Rf 0.19, EtOAc-n-BuOH-물 (8 : 3 : 1), TLC (RP-18 F254S) Rf 0.65, 아세톤-물 (1 : 4)]를 수득하였다.Fraction MVB-5 (2.4 g, V e / V t 0.036-0.051) was subjected to silica gel column chromatography (φ 3.5 Х 15 cm) and ethyl acetate- n -butanol-water (30: 3: 1,2.4 L) Purified with 13 fractions (MVB-5-1 to MVB-5-13), purified 4 [MVB-5-12, 76.4 mg, V e / V t 0.766-0.874, TLC (Kie 60 F 254 ) R f 0.19, EtOAc- n - BuOH -water (8: 3: 1), TLC (RP-18 F 254S ) R f 0.65, acetone-water (1: 4) ] Was obtained.
3-2. 분리된 화합물의 동정3-2. Identification of Isolated Compounds
실시예 3-1에서 수득한 화합물 1 내지 4를 대상으로 NMR, IR, FAB-MS 및 GC-MS 분석을 수행하여, 각 화합물의 구조를 동정하였다.The
화합물 1을 분석한 결과는 다음과 같다.The result of analyzing
- 담황색 왁스 (pale yellow wax)Pale yellow wax
- [α]D -1.2° (c 0.10, CHCl3)[α] D -1.2 ° ( c 0.10, CHCl 3 )
- 녹는점 98-100 ℃-Melting point 98-100 ℃
- positive FAB-MS m/z 331 [M+H]+ positive FAB-MS m / z 331 [M + H] +
- IR (KBr, v ) 3383 cm-1(hydroxyl absorbance band), 1723 cm-1(ester absorbance band)-IR (KBr, v) 3383 cm -1 (hydroxyl absorbance band), 1723 cm -1 (ester absorbance band)
- 1H-NMR (CD3OD, 400 MHz, δ H): 0.88 (3H, t, J = 7.2, H-16'), 1.27-1.34 (24H, overlapped, H-4'-15'), 1.59 (2H, m, H-3'), 2.33 (2H, t, J = 8.0, H-2'), 3.87 (2H, m, H-3), 3.96 (1H, m, H-2), 4.10 (1H, dd, J = 11.4, 4.4, H-1a); 1 H-NMR (CD 3 OD, 400 MHz, δ H ): 0.88 (3H, t, J = 7.2, H-16 '), 1.27-1.34 (24H, overlapped, H-4'-15'), 1.59 (2H, m, H-3 '), 2.33 (2H, t, J = 8.0, H-2'), 3.87 (2H, m, H-3), 3.96 (1H, m, H-2), 4.10 (1H, doublet of doublets, J = 11.4, 4.4, H-1a);
- 13C-NMR (100 MHz, CD3OD, δ C): 14.4 (C-16'), 23.6 (C-15'), 25.9 (C-3'), 29.9-30.1 (C-4'-13'), 33.0 (C-14'), 34.9 (C-2'), 66.1 (C-1), 67.4 (C-3), 69.8 (C-2), 175.1 (C-1'); 13 C-NMR (100 MHz, CD 3 OD, δ C ): 14.4 (C-16 '), 23.6 (C-15'), 25.9 (C-3 '), 29.9-30.1 (C-4'- 13 '), 33.0 (C-14'), 34.9 (C-2 '), 66.1 (C-1), 67.4 (C-3), 69.8 (C-2), 175.1 (C-1');
- GC-MS tR = 10.27 분 (palimic acid methyl ester)GC-MS t R = 10.27 min (palimic acid methyl ester)
분석 결과, 화합물 1은 포화 지방산을 가진 모노글리세라이드이고, 구체적으로는 (2S)-1-O-팔미토일 글리세라이드임을 확인하였다.Analysis showed that
화합물 2를 분석한 결과는 다음과 같다.The result of analyzing
- 담황색 왁스 (pale yellow wax)Pale yellow wax
- [α]D +1.5° (c 0.10, CHCl3)[α] D + 1.5 ° ( c 0.10, CHCl 3 )
- positive FAB-MS m/z 359 [M+H]+ positive FAB-MS m / z 359 [M + H] +
- IR (KBr, v ) 3386 cm-1(hydroxyl absorbance band), 1724 cm-1(ester absorbance band)-IR (KBr, v) 3386 cm -1 (hydroxyl absorbance band), 1724 cm -1 (ester absorbance band)
- 1H-NMR (CD3OD, 400 MHz, δ H): 0.88 (3H, t, J = 7.2, H-18'), 1.27-1.34 (28H, overlapped, H-4'-17'), 1.59 (2H, m, H-3'), 2.34 (2H, t, J = 8.0, H-2'), δ: 3.90 (2H, m, H-3), 3.96 (1H, m, H-2), 4.10 (1H, dd, J = 11.4, 4.4, H-1a); 1 H-NMR (CD 3 OD, 400 MHz, δ H ): 0.88 (3H, t, J = 7.2, H-18 ′), 1.27-1.34 (28H, overlapped, H-4′-17 ′), 1.59 (2H, m, H-3 '), 2.34 (2H, t, J = 8.0, H-2'), δ : 3.90 (2H, m, H-3), 3.96 (1H, m, H-2 ), 4.10 (1H, doublet of doublets, J = 11.4, 4.4, H-1a);
- 13C-NMR (CD3OD, 100 MHz, δ C): 14.2 (C-18'), 22.7 (C-17'), 25.1 (C-3'), 29.4-30.0 (C-4'-15'), 173.6 (C-1'); 13 C-NMR (CD 3 OD, 100 MHz, δ C ): 14.2 (C-18 '), 22.7 (C-17'), 25.1 (C-3 '), 29.4-30.0 (C-4'- 15 '), 173.6 (C-1');
- GC-MS tR = 14.37 분 (stearic acid methyl ester)GC-MS t R = 14.37 min (stearic acid methyl ester)
분석 결과, 화합물 2는 포화 지방산을 가진 모노글리세라이드이고, 구체적으로는 (2S)-1-O-스테아로일 글리세라이드임을 확인하였다.Analysis showed that
화합물 3을 분석한 결과는 다음과 같다.The result of analyzing
- 짙은 녹색 왁스 (dark green wax)Dark green wax
- [α]D +3.5° (c 0.10, CHCl3)[α] D + 3.5 ° ( c 0.10, CHCl 3 )
- positive FAB-MS m/z 353 [M+H]+ positive FAB-MS m / z 353 [M + H] +
- IR (KBr, v ) 3386 cm-1(hydroxyl absorbance band), 1722 cm-1(ester absorbance band), 1621 cm-1(double bond absorbance band)-IR (KBr, v) 3386 cm -1 (hydroxyl absorbance band), 1722 cm -1 (ester absorbance band), 1621 cm -1 (double bond absorbance band)
- 1H-NMR (CD3OD, 400 MHz, δ H): 0.96 (3H, t, J = 7.2, H-18'), 1.30-1.35 (8H, overlapped, H-4'-7'), 1.60 (2H, m, H-3'), 2.07 (4H, m, H-8'-17'), 2.34 (2H, t, J = 8.0, H-2'), 2.80 (4H, overlapped, H-11',14'), 3.90 (2H, m, H-3), 3.96 (1H, m, H-2), 4.10 (1H, dd, J = 11.4, 6.0, H-1b), 4.17 (1H, dd, J = 11.4, H-1a), 5.27-5.40 (6H, overlapped, H-9',10',12',13',15',16'); 1 H-NMR (CD 3 OD, 400 MHz, δ H ): 0.96 (3H, t, J = 7.2, H-18 ′), 1.30-1.35 (8H, overlapped, H-4′-7 ′), 1.60 (2H, m, H-3 '), 2.07 (4H, m, H-8'-17'), 2.34 (2H, t, J = 8.0, H-2 '), 2.80 (4H, overlapped, H -11 ', 14'), 3.90 (2H, m, H-3), 3.96 (1H, m, H-2), 4.10 (1H, dd, J = 11.4, 6.0, H-1b), 4.17 (1H , dd, J = 11.4, H-1a), 5.27-5.40 (6H, overlapped, H-9 ', 10', 12 ', 13', 15 ', 16');
- 13C-NMR (CD3OD, 100 MHz, δ C): 14.6 (C-18'), 21.5 (C-17'), 26.0 (C-3'), 26.4 (C-11'), 26.5 (C-14'), 28.1 (C-8'), 30.2-30.7 (C-4'-7'), 34.9 (C-2'), 66.2 (C-1), 67.4 (C-3), 69.9 (C-2), 128.2 (C-15'), 128.8 (C-10'), 129.2 (x 2, C-12',13'), 131.0 (C-9'), 132.7 (C-16'), 175.3 (C-1'); 13 C-NMR (CD 3 OD, 100 MHz, δ C ): 14.6 (C-18 '), 21.5 (C-17'), 26.0 (C-3 '), 26.4 (C-11'), 26.5 (C-14 '), 28.1 (C-8'), 30.2-30.7 (C-4'-7 '), 34.9 (C-2'), 66.2 (C-1), 67.4 (C-3), 69.9 (C-2), 128.2 (C-15 '), 128.8 (C-10'), 129.2 (x 2, C-12 ', 13'), 131.0 (C-9 '), 132.7 (C-16 '), 175.3 (C-1');
- GC-MS tR = 13.76 분 (linolenic acid methyl ester)GC-MS t R = 13.76 min (linolenic acid methyl ester)
분석 결과, 화합물 3은 불포화 지방산을 가진 모노글리세라이드이고, 구체적으로는 (2S)-1-O-리노레노일 글리세라이드임을 확인하였다.Analysis showed that
화합물 4를 분석한 결과는 다음과 같다.The result of analyzing Compound 4 is as follows.
- 담황색 왁스 (pale yellow wax)Pale yellow wax
- [α]D -2.0° (c 1.00, CHCl3)[α] D -2.0 ° ( c 1.00, CHCl 3 )
- negative FAB-MS m/z 615 [M-H]- negative FAB-MS m / z 615 [MH] -
- IR (KBr, v ) 3389 cm-1(hydroxyl absorbance band), 1725 cm-1(ester absorbance band), 1610 cm-1(double bond absorbance band)-IR (KBr, v) 3389 cm -1 (hydroxyl absorbance band), 1725 cm -1 (ester absorbance band), 1610 cm -1 (double bond absorbance band)
- 1H-NMR (CD3OD, 400 MHz, δ H): 0.89 (6H, t, J = 6.8, H-18',18''), 1.28-1.32 (28H, overlapped, H-4'-7',4''-7'',15'-17',15''-17''), 1.60 (4H, m, H-3',3''), 2.06 (8H, overlapped, H-8',8'',14',14''), 2.30 (2H, t, J = 7.6, H-2'), 2.33 (2H, t, J = 7.6, H-2''), 2.80 (4H, m, H-11',11''), 3.96 (2H, m, H-3), 4.17 (1H, dd, J = 12.0, 6.4, H-1b), 4.43 (1H, dd, J = 12.0,2.8, H-1a), 5.20 (1H, m, H-2), 5.32-5.36 (8H, overlapped, H-9',9'',10',10'',12',12'',13',13''); 1 H-NMR (CD 3 OD, 400 MHz, δ H ): 0.89 (6H, t, J = 6.8, H-18 ', 18``), 1.28-1.32 (28H, overlapped, H-4'- 7 ', 4''-7'',15'-17', 15 ''-17 ''), 1.60 (4H, m, H-3 ', 3''), 2.06 (8H, overlapped, H- 8 ', 8'',14', 14 ''), 2.30 (2H, t, J = 7.6, H-2 '), 2.33 (2H, t, J = 7.6, H-2''), 2.80 ( 4H, m, H-11 ', 11''), 3.96 (2H, m, H-3), 4.17 (1H, dd, J = 12.0, 6.4, H-1b), 4.43 (1H, dd, J = 12.0,2.8, H-1a), 5.20 (1H, m, H-2), 5.32-5.36 (8H, overlapped, H-9 ', 9'',10', 10 '', 12 ', 12'' , 13 ', 13'');
- 13C-NMR (CD3OD, 100 MHz, δ C): 14.5 (x 2, C-18',18''), 21.8 (x 2, C-17',17''), 23.8 (x 2, C-17',17''), 26.0 (x 2, C-3',3''), 26.5 (x 2, C-11',11''), 28.2 (x 4, C-8',8'',14',14''), 30.2-30.8 (C-4'-7',4''-7'',15'-16',15''-16''), 34.9 (C-2'), 35.1 (C-2''), 63.9 (C-3), 64.7 (C-1), 72.0 (C-2), 129.2 (x 4, C-10',10'',12',12''), 131.1 (x 4, C-9',9'',13',13''), 174.6 (C-1'), 174.9 (C-1'); 13 C-NMR (CD 3 OD, 100 MHz, δ C ): 14.5 (
- GC-MS tR = 13.99 분 (linoleic acid methyl ester)GC-MS t R = 13.99 min (linoleic acid methyl ester)
분석 결과, 화합물 4는 2개의 불포화 지방산을 가진 디아실글리세라이드이고, 구체적으로는 (2S)-1,2-디-O-리노레오일 글리세라이드임을 확인하였다.As a result of the analysis, it was confirmed that Compound 4 is a diacylglyceride having two unsaturated fatty acids, specifically (2S) -1,2-di- O -linoreoyl glyceride.
<< 실시예Example 4> 4> 비장세포Splenocytes 증식 분석( Proliferation analysis SpelnocyteSpelnocyte proliferation assay) proliferation assay
모든 실험 과정은 Principles of Laboratory Animal Care (NIH publication, #80-23, 1996 개정) 및 경희대학교 동물 관리 및 사용 지침에 따라 수행하였다. 성인 수컷 ICR 마우스 (7-10주령)를 Young Bio Lab Co.(오산, 한국)으로부터 수득하였다. 마우스를 음식과 물을 자유로이 공급하며 12시간의 빛/어둠 주기 하에 표준 실험실 동물 시설에서 유지 관리하였다.All experimental procedures were performed according to the Principles of Laboratory Animal Care (NIH publication, revised # 80-23, 1996) and Kyung Hee University Animal Care and Use Guidelines. Adult male ICR mice (7-10 weeks old) were obtained from Young Bio Lab Co. (Osan, Korea). Mice were freely fed food and water and maintained in a standard laboratory animal facility under a 12 hour light / dark cycle.
비장세포(Splenocyte) 분리를 위해, ICR 마우스로부터 무균 상태로 각 비장을 제거하였고, 냉각된 HBSS에서 보관하였다. 비장세포를 세포 여과기에서 주사기의 말단부로 부드럽게 균질화함으로써, 단일 세포 현탁액을 제조하였고 HBSS로 세척하였다. 세포 현탁액은 400 x g에서 원심분리하였고, 적혈구 용해 완충액으로 15분 동안 추가로 인큐베이션하였다. 이후, 세포를 400 x g에서 원심분리하였고, 세척하였고, RPMI 1640 배지(10% FBS로 보충됨)에서 배양하였다. 1차 마우스 비장세포를 5% CO2 대기 인큐베이터에서 37 ℃에서 10% FBS로 보충된 RPMI 1640 배지에서 배양하였다.For splenocyte isolation, each spleen was removed aseptically from ICR mice and stored in cold HBSS. Single cell suspensions were prepared and washed with HBSS by gently homogenizing the splenocytes to the distal end of the syringe in a cell filter. The cell suspension was centrifuged at 400 × g and further incubated with red blood lysis buffer for 15 minutes. Cells were then centrifuged at 400 × g, washed and incubated in RPMI 1640 medium (supplemented with 10% FBS). Primary mouse splenocytes were cultured in RPMI 1640 medium supplemented with 10% FBS at 37 ° C. in a 5% CO 2 atmospheric incubator.
YAC-I (KCLB no. 40160) 세포주는 한국 세포주 은행(Korean Cell Line Bank, 서울, 한국)으로부터 구매하였다. 세포주는 RPMI 1640 배지 또는 10% FBS 및 1% 페니실린-스트렙토마이신을 함유하는 DMEM에서 생장시켰고, 5% CO2, 37 ℃에서 인큐베이션하였다. 모든 실험에 있어, 5번 미만의 계대 접종(passage)의 세포 배양액을 사용하였다.YAC-I (KCLB no. 40160) cell line was purchased from Korean Cell Line Bank (Seoul, Korea). Cell lines were grown in RPMI 1640 medium or DMEM containing 10% FBS and 1% penicillin-streptomycin and incubated at 5% CO 2 , 37 ° C. For all experiments, cell cultures of less than 5 passages were used.
비장세포 증식을 측정하기 위해 MTT 분석을 사용하였다. 결론적으로, 4 x 106 세포/웰의 50 ㎍을 96-웰 배양 플레이트에 시딩하였다. 2시간 후, 각각의 세포에 각 분획물의 10 ㎍/mL 및 각 화합물의 10 μM을 48시간 동안 처리하였다. MTT 용액을 첨가하였고, 세포를 추가로 4시간 동안 인큐베이션하였다. 배지를 제거한 후, MTT-포르마잔 산물을 용해시키기 위해 DMSO를 각 웰에 첨가하였다. 생성된 흡광도를 570 및 630 nm에서 microtitier plate reader(Synergy HT, Multi-mode microplate reader, BioTek Instruments, Inc., Winooski, VT, USA)를 사용하여 측정하였다. 세포 증식은 대조군 세포에 대한 처리된 샘플 생세포(viable cell)의 백분율로 표현하였다. 모든 시험은 4회 반복하여 수행하였다.MTT assay was used to measure splenocyte proliferation. In conclusion, 50 μg of 4 × 10 6 cells / well were seeded in 96-well culture plates. After 2 hours, each cell was treated with 10 μg / mL of each fraction and 10 μM of each compound for 48 hours. MTT solution was added and cells were incubated for an additional 4 hours. After removing the medium, DMSO was added to each well to dissolve the MTT-formazan product. The resulting absorbance was measured using a microtitier plate reader (Synergy HT, Multi-mode microplate reader, BioTek Instruments, Inc., Winooski, VT, USA) at 570 and 630 nm. Cell proliferation is expressed as percentage of treated sample viable cells relative to control cells. All tests were performed in four replicates.
아울러, 실시예 2 및 3으로부터 수득한 아욱 지상부 유래의 분획물의 10 ㎍/mL 및 화합물 1 내지 4의 10 μM 각각은 비장세포에 유의적인 독성을 나타내지 않으므로, 이들 농도를 모든 분석에 사용하였다.In addition, 10 μg / mL of the marrow-derived fractions obtained from Examples 2 and 3 and 10 μM of
비장세포에 아욱 분획물 및 화합물 1 내지 4를 처리한 결과, 도 1에서 확인할 수 있는 바와 같이, 아욱 유래 분획물 및 화합물 1 내지 4의 처리는 비장세포 증식에 유의적인 영향을 미치며, 구체적으로는 EtOAc 분획물, n-BuOH 분획물 및 화합물 3은 음성 대조군에 비하여 각각 약 1.5- 및 1.2배 증식을 유도하였다.As a result of treatment of marrow fractions and
이를 통해, 아욱 유래 분획물 및 화합물 1 내지 4는 비장세포에 어떠한 유의적인 독성을 나타내지 않으므로, 이들 분획물 및 화합물의 안정성을 확인하였다.Through this, since mallow derived fractions and
<< 실시예Example 5> 세포독성 5> cytotoxicity NKNK 세포 분석 Cell analysis
NK 세포 활성을 측정하기 위해, non-adherent 비장세포를 effector 세포로 사용하였고, NK-sensitive 종양 세포인 YAC-1을 표적 세포로 사용하였다 [10:1의 E:T 비율이 되도록, 4 x 106 세포/웰의 50 μL effector (E)를 2 x 105 표적 (T) 세포/웰의 100 μL에 첨가하였다]. 분획물 (10 ㎍/mL) 또는 화합물(10 μM)의 존재 또는 부재 하에, 96-웰 플레이트에서 배양하였고, 24시간 동안 5% CO2 인큐베이터, 37 ℃에서 인큐베이션하였다. 이후, MTT 분석에 의해 NK 세포의 종양 사멸 활성을 측정하였다. NK 세포 활성은 하기 식에 따라, 대조군과 비교한 세포 생존능에 의해 표현하였다. YAC-1 세포 생존능의 감소는 NK 세포의 활성의 증가, 즉 항-종양 활성의 증가로 판단하였다.To measure NK cell activity, non-adherent splenocytes were used as effector cells, and NK-sensitive tumor cells, YAC-1, were used as target cells [4 x 10, with an E: T ratio of 10: 1. 50 μL effector (E) of 6 cells / well was added to 100 μL of 2 × 10 5 target (T) cells / well]. In the presence or absence of a fraction (10 ㎍ / mL) or compound (10 μM), they were cultured in 96-well plates and incubated in a 5% CO 2 incubator, 37 ℃ for 24 hours. Thereafter, tumor killing activity of NK cells was measured by MTT assay. NK cell activity was expressed by cell viability compared to the control according to the following formula. The decrease in YAC-1 cell viability was judged to be an increase in NK cell activity, ie an increase in anti-tumor activity.
세포 생존능 = (ODsample - ODeffector control)/ODtarget control x 100Cell viability = (OD sample -OD effector control ) / OD target control x 100
NK-sensitive 종양 세포인 YAC-1에 대한 비장세포의 세포 독성을 분석한 결과, 도 2에서 확인할 수 있는 바와 같이, 아욱 분획물 및 화합물 1 내지 4의 처리는 NK 세포의 세포 독성을 증가시키고, 구체적으로는 모든 분획물 및 화합물 1 내지 3을 처리한 경우에 대조군에 비하여 NK 세포의 세포 독성을 각각 약 65% 및 50% 증가시켰다. 이를 통해, 아욱 유래 분획물 및 화합물 1 내지 4는 NK 세포의 세포 독성 활성을 유의적으로 증가시켜, 이들 분획물 및 화합물들의 존재 하에 종양 세포에 대응하는 선천성 면역 반응이 증가됨을 알 수 있었다.As a result of analyzing the cytotoxicity of splenocytes against YAC-1, a NK-sensitive tumor cell, as shown in FIG . 2 , treatment of mallow fractions and
특히, 아욱 분획물 중 n-BuOH 분획물을 처리할 경우에 가장 효과적인 면역 조절 활성을 나타내고, 또한 이로부터 분리된 화합물들 중 화합물 1 내지 3을 처리할 경우에 우수한 면역 조절 활성을 나타냄을 확인하였다. 보다 구체적으로, 면역 조절 활성에 있어 모노아실 글리세라이드 화합물(화합물 1 내지 3)이 디아실 글리세라이드 화합물(화합물 4)에 비해 NK 세포 매개된 종양 세포의 생존능을 더욱 감소시키고, 모노아실 글리세라이드 화합물의 지방산의 탄소수가 길고 불포화 지방산을 포함할수록(화합물 3) 지방산의 탄소수가 짧고 포화 지방산을 포함한 모노아실 글리세라이드 화합물(화합물 1 또는 2)에 비해 NK 세포 활성을 더욱 증가시킴을 확인하였다.In particular, it was confirmed that the most effective immunomodulatory activity when the n- BuOH fraction in the mallow fraction was treated, and also when the
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, it should be understood that the embodiments described above are exemplary in all respects and not limiting. The scope of the present invention should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present invention.
Claims (9)
[화학식 1]
상기 화학식에서 R1이 팔미토일(palmitoyl), 스테아로일(stearoyl), 리노레노일(linolenoyl) 및 리노레오일(linoleoyl)로 이루어진 군으로부터 선택되는 것이고, R2가 수소(H) 및 리노레오일로 이루어진 군으로부터 선택되는 것인, 항암용 약학적 조성물.
As an active ingredient comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient,
[Formula 1]
In the above formula, R 1 is selected from the group consisting of palmitoyl, stearoyl, linolenoyl and linoleoyl, and R 2 is hydrogen (H) and linoleo It is selected from the group consisting of, anticancer pharmaceutical composition.
상기 화합물은 하기 화학식 2 내지 5로 표시되는 (2S)-1-O-팔미토일 글리세라이드((2S)-1-O-palmitoyl glyceride), (2S)-1-O-스테아로일 글리세라이드((2S)-1-O-stearoyl glyceride), (2S)-1-O-리노레노일 글리세라이드((2S)-1-O-linolenoyl glyceride) 및 (2S)-1,2―디-O-리노레오일 글리세라이드((2S)-1,2―di-O-linoleoyl glyceride)로 이루어진 군으로부터 선택되는 것인, 항암용 약학적 조성물.
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
The method of claim 1,
The compound may be represented by (2S) -1-O-palmitoyl glyceride ((2S) -1-O-palmitoyl glyceride), (2S) -1-O-stearoyl glyceride represented by the following Chemical Formulas 2 to 5 (2S) -1-O-stearoyl glyceride), (2S) -1-O-linolenoyl glyceride ((2S) -1-O-linolenoyl glyceride) and (2S) -1,2-di-O- Linoleoyl glyceride ((2S) -1,2-di-O-linoleoyl glyceride) is selected from the group consisting of, anticancer pharmaceutical composition.
[Formula 2]
[Formula 3]
[Formula 4]
[Formula 5]
The pharmaceutical composition for anticancer according to claim 1 or 2, wherein the compound is derived from mallow extract or a fraction thereof.
The pharmaceutical composition of claim 3, wherein the compound is extracted with water, a lower alcohol having 1 to 4 carbon atoms, butylene glycol, or a mixed solvent thereof.
The pharmaceutical composition of claim 1 or 2, wherein the composition enhances the activity of NK cells.
[화학식 1]
상기 화학식에서 R1이 팔미토일(palmitoyl), 스테아로일(stearoyl), 리노레노일(linolenoyl) 및 리노레오일(linoleoyl)로 이루어진 군으로부터 선택되는 것이고, R2가 수소(H) 및 리노레오일로 이루어진 군으로부터 선택되는 것인, 암 예방 또는 개선용 식품 조성물.
A food composition for preventing or improving cancer, comprising the compound represented by the following Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]
In the above formula, R 1 is selected from the group consisting of palmitoyl, stearoyl, linolenoyl and linoleoyl, and R 2 is hydrogen (H) and linoleo The food composition for preventing or improving cancer, which is selected from the group consisting of one.
상기 화합물은 하기 화학식 2 내지 5로 표시되는 (2S)-1-O-팔미토일 글리세라이드((2S)-1-O-palmitoyl glyceride), (2S)-1-O-스테아로일 글리세라이드((2S)-1-O-stearoyl glyceride), (2S)-1-O-리노레노일 글리세라이드((2S)-1-O-linolenoyl glyceride) 및 (2S)-1,2―디-O-리노레오일 글리세라이드((2S)-1,2―di-O-linoleoyl glyceride)로 이루어진 군으로부터 선택되는 것인, 암 예방 또는 개선용 식품 조성물.
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
The method of claim 6,
The compound may be represented by (2S) -1-O-palmitoyl glyceride ((2S) -1-O-palmitoyl glyceride), (2S) -1-O-stearoyl glyceride represented by the following Chemical Formulas 2 to 5 (2S) -1-O-stearoyl glyceride), (2S) -1-O-linolenoyl glyceride ((2S) -1-O-linolenoyl glyceride) and (2S) -1,2-di-O- Linoleoyl glyceride ((2S) -1,2-di-O-linoleoyl glyceride) is selected from the group consisting of, food composition for preventing or improving cancer.
[Formula 2]
[Formula 3]
[Formula 4]
[Formula 5]
The food composition for preventing or improving cancer according to claim 6 or 7, wherein the compound is derived from mallow extract or a fraction thereof.
[화학식 1]
상기 화학식에서 R1이 팔미토일(palmitoyl), 스테아로일(stearoyl), 리노레노일(linolenoyl) 및 리노레오일(linoleoyl)로 이루어진 군으로부터 선택되는 것이고, R2가 수소(H) 및 리노레오일로 이루어진 군으로부터 선택되는 것인, 화합물의 제조방법.A method for preparing a compound represented by Formula 1, comprising separating a compound represented by Formula 1 from mallow extract or a fraction thereof
[Formula 1]
In the above formula, R 1 is selected from the group consisting of palmitoyl, stearoyl, linolenoyl and linoleoyl, and R 2 is hydrogen (H) and linoleo Method for producing a compound, which is selected from the group consisting of.
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