KR20120047503A - Calcone derivatives having apoptosis-inducing activation - Google Patents
Calcone derivatives having apoptosis-inducing activation Download PDFInfo
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- KR20120047503A KR20120047503A KR1020100109098A KR20100109098A KR20120047503A KR 20120047503 A KR20120047503 A KR 20120047503A KR 1020100109098 A KR1020100109098 A KR 1020100109098A KR 20100109098 A KR20100109098 A KR 20100109098A KR 20120047503 A KR20120047503 A KR 20120047503A
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- cancer
- hydroxy
- trimethoxychalcone
- benzo
- acceptable salt
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Abstract
Description
본 발명은 세포사멸 유도 활성을 갖는 칼콘 유도체에 관한 것으로서, 보다 구체적으로는 하기의 화학식 1로 표시되며 암세포에서 Type-Ⅰ 세포자기사멸 활성을 유도함으로써 암의 예방 또는 치료용 조성물로 사용될 수 있는 신규한 칼콘 유도체, 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 및 그의 제조방법, 이를 함유하는 약학 조성물 및 건강기능식품에 관한 것이다.The present invention relates to a chalcone derivative having apoptosis-inducing activity, and more specifically, represented by the following Chemical Formula 1, which can be used as a composition for preventing or treating cancer by inducing Type-I apoptosis activity in cancer cells. One chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, and a method for preparing the same, a pharmaceutical composition containing the same and a health functional food.
[화학식 1][Formula 1]
세포가 사멸하는 방법은 외부의 물리적 자극에 의해 사멸되는 괴사(Necrosis)와 세포 신호전달계의 활성 또는 비활성 조절 기작에 의해 계획된 사멸 과정이 유도되는 세포자기사멸(Programmed cell death)로 구분할 수 있다.Cell death can be divided into necrosis, which is killed by external physical stimuli, and programmed cell death, in which a planned killing process is induced by a mechanism of activation or inactivation of the cell signaling system.
괴사에 의한 사멸은 세포 자체가 팽창하고 파열되는 반응으로 손상된 세포 주변에는 염증이 유발되기도 한다. 세포자기사멸은 불완전한 세포의 성장을 제어하기 위한 과정으로 세포의 정상적인 기능과 양적 균형을 이루기위해서 스스로 조절하는 반응이다. Necrosis killing is a reaction in which the cells themselves expand and rupture, causing inflammation around the damaged cells. Apoptosis is a process that controls the growth of incomplete cells and is a self-regulating response to balance the normal function of the cells.
세포자기사멸은 type-I(apoptosis)과 type-II(autophagic cell death) 두 가지 형태가 있다. 일반적으로 type-I 자기사멸 현상은 염색사(Chromatin)의 응축 (Condensation)과 DNA의 단편 형성, 그리고 작은 세포 조각(Apoptotic body)들이 생성되는 과정으로 진행된다. 특히, 세포자기사멸에 의한 과정은 주변 세포의 탐식 작용(phagocytosis)으로 염증을 유발하지 않는 것이 특징이다(Experimental Cell Research 256,12-18,2000).There are two types of apoptosis, type-I (apoptosis) and type-II (autophagic cell death). In general, type-I self-killing involves condensation of chromatin, fragmentation of DNA, and formation of small apoptotic bodies. In particular, the process by apoptosis is characterized by not causing inflammation due to phagocytosis of surrounding cells (Experimental Cell Research 256,12-18,2000).
Type-I 세포자기사멸은 시스테인 단백분해 효소(Cysteine protease)의 일종인 카스파제(Caspase)의 활성에 의해 유도 된다(Cell (1996) 87;171, Biochem J (1997) 326;1-16). 카스파제는 현재까지 10종류 이상이 발견되었다. 그 중에서 세포사멸을 유도하는 세포자극에 의해 미토콘드리아 막에 존재하는 시토크롬-씨(Cytochrome-C)가 분비되면 카스파제-9이 활성화되고, 활성 카스파제-9은 카스파제-3를 활성화 시킨다. 활성 카스파제-3는 세포 활성에 중요한 여러 가지 단백질을 분해시킴으로써 세포사멸을 유도시킨다. Type-I apoptosis is induced by the activity of Caspase, a type of Cysteine protease (Cell (1996) 87; 171, Biochem J (1997) 326; 1-16). More than 10 types of caspases have been found to date. Among them, when cytochrome-C is released from the mitochondrial membrane by cell stimulation that induces cell death, caspase-9 is activated, and active caspase-9 activates caspase-3. Active caspase-3 induces apoptosis by breaking down a variety of proteins important for cell activity.
PARP(Poly ADP-Ribose Polymerase)는 손상된 DNA를 복구시켜주는 113 kDa 크기의 DNA 수복 효소이다. PARP 단백질은 type-I 세포자기사멸 과정 중 카스파제(Caspase) 효소에 의해 89-kDa과 24-kDa 크기의 단편으로 잘려지기 때문에, PARP 단백질의 89-kDa과 24-kDa 단편 생성 현상은 type-I 세포 자기사멸 과정을 검증하는 주요 생화학적 표지로 간주 되고 있다(Nature (1994) 371:346-347). Poly ADP-Ribose Polymerase (PARP) is a 113 kDa DNA repair enzyme that repairs damaged DNA. Since PARP protein is cut into 89-kDa and 24-kDa fragments by caspase enzymes during type-I apoptosis, the production of 89-kDa and 24-kDa fragments of PARP protein is type- It is considered a major biochemical marker to validate the I cell self-killing process (Nature (1994) 371: 346-347).
이에 본 발명에서는 신규 칼콘 유도체의 암세포의 세포사멸을 유도하는 효과를 측정하는 수단으로써 PARP 단백질의 단편 생성 정도를 측정하였으며, 본 발명자들은 89-kDa과 24-kDa의 PARP 조각 단편이 증가되는 현상과 유세포 측정 시 세포의 DNA 함량이 G1기의 2N DNA 함량보다 작은 sub-G1 세포가 나타나는 현상이 type-I 세포자기사멸이 유도되는 현상과 일치하는 것에 착안하여, 113-kDa의 PARP 단백질이 89-kDa과 24-kDa의 PARP 조각 단편을 유도하는 효과적인 화합물을 찾고자 예의 노력한 결과 신규 칼콘 유도체, 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘에 의해 type-I 세포자기사멸이 유도되는 것을 확인하고 본 발명을 완성하였다.
Therefore, in the present invention, the generation of PARP protein fragments was measured as a means of measuring the effect of inducing apoptosis of cancer cells of the novel chalcone derivatives. In the flow cytometry, we observed that sub-G1 cells with a DNA content of less than 2N DNA content of G1 phase were consistent with the induction of type-I apoptosis, suggesting that 113-kDa PARP protein was 89- Efforts to find an effective compound that induces PAD fragment fragments of kDa and 24-kDa resulted in a novel chalcone derivative, type 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone. It was confirmed that -I apoptosis was induced and completed the present invention.
본 발명은 상기의 문제점을 해결하고 상기의 필요성에 의하여 안출된 것으로서, 본 발명이 이루고자 하는 기술적 과제는 Type-Ⅰ 세포자기사멸 유도 효과를 나타내는 신규 화합물과 이를 유효성분으로 함유하는 항암제용 약학 조성물 및 건강기능식품을 제공하는 것이다.
The present invention has been made to solve the above problems and by the necessity of the above, the technical problem to be achieved by the present invention is a novel compound exhibiting Type-I apoptosis inducing effect and an anticancer pharmaceutical composition containing the same as an active ingredient and It is to provide health functional food.
상기의 목적을 달성하기 위하여, 본 발명은 하기의 화학식 1로 표시되는 칼콘 유도체, 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 또는 그의 약학적으로 허용되는 염과 이의 제조방법을 제공한다.In order to achieve the above object, the present invention is a chalcone derivative represented by the following formula (1), 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or pharmaceutically thereof Acceptable salts and methods for their preparation are provided.
[화학식 1][Formula 1]
본 발명에서 상기 제조방법은 (1) 2-히드록시-1-아세토나프톤과 2,4,6-트리메톡시벤즈알데하이드를 에탄올에 용해시키는 단계; (2) 상기 용액에 50% KOH 수용액을 3 ~ 5℃에서 첨가하는 단계; (3) 상기 혼합 용액을 15 ~ 20시간 동안 교반한 후에 온도를 3 ~ 5℃로 낮추는 단계; (4) 상기 냉각된 용액에 HCl 용액을 첨가하는 중화 단계; (5) 상기 수용액을 클로로포름으로 추출하는 단계; (6) 상기 추출된 유기층을 분별 깔때기로 분리하고 황산마그네슘으로 제습하는 단계; 및 (7) 상기 물을 제거한 혼합물을 감압여과 한 후 여액의 용매를 제거하고, 관 크로마토그래피를 이용하여 분리 정제하는 단계를 포함한다.In the present invention, the preparation method comprises the steps of (1) dissolving 2-hydroxy-1-acetonaphtone and 2,4,6-trimethoxybenzaldehyde in ethanol; (2) adding 50% KOH aqueous solution to the solution at 3 to 5 ° C; (3) stirring the mixed solution for 15 to 20 hours and then lowering the temperature to 3 to 5 ° C; (4) neutralizing adding HCl solution to the cooled solution; (5) extracting the aqueous solution with chloroform; (6) separating the extracted organic layer with a separatory funnel and dehumidifying with magnesium sulfate; And (7) filtering the mixture from which the water was removed under reduced pressure, removing the solvent from the filtrate, and separating and purifying by using column chromatography.
또한 본 발명은 상기 화학식 1로 표시되는 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물을 제공한다.In another aspect, the present invention is a cancer containing a 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient Provided is a prophylactic or therapeutic pharmaceutical composition.
본 발명에 있어서, 상기 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 또는 그의 약학적으로 허용되는 염은 암세포에서 Type-Ⅰ 세포자기사멸 활성을 유도함으로써 암을 예방하거나 치료하는 것을 특징으로 한다.In the present invention, the 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof induces Type-I apoptosis activity in cancer cells It is characterized by preventing or treating cancer.
또한 본 발명은 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 건강기능식품을 제공한다.
The present invention also provides a health functional food containing 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따른 신규 칼콘 유도체, 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘은 세포자기사멸을 유도하는 활성을 갖는 항암효과 특성을 나타내므로 항암제 또는 건강기능식품으로서 유용하게 사용될 수 있다.
The novel chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, according to the present invention exhibits anticancer effect properties having activity of inducing apoptosis, and thus, anticancer agents or It can be usefully used as a dietary supplement.
도 1은 브루커(Bruker) 400 MHz 핵자기공명분광기로 측정한 본 발명에 따른 4,5-벤조-1-하이드록시-2',4',6'-트리메톡시칼콘의 수소핵자기공명분광스펙트럼(1H-NMR)을 나타낸 것이다.
도 2는 브루커(Bruker) 400 MHz 핵자기공명분광기로 측정한 본 발명에 따른 4,5-벤조-1-하이드록시-2',4',6'-트리메톡시칼콘의 탄소핵자기공명분광스펙트럼(13C-NMR)을 나타낸 것이다.
도 3은 본 발명에 따른 신규 칼콘 유도체, 4,5-벤조-1-하이드록시-2',4',6'-트리메톡시칼콘(#74로 표기함)에 의해 113-kDa 크기의 PARP가 89-kDa 크기의 PARP 단편 조각이 유발되는 웨스턴 블롯 분석(Western blot analysis) 결과를 나타낸 것이다.1 is a hydrogen nuclear magnetic resonance of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone according to the present invention measured by a Bruker 400 MHz nuclear magnetic resonance spectrometer Spectral spectrum ( 1 H-NMR) is shown.
2 is a carbon nuclear magnetic resonance of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone according to the present invention measured by a Bruker 400 MHz nuclear magnetic resonance spectrometer Spectral spectrum ( 13 C-NMR) is shown.
Figure 3 is a novel chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone (denoted by # 74) PARP of 113-kDa size according to the present invention Shows the result of Western blot analysis in which a piece of PARP fragment of 89-kDa size is induced.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기의 화학식 1로 표시되는 칼콘 유도체, 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 또는 그의 약학적으로 허용되는 염을 제공한다.The present invention provides a chalcone derivative represented by Formula 1 below, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
또한, 본 발명은 상기 화학식 1로 표시되는 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘의 제조방법을 제공한다.The present invention also provides a method for preparing 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone represented by the formula (1).
본 발명의 제조방법은 (1) 2-히드록시-1-아세토나프톤과 2,4,6-트리메톡시벤즈알데하이드를 에탄올에 용해시키는 단계; (2) 상기 용액에 50% KOH 수용액을 3 ~ 5℃에서 첨가하는 단계; (3) 상기 혼합 용액을 15 ~ 20시간 동안 교반한 후에 온도를 3 ~ 5℃로 낮추는 단계; (4) 상기 냉각된 용액에 HCl 용액을 첨가하는 중화 단계; (5) 상기 수용액을 클로로포름으로 추출하는 단계; (6) 상기 추출된 유기층을 분별 깔때기로 분리하고 황산마그네슘으로 제습하는 단계; 및 (7) 상기 물을 제거한 혼합물을 감압여과 한 후 여액의 용매를 제거하고, 관 크로마토그래피를 이용하여 분리 정제하는 단계를 포함한다.
The preparation method of the present invention comprises the steps of (1) dissolving 2-hydroxy-1-acetonaphtone and 2,4,6-trimethoxybenzaldehyde in ethanol; (2) adding 50% KOH aqueous solution to the solution at 3 to 5 ° C; (3) stirring the mixed solution for 15 to 20 hours and then lowering the temperature to 3 to 5 ° C; (4) neutralizing adding HCl solution to the cooled solution; (5) extracting the aqueous solution with chloroform; (6) separating the extracted organic layer with a separatory funnel and dehumidifying with magnesium sulfate; And (7) filtering the mixture from which the water was removed under reduced pressure, removing the solvent from the filtrate, and separating and purifying by using column chromatography.
본 발명의 신규 칼콘 유도체인 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘은 Type-Ⅰ 세포자기사멸 활성을 유도함으로써 암을 예방하거나 치료하는 효과를 갖는다.4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, a novel chalcone derivative of the present invention, has the effect of preventing or treating cancer by inducing Type-I apoptosis activity. Have
따라서 본 발명은 상기 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학 조성물을 제공한다.Therefore, the present invention provides a pharmaceutical for the prevention or treatment of cancer containing the 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof as an active ingredient. To provide a composition.
본 발명의 화합물을 포함하는 조성물은 바람직하게는 대장암, 위암, 전립선암, 유방암, 신장암, 간암, 뇌종양, 폐암, 자궁암, 결장암, 방광암, 췌장암, 혈액암 등의 예방 또는 치료에 사용될 수 있으며 이들로 한정되는 것은 아니다.The composition comprising the compound of the present invention is preferably used for the prevention or treatment of colon cancer, stomach cancer, prostate cancer, breast cancer, kidney cancer, liver cancer, brain tumors, lung cancer, uterine cancer, colon cancer, bladder cancer, pancreatic cancer, blood cancer, etc. It is not limited to these.
본 발명의 조성물에 포함되는 화학식 1의 화합물은 또한 이의 염의 형태로도 사용될 수 있으며, 이러한 염은 약제학적으로나 생리학적으로 허용되는 다양한 유기산 또는 무기산과의 산 부가 염을 포함한다. 적합한 무기산으로는, 예를 들면 염산, 황산 등의 할로겐산 또는 인산이 있다. 적합한 유기산으로는, 예를 들면 카르복실산, 포스폰산, 술폰산, 아세트산, 프로피온산, 옥탄산, 데칸산, 글리콜산, 락트산, 푸마르산, 숙신산, 아디프산, 말산, 타르타르산, 시트르산, 글루탐산, 아스파르트산, 말레산, 벤조산, 살리실산, 프탈산, 페닐아세트산, 벤젠술폰산, 2-나프탈렌술폰산, 메틸황산, 에틸황산, 도데실황산 등이 있다.Compounds of formula (1) included in the compositions of the present invention may also be used in the form of their salts, which include acid addition salts with various organic or inorganic acids that are pharmaceutically or physiologically acceptable. Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid or phosphoric acid. Suitable organic acids include, for example, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid. , Maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfate.
본 발명의 조성물은 상기한 화학식 1의 화합물 또는 이들의 화합물 이외에 약리학적으로나 생리학적으로 허용되는 담체, 부형제, 희석제를 추가로 포함할 수 있다.The composition of the present invention may further comprise a pharmacologically or physiologically acceptable carrier, excipient, diluent in addition to the compound of Formula 1 or a compound thereof.
이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 및 희석제의 예로는 락토오스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 비정질 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수있다. 상기 조성물은 약제화하는 경우, 통상의 충진제, 증량제, 결합제, 붕해제, 계면활성제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.Examples of suitable carriers, excipients and diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like. When formulated, the composition may further include conventional fillers, extenders, binders, disintegrants, surfactants, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like.
본 발명의 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사용액의 형태 등 다양한 형태로 제형화 하여 사용할 수 있으며, 경구투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다. The composition of the present invention may be formulated in various forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral formulations, sterile injectable solutions, etc. It may be used orally or may be administered through various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration and the like.
경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토오스, 젤라틴 등을 섞어 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제들도 사용된다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, and the like. Mix and formulate. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to commonly used simple diluents such as water and liquid paraffin.
비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 주사제의 기제로는 용해제, 등장화제, 현탁화제, 유화제, 안정화제 및 방부제와 같은 종래의 첨가제를 포함할 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. Bases for injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
본 발명에 있어서 "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 일반적인 모든 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 조성물은 활성물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.By "administration" in the present invention is meant to provide the patient with the desired material in any suitable way, the route of administration of the composition of the present invention being oral or parenteral via all common routes as long as the target tissue can be reached. May be administered. In addition, the composition can be administered by any device in which the active agent can migrate to the target cell.
본 발명에서 "환자"는 본 발명의 조성물을 투여하여 증상이 호전될 수 있는 질환을 가진 인간과 원숭이, 개, 염소, 돼지, 또는 쥐 등의 동물을 의미한다. 본 발명에 따른 조성물은 인간(치료, 억제 또는 예방)용일 뿐만 아니라 상업적으로 유용한 다른 동물들에게도 적용될 수 있다.In the present invention, "patient" means a human and an animal such as a monkey, dog, goat, pig, or rat having a disease that can improve symptoms by administering the composition of the present invention. The composition according to the invention can be applied not only for humans (treatment, inhibition or prevention) but also to other commercially useful animals.
다른 양태로서, 본 발명은 상기 화학식 1의 화합물 또는 약제학적으로 허용가능한 이들의 염을 포함하는 조성물을 환자에게 투여함으로써 암과 암 전이를 억제하고,예방 및 치료하는 방법을 제공한다. 본 발명의 조성물은 종래의 상기 질환 치료제와 병행하여 투여할 수 있다.In another aspect, the present invention provides a method for inhibiting, preventing and treating cancer and cancer metastasis by administering to a patient a composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The composition of the present invention can be administered in parallel with the conventional disease treatment.
본 발명의 조성물은 약제학적으로 유효한 양으로 투여한다.The composition of the present invention is administered in a pharmaceutically effective amount.
본 발명에 있어서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level means the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent drug use, and other factors well known in the medical arts. The compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.
또한, 본 발명에 따른 화합물의 투여량은 체내 흡수도, 체중, 환자의 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율, 질환의 중증도 등에 따라 변화될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 화합물은 체중 1 ㎏당 1일 0.001 ~ 150 ㎎으로, 바람직하게는 0.01 ~ 100 ㎎으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. In addition, the dosage of the compound according to the present invention may be changed according to body absorption, weight, age, sex, health condition, diet, administration time, administration method, excretion rate, severity of disease, and the like. However, for the desired effect, the compound of the present invention is preferably administered at 0.001 to 150 mg, preferably 0.01 to 100 mg per kg of body weight per day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
본 발명의 화학식 1의 화합물은 하기 반응식 1의 합성방법 또는 당 분야에 널리 공지된 다양한 방법을 이용하여 합성할 수 있다.The compound of formula 1 of the present invention can be synthesized using the synthesis method of Scheme 1 or various methods well known in the art.
또한, 본 발명은 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 건강기능식품을 제공한다.
The present invention also provides a dietary supplement containing 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof as an active ingredient.
이하, 실시예에 의하여 본 발명을 더욱 상세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail with reference to Examples.
단, 하기 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
However, the following examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not interpreted to be limited by these examples.
실시예 1: 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘의 제조Example 1: Preparation of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone
본 발명에서는 신규 칼콘 유도체, 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘을 합성하기 위해 아래 반응식 1의 방법을 사용하여 다음과 같이 합성하였다.In the present invention, to synthesize a novel chalcone derivative, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, was synthesized as follows using the method of Scheme 1 below.
[반응식 1]Scheme 1
2-히드록시-1-아세토나프톤(2-hydroxy-1-acetonaphthone, 1864 mg, 10 mmol)과 2,4,6-트리메톡시벤즈알데하이드(2,4,6-trimethoxybenzaldehyde, 1964 mg, 10 mmol)를 70 ㎖의 에탄올에 녹인 후에 4℃에서 50% KOH수용액 15 ㎖을 약 10분 간 천천히 가한다. 위 혼합용액을 상온에서 18시간 교반한 후에 온도를 약 4℃로 낮춘다. 위의 냉각된 용액에 6 N HCl용액 40 ㎖를 가하여 중화시킨 후, 이 수용액을 클로로폼 100 ㎖로 두 번 추출한다. 추출된 각각의 유기 용매를 합친 후 황산마그네슘을 가하여 물을 제거하고, 남은 혼합물을 감압여과 한다. 다음으로, 회전증발기를 이용하여 여액의 용매를 제거한 후 남은 혼합물을 관 크로마토그라피로 분리정제 함으로써 목적 혼합물 2.9 g을 고체 상태로 얻었다(72%의 수율). 2-hydroxy-1-acetonaphthone (1864 mg, 10 mmol) and 2,4,6-trimethoxybenzaldehyde (2,4,6-trimethoxybenzaldehyde, 1964 mg, 10 mmol) is dissolved in 70 ml of ethanol, and then 15 ml of 50% aqueous KOH solution is added slowly at about 4 minutes at 4 ° C. After stirring the mixed solution at room temperature for 18 hours, the temperature is lowered to about 4 ° C. After neutralizing by adding 40 ml of 6 N HCl solution to the cooled solution, the aqueous solution was extracted twice with 100 ml of chloroform. Each of the extracted organic solvents is combined, magnesium sulfate is added to remove water, and the remaining mixture is filtered under reduced pressure. Next, after removing the solvent of the filtrate by using a rotary evaporator, the remaining mixture was purified by column chromatography to obtain 2.9 g of the target mixture in a solid state (72% yield).
합성된 물질의 녹는점은 96 ~ 99℃였으며, 목적 화합물의 생성여부를 확인하기 위하여 도 1에 나타난 수소핵자기공명분광스펙트럼(Bruker 400㎒)과 도 2에 나타난 탄소핵자기공명스펙트럼(Bruker 100㎒)을 통하여 확인한 결과 이 화합물은 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘이었다.
The melting point of the synthesized material was 96 ~ 99 ℃, to confirm the formation of the target compound hydrogen nuclear magnetic resonance spectra spectrum shown in Figure 1 (Bruker 400MHz) and carbon nuclear magnetic resonance spectrum shown in Figure 2 (
실시예 2. 웨스턴 블롯 분석Example 2. Western Blot Analysis
본 발명에서 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘의 암 억제 활성 효과를 확인하기 위하여, 인간 자궁 암세포주(HeLa)를 ATCC(American Type Culture Collection, 미국)에서 분양받아 상기 실시예 1에서 수득한 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘을 처리한 후 세포의 89-kDa 크기의 PARP 단편 생성 여부를 측정함으로써 세포의 type-I 자기사멸 유도 효과를 분석하였다. In order to confirm the cancer-inhibitory activity of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone in the present invention, human uterine cancer cell line (HeLa) in the ATCC (American Type Culture) Collection, USA), treated with 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone obtained in Example 1, and then the cells were 89-kDa sized PARP. The type-I self-apoptotic induction effect of the cells was analyzed by measuring fragment generation.
구체적으로, 1×106개의 HeLa 세포를 60 ㎜짜리 세포배양접시에 분주한 후 5% CO2가 공급되는 37℃ 세포배양기에서 24시간 배양하고, 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘을 20 μM 농도로 처리하고, 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘이 유발하는 PARP의 조각단편을 조사하기 위하여 웨스턴 블롯으로 분석하였다.Specifically, 1 × 10 6 HeLa cells were dispensed into a 60 mm cell culture dish, followed by incubation for 24 hours in a 37 ° C. cell culture cell supplied with 5% CO 2 , and 4,5-benzo-1-hydroxy-2. Fragment of PARP induced by 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone after treatment with ', 4', 6'-trimethoxychalcone at 20 μM concentration The fragments were analyzed by Western blot to investigate.
HeLa 자궁경부암세포에 20 μM 농도의 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘을 처리하고 24시간 경과 후에 세포를 수확한 후, 20 mM HEPES (pH 7.2), 1% Triton X-100, 10% glycerol, 150 mM NaCl, 10 ㎍/㎖ leupeptin 및 1 mM PMSF이 함유되어 있는 세포용해액(cell lysis buffer) 200 ㎍를 첨가하여 세포를 용해시키고, 15,000 ×g에서 30분 간 원심분리 하여 상층의 세포 용해액을 수확하였다. 20 ㎍의 단백질이 포함하도록 제조된 시료를 SDS-폴리아크릴아마이드 겔 전기영동(SDS-polyacrylamide gel electrophoresis; SDS-PAGE)을 실시하여 세포에 존재하는 단백질들을 분리하였다. 전기영동으로 분리된 단백질을 폴리스틸렌 막(polystyrene membrane)으로 옮긴 후 토끼 항PARP 항체(rabbit anti-PARP antibody)와 HRP(horse radish peroxidase)가 부착된 항토끼 이차항체(anti-rabbit secondary antibody)를 표준 방법으로 반응시킨 후 Amersham Pharmacia Biotech (Piscataway, NJ)에서 구입한 화학형광감지 시스템(chemiluminescence) 키트를 이용하여 PARP 단백질이 89-kDa 크기로 잘려나가는 정도를 측정하였다. HeLa cervical cancer cells were treated with 20 μM concentration of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone and harvested cells 24 hours later, followed by 20 mM HEPES ( pH 7.2), 200 μg of cell lysis buffer containing 1% Triton X-100, 10% glycerol, 150 mM NaCl, 10 μg / ml leupeptin and 1 mM PMSF were lysed, The top cell lysate was harvested by centrifugation at 15,000 xg for 30 minutes. Samples prepared to contain 20 μg of protein were subjected to SDS-polyacrylamide gel electrophoresis (SDS-PAGE) to separate proteins present in cells. Electrophoresis of the separated proteins into a polystyrene membrane followed by standardization of a rabbit anti-PARP antibody and an anti-rabbit secondary antibody with horse radish peroxidase (HRP) After the reaction, the degree of PARP protein truncation to 89-kDa size was measured using a chemiluminescence kit purchased from Amersham Pharmacia Biotech (Piscataway, NJ).
실험 결과, 도 3에 나타낸 바와 같이 HeLa 암세포에 아무 처리도 하지 않은 대조군 세포에서는 PARP 단백질이 113-kDa 크기로 관찰되었으나, 신규 화합물인 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘을 처리하였을 때는 89-kDa 크기의 PARP 조각 단편이 생성되었다. 이때 약물 반응에 의해 발현 변화가 나타나지 않는 GAPDH(glyceraldehyde 3-phosphate dehydrogenase)는 두 세포 그룹 간의 양적 변화가 관찰되지 않았다. 이와 같은 결과를 통하여 신규 칼콘 유도체 화합물인 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘은 HeLa 암세포에서 Type-I 세포자기사멸을 유도하는 효과가 있음을 확인하였다.
As a result, as shown in FIG. 3, PARP protein was observed to be 113-kDa in control cells which had not been treated with HeLa cancer cells, but it was a novel compound 4,5-benzo-1-hydroxy-2 ', 4'. Treatment with, 6'-trimethoxychalcone produced PARP fragment fragments of 89-kDa size. At this time, GAPDH (glyceraldehyde 3-phosphate dehydrogenase), which does not show a change in expression by the drug response, was not observed between the two cell groups. Through these results, 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone, a novel chalcone derivative compound, has the effect of inducing Type-I apoptosis in HeLa cancer cells. It was confirmed.
Claims (6)
[화학식 1]
The chalcone derivative 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Formula 1]
상기 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘 또는 그의 약학적으로 허용되는 염은 암세포에서 Type-Ⅰ 세포자기사멸 활성을 유도함으로써 암을 예방하거나 치료하는 것을 특징으로 하는 암의 예방 또는 치료용 약학 조성물. The method of claim 2,
The 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone or a pharmaceutically acceptable salt thereof may be used to prevent cancer by inducing Type-I apoptosis activity in cancer cells. A pharmaceutical composition for preventing or treating cancer, characterized in that the treatment.
상기 암은 유방암, 대장암, 위암, 전립선암, 신장암, 간암, 뇌종양, 폐암, 자궁암, 결장암, 방광암, 췌장암, 혈액암, 비소세포폐암, 갑상선암, 급성임파구성 백혈병 및 바이러스에 의한 종양으로 이루어진 군에서 선택되는 1 이상인 것을 특징으로 하는 질병의 예방 또는 치료용 약학 조성물.4. The method according to claim 2 or 3,
The cancer is composed of breast cancer, colon cancer, stomach cancer, prostate cancer, kidney cancer, liver cancer, brain tumor, lung cancer, uterine cancer, colon cancer, bladder cancer, pancreatic cancer, blood cancer, non-small cell lung cancer, thyroid cancer, acute lymphocytic leukemia, and tumors caused by viruses. Pharmaceutical composition for the prevention or treatment of diseases, characterized in that at least one selected from the group.
(1) 2-히드록시-1-아세토나프톤과 2,4,6-트리메톡시벤즈알데하이드를 에탄올에 용해시키는 단계;
(2) 상기 용액에 50% KOH 수용액을 3 ~ 5℃에서 첨가하는 단계;
(3) 상기 혼합 용액을 15 ~ 20시간 동안 교반한 후에 온도를 3 ~ 5℃로 낮추는 단계;
(4) 상기 냉각된 용액에 HCl 용액을 첨가하는 중화 단계;
(5) 상기 수용액을 클로로포름으로 추출하는 단계;
(6) 상기 추출된 유기층을 분별 깔때기로 분리하고 황산마그네슘으로 제습하는 단계; 및
(7) 상기 물을 제거한 혼합물을 감압여과 한 후 여액의 용매를 제거하고, 관 크로마토그래피를 이용하여 분리 정제하는 단계;
를 포함하는 것을 특징으로 하는 4,5-벤조-1-히드록시-2',4',6'-트리메톡시칼콘의 제조방법.
In the production method of 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone represented by the formula (1),
(1) dissolving 2-hydroxy-1-acetonaphtone and 2,4,6-trimethoxybenzaldehyde in ethanol;
(2) adding 50% KOH aqueous solution to the solution at 3 to 5 ° C;
(3) stirring the mixed solution for 15 to 20 hours and then lowering the temperature to 3 to 5 ° C;
(4) neutralizing adding HCl solution to the cooled solution;
(5) extracting the aqueous solution with chloroform;
(6) separating the extracted organic layer with a separatory funnel and dehumidifying with magnesium sulfate; And
(7) filtering the mixture from which the water has been removed under reduced pressure, removing the solvent from the filtrate, and separating and purifying by using column chromatography;
Method for producing 4,5-benzo-1-hydroxy-2 ', 4', 6'-trimethoxychalcone comprising a.
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2010
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101306958B1 (en) * | 2010-11-08 | 2013-09-10 | 건국대학교 산학협력단 | Trimethoxyphenyl-4,5-dihydro-1h-pirazol-3-yl-naphthalen-2-ol derivatives having apoptosis-inducing activation |
DE102013104196A1 (en) | 2012-05-04 | 2013-11-07 | Samsung Electronics Co., Ltd. | Method for programming e.g. static RAM in computer system, involves programming received program data, programming bits of multi-page data into memory cells by page buffer, and storing received program data in RAM of memory system |
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