KR20200005886A - (-)-epigallocatechin gallate prodrugs, preparation method thereof and composition for inducing autophagy activation - Google Patents
(-)-epigallocatechin gallate prodrugs, preparation method thereof and composition for inducing autophagy activation Download PDFInfo
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- KR20200005886A KR20200005886A KR1020180079444A KR20180079444A KR20200005886A KR 20200005886 A KR20200005886 A KR 20200005886A KR 1020180079444 A KR1020180079444 A KR 1020180079444A KR 20180079444 A KR20180079444 A KR 20180079444A KR 20200005886 A KR20200005886 A KR 20200005886A
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Abstract
Description
본 발명은 에피갈로카테킨 갈레이트 프로드러그, 이의 제조방법 및 이를 포함하는 자가포식 조절용 조성물에 관한 것이다.The present invention relates to an epigallocatechin gallate prodrug, a preparation method thereof, and a composition for controlling autophagy comprising the same.
자가포식(autophagy)은 세포 내 에너지원이 고갈되거나 세포 내 스트레스 요인이 과도하게 발생했을 때 노후 혹은 손상된 세포 내 물질 및 기관을 분해함으로 에너지 재생산 및 손상 물질을 제거하는 기작을 말하며, 정상적인 세포의 유지를 가능하게 한다. 최근 다양한 연구를 통해 노화가 진행될수록 또는 노화를 가속화시킬수록 세포 내 자가포식 활성이 급격히 감소한다고 보고되고 있으며, 반대로 자가포식을 억제시킨 경우 세포 내에 노후 미토콘드리아나 잘못 접힌 단백질 등이 과도하게 축적되어 세포 내 자유 라디칼 및 산화 스트레스가 증가하여 결국에 세포의 사멸이 증가하고 노화가 촉진되는 결과를 야기하게 된다.Autophagy refers to the mechanism of removing energy reproduction and damaging substances by decomposing aging or damaged intracellular substances and organs when the energy sources in the cells are depleted or excessive stress factors occur. To make it possible. Recently, various studies have reported that intracellular autophagy activity decreases rapidly as aging progresses or accelerates aging. On the contrary, when autophagy is suppressed, aging mitochondria and misfolded proteins are accumulated excessively in cells. Increasing free radicals and oxidative stress in the end result in increased cell death and accelerated aging.
또한, 미토콘드리아에서는 에너지 생성 과정을 가동하면서 부산물로 활성 산소군이 생성되며, 외부 스트레스로 자외선, 약물, 섭취 물질 및 환경 오염 요인 등의 자극에 의해 과산화지질(lipid peroxide), 지질과산화 라디칼(lipid peroxy radical) 또는 과산화아질산염(peroxynitrite) 등이 생성되어 광범위한 산화 스트레스를 가하게 된다. 이러한 산화 스트레스 산물들은 매우 불안정하고 주변 물질과의 반응성이 매우 강하여, 세포 내의 단백질, 지질 및 DNA 등과 매우 강한 결합을 일으키며, 각종 변성을 야기하여 결국에 치명적인 문제를 야기하게 된다.In addition, in the mitochondria, active oxygen groups are generated as by-products during the energy generation process, and lipid peroxide and lipid peroxy radicals are stimulated by external stress by stimulation such as ultraviolet rays, drugs, ingested substances and environmental pollution factors. radicals, or peroxynitrite, are produced, exerting extensive oxidative stress. These oxidative stress products are very unstable and highly reactive with surrounding materials, resulting in very strong binding to proteins, lipids, DNA, etc. in the cell, causing various degenerations and eventually causing fatal problems.
세포 내에서의 항산화 활성을 증가시키는 물질로는, 비타민류, 글루타치온, 코엔자임Q-10 등과 같은 항산화 물질들, 혹은 카탈라아제(catalase), 수퍼옥사이드 디스뮤타제(superoxide dismutase), 글루타치온-의존성 페록시다제(glutathione-dependent peroxidase) 및 퍼옥시리독신(peroxiredoxin) 등과 같은 항산화 단백질들을 예로 들 수 있다. 그러나, 이들 종래의 항산화 물질들은 in-vitro 및 혈액 내에서는 활성 산소 소거능이 잘 발휘되지만, 세포 내에서는 농도에 따라 오히려 활성 산소의 형성을 증가시키는 부작용을 나타내는 문제가 있다. 또한 세포 내 노후된 물질 및 기관을 분해하는 재활용 기작인 자가포식의 활성화를 통해 산화 스트레스로 인해 변형된 단백질, 지질 및 미토콘드리아 등을 빠르게 제거하고, 이를 통해 세포가 좀 더 건강한 상태로 생존할 수 있는 환경을 제공하게 된다.Substances that increase antioxidant activity in cells include vitamins, antioxidants such as glutathione and coenzyme Q-10, or catalase, superoxide dismutase, and glutathione-dependent peroxidase. Examples include antioxidant proteins such as glutathione-dependent peroxidase and peroxiredoxin. However, these conventional antioxidants are well exhibited free radical scavenging ability in-vitro and in the blood, but there is a problem that shows the side effect of increasing the formation of free radicals in accordance with the concentration in the cell. In addition, activation of autophagy, a recycling mechanism that breaks down old substances and organs in cells, quickly removes proteins, lipids, and mitochondria modified by oxidative stress, thereby enabling cells to survive in a healthier state. Will be provided.
세포 내에서 발생하는 이러한 산화 스트레스를 제거하고, 개체, 조직 및 세포의 건강성을 회복시키기 위해서는, 세포 내에서 나타나는 항산화 활성 및 자가포식 활성화가 매우 중요하다. 따라서, 종래 항산화 물질들이 가지는 문제점을 근본적으로 해결하고 우수한 항노화 효능을 제공하기 위해서는, 세포 내 항산화 단백질의 발현을 증가시켜 항산화 활성을 높일 뿐만 아니라 자가포식 활성화를 유도하는 능력이 우수한 물질을 개발할 필요가 있다.In order to eliminate these oxidative stress occurring in the cell and to restore the health of the individual, tissue and cell, the antioxidant activity and autophagy activation occurring in the cell are very important. Therefore, in order to fundamentally solve the problems of conventional antioxidants and provide excellent anti-aging efficacy, it is necessary to develop a material having an excellent ability to induce autophagy activation as well as to increase antioxidant activity by increasing the expression of antioxidant proteins in cells. There is.
에피갈로카테긴 갈레이트((-)-epigallocatechin gallate, (-)-EGCG) (이하 EGCG로 표기)는 녹차에 포함된 대표적인 카테친 화합물 중 하나로, 오토파지의 중요한 marker인 LC3B (Microtubule-associated protein light chain 3 B) 및 AMPK (AMP-activated protein kinase)의 활성을 조절하는 것으로 알려져 있다.Epigallocategin gallate ((-)-epigallocatechin gallate, (-)-EGCG) (hereinafter referred to as EGCG) is one of the representative catechin compounds included in green tea, and is an important marker of autophagy LC3B (Microtubule-associated
그러나 EGCG는 체 내 용해도가 낮고, 쉽게 분해되며, 흡수도가 떨어지고, 대사시간이 매우 빨라 체 내 이용이 어려운 단점들을 가지고 있기 때문에 이러한 문제점을 극복하기 위해 프로드러그 접근법이 관심을 모으고 있다.However, the prodrug approach is drawing attention to overcome this problem because EGCG has low disadvantages such as low solubility in the body, easy decomposition, low absorption, and fast metabolic time, making it difficult to use in the body.
이에 본 발명자들은 EGCG 프로드러그들을 합성하고, 이 물질들에 의한 자가포식 조절 효과를 검증함으로써 발명을 완성하였다.The present inventors have completed the invention by synthesizing EGCG prodrugs and verifying the effect of autophagy control by these substances.
본 발명의 목적은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식(autophagy) 활성화 유도 조성물을 제공하는 것이다.An object of the present invention is to provide an autophagy activation inducing composition comprising a compound represented by the following formula (1) or (2), or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of autophagy-related diseases comprising a compound represented by the following formula (1) or (2), or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Still another object of the present invention is to provide a nutraceutical composition for preventing or ameliorating autophagy related diseases including a compound represented by the following Chemical Formula 1 or Chemical Formula 2, or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식 관련 질환의 예방 또는 개선용 건강식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health food composition for preventing or ameliorating autophagy related diseases, including a compound represented by the following Chemical Formula 1 or Chemical Formula 2, or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 본 발명의 자가포식 활성화 유도 조성물을 세포에 처리하는 단계를 포함하는, 인비트로에서 자가포식 활성화 유도방법을 제공하는 것이다.Still another object of the present invention is to provide a method for inducing autophagy activation in vitro, comprising treating a cell with the autophagy activation inducing composition of the present invention.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식(autophagy) 활성화 유도 조성물을 제공한다.The present invention provides an autophagy activation inducing composition comprising a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
(상기 화학식 1에 있어서,(In the above formula 1,
RA는 C1-4의 직쇄 또는 측쇄 알킬, C6-8의 아릴C1-4의 직쇄 또는 측쇄 알킬, 또는 C1-4의 직쇄 또는 측쇄 알케닐이다.)R A is C 1-4 straight or branched alkyl, C 6-8 arylC 1-4 straight or branched alkyl, or C 1-4 straight or branched alkenyl.
[화학식 2][Formula 2]
(상기 화학식 2에 있어서,(In the
RB는 
R1는 H, 또는 C1-3의 직쇄 또는 측쇄 알콕시이고; R 1 is H, or C 1-3 straight or branched alkoxy;
R2는 H, 또는 C1-3의 직쇄 또는 측쇄 알킬이고;R 2 is H, or C 1-3 straight or branched alkyl;
R3은 C1-4의 직쇄 또는 측쇄 알킬, 또는 C1-4의 직쇄 또는 측쇄 알콕시이고;R 3 is C 1-4 straight or branched alkyl, or C 1-4 straight or branched alkoxy;
R4는 C1-4의 직쇄 또는 측쇄 알킬, C1-4의 직쇄 또는 측쇄 알콕시카르보닐C1-4의 직쇄 또는 측쇄 알킬, 또는 C6-8의 아릴C1-4의 직쇄 또는 측쇄 알킬이고;R 4 is C 1-4 straight or branched alkyl, C 1-4 straight or branched alkoxycarbonylC 1-4 straight or branched alkyl, or C 6-8 aryl C 1-4 straight or branched alkyl ego;
R5은 C1-4의 직쇄 또는 측쇄 알킬이다).R 5 is C 1-4 straight or branched alkyl).
또한, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating autophagy-related diseases, including the compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof.
나아가 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Furthermore, the present invention provides a health functional food composition for preventing or ameliorating autophagy-related diseases, including a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식 관련 질환의 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention provides a health food composition for preventing or ameliorating autophagy-related diseases comprising a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof.
나아가 본 발명은 본 발명의 자가포식 활성화 유도 조성물을 세포에 처리하는 단계를 포함하는, 인비트로에서 자가포식 활성화 유도방법을 제공한다.Furthermore, the present invention provides a method for inducing autophagy activation in vitro, comprising treating a cell with the autophagy activation inducing composition of the present invention.
본 발명에 따른 화학식 1 또는 2로 표시되는 화합물은 자가포식 관련 단백질의 발현을 증가시켜 자가포식을 조절, 활성화를 유도할 수 있고, 또한 산화 스트레스로부터 세포를 보호할 수 있으며, 자가포식(autophagy) 관련 질환의 예방 또는 치료의 목적으로 유용할 수 있다.Compounds represented by Formula 1 or 2 according to the present invention can increase the expression of autophagy-related proteins to regulate and activate autophagy, and also to protect cells from oxidative stress and autophagy It may be useful for the purpose of preventing or treating related diseases.
도1은 Huh7 cell line에서 LC3B의 발현량을 western blot으로 관찰한 결과를 나타낸 것이다.
도2는 Huh7 cell line에서 AMPK의 phosphorylation 정도를 western blot으로 관찰한 결과를 나타낸 것이다.
도3은 Huh7 cell line에서 p62의 degradation정도를 western blot으로 관찰한 결과를 나타낸 것이다.
도4는 Huh cell line에서 autophagosome의 양을 CYTO-ID staining으로 관찰한 결과를 나타낸 것이다.Figure 1 shows the result of observing the expression level of LC3B in Western blot in Huh7 cell line.
Figure 2 shows the results observed by Western blot phosphorylation degree of AMPK in Huh7 cell line.
Figure 3 shows the result of observing the degradation degree of p62 in the Huh7 cell line by western blot.
Figure 4 shows the results of observing the amount of autophagosome in the Huh cell line by CYTO-ID staining.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
자가포식 활성화 유도 조성물Autophagy Activation Induction Composition
본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식(autophagy) 활성화 유도 조성물을 제공한다.The present invention provides an autophagy activation inducing composition comprising a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
(상기 화학식 1에 있어서,(In the above formula 1,
RA는 C1-4의 직쇄 또는 측쇄 알킬, C6-8의 아릴C1-4의 직쇄 또는 측쇄 알킬, 또는 C1-4의 직쇄 또는 측쇄 알케닐이다.)R A is C 1-4 straight or branched alkyl, C 6-8 arylC 1-4 straight or branched alkyl, or C 1-4 straight or branched alkenyl.
바람직하게는, Preferably,
상기 RA는 메틸, 
[화학식 2][Formula 2]
(상기 화학식 2에 있어서,(In the
RB는 
R1는 H, 또는 C1-3의 직쇄 또는 측쇄 알콕시이고; R 1 is H, or C 1-3 straight or branched alkoxy;
R2는 H, 또는 C1-3의 직쇄 또는 측쇄 알킬이고;R 2 is H, or C 1-3 straight or branched alkyl;
R3은 C1-4의 직쇄 또는 측쇄 알킬, 또는 C1-4의 직쇄 또는 측쇄 알콕시이고;R 3 is C 1-4 straight or branched alkyl, or C 1-4 straight or branched alkoxy;
R4는 C1-4의 직쇄 또는 측쇄 알킬, C1-4의 직쇄 또는 측쇄 알콕시카르보닐C1-4의 직쇄 또는 측쇄 알킬, 또는 C6-8의 아릴C1-4의 직쇄 또는 측쇄 알킬이고;R 4 is C 1-4 straight or branched alkyl, C 1-4 straight or branched alkoxycarbonylC 1-4 straight or branched alkyl, or C 6-8 aryl C 1-4 straight or branched alkyl ego;
R5은 C1-4의 직쇄 또는 측쇄 알킬이다).R 5 is C 1-4 straight or branched alkyl).
바람직하게는, Preferably,
RB는 ,
R1는 H 또는 메톡시이고;R 1 is H or methoxy;
R2는 H 또는 메틸이고;R 2 is H or methyl;
R3은 t-부틸, t-부톡시, 이소프로폭시 또는 에톡시이고;R 3 is t-butyl, t-butoxy, isopropoxy or ethoxy;
R4는 메틸, 메톡시카르보닐에틸 또는 페닐메틸이고;R 4 is methyl, methoxycarbonylethyl or phenylmethyl;
R5은 메틸 또는 t-부틸이다.R 5 is methyl or t-butyl.
본 발명에 따른 화학식 1로 표시되는 화합물의 바람직한 예로는 하기의 화합물 군을 들 수 있다.Preferred examples of the compound represented by Formula 1 according to the present invention include the following compound groups.
1) (2R,3R)-5,7-디하이드록시-2-(3,4,5-트리하이드록시페닐)크로만-3-일 4-(벤질옥시)-3,5-디하이드록시벤조에이트;1) (2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl 4- (benzyloxy) -3,5-dihydroxy Benzoate;
2) (2R,3R)-5,7-디하이드록시-2-(3,4,5-트리하이드록시페닐)크로만-3-일 4-(알릴옥시)-3,5-디하이드록시벤조에이트; 및2) (2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl 4- (allyloxy) -3,5-dihydroxy Benzoate; And
3) (2R,3R)-5,7-디하이드록시-2-(3,4,5-트리하이드록시페닐)크로만-3-일 3,5-디하이드록시-4-메톡시벤조에이트.3) (2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-
본 발명에 따른 화학식 2로 표시되는 화합물의 바람직한 예로는 하기의 화합물 군을 들 수 있다.Preferred examples of the compound represented by the formula (2) according to the present invention include the following compound groups.
1) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(에톡시메톡시)벤조일)옥시)-크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;1) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (ethoxymethoxy) benzoyl) oxy) -chroman-2-yl ) Benzene-1,2,3-triyl triacetate;
2) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-((2-메톡시에톡시)메톡시)-벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;2) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4-((2-methoxyethoxy) methoxy) -benzoyl) oxy) Chroman-2-yl) benzene-1,2,3-triyl triacetate;
3) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-((피발로일옥시)메톡시-벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;3) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4-((pivaloyloxy) methoxy-benzoyl) oxy) chromen- 2-yl) benzene-1,2,3-triyl triacetate;
4) 5-((2R,3R)-5,7-디아세톡시-3-(3,5-디아세톡시-4-((이소프로폭시카르보닐옥시)메톡시)벤조일옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;4) 5-((2R, 3R) -5,7-Diacetoxy-3- (3,5-diacetoxy-4-((isopropoxycarbonyloxy) methoxy) benzoyloxy) chroman- 2-yl) benzene-1,2,3-triyl triacetate;
5) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(1-((이소프로폭시카르보닐)옥시)-에톡시)벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;5) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (1-((isopropoxycarbonyl) oxy) -ethoxy) Benzoyl) oxy) chroman-2-yl) benzene-1,2,3-triyl triacetate;
6) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(1-((에톡시카르보닐)옥시)에톡시)-벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;6) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (1-((ethoxycarbonyl) oxy) ethoxy) -benzoyl ) Oxy) chroman-2-yl) benzene-1,2,3-triyl triacetate;
7) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(((tert-부톡시카르보닐)옥시)-메톡시)벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;7) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4-(((tert-butoxycarbonyl) oxy) -methoxy) benzoyl ) Oxy) chroman-2-yl) benzene-1,2,3-triyl triacetate;
8) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(2-(((S)-1-메톡시-1-옥소프로판-2-일)아미노)-2-옥소에톡시)벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;8) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (2-(((S) -1-methoxy-1-oxo) Propan-2-yl) amino) -2-oxoethoxy) benzoyl) oxy) chroman-2-yl) benzene-1,2,3-tritriacetate;
9) (S)-디메틸 2-(2-(2,6-디아세톡시-4-((((2R,3R)-5,7-디아세톡시-2-(3,4,5 -트리아세톡시페닐)크로만-3-일)옥시)카르보닐)페녹시)아세트아미도)펜탄디오에이트; 및9) (S) -dimethyl 2- (2- (2,6-diacetoxy-4-((((2R, 3R) -5,7-diacetoxy-2- (3,4,5-tria) Cetoxyphenyl) chroman-3-yl) oxy) carbonyl) phenoxy) acetamido) pentanedioate; And
10) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(2-(((S)-1-메톡시-1-옥소-3-페닐프로판-2-일)아미노)-2-옥소에톡시)벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트.10) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (2-(((S) -1-methoxy-1-oxo) -3-phenylpropan-2-yl) amino) -2-oxoethoxy) benzoyl) oxy) chroman-2-yl) benzene-1,2,3-triyl triacetate.
자가포식 관련 질환의 예방 또는 치료용 약학적 조성물Pharmaceutical composition for the prevention or treatment of autophagy related diseases
본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식 관련질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating autophagy-related diseases comprising a compound represented by the following Chemical Formula 1 or
[화학식 1][Formula 1]
(상기 화학식 1에 있어서,(In the above formula 1,
RA는 제1항에서 정의한 바와 같다.)R A is as defined in claim 1.
[화학식 2][Formula 2]
(상기 화학식 2에 있어서,(In the
RB는 제1항에서 정의한 바와 같다).R B is as defined in claim 1).
본 발명의 일 실시예에 있어서, 상기 자가포식 관련 질환은 암, 아테롬성 동맥 경화증, 알츠하이머병, 파킨슨병, 근위측성측삭 경화증(amyotrophic lateral sclerosis), 헌팅톤병, 척수소뇌성 운동실조(spinocerebellar ataxia), 안 인후증 이영양증(oculopharyngeal muscular dystrophy), 프라이온병, 치명적 가족성 불면증, 알파-1 안티트립신 결핍증, 담창구 시상하부 위측증(dentatorubral pallidoluysian atrophy), 전측두엽 치매, 전진성 상핵 마비(progressive supranuclear palsy), 척추 인경 근위축증(x-linked spinobulbar muscular atrophy) 및 신경 핵내 유리질 봉입증(neuronal intranuclear hyaline inclusion disease)과 같은 질환일 수 있다.In one embodiment of the present invention, the autophagy-related diseases include cancer, atherosclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia, Oculopharyngeal muscular dystrophy, prion disease, fatal familial insomnia, alpha-1 antitrypsin deficiency, dentatorubral pallidoluysian atrophy, frontal lobe dementia, progressive supranuclear palsy, Diseases such as x-linked spinobulbar muscular atrophy and neuronal intranuclear hyaline inclusion disease.
또한, 본 발명의 일실시예에 있어, 상기 암은 뇌하수체선종, 신경교종, 뇌종양, 상인두암, 후두암, 흉선종, 중피종, 유방암, 폐암, 위암, 식도암, 대장암, 간암, 췌장암, 췌내분비종양, 담낭암, 음경암, 요관암, 신세포암, 전립선암, 방광암, 비호지킨성림프종, 골수이형성증후군, 다발성골수종, 형질세포성종양, 백혈병, 소아암, 피부암, 난소암 및 자궁경부암 일 수 있다.In addition, in one embodiment of the present invention, the cancer is pituitary adenoma, glioma, cerebral tumor, epiglottis cancer, laryngeal cancer, thymoma, mesothelioma, breast cancer, lung cancer, gastric cancer, esophageal cancer, colon cancer, liver cancer, pancreatic cancer, pancreatic endocrine tumor, Gallbladder cancer, penile cancer, ureter cancer, renal cell carcinoma, prostate cancer, bladder cancer, non-Hodgkin's lymphoma, myelodysplastic syndrome, multiple myeloma, plasmacytoma, leukemia, childhood cancer, skin cancer, ovarian cancer and cervical cancer.
본 발명의 화합물은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다.The compound of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are manufactured.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose), 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or 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.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 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, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. 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, glycerol, gelatin and the like can be used.
또한, 본 발명의 화합물의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 일반적으로 약 0.001~100 mg/kg/일이며, 바람직하게는 0.01~35 mg/kg/일이다. 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.07~7000 mg/일이며, 바람직하게는 0.7~2500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the effective dosage of the compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is generally about 0.001 to 100 mg / kg / day, preferably Preferably 0.01-35 mg / kg / day. Based on an adult patient with a weight of 70 kg, it is generally 0.07 ~ 7000 mg / day, preferably 0.7 ~ 2500 mg / day, once a day at regular intervals depending on the judgment of the doctor or pharmacist Multiple doses may be administered.
건강기능식품 또는 건강식품 조성물Nutraceutical or health food composition
본 발명은 하기 화학식 1 또는 화학식 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염을 포함하는 자가포식 관련 질환의 예방 또는 개선용 건강기능식품 또는 건강식품 조성물을 제공한다.The present invention provides a health functional food or health food composition for preventing or ameliorating autophagy related diseases, including a compound represented by the following Chemical Formula 1 or
[화학식 1][Formula 1]
(상기 화학식 1에 있어서,(In the above formula 1,
RA는 제1항에서 정의한 바와 같다.)R A is as defined in claim 1.
[화학식 2][Formula 2]
(상기 화학식 2에 있어서,(In the
RB는 제1항에서 정의한 바와 같다).R B is as defined in claim 1).
본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물을 건강기능식품 및 건강식품으로 사용하는 경우, 식품의 종류에는 특별한 제한은 없다. 본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품 및 건강식품을 모두 포함한다.When the compound represented by Formula 1 or
본 발명에 따른 화학식 1 또는 화학식 2로 표시되는 화합물을 함유하는 건강기능식품 및 건강식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 화학식 1 또는 화학식 2로 표시되는 화합물의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 및 건강식품 중의 상기 조성물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 유지를 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 화학식 1 또는 화학식 2로 표시되는 화합물은 상기 범위 이상의 양으로도 사용될 수 있다.Nutraceuticals and health food compositions containing a compound represented by the formula (1) or (2) according to the present invention can be added to the food as it is, or used with other food or food ingredients, and may be appropriately used according to conventional methods. . The mixed amount of the compound represented by the formula (1) or (2) can be suitably determined according to the purpose of use (prevention or improvement). In general, the amount of the composition in the nutraceutical and health food can be added to 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for the purpose of maintaining health or controlling the health, the amount may be below the above range, and since there is no problem in terms of safety, the compound represented by the formula (1) or (2) may be present in an amount above the above range. Can also be used as.
본 발명의 건강기능식품 및 건강식품 조성물은 지시된 비율로 필수 성분으로서 본 발명 화학식 1 또는 화학식 2로 표시되는 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트라이톨 등의 당알코올이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강기능식품 및 건강식품 조성물 100 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The health functional food and the health food composition of the present invention are not particularly limited to other ingredients except for containing the compound represented by the formula (1) or (2) as essential ingredients in the indicated ratios, and various flavors or Natural carbohydrates and the like may be included as additional components. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 nutraceutical and health food composition of the present invention.
상기 외에 본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물을 함유하는 건강기능식품 및 건강식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강기능식품 및 건강식품 조성물은 천연 과일쥬스 및 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the health functional food and health food composition containing the compound represented by the general formula (1) or the general formula (2) of the present invention include various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavoring agents, such as colorants and Neutralizers (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. Can be. In addition, the nutraceutical and health food composition of the present invention may contain the flesh for the production of natural fruit juice and fruit juice drinks and vegetable drinks.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물을 함유하는 건강기능식품 및 건강식품 조성물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.These components can be used independently or in combination. The proportion of such additives is not so critical but is generally selected from 0.1 to about 20 parts by weight per 100 parts by weight of the nutraceutical and health food composition containing the compound represented by the formula (1) or (2) of the present invention.
자가포식 활성화 유도방법Induction method of autophagy activation
본 발명은 본 발명의 자가포식 활성화 유도 조성물을 세포에 처리하는 단계를 포함하는, 인비트로에서 자가포식 활성화 유도방법을 제공한다.The present invention provides a method for inducing autophagy activation in vitro, comprising treating a cell with the autophagy activation inducing composition of the present invention.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 단, 하기의 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited by the following examples.
EGCG 프로드러그 제조 1EGCG Prodrug Manufacturing 1
실시예13 내지 15의 EGCG 프로드러그를 합성한 방법은 하기 반응식 1에 나타낸 바와 같다. 이중 구체적으로 실시예 13의 제조 방법은 다음과 같고 나머지 화합물들(실시예 11 또는 실시예12)도 유사한 방법에 의해 합성하였다.The method for synthesizing the EGCG prodrugs of Examples 13 to 15 is as shown in Scheme 1 below. Specifically, the preparation method of Example 13 was as follows, and the remaining compounds (Example 11 or Example 12) were also synthesized by a similar method.
[반응식 1]Scheme 1
단계 1: 5-((((2Step 1: 5-((((2 RR ,3, 3 RR )-5,7-디아세톡시-2-(3,4,5-트리아세톡시페닐)크로만-3-일)옥시)카보닐)벤젠-1,2,3-트릴 트리아세테이트의 제조Preparation of) -5,7-diacetoxy-2- (3,4,5-triacetoxyphenyl) chroman-3-yl) oxy) carbonyl) benzene-1,2,3-trile triacetate
피리딘 (pyrdine) (25 mL)에 EGCG (화합물 2) (1 g, 2.2 mmol), 아세트산무수물 (acetic anhydride, Ac2O) (3.1 mL, 32.8 mmol)을 넣고 6 시간 동안 실온에서 교반한다. 6시간 뒤 혼합물을 감압농축 한 후, 농축물을 실리카겔 컬럼크로마토그래피 (헥세인 : 아세톤 = 1 : 1)로 정제하여 하얀색 가루 형태인 화합물 3을 88% 수율로 얻을 수 있다.To pyrdine (25 mL) add EGCG (Compound 2) (1 g, 2.2 mmol) and acetic anhydride (acetic anhydride, Ac 2 O) (3.1 mL, 32.8 mmol) and stir at room temperature for 6 hours. After 6 hours, the mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane: acetone = 1: 1) to obtain
단계 2: 5-((2Step 2: 5-((2 RR ,3, 3 RR )-5,7-디아세톡시-3-((3,5-디아세톡시-4-메톡시벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트의 제조) -5,7-diacetoxy-3-((3,5-diacetoxy-4-methoxybenzoyl) oxy) chroman-2-yl) benzene-1,2,3-tritriacetate Produce
화합물 3 (0.30 g, 0.38 mmol)를 아세톤 (acetone) (5 mL)에 녹인 후 탄산 칼륨 (potassium carbonate, K2CO3) (0.09 g, 0.05 mmol)과 요오드화 칼륨 (potassium iodide, KI) (0.13 g, 0.76 mmol)를 넣어준다. 그런 후 요오드화 메틸 (methyl iodide, MeI) (0.06 mL, 0.76 mmol)를 넣어주고 50 oC에서 4 시간 동안 가열한다. 반응이 끝난 후, 혼합물을 상온에서 냉각 시킨 후, 거름종이로 탄산 칼륨을 여과 후 감압 농축 한다. 농축물을 실리카겔 컬럼크로마토그래피 (헥세인 : 아세톤 = 1 : 1)로 정제하여 하얀색 가루 형태인 화합물 4를 수율 68%로 얻을 수 있다.Compound 3 (0.30 g, 0.38 mmol) was dissolved in acetone (5 mL), followed by potassium carbonate (K 2 CO 3 ) (0.09 g, 0.05 mmol) and potassium iodide (KI) (0.13 g, 0.76 mmol). Then add methyl iodide (MeI) (0.06 mL, 0.76 mmol) and heat at 50 o C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, and then filtered through potassium carbonate with filter paper and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane: acetone = 1: 1) to afford compound 4 in a white powdery form in 68% yield.
단계 3: (2Step 3: (2
RR
,3, 3
RR
)-5,7-디하이드록시-2-(3,4,5-트리하이드록시페닐)크로만-3-일 3,5-디하이드록시-4-메톡시벤조에이트의 제조) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-
화합물 4를 메탄올 (methanol, MeOH) (5 mL)에 녹인 후, 수소화붕소나트륨 (sodium borohydride, NaBH4)를 0 oC에서 넣어준다. 30 분 뒤 실온에서 혼합물을 6 시간 동안 교반한다. 반응이 끝난 후, 2 N의 염산 (HCl)과 에틸아세테이트 (ethyl acetate, EtOAc)를 사용하여 혼합물을 축출한다. 유기용매 층을 모아 황산마그네슘 (magnesium sulfate, MgSO4)으로 수분을 제거한 후 감압 농축 한다. 농축물을 실리카겔 컬럼크로마토그래피 (디클로로메테인 : 메탄올 = 10 : 1)로 정제하여 분홍색 가루 형태인 (2R,3R)-5,7-디하이드록시-2-(3,4,5-트리하이드록시페닐)크로만-3-일 3,5-디하이드록시-4-메톡시벤조에이트를 수득률 72%로 얻을 수 있다.Compound 4 is dissolved in methanol (methanol, MeOH) (5 mL), and then sodium borohydride (NaBH 4 ) is added at 0 ° C. After 30 minutes the mixture is stirred for 6 hours at room temperature. After the reaction was completed, the mixture was extracted using 2N hydrochloric acid (HCl) and ethyl acetate (ethyl acetate, EtOAc). Collect the organic solvent layer and remove the moisture with magnesium sulfate (MgSO 4 ), and then concentrated under reduced pressure. Silica gel, the concentrate was purified by column chromatography (dichloro methane: methanol = 10: 1) to give a pink powder form to (2 R, 3 R) -5,7- dihydroxy-2- (3,4,5 Trihydroxyphenyl) chroman-3-
EGCG 프로드러그 제조 2
실시예1 내지 10의 EGCG 프로드러그를 합성한 방법은 하기 반응식에 나타낸 바와 같다. 이중 구체적으로 실시예 1의 제조 방법은 다음과 같고 나머지 화합물(실시예 2 내지 10)들도 유사한 방법에 의해 합성하였다.The method for synthesizing the EGCG prodrugs of Examples 1 to 10 is as shown in the following scheme. Specifically, the preparation method of Example 1 was as follows, and the remaining compounds (Examples 2 to 10) were synthesized by a similar method.
[반응식 2]
(상기 반응식 2에 있어서,(In
상기 Ac2O는 아세트산무수물 (acetic anhydride)이고, 상기 Pyr은 피리딘 (pyrdine)이고, X는 할로겐이고, RB는 상기 화학식 2에서 정의한 바와 같다).Ac 2 O is acetic anhydride, Pyr is pyrdine, X is halogen, and R B is as defined in Chemical Formula 2).
단계 1: 5-((((2Step 1: 5-((((2 RR ,3, 3 RR )-5,7-디아세톡시-2-(3,4,5-트리아세톡시페닐)크로만-3-일)옥시)카르보닐)벤젠-1,2,3-트라일 트리아세테이트의 제조Preparation of) -5,7-diacetoxy-2- (3,4,5-triacetoxyphenyl) chroman-3-yl) oxy) carbonyl) benzene-1,2,3-tritriacetate
피리딘 (pyrdine) (25 mL)에 EGCG (화합물 6) (1 g, 2.2 mmol), 아세트산무수물 (acetic anhydride, Ac2O) (3.1 mL, 32.8 mmol)을 넣고 6 시간 동안 실온에서 교반한다. 6시간 뒤 혼합물을 감압농축 한 후, 농축물을 실리카겔 컬럼크로마토그래피 (헥세인 : 아세톤 = 1 : 1)로 정제하여 하얀색 가루 형태인 화합물 7을 88% 수율로 얻을 수 있다.To pyrdine (25 mL), add EGCG (Compound 6) (1 g, 2.2 mmol) and acetic anhydride (acetic anhydride, Ac 2 O) (3.1 mL, 32.8 mmol) and stir at room temperature for 6 hours. After 6 hours, the mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (hexane: acetone = 1: 1) to obtain a white powdery compound 7 in 88% yield.
단계 2 : 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(에톡시메톡시)벤조일)옥시)-크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트의 제조Step 2: 5-((2R, 3R) -5,7-Diacetoxy-3-((3,5-diacetoxy-4- (ethoxymethoxy) benzoyl) oxy) -chroman-2- (1) Preparation of Benzene-1,2,3-Trial Triacetate
화합물 7 (0.30 g, 0.38 mmol)를 아세톤 (acetone) (5 mL)에 녹인 후 탄산 칼륨 (potassium carbonate, K2CO3) (0.09 g, 0.05 mmol)과 요오드화 칼륨 (potassium iodide, KI) (0.13 g, 0.76 mmol)를 넣어준다. 그런 후 RBX(X는 할로겐이고, RB는 상기 화학식 2에서 정의한 바와 같다)을 넣어주고 50 oC에서 4 시간 동안 가열한다. 반응이 끝난 후, 혼합물을 상온에서 냉각 시킨 후, 거름종이로 탄산 칼륨을 여과 후 감압 농축 한다. 농축물을 실리카겔 컬럼크로마토그래피 (헥세인 : 아세톤 = 1 : 1)로 정제하여 화학식 5로 표시되는 화합물 중 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(에톡시메톡시)벤조일)옥시)-크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트를 제조하였다.Compound 7 (0.30 g, 0.38 mmol) in acetone (5 mL), followed by potassium carbonate (K 2 CO 3 ) (0.09 g, 0.05 mmol) and potassium iodide (potassium iodide, KI) (0.13 g, 0.76 mmol). Then R B X (X is halogen and R B is as defined in Formula 2) is added and heated at 50 ° C. for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, potassium carbonate was filtered through a filter paper and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (hexane: acetone = 1: 1) to give 5-((2R, 3R) -5,7-diacetoxy-3-((3, 5-Diacetoxy-4- (ethoxymethoxy) benzoyl) oxy) -chroman-2-yl) benzene-1,2,3-trile triacetate was prepared.
하기 표 1에 실시예 1 내지 13의 치환기 R 및 화합물 명을 나타내었다.In Table 1 below, the substituents R and the compound names of Examples 1 to 13 are shown.
<실험예 1> Western blotExperimental Example 1 Western blot
(1) LC3B 발현량 측정: Huh7 세포를(1 x 105 cells/plate) 6-well plates에 분주한다. 24 시간 후, 세포를 대조군, EGCG(에피갈로카테킨갈레이트; E). 실시예 10(E10), 실시예 11(E11) 및 실시예 13(E13)으로 처리된 배지에서 배양한다. 24 시간 후, 세포를 차가운 PBS로 씻고 scraping한다. 이렇게 얻어진 시료를 4 oC에서 원심분리(5 min x 1500 x g) 하고, pellet을 protease inhibitors (Thermo Fisher) 및PMSF (Thermo Fisher)를 포함하는 lysis buffer (1 M HEPES, pH 7.9, 400 mM NaCl, 0.1 mM EDTA, 5% Glycerol, 1 mM DTT)에 resuspend한다. 이렇게 얻어진 시료를 다시 4 oC에서 원심분리하고(20 min x 16100 x g), 시료에 포함된 단백질의 농도를 BCA assay를 통해 측정한다. 세포용해물 총액(20 μg/well)을 SDS-PAGE (Bio-Rad)를 통해 분리한 후, nitrocellulose membrane (Bio-Rad)으로 transfer한다. Membrane을 TBST (Tris-buffered saline containing 0.1% Tween 20)에 녹여진 5% nonfat milk를 통해 36 oC에서 1 시간 동안 blocking한다. Membrane을 TBST에서 mouse anti-LC3B (Cell Signaling Technology)와 함께 4 oC에서 12 시간 동안 배양한 후, horseradish peroxidase와 접합된 horse anti-mouse IgG (1:1000 in TBST, Cell Signaling Technology)과 함께 1 시간 동안 배양한다. Band는 enhanced chemiluminescence (Bio-rad)를 통해 visualize하고, 이 때 densitometry (ChemiDocTM Imaging Systems, Bio-rad)를 이용하여 정량한다.(1) LC3B expression level measurement: Dispense Huh7 cells (1 x 10 5 cells / plate) into 6-well plates. After 24 hours, cells were control, EGCG (epigallocatechingallate; E). Incubate in the medium treated with Example 10 (E10), Example 11 (E11) and Example 13 (E13). After 24 hours, cells are washed with cold PBS and scraped. The sample thus obtained was centrifuged (5 min x 1500 xg) at 4 o C, and the pellet was lysis buffer (1 M HEPES, pH 7.9, 400 mM NaCl, containing protease inhibitors (Thermo Fisher) and PMSF (Thermo Fisher)). 0.1 mM EDTA, 5% Glycerol, 1 mM DTT). The sample thus obtained is again centrifuged at 4 o C (20 min x 16100 xg), and the concentration of the protein contained in the sample is measured by BCA assay. The total cell lysate (20 μg / well) is separated through SDS-PAGE (Bio-Rad) and then transferred to the nitrocellulose membrane (Bio-Rad). Membrane is blocked for 1 hour at 36 o C through 5% nonfat milk dissolved in TBST (Tris-buffered saline containing 0.1% Tween 20). Membrane was incubated with mouse anti-LC3B (Cell Signaling Technology) in TBST for 12 hours at 4 o C, followed by horse anti-mouse IgG conjugated with horseradish peroxidase (1: 1000 in TBST, Cell Signaling Technology). Incubate for hours. Bands are visualized by enhanced chemiluminescence (Bio-rad) and quantified using densitometry (ChemiDocTM Imaging Systems, Bio-rad).
그 결과, 도 1에서와 같이, 40 μM 농도에서, EGCG대비 E10이 3배 (CQ co-treat시 3.3배), E11이 2배 (CQ co-treat시 2.9배), E13이 3배 (CQ co-treat시 2.9배) LC3B의 발현을 증가시키는 효과를 보였다. As a result, as shown in FIG. 1, at a concentration of 40 μM, E10 was 3 times (3.3 times in CQ co-treat), E11 was double (2.9 times in CQ co-treat), and E13 was 3 times (CQ in comparison with EGCG). 2.9-fold at co-treat) increased the expression of LC3B.
(2) AMPK 발현량 및 인산화 정도 측정: Huh7 세포의 단백질은 상기한 바와 같이 분리정제한다. Thr172에 인산화된 AMPK와 total AMPK는 각각의 항체(phosphothreonine-specific antibody 및 total AMPK antibody, Cell signaling Technology)를 이용하여 immunoblotting을 통해 측정한다. Densitometry에 의해 측정된 인산화된 AMPK의 양을 total AMPK양으로 나누어 그 비율을 계산한다. Western blotting은 상기한 바와 같이 진행한다.(2) Measurement of AMPK expression level and phosphorylation level: The protein of Huh7 cells is separated and purified as described above. Phosphorylated AMPK and total AMPK in Thr172 were measured by immunoblotting using respective antibodies (phosphothreonine-specific and total AMPK antibodies, Cell signaling Technology). The ratio of phosphorylated AMPK measured by densitometry is divided by the total amount of AMPK. Western blotting proceeds as described above.
그 결과, 도 2에서와 같이, 동일한 농도에서 autophagic flux의 eraly stage에서 가장 중요한 인자인 AMP-activated protein kinase (AMPK, 이하 AMPK로 표기) 의 인산화정도를 western blot을 통해 관찰하였다. Western blot 결과, EGCG 대비 E10이 1.6배로 가장 많이 AMPK의 인산화를 증가시키는 효과를 보였다.As a result, as shown in Figure 2, the phosphorylation degree of AMP-activated protein kinase (AMPK, AMPK, hereinafter AMPK) which is the most important factor in the eraly stage of the autophagic flux at the same concentration was observed through western blot. As a result of Western blot, E10 was 1.6 times higher than EGCG, which showed the effect of increasing phosphorylation of AMPK.
(3) p62 degradation : Huh7 세포의 단백질은 상기한 바와 같이 분리정제한다. P62 단백질의 양은 p62 mouse monoclonal antibody (Cell Signaling Technology)를 이용하여 immunoblotting을 통해 측정한다. Western blotting은 상기한 바와 같이 진행한다.(3) p62 degradation: The protein of Huh7 cells is isolated and purified as described above. The amount of P62 protein was measured by immunoblotting using p62 mouse monoclonal antibody (Cell Signaling Technology). Western blotting proceeds as described above.
그 결과, 도 3에서와 같이, 동일한 농도에서 autophagy에 의해 분해되는 단백질인 Sequestosome1 (p62, 이하 p62로 표기) 의 분해정도를 western blot을 통해 관찰하였다. Western blot결과, EGCG 대비 E10이 1.6배로 가장 많이 p62의 분해를 증가시키는 효과를 보였다. As a result, as shown in Figure 3, the degree of degradation of Sequestosome1 (p62, hereinafter referred to as p62), a protein that is degraded by autophagy at the same concentration was observed through western blot. Western blot showed that E10 was 1.6-fold higher than EGCG, increasing the degradation of p62.
<실험예 2> CYTO-ID stainingExperimental Example 2 CYTO-ID staining
Huh7 세포의 autophagosome과 핵은 CYTO-ID (ENZO life sciences)와 Hoechest33342 (Thermo Fisher)를 이용하여 각각 염색한다. 세포를 microscopy assay를 위해 96-well clear bottom black plate (2 X 103 cells/well)에 분주한다. 24 시간 후, 세포는 control 혹은 EGCG 프로드러그가 포함된 배지에서 배양한다. 24 시간 후, 세포를 차가운 PBS로 씻고, CYTO-ID (1mg/ml) 및 Hoechst 33342를 이용하여 30분 동안 염색한다. 세포를 PBS를 이용하여 세 차례 씻어준 후, Cytation 5 imaging Multi-Mode Reader (BioTek instruments Inc., VT, USA; CYTO-ID GFP Filter cube excitation 469/435 nm, emission 525/535 nm; Hoeschst 33342, DAIP Filter cube, excitation 377/350 nm, emission 447/450 nm)를 이용하여 염색된 양을 측정한다. 이 때, Gen5 Image Plus software (BioTek Instruments, Inc., VT, USA)를 이용하였다.Autophagosomes and nuclei of Huh7 cells were stained using CYTO-ID (ENZO life sciences) and Hoechest33342 (Thermo Fisher), respectively. Dispense cells into a 96-well clear bottom black plate (2 X 10 3 cells / well) for microscopy assay. After 24 hours, cells are cultured in medium containing control or EGCG prodrugs. After 24 hours, cells are washed with cold PBS and stained for 30 minutes using CYTO-ID (1 mg / ml) and Hoechst 33342. After washing the cells three times with PBS, Cytation 5 imaging Multi-Mode Reader (BioTek instruments Inc., VT, USA; CYTO-ID GFP Filter cube excitation 469/435 nm, emission 525/535 nm; Hoeschst 33342, DAIP Filter cube, excitation 377/350 nm, emission 447/450 nm) is used to measure the amount of staining. At this time, Gen5 Image Plus software (BioTek Instruments, Inc., VT, USA) was used.
그 결과, 도 4에서와 같이, Autophagic flux의 과정을 image로 관찰하기 위하여 Huh7 세포를 40 μM의 E10, E11, E13로 처리한 후 (CQ co-treatment) 핵 염색제인 Hoechecst (파란색), autophagosome 염색제인 CYTO-ID (녹색)으로 염색하여 형광을 측정하였다. Autophagosome의 membrane 표면에는 LC3B가 존재하기 때문에 autophagosome의 양을 통해 LC3B의 양을 간접적으로 알 수 있으며, autophagy 증감 여부를 파악할 수 있다. 세포의 수 대비 CYTO-ID에 의해 염색된 autophagosome의 형광을 측정하여 정량적으로 autophagy를 검증한 결과, EGCG대비 E10에서 2.3배 (CQ co-treatment시 2배) autophagosome의 양을 증가시키는 효과를 보였다.As a result, as shown in Fig. 4, in order to observe the process of the autophagic flux, Huh7 cells were treated with 40 μM of E10, E11, and E13 (CQ co-treatment) nuclear stains, Hoechecst (blue), autophagosome stains. Fluorescence was measured by staining with phosphorus CYTO-ID (green). Because LC3B is present on the membrane surface of autophagosome, the amount of LC3B can be indirectly determined by the amount of autophagosome. Quantitative verification of autophagy by measuring the fluorescence of autophagosome stained by CYTO-ID compared to the number of cells showed an effect of increasing the amount of autophagosome by 2.3 times (2 times in CQ co-treatment) at E10 compared to EGCG.
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특히 청구범위에 나타나 있으며, 그와 동등한 범위내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in descriptive sense only and not for purposes of limitation. The scope of the present invention is shown not in the above description but in particular in the claims, and all differences within the scope will be construed as being included in the present invention.
Claims (11)
[화학식 1]
(상기 화학식 1에 있어서,
RA는 C1-4의 직쇄 또는 측쇄 알킬, C6-8의 아릴C1 -4의 직쇄 또는 측쇄 알킬, 또는 C1-4의 직쇄 또는 측쇄 알케닐이다.)
[화학식 2]
(상기 화학식 2에 있어서,
RB는
R1는 H, 또는 C1-3의 직쇄 또는 측쇄 알콕시이고;
R2는 H, 또는 C1-3의 직쇄 또는 측쇄 알킬이고;
R3은 C1-4의 직쇄 또는 측쇄 알킬, 또는 C1-4의 직쇄 또는 측쇄 알콕시이고;
R4는 C1-4의 직쇄 또는 측쇄 알킬, C1-4의 직쇄 또는 측쇄 알콕시카르보닐C1 -4의 직쇄 또는 측쇄 알킬, 또는 C6-8의 아릴C1-4의 직쇄 또는 측쇄 알킬이고;
R5은 C1-4의 직쇄 또는 측쇄 알킬이다).
An autophagy activation inducing composition comprising a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof:
[Formula 1]
(In the above formula 1,
R A is a straight or branched chain alkyl alkenyl, linear or branched aryl C 1 -4 straight or branched chain alkyl, or C 1-4 of C 6-8 of C 1-4.)
[Formula 2]
(In Formula 2,
R B is
R 1 is H, or C 1-3 straight or branched alkoxy;
R 2 is H, or C 1-3 straight or branched alkyl;
R 3 is C 1-4 straight or branched alkyl, or C 1-4 straight or branched alkoxy;
R 4 is C 1-4 straight or branched alkyl, a straight or branched alkoxycarbonyl C 1 -4 of C 1-4 straight or branched chain alkyl, or straight or branched chain alkyl of C 1-4 aryl C 6-8 of ego;
R 5 is C 1-4 straight or branched alkyl).
상기 화학식 1에서,
상기 RA는 메틸,
The method of claim 1,
In Chemical Formula 1,
R A is methyl,
상기 화학식 2에서,
RB는 ,
R1는 H 또는 메톡시이고;
R2는 H 또는 메틸이고;
R3은 t-부틸, t-부톡시, 이소프로폭시 또는 에톡시이고;
R4는 메틸, 메톡시카르보닐에틸 또는 페닐메틸이고;
R5은 메틸 또는 t-부틸인 것을 특징으로 하는 조성물.
The method of claim 1,
In Chemical Formula 2,
R B is
R 1 is H or methoxy;
R 2 is H or methyl;
R 3 is t-butyl, t-butoxy, isopropoxy or ethoxy;
R 4 is methyl, methoxycarbonylethyl or phenylmethyl;
R 5 is methyl or t-butyl.
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 조성물:
1) (2R,3R)-5,7-디하이드록시-2-(3,4,5-트리하이드록시페닐)크로만-3-일 4-(벤질옥시)-3,5-디하이드록시벤조에이트;
2) (2R,3R)-5,7-디하이드록시-2-(3,4,5-트리하이드록시페닐)크로만-3-일 4-(알릴옥시)-3,5-디하이드록시벤조에이트; 및
3) (2R,3R)-5,7-디하이드록시-2-(3,4,5-트리하이드록시페닐)크로만-3-일 3,5-디하이드록시-4-메톡시벤조에이트.
The method of claim 1,
Compound represented by Formula 1 is any one selected from the following compound group:
1) (2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl 4- (benzyloxy) -3,5-dihydroxy Benzoate;
2) (2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl 4- (allyloxy) -3,5-dihydroxy Benzoate; And
3) (2R, 3R) -5,7-dihydroxy-2- (3,4,5-trihydroxyphenyl) chroman-3-yl 3,5-dihydroxy-4-methoxybenzoate .
상기 화학식 2로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 조성물:
1) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(에톡시메톡시)벤조일)옥시)-크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;
2) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-((2-메톡시에톡시)메톡시)-벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;
3) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-((피발로일옥시)메톡시-벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;
4) 5-((2R,3R)-5,7-디아세톡시-3-(3,5-디아세톡시-4-((이소프로폭시카르보닐옥시)메톡시)벤조일옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;
5) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(1-((이소프로폭시카르보닐)옥시)-에톡시)벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;
6) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(1-((에톡시카르보닐)옥시)에톡시)-벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;
7) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(((tert-부톡시카르보닐)옥시)-메톡시)벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;
8) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(2-(((S)-1-메톡시-1-옥소프로판-2-일)아미노)-2-옥소에톡시)벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트;
9) (S)-디메틸 2-(2-(2,6-디아세톡시-4-((((2R,3R)-5,7-디아세톡시-2-(3,4,5 -트리아세톡시페닐)크로만-3-일)옥시)카르보닐)페녹시)아세트아미도)펜탄디오에이트; 및
10) 5-((2R,3R)-5,7-디아세톡시-3-((3,5-디아세톡시-4-(2-(((S)-1-메톡시-1-옥소-3-페닐프로판-2-일)아미노)-2-옥소에톡시)벤조일)옥시)크로만-2-일)벤젠-1,2,3-트라일 트리아세테이트.
The method of claim 1,
The compound represented by Formula 2 is any one selected from the following compound group:
1) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (ethoxymethoxy) benzoyl) oxy) -chroman-2-yl ) Benzene-1,2,3-triyl triacetate;
2) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4-((2-methoxyethoxy) methoxy) -benzoyl) oxy) Chroman-2-yl) benzene-1,2,3-triyl triacetate;
3) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4-((pivaloyloxy) methoxy-benzoyl) oxy) chromen- 2-yl) benzene-1,2,3-triyl triacetate;
4) 5-((2R, 3R) -5,7-Diacetoxy-3- (3,5-diacetoxy-4-((isopropoxycarbonyloxy) methoxy) benzoyloxy) chroman- 2-yl) benzene-1,2,3-triyl triacetate;
5) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (1-((isopropoxycarbonyl) oxy) -ethoxy) Benzoyl) oxy) chroman-2-yl) benzene-1,2,3-triyl triacetate;
6) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (1-((ethoxycarbonyl) oxy) ethoxy) -benzoyl ) Oxy) chroman-2-yl) benzene-1,2,3-triyl triacetate;
7) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4-(((tert-butoxycarbonyl) oxy) -methoxy) benzoyl ) Oxy) chroman-2-yl) benzene-1,2,3-triyl triacetate;
8) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (2-(((S) -1-methoxy-1-oxo) Propan-2-yl) amino) -2-oxoethoxy) benzoyl) oxy) chroman-2-yl) benzene-1,2,3-tritriacetate;
9) (S) -dimethyl 2- (2- (2,6-diacetoxy-4-((((2R, 3R) -5,7-diacetoxy-2- (3,4,5-tria) Cetoxyphenyl) chroman-3-yl) oxy) carbonyl) phenoxy) acetamido) pentanedioate; And
10) 5-((2R, 3R) -5,7-diacetoxy-3-((3,5-diacetoxy-4- (2-(((S) -1-methoxy-1-oxo) -3-phenylpropan-2-yl) amino) -2-oxoethoxy) benzoyl) oxy) chroman-2-yl) benzene-1,2,3-triyl triacetate.
[화학식 1]
(상기 화학식 1에 있어서,
RA는 제1항에서 정의한 바와 같다.)
[화학식 2]
(상기 화학식 2에 있어서,
RB는 제1항에서 정의한 바와 같다).
A pharmaceutical composition for preventing or treating autophagy-related diseases comprising a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof:
[Formula 1]
(In the above formula 1,
R A is as defined in claim 1.
[Formula 2]
(In the above formula 2,
R B is as defined in claim 1).
상기 자가포식 관련 질환은 암, 아테롬성 동맥 경화증, 알츠하이머병, 파킨슨병, 근위측성측삭 경화증(amyotrophic lateral sclerosis), 헌팅톤병, 척수소뇌성 운동실조(spinocerebellar ataxia), 안 인후증 이영양증(oculopharyngeal muscular dystrophy), 프라이온병, 치명적 가족성 불면증, 알파-1 안티트립신 결핍증, 담창구 시상하부 위측증(dentatorubral pallidoluysian atrophy), 전측두엽 치매, 전진성 상핵 마비(progressive supranuclear palsy), 척추 인경 근위축증(x-linked spinobulbar muscular atrophy) 및 신경 핵내 유리질 봉입증(neuronal intranuclear hyaline inclusion disease)으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 조성물.
The method of claim 6,
The autophagy-related diseases include cancer, atherosclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia, and ocular pharyngeal dystrophy. , Prion disease, fatal familial insomnia, alpha-1 antitrypsin deficiency, dentatorubral pallidoluysian atrophy, frontal lobe dementia, progressive supranuclear palsy, x-linked spinobulbar muscular dystrophy atrophy) and neuronal intranuclear hyaline inclusion disease.
상기 암은 뇌하수체선종, 신경교종, 뇌종양, 상인두암, 후두암, 흉선종, 중피종, 유방암, 폐암, 위암, 식도암, 대장암, 간암, 췌장암, 췌내분비종양, 담낭암, 음경암, 요관암, 신세포암, 전립선암, 방광암, 비호지킨성림프종, 골수이형성증후군, 다발성골수종, 형질세포성종양, 백혈병, 소아암, 피부암, 난소암 및 자궁경부암으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 조성물.
The method of claim 7, wherein
The cancers include pituitary adenoma, glioma, brain tumor, glandular cancer, laryngeal cancer, thymoma, mesothelioma, breast cancer, lung cancer, gastric cancer, esophageal cancer, colon cancer, liver cancer, pancreatic cancer, pancreatic endocrine tumor, gallbladder cancer, penile cancer, ureter cancer, renal cell carcinoma Prostate cancer, bladder cancer, non-Hodgkin's lymphoma, myelodysplastic syndrome, multiple myeloma, plasmacytoma, leukemia, childhood cancer, skin cancer, ovarian cancer and cervical cancer.
[화학식 1]
(상기 화학식 1에 있어서,
RA는 제1항에서 정의한 바와 같다.)
[화학식 2]
(상기 화학식 2에 있어서,
RB는 제1항에서 정의한 바와 같다).
A nutraceutical composition for preventing or ameliorating autophagy related diseases comprising a compound represented by the following Chemical Formula 1 or Chemical Formula 2, or a pharmaceutically acceptable salt thereof:
[Formula 1]
(In the above formula 1,
R A is as defined in claim 1.
[Formula 2]
(In the above formula 2,
R B is as defined in claim 1).
[화학식 1]
(상기 화학식 1에 있어서,
RA는 제1항에서 정의한 바와 같다.)
[화학식 2]
(상기 화학식 2에 있어서,
RB는 제1항에서 정의한 바와 같다).
A health food composition for preventing or ameliorating autophagy related diseases comprising a compound represented by the following Chemical Formula 1 or Chemical Formula 2, or a pharmaceutically acceptable salt thereof:
[Formula 1]
(In the above formula 1,
R A is as defined in claim 1.
[Formula 2]
(In the above formula 2,
R B is as defined in claim 1).
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| KR20160069737A (en) * | 2014-12-09 | 2016-06-17 | (주)아모레퍼시픽 | COMPOSITION COMPRISING METHYLATED CATECHIN FOR ACTIVATING Sirt-1 GENE |
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| WO2021187569A1 (en) * | 2020-03-18 | 2021-09-23 | 花王株式会社 | Method for producing epigallocatechin gallate conjugate |
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