KR20230052446A - Composition for Preventing or Treating Inflammatory Diseases Comprising Metabolites from Antarctic Fungal Strain Pleosporales sp. SF-7343 - Google Patents
Composition for Preventing or Treating Inflammatory Diseases Comprising Metabolites from Antarctic Fungal Strain Pleosporales sp. SF-7343 Download PDFInfo
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Abstract
Description
본 발명은 남극 진균 유래 대사화합물을 포함하는 염증질환 예방 또는 치료용 약학 조성물 및 염증 개선용 식품에 관한 것으로, 더욱 상세하게는 남극 진균 Pleosporales sp. SF-7343 유래 대사화합물을 포함하는 염증질환 예방 또는 치료용 약학 조성물 및 염증 개선용 식품에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases containing a metabolite derived from an Antarctic fungus and a food for improving inflammation, and more particularly, to a pharmaceutical composition comprising an Antarctic fungus Pleossporales sp. It relates to a pharmaceutical composition for preventing or treating inflammatory diseases and a food for improving inflammation, including a metabolite derived from SF-7343.
아토피 피부염(Atopic dermatitis, AD)은 만성 염증성 피부 질환으로, 이 질환의 원인은 복잡하고 여러 요인이 존재한다. 아토피 피부염의 유병률은 소아에서 20%, 성인에서 10%로 상당히 높다. AD의 일반적인 증상은 건조하고 가려운 피부, 습진 및 발적(redness)을 포함한다. 또한 AD는 다른 아토피 장애, 피부궤양, 수면 장애와도 연관되어 삶의 질을 저하시킨다. 면역학적 관점에서 AD는 헬퍼(Th) 2 세포 매개 피부 질환이다. 이는 Th1세포와 Th2 세포 수준의 불균형으로 인해 발생한다(Woods, C, A., Am J Manag Care 2017, 23,115-123). Th2 세포에서 분비되는 일부 염증성 사이토카인 및 케모카인은 각질형성세포(keratinocytes) 및 비만세포와 같은 피부 세포에 영향을 미칠 수 있다. 비만세포가 활성화되면 히스타민과 다른 많은 사이토카인 및 케모카인이 방출되어 면역세포가 염증성 병변으로 침투하는 것을 촉진한다. 병변 부위에서는 추가적인 염증 관련 피부 장벽 기능 저하, 과민성 강화, 긁기 관련 자극이 습진을 악화시켜 염증의 악순환을 일으킨다. 또한 면역글로불린 E(IgE)의 과잉 생산을 유도하여 결국 AD의 진행을 가속화한다.Atopic dermatitis (AD) is a chronic inflammatory skin disease, the cause of which is complex and has multiple factors. The prevalence of atopic dermatitis is quite high at 20% in children and 10% in adults. Common symptoms of AD include dry, itchy skin, eczema and redness. In addition, AD is associated with other atopic disorders, skin ulcers, and sleep disorders, thereby reducing quality of life. From an immunological point of view, AD is a helper (Th) 2 cell mediated skin disease. It occurs due to an imbalance between the levels of Th1 and Th2 cells (Woods, C, A., Am J Manag Care 2017 , 23 , 115-123). Some inflammatory cytokines and chemokines secreted by Th2 cells can affect skin cells such as keratinocytes and mast cells. When mast cells are activated, histamine and many other cytokines and chemokines are released, promoting the infiltration of immune cells into inflammatory lesions. At the lesion site, additional inflammation-related skin barrier function degradation, hypersensitivity enhancement, and scratch-related irritation exacerbate eczema, causing a vicious cycle of inflammation. It also induces overproduction of immunoglobulin E (IgE), which in turn accelerates the progression of AD.
각질형성세포(keratinocytes)는 표피에서 가장 풍부한 세포이며 숙주 방어 시스템의 첫 번째 라인을 나타낸다. 이들 세포는 선천성 면역 수용체를 통해 병원체를 감지하고, 항균 반응을 개시하고, 다양한 사이토카인, 케모카인 및 항균 펩타이드를 생성함으로써 물리적 피부 장벽을 형성한다(Boguniewicz, M., Leung, D, Y, G. Immunol Rev 2011,242, 233-246). AD로 인해 손상된 표피 장벽에서, 잠재적인 알레르겐과 병원체의 침투는 각질형성세포를 활성화한다. AD의 면역 반응 조절 장애 중에서, 활성화된 각질형성세포는 AD 발병에 기여하는 여러 생물학적 과정에서 중요한 역할을 한다(Wilson, V, G., Methods Mol Biol 2014, 1195, 33-41).Keratinocytes are the most abundant cells in the epidermis and represent the first line of the host defense system. These cells form a physical skin barrier by sensing pathogens through innate immune receptors, initiating antibacterial responses, and producing various cytokines, chemokines, and antimicrobial peptides (Boguniewicz, M., Leung, D, Y, G. Immunol Rev 2011 , 242 , 233-246). In the epidermal barrier damaged by AD, penetration of latent allergens and pathogens activates keratinocytes. Among the dysregulation of the immune response in AD, activated keratinocytes play an important role in several biological processes contributing to AD pathogenesis (Wilson, V, G., Methods Mol Biol 2014 , 1195 , 33-41).
한편, 남극 대륙의 독특한 위치와 기후로 인해 남극 대륙의 미생물은 극한 조건에 잘 적응하고 견딜 수 있다. 진균(fungi)은 구조적으로 독특한 이차 대사화합물을 찾는 데 중요한 역할을 한다. 많은 연구에서 남극 진균이 생활성 대사화합물을 생산한다는 사실이 밝혀졌다(Barnes, D, K, A, Clarke, A., Curr Biol 2011, 21, 451-457). 남극 진균에서 유래한 2차 대사화합물은 알칼로이드, 테르페노이드, 폴리케타이드, 펩타이드, 스테롤로 분류할 수 있다. 따라서 남극 진균은 새로운 구조를 가진 새로운 2차 대사화합물을 분리할 수 있는 매력적인 원천이다. 그러나, 이전 연구에서는 알터나리올(alternariol)은 THP-1 유래 대식세포에서 LPS 유도된 염증을 억제한다는 사실만이 보고되었으며(Kollarova, J, et al., Arch Toxicol 2018, 92, 3347-3358), 알터나리올(alternariol)과 알테누엔(altenuene)이 항염증 효과를 가진다는 사실은 아직까지 보고된 바 없다. Meanwhile, because of Antarctica's unique location and climate, its microbes are well adapted and able to withstand extreme conditions. Fungi play an important role in finding structurally unique secondary metabolites. A number of studies have shown that Antarctic fungi produce bioactive metabolites (Barnes, D, K, A, Clarke, A., Curr Biol 2011 , 21 , 451-457). Secondary metabolites derived from Antarctic fungi can be classified into alkaloids, terpenoids, polyketides, peptides, and sterols. Therefore, Antarctic fungi are an attractive source for the isolation of novel secondary metabolites with novel structures. However, previous studies have only reported that alternariol inhibits LPS-induced inflammation in THP-1-derived macrophages (Kollarova, J, et al., Arch Toxicol 2018 , 92 , 3347-3358). However, the fact that alternariol and altenuene have anti-inflammatory effects has not been reported yet.
이에, 본 발명자들은 항염증 활성이 우수한 대사화합물을 스크리닝하고자 예의 노력한 결과, 남극 진균 Pleosporales sp. SF-7343로부터 대사화합물들을 분리하고, 상기 대사화합물이 HaCaT 세포에서 TNF-α/IFN-γ에 의해 유도되는 염증반응에 대한 항염증 효과를 갖는 것을 확인하고, 본 발명을 완성하였다.Accordingly, the present inventors have made diligent efforts to screen metabolites with excellent anti-inflammatory activity, and as a result, the Antarctic fungus Pleossporales sp. Metabolic compounds were isolated from SF-7343, and it was confirmed that the metabolites had anti-inflammatory effects on the inflammatory response induced by TNF-α/IFN-γ in HaCaT cells, thereby completing the present invention.
본 배경기술 부분에 기재된 상기 정보는 오직 본 발명의 배경에 대한 이해를 향상시키기 위한 것이며, 이에 본 발명이 속하는 기술분야에서 통상의 지식을 가지는 자에게 있어 이미 알려진 선행기술을 형성하는 정보를 포함하지 않을 수 있다.The above information described in this background section is only for improving the understanding of the background of the present invention, and therefore does not include information that forms prior art known to those skilled in the art to which the present invention belongs. may not be
본 발명의 목적은 항염증 활성이 우수한 남극 진균 유래 대사화합물을 포함하는 염증질환 예방 또는 치료용 약학 조성물 및 염증 개선용 식품을 제공하는 데 있다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases and a food for improving inflammation, including a metabolite derived from Antarctic fungi having excellent anti-inflammatory activity.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1 내지 화학식 3으로 구성된 군에서 선택되는 하나 이상의 화합물을 포함하는 염증질환 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases comprising one or more compounds selected from the group consisting of
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
여기서, 상기 R1 내지 R6은 각각 독립적으로 H, 직쇄형 또는 분지쇄형의 C1-10 알킬, C1-10 알콕시, C3-10 사이클로알킬, C2-10 알케닐 또는 C6-10 아릴이다.Here, the R 1 to R 6 are each independently H, straight-chain or branched-chain C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 it is aryl
본 발명은 또한, 상기 화학식 1 내지 화학식 3으로 구성된 군에서 선택되는 하나 이상의 화합물을 포함하는 염증 개선용 식품을 제공한다.The present invention also provides a food for improving inflammation containing at least one compound selected from the group consisting of
본 발명에 따르면 남극 진균 Pleosporales sp. SF-7343 유래 대사화합물을 포함하는 조성물은 TNF-α/IFN-γ로 자극된 HaCaT 세포에서 염증 촉진성(pro-inflammatory) 사이토카인, 케모카인 및 매개체의 생성을 억제하므로, 염증질환의 예방 또는 치료 용도로 유용하게 사용될 수 있으며, 특히 아토피 피부염과 같은 피부 염증을 조절할 수 있다.According to the present invention, the Antarctic fungus Pleosporeles sp. Since the composition containing metabolites derived from SF-7343 inhibits the production of pro-inflammatory cytokines, chemokines and mediators in HaCaT cells stimulated with TNF-α/IFN-γ, preventing or treating inflammatory diseases It can be usefully used for various purposes, and in particular, it can control skin inflammation such as atopic dermatitis.
도 1은 화합물 1-3의 세포독성을 도시한다. 24시간 동안 표시된 농도로 처리한 세포에서 세포독성을 평가했다. 데이터는 3개의 독립적인 실험의 평균 ± SD 값으로 표시된다. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군.
도 2는 TNF-α/IFN-γ 자극된 HaCaT 세포에서 IL-6 분비에 대한 화합물 1-3의 효과를 도시한다. IL-6의 분비는 TNF-α/IFN-γ로 자극된 HaCaT 세포의 배양 상등액을 이용하여 측정하였다. 세포를 표시된 농도의 화합물 1-3으로 3시간 동안 전처리한 다음, TNF-α/IFN-γ로 24시간 동안 자극하였다. 데이터는 3개의 독립적인 실험의 평균 ± SD로 표시된다. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군.*p < 0.05, **p < 0.01, ***p < 0.001 vs. TNF-α/IFN-γ-처리군.
도 3은 TNF-α/IFN-γ 자극된 HaCaT 세포에서 IL-8, MDC 및 RANTES 분비에 대한 화합물 1-3의 효과를 도시한다. IL-8, MDC 및 RANTES의 수준은 TNF-α/IFN-γ로 자극된 HaCaT 세포의 배양 상등액을 이용하여 측정하였다. 세포를 표시된 농도의 화합물 1 및 화합물 2로 3시간 동안 전처리한 다음, 24시간 동안 TNF-α/IFN-γ로 자극하였다. 데이터는 3개의 독립적인 실험의 평균 ± SD로 표시된다. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군.*p < 0.05, **p < 0.01, ***p < 0.001 vs. TNF-α/IFN-γ-처리군.
도 4는 HaCaT 세포에서 TNF-α/IFN-γ-유도된 ICAM-1의 발현에 대한 화합물 1 및 화합물 2의 효과를 도시한다. ICAM-1의 발현은 웨스턴 블롯팅을 이용하여 측정하였다. 세포를 표시된 농도의 화합물 1 및 2로 3시간 동안 전처리한 다음, 24시간 동안 TNF-α/IFN-γ로 자극하였다. 데이터는 3개의 독립적인 실험의 평균 ± SD로 표시된다. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군.*p < 0.05, **p < 0.01, ***p < 0.001 vs. TNF-α/IFN-γ-처리군.
도 5는 HaCaT 세포에서 FLG 및 IVL의 발현에 대한 화합물 1 및 화합물 2의 효과를 도시한다. FLG 및 IVL의 발현은 세포 용해를 사용하여 측정하였다. 세포를 표시된 농도의 화합물 1 및 2로 3시간 동안 전처리한 다음, 24시간 동안 TNF-α/IFN-γ로 자극하였다. 데이터는 3개의 독립적인 실험의 평균 ± SD로 표시된다. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군.*p < 0.05, **p < 0.01, ***p < 0.001 vs. TNF-α/IFN-γ-처리군.
도 6a 및 도 6b는 HaCaT 세포에서 NF-κB, p-STAT1 및 p-STAT3 신호 전달 경로에 대한 화합물 1 및 화합물 2의 효과를 도시한다. 세포를 3시간 동안 표시된 농도의 화합물 1 및 2로 사전 처리한 다음, 15분 동안 TNF-α/IFN-γ로 자극하였다. Cytosol과 핵추출물을 분리하고, 부분적으로 p65, p-IκBα 및 IκBα의 수준을 웨스턴 블롯팅에 의해 결정하였다. 웨스턴 블롯을 이용하여 p-stat3, stat3, p-stat1, stat1의 발현과 총단백을 측정하였다. 막대 그래프는 밴드의 정량적 밀도를 나타낸다. 데이터는 3개의 독립적인 실험의 평균 ± SD로 표시된다. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군.*p < 0.05, **p < 0.01, ***p < 0.001 vs. TNF-α/IFN-γ-처리군.
도 7a 및 도 7b는 헴 옥시게나제(HO)-1 발현 및 Nrf2 전좌에 대한 화합물 1 및 2의 효과를 도시한다. HaCaT 세포를 표시된 농도의 화합물 1(20-60μM)과 화합물 2(2.5-10μM)(A-D)으로 12시간 동안 배양했다. HaCaT 세포는 60 μM의 화합물 1과 함께 0-24시간 동안 배양되었다(E,F). HaCaT 세포를 0.5, 1, 1.5시간(G,H) 동안 60μM의 화합물 1로 처리했다. 핵을 분획화하고 HO-1 및 Nrf2 발현에 대한 웨스턴 블롯 분석을 수행하였다. 데이터는 3개의 독립적인 실험의 평균 ± SD로 표시된다. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군.*p < 0.05, **p < 0.01, ***p < 0.001 vs. TNF-α/IFN-γ-처리군.
도 8은 TNF-α/IFN-γ로 자극된 HaCaT 세포에서 화합물 1의 효과를 도시한다. HaCaT 세포를 SnPP(40μM)의 존재 또는 부재 하에 화합물 1(60μM)로 3시간 동안 전처리하고 24시간 동안 TNF-α/IFN-γ로 자극하여 IL-6, IL-8, 및 RANTES를 측정하거나 15분 동안 NF-κB 결합 활성을 측정하였다. IL-6, IL-8 및 RANTES의 수준 및 NF-κB 결합 활성은 ELISA에 의해 검출되었다. 데이터는 3개의 독립적인 실험의 평균 ± SD로 표시된다. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군.*p < 0.05, **p < 0.01, ***p < 0.001 vs. TNF-α/IFN-γ-처리군. △ p < 0.05, △△ p < 0.01, △△△ p < 0.001 vs. 화합물 1+TNF-α/IFN-γ-처리군.Figure 1 depicts the cytotoxicity of compounds 1-3. Cytotoxicity was evaluated in cells treated at the indicated concentrations for 24 hours. Data are presented as mean ± SD values of three independent experiments. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. control group.
Figure 2 shows the effect of compounds 1-3 on IL-6 secretion in TNF-α/IFN-γ stimulated HaCaT cells. IL-6 secretion was measured using the culture supernatant of HaCaT cells stimulated with TNF-α/IFN-γ. Cells were pretreated with the indicated concentrations of compounds 1-3 for 3 hours and then stimulated with TNF-α/IFN-γ for 24 hours. Data are presented as the mean ± SD of three independent experiments. # p < 0.05, ## p < 0.01, ### p < 0.001 vs. Control. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. TNF-α/IFN-γ-treated group.
Figure 3 shows the effect of compounds 1-3 on IL-8, MDC and RANTES secretion in TNF-α/IFN-γ stimulated HaCaT cells. Levels of IL-8, MDC and RANTES were measured using culture supernatants of HaCaT cells stimulated with TNF-α/IFN-γ. Cells were pretreated with the indicated concentrations of
Figure 4 shows the effect of
Figure 5 shows the effect of
6A and 6B show the effects of
7A and 7B show the effect of
8 shows the effect of
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로 본 명세서에서 사용된 명명법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is one well known and commonly used in the art.
본 발명의 일 실시예에서, 남극 진균 Pleosporales sp. SF-7343(기탁번호: KCTC 14724BP)의 추출물로부터 화합물 1 내지 3의 대사화합물을 분리하고 그 구조를 확인하였다. 또한, 상기 대사화합물(화합물 1 내지 3)가 TNF-α/IFN-γ로 자극된 HaCaT 세포에서 IL-6, IL-8, MDC 및 RANTES의 분비를 억제하고, ICAM-1, FLG 및 IVL의 발현을 억제하며, NF-κB, p-STAT1 및 p-STAT3의 활성화를 억제시킴으로써, 염증질환의 예방 또는 치료 효과를 갖는 것을 확인하였다. In one embodiment of the present invention, the Antarctic fungus Pleosporeles sp. Metabolites of
따라서, 본 발명은 일 관점에서, 하기 화학식 1 내지 화학식 3으로 구성된 군에서 선택되는 하나 이상의 화합물을 포함하는 염증질환 예방 또는 치료용 약학 조성물에 관한 것이다.Accordingly, in one aspect, the present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases comprising at least one compound selected from the group consisting of
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
여기서, 상기 R1 내지 R6은 각각 독립적으로 H, 직쇄형 또는 분지쇄형의 C1-10 알킬, C1-10 알콕시, C3-10 사이클로알킬, C2-10 알케닐 또는 C6-10 아릴이다.Here, the R 1 to R 6 are each independently H, straight-chain or branched-chain C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 it is aryl
본 발명에 있어서, C1-10 알킬기는 탄소수 1~10의 직쇄형 또는 분지쇄형의 포화 탄화수소기를 의미하고, 예를 들어, 메틸, 에틸, 프로필, 이소프로필, n-부틸, sec-부틸, tert-부틸, 이소부틸, n-펜틸, n-헥실, 1-에틸프로필, 2,2-디메틸프로필 등을 들 수 있다.In the present invention, the C 1-10 alkyl group means a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert -Butyl, isobutyl, n-pentyl, n-hexyl, 1-ethylpropyl, 2,2-dimethylpropyl, etc. are mentioned.
본 발명에 있어서, C1-10 알콕시기는 탄소수 1~10의 직쇄형 또는 분지쇄형의 알킬옥시기를 의미하고, 예를 들어, 메톡시, 에톡시, 프로폭시, 프로프-2-옥시, 부톡시, 부트-2-옥시, 메틸프로프-2-옥시, 이소프로폭시, tert-부톡시 등을 들 수 있다.In the present invention, the C 1-10 alkoxy group means a straight-chain or branched-chain alkyloxy group having 1 to 10 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, prop-2-oxy, butoxy , but-2-oxy, methyl prop-2-oxy, isopropoxy, tert-butoxy and the like.
본 발명에 있어서, C3-10 사이클로알킬기는 탄소수 3~10의 포화 탄화수소 고리를 의미하고, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 사이클로옥틸 등으로 예시되는 모노사이클로알킬기 외에, 폴리사이클로알킬기, 예를 들어, 비사이클로알킬기, 트리사이클로알킬기 등도 포함되며, 비사이클로알킬기로는, 노르보르닐, 예를 들어, exo-2-노르보르닐, endo-2-노르보르닐, 3-피나닐, 비사이클로[3.1.0]헥실기, 비사이클로[2.2.1]헵틸기, 비사이클로[2.2.2]옥토-2-일기 등, 트리사이클로알킬기로는 아다만틸, 예를 들어, 1-아다만틸기, 2-아다만틸 등을 들 수 있다.In the present invention, a C 3-10 cycloalkyl group means a saturated hydrocarbon ring having 3 to 10 carbon atoms, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. In addition to monocycloalkyl groups, Polycycloalkyl groups, such as bicycloalkyl groups and tricycloalkyl groups, are also included, and bicycloalkyl groups include norbornyl, such as exo-2-norbornyl, endo-2-norbornyl, 3 -Pynanyl, bicyclo[3.1.0]hexyl group, bicyclo[2.2.1]heptyl group, bicyclo[2.2.2]octo-2-yl group, etc., tricycloalkyl group is adamantyl, for example , 1-adamantyl group, 2-adamantyl group, etc. are mentioned.
본 발명에 있어서, C2-10 알케닐기는 하나 이상의 이중 결합을 함유하고 2 내지 10개의 탄소 원자를 갖는 직쇄형 또는 분지쇄형 탄화수소 라디칼, 예를 들면, 에테닐, 2-프로페닐, 3-부테닐, 2-부테닐, 2-펜테닐, 3-펜테닐, 3-메틸-2-부테닐 또는 3-헥세닐 등을 의미한다.In the present invention, a C 2-10 alkenyl group is a straight-chain or branched-chain hydrocarbon radical containing at least one double bond and having 2 to 10 carbon atoms, such as ethenyl, 2-propenyl, 3-part tenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl; and the like.
본 발명에 있어서, C6-10 아릴기는 탄소수 6~10의 아릴기를 의미하고, 예를 들어 페닐기, 나프틸기, 안트릴기, 페난트릴기를 들 수 있다.In the present invention, the C 6-10 aryl group means an aryl group having 6 to 10 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
본 발명에 있어서, 상기 R1 내지 R6은 각각 독립적으로 H, CH3 또는 CH2CH3인 것을 특징으로 할 수 있으며, 바람직하게는 R1은 H 또는 CH3이고, R2 내지 R6은 각각 CH3이다.In the present invention, the R 1 to R 6 may each independently represent H, CH 3 or CH 2 CH 3 , preferably R 1 is H or CH 3 , and R 2 to R 6 are Each is CH 3 .
본 발명에 있어서, R1이 CH3이고, R2 및 R3가 각각 CH3인 화학식 1의 대사화합물은 알터네이트 C(alternate C)로 정의되며, R1이 H이고, R2 및 R3가 각각 CH3인 화학식 1의 대사화합물은 알테누신(altenusin)으로 정의되고, 용어 "화합물 1"은 상기 화학식 1에서 R1이 CH3 또는 H이고, R2 및 R3가 각각 CH3인 대사화합물을 의미한다.In the present invention, R 1 is CH 3 and R 2 and R 3 are each CH 3 The metabolite of
본 발명에 있어서, R4가 CH3인 화학식 2의 대사화합물은 알터나리올(alternariol)로 정의되며, 용어 "화합물 2"는 상기 화학식 2에서 R4가 CH3인 대사화합물을 의미한다.In the present invention, the metabolite of
본 발명에 있어서, R5 및 R6이 각각 CH3인 화학식 3의 대사화합물은 알테누엔(altenuene)으로 정의되며, 용어 "화합물 3"은 상기 화학식 3에서 R5 및 R6이 각각 CH3인 대사화합물을 의미한다.In the present invention, the metabolite of Formula 3 in which R 5 and R 6 are each CH 3 is defined as altenuene, and the term "Compound 3" in Formula 3 wherein R 5 and R 6 are each CH 3 means a metabolite.
본 발명에 있어서, 상기 대사화합물은 남극 진균 Pleosporales sp. SF-7343에서 분리된 것을 특징으로 할 수 있다.In the present invention, the metabolite is an Antarctic fungus Pleosporeles sp. It can be characterized as isolated from SF-7343.
본 발명에서 용어 "항염증"은 염증을 억제하거나 감소시키는 작용을 의미한다.In the present invention, the term "anti-inflammatory" means an action that inhibits or reduces inflammation.
본 발명에서 용어 "염증"이란, 어떤 자극에 대한 생체조직의 방어반응의 하나로, 각종 유해한 자극에 의한 상해를 제거하여 원래의 상태로 회복하려는 생체방어 기전이다. 염증의 자극에는, 감염 혹은 화학적, 물리적 자극이 있으며, 염증의 과정은 급성과 만성 염증의 2가지로 나눌 수 있다. 급성염증은 수일 이내의 단기적인 반응이며, 혈장성분이나 혈구 등이 미소순환계를 게재하여 이물 제거에 관련한다. 만성염증은 지속시간이 길며, 조직의 증식 등이 보여진다.In the present invention, the term "inflammation" is one of the defense reactions of biological tissues to certain stimuli, and is a biological defense mechanism to restore the original state by removing injuries caused by various harmful stimuli. Stimulation of inflammation includes infection or chemical and physical stimulation, and the process of inflammation can be divided into two types: acute and chronic inflammation. Acute inflammation is a short-term reaction within a few days, and plasma components or blood cells enter the microcirculatory system and are involved in the removal of foreign substances. Chronic inflammation lasts for a long time, and tissue proliferation is seen.
본 발명에서 용어 "염증질환"은 염증을 주 병변으로 하는 질병을 총칭하는 것이다.In the present invention, the term "inflammatory disease" is a general term for diseases in which inflammation is the main lesion.
본 발명에 있어서, 상기 염증질환은 관절염, 비염, 간염, 각막염, 위염, 장염, 신장염, 기관지염, 흉막염, 복막염, 척추염, 췌장염, 염증성 통증, 요도염, 방광염, 화상 염증, 피부염, 치주염, 치은염 및 퇴행성 신경염증으로 구성되는 군에서 선택되는 것을 특징으로 할 수 있으나, 이에 제한되는 것은 아니며, 바람직하게는 피부염이고, 더 바람직하게는 아토피 피부염이다.In the present invention, the inflammatory disease is arthritis, rhinitis, hepatitis, keratitis, gastritis, enteritis, nephritis, bronchitis, pleurisy, peritonitis, spondylitis, pancreatitis, inflammatory pain, urethritis, cystitis, burn inflammation, dermatitis, periodontitis, gingivitis and degenerative It may be characterized in that it is selected from the group consisting of neuroinflammation, but is not limited thereto, preferably dermatitis, more preferably atopic dermatitis.
본 발명에 있어서, 상기 약학 조성물은 하나 이상의 하기 특성을 가지는 것을 특징으로 할 수 있다.In the present invention, the pharmaceutical composition may be characterized by having one or more of the following properties.
1) IL-6, IL-8, MDC(macrophage-derived chemokine) 및 RANTES의 분비 억제;1) inhibition of secretion of IL-6, IL-8, MDC (macrophage-derived chemokine) and RANTES;
2) ICAM-1의 발현 억제;2) inhibition of expression of ICAM-1;
3) 필라그린(filaggrin, FLG)과 인볼큐린(involcurin, IVL)의 발현 억제;3) inhibition of expression of filaggrin (FLG) and involcurin (IVL);
4) NF-κB, p-STAT1 및 p-STAT3의 활성화 억제; 및4) inhibition of activation of NF-κB, p-STAT1 and p-STAT3; and
5) HO-1 발현 및 Nrf2 전좌 촉진.5) Promotion of HO-1 expression and Nrf2 translocation.
본 발명의 일 실시예에서는 R1이 CH3인 화합물 1 및 화합물 2가 IL-6, IL-8, MDC 및 RANTES의 분비를 감소시켜 항염증 효과를 발휘함을 확인하였다(실시예 3 및 4). 각질형성세포는 건선 및 AD와 같은 만성 염증성 피부 질환에서 수많은 염증 매개체의 발현에 관여하는 TNF-α 및 IFN-γ와 같은 염증 촉진성 사이토카인과 반응한다. 활성화된 각질형성세포는 염증성 면역 세포의 침투에 중요한 역할을 하는 염증 촉진성 사이토카인과 케모카인을 AD 병변으로 방출한다. 결과적으로 염증성 AD 병변에서 일부 염증 촉진성 사이토카인 및 케모카인 수준이 증가한다. IL-6은 염증 촉진성 사이토카인으로서 건선 상피의 표피 증식에 관여하고, 진피 염증 세포의 기능에 영향을 미치며, 인간 Th17 세포의 분화를 유도한다. IL-8, RANTES, TARC 및 MDC와 같은 케모카인은 혈액에서 피부로 백혈구 모집을 매개하고 미세 환경을 구축하는 데 중요한 역할을 한다. 따라서, 본 발명에서는 기존 치료법에 내성이 있는 다양한 피부 질환을 치료하기 위해, 염증 촉진성 사이토카인과 케모카인을 표적으로 하였다.In one embodiment of the present invention, it was confirmed that
본 발명의 다른 실시예에서는 R1이 CH3인 화합물 1 및 화합물 2가 IVL의 발현을 상향 조절하였으며, 화합물 1은 FLG의 발현을 상향 조절하였음을 확인하였다(실시예 6). 증가된 염증 촉진성 사이토카인과 케모카인은 AD 발병의 주요 초기 요인 중 하나인 피부 장벽 단백질의 변화를 유발한다. 각질형성세포 분화와 피부 장벽 기능에 중요한 역할을 하는 FLG 및 IVL과 같은 일부 단백질은 세포 표면에서 저항한다. 각질형성세포 및 다른 피부 주변 세포(skin-inhabited cells)에서 분비되는 사이토카인은 세포간 통신에 관여하여 피부의 장벽 기능을 변경한다. 예를 들어, 사이토카인은 이들 세포 내에서 유전자 발현을 조절함으로써 각질형성세포 증식 및 분화를 조작한다. 제어되지 않은 사이토카인 발현은 AD 및 건선과 같은 질병에서 볼 수 있듯이 표피 장벽의 기능 장애를 유발할 수 있다. 24시간 동안 TNF-α/IFN-γ로 공동 자극하면 FLG와 IVL이 감소하는데, 이는 피부 장벽 기능이 부분적으로 손상되었음을 의미한다.In another example of the present invention, it was confirmed that
본 발명의 다른 실시예에서는 R1이 CH3인 화합물 1 및 화합물 2가 STAT1, STAT3 및 NF-κB 신호 전달 경로의 억제를 통해 염증성 사이토카인 및 케모카인의 발현에 억제 효과가 있음을 확인하였다(실시예 7). STAT 및 NF-κB의 활성화는 HaCaT 세포에서 AD 관련 염증성 유전자 발현을 증가시키는 데 중요하다. STAT1, STAT3 및 NF-κB가 염증 촉진성 사이토카인에 의해 활성화되면, STAT1, STAT3 및 NF-κB가 각질형성세포의 세포질에서 핵으로 전좌되어 염증 매개체의 발현을 유발한다. TNF-α 및 IFN-γ로 자극된 HaCaT 세포에 화합물 1 및 화합물 2를 투여하면, 증가되었던 염증 매개체의 분비가 약화되고 STAT1 및 STAT3 인산화, IκBα 분해 및 NF-κB핵 전좌도 억제됨을 확인하였다.In another embodiment of the present invention, it was confirmed that
본 발명의 다른 실시예에서는 R1이 CH3인 화합물 1은 HO-1의 발현을 유의하게 유도하며, 세포질에서 핵으로의 Nrf2의 전좌를 촉진함을 확인하였다(실시예 8). 많은 연구에서 다양한 생활성 화합물이 염증성 질환 모델에서 HO-1의 발현을 유도함으로써 항염증 활성을 발휘하는 것으로 나타났다(Lee, J, H., et al., Front Pharmacol 2020, 11, 1018.). HO-1은 헴 분해를 위한 속도 제한 효소이며 2가 철(ferrous iron), 일산화탄소 및 빌리베르딘을 생성한다. 이 세 가지 부산물은 많은 병리학적 조건에서 항염증, 항산화 및 세포 보호 효과를 포함하여 다양한 유익한 효과를 나타낸다. 몇몇 연구에서는 HO-1 발현이 AD와 같은 염증성 피부 질환에 대한 면역 조절 효과를 발휘하는 것으로 나타났다(Wu, W,Q, et al., Mol Med Rep 2019, 20, 1761-1771). 전사인자인 Nrf2는 세포질의 Keap1에 결합하여 활성화되면 Nrf2가 Keap1에서 분리되어 핵으로 전좌되어 항산화반응요소(antioxidant response element, ARE)와 결합하여 HO-1을 비롯한 항산화 효소의 발현을 상향조절하고 세포 보호를 유도한다. In another example of the present invention, it was confirmed that
본 발명에 있어서, 상기 약학 조성물은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것을 특징으로 할 수 있다.In the present invention, the pharmaceutical composition may be characterized in that it further comprises a pharmaceutically acceptable carrier, excipient or diluent.
상기 조성물에 포함될 수 있는 담체, 부형제 및 희석제는 비제한적으로 락토오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 있다. 상기 조성물을 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.Carriers, excipients and diluents that may be included in the composition include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil. When formulating the composition, it may be prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
본 발명에 따른 약학 조성물은 통상의 방법에 따라 다양한 형태로 제형화하여 사용될 수 있다. 적합한 제형으로는 정제, 환제, 산제, 과립제, 당의정, 경질 또는 연질의 캡슐제, 용액제, 현탁제 또는 유화액제, 주사제, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액 등이 있으나, 이에 한정되는 것은 아니다.The pharmaceutical composition according to the present invention may be formulated and used in various forms according to conventional methods. Suitable formulations include tablets, pills, powders, granules, dragees, hard or soft capsules, solutions, suspensions or emulsions, injections, oral formulations such as aerosols, external preparations, suppositories, and sterile injection solutions. It is not limited to this.
본 발명에 따른 약학 조성물은 약학적으로 불활성인 유기 또는 무기 담체를 이용하여 적합한 제형으로 제조할 수 있다. 즉, 제형이 정제, 코팅된 정제, 당의정 및 경질 캡슐제인 경우 락토스, 수크로스, 전분 또는 그 유도체, 탈크, 칼슘 카보네이트, 젤라틴, 스테아르산 또는 그 약학적으로 허용가능한 염을 포함할 수 있다. 또한, 제형이 연질 캡슐제인 경우에는 식물성 오일, 왁스, 지방, 반고체 및 액체의 폴리올을 포함할 수 있다. 또한, 제형이 용액 또는 시럽 형태인 경우, 물, 폴리올, 글리세롤, 및 식물성 오일 등을 포함할 수 있다.The pharmaceutical composition according to the present invention can be prepared in a suitable dosage form using a pharmaceutically inert organic or inorganic carrier. That is, when the dosage form is a tablet, coated tablet, dragee and hard capsule, it may contain lactose, sucrose, starch or a derivative thereof, talc, calcium carbonate, gelatin, stearic acid or a pharmaceutically acceptable salt thereof. In addition, if the dosage form is a soft capsule, it may contain vegetable oil, wax, fat, semi-solid and liquid polyol. In addition, when the formulation is in the form of a solution or syrup, water, polyol, glycerol, and vegetable oil may be included.
상기 "약학적으로 허용가능한 염"이란, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 화합물의 제형을 의미한다. 상기 약학적 염은, 약학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어, 염산, 황산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플로로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리신산 등과 같은 유기 카본산, 메탄설폰산, 에탄술폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 예를 들어, 약학적으로 허용되는 카르복실산 염에는, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 금속염 또는 알칼리 토금속 염, 라이신, 아르지닌, 구아니딘 등의 아미노산 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸) 메틸아민, 디에탄올아민, 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다. 옥살산 (oxalic)과 같은 산은 약학적으로 허용되는 것은 아니지만 약학적으로 허용되는 염을 얻기 위한 중간체로서, 유용한 염의 제조에 사용될 수 있다. The "pharmaceutically acceptable salt" means a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The pharmaceutical salt is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, citric acid , organic carbonic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid Acid addition salts formed with phonic acids and the like are included. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N organic salts such as -methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine; and the like. Acids such as oxalic acid are not pharmaceutically acceptable, but as intermediates for obtaining pharmaceutically acceptable salts, they can be used in the preparation of useful salts.
본 발명에 따른 약학 조성물은 상기의 담체 외에도 보존제, 안정화제, 습윤제, 유화제, 용해제, 감미제, 착색제, 삼투압 조절제, 산화방지제 등을 더 포함할 수 있다.The pharmaceutical composition according to the present invention may further include a preservative, a stabilizer, a wetting agent, an emulsifier, a solubilizing agent, a sweetening agent, a coloring agent, an osmotic pressure regulator, an antioxidant, and the like, in addition to the above carriers.
본 발명에 따른 약학 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 따른 약학 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.The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type, severity, and activity of the drug of the patient's disease , sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 조성물은 염증질환의 예방 또는 치료에 효과가 있는 것으로 당업자에게 인식될 수 있는 면역요법, 화학요법 및 방사선요법 등과 같은 염증질환의 치료법 및 다른 염증질환의 치료용 약학 조성물 등과 함께 사용될 수 있다.The composition of the present invention can be used in conjunction with the treatment of inflammatory diseases such as immunotherapy, chemotherapy and radiation therapy, which can be recognized by those skilled in the art as being effective in preventing or treating inflammatory diseases, and pharmaceutical compositions for treating other inflammatory diseases. .
본 발명의 약학 조성물은 개체에 다양한 경로로 투여될 수 있다. 투여의 방식은, 예를 들면, 피하, 정맥, 근육 또는 자궁 내 경막 또는 뇌혈관 내 주사에 의해 투여될 수 있다. 본 발명의 약학 조성물은 치료할 질환, 투여 경로, 환자의 연령, 성별 및 체중 및 질환의 중등도 등의 여러 관련 인자와 함께, 활성성분인 약물의 종류에 따라 결정된다.The pharmaceutical composition of the present invention can be administered to a subject by various routes. The mode of administration may be, for example, by subcutaneous, intravenous, intramuscular or intrauterine intrathecal or intracerebrovascular injection. The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient, together with various related factors such as the disease to be treated, the route of administration, the patient's age, sex and weight, and the severity of the disease.
본 발명은 다른 관점에서, 상기 화학식 1 내지 화학식 3으로 구성된 군에서 선택되는 하나 이상의 화합물을 포함하는 염증 개선용 식품에 관한 것이다.In another aspect, the present invention relates to a food for improving inflammation comprising at least one compound selected from the group consisting of
본 발명에 있어서, 상기 대사화합물의 R1 내지 R6은 각각 독립적으로 H, CH3 또는 CH2CH3인 것을 특징으로 할 수 있으며, 바람직하게는 R1은 H 또는 CH3이고, R2 내지 R6은 각각 CH3이다.In the present invention, R 1 to R 6 of the metabolite may be each independently H, CH 3 or CH 2 CH 3 , preferably R 1 is H or CH 3 , and R 2 to R 6 is each CH 3 .
본 발명에서 용어 "식품"은 육류, 소시지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합제, 건강기능식품 및 건강식품 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.In the present invention, the term "food" refers to meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, There are vitamin complexes, health functional food and health food, etc., and includes all foods in a conventional sense.
상기 건강기능(성) 식품(functional food)이란, 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 "기능(성)"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한 없이 제조될 수 있으며, 본 발명에 따른 건강기능식품은 분말, 과립, 정제, 캡슐 또는 음료의 형태일 수 있다.The health functional (sex) food (functional food) is the same term as food for special health use (FoSHU), and is a medicine processed to efficiently display bioregulatory functions in addition to nutrient supply, and has high medical effect. means food. Here, "function (sex)" means to obtain useful effects for health purposes such as regulating nutrients for the structure and function of the human body or physiological functions. The food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and ingredients commonly added in the art during the preparation. In addition, the formulation of the food may be prepared without limitation as long as the formulation is recognized as food, and the health functional food according to the present invention may be in the form of powder, granule, tablet, capsule or beverage.
상기 건강식품(health food)은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품(health supplement food)은 건강보조 목적의 식품을 의미한다. 경우에 따라, 건강 기능 식품, 건강 식품, 건강보조식품의 용어는 혼용된다.The health food (health food) means a food that has an active health maintenance or promotion effect compared to general food, and health supplement food (health supplement food) means food for the purpose of health supplement. In some cases, the terms health functional food, health food, and health supplement food are used interchangeably.
상기 식품조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다.The food composition may further include a physiologically acceptable carrier. The type of carrier is not particularly limited, and any carrier commonly used in the art may be used.
또한, 상기 조성물은 식품에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예들 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu), 크륨(Cr) 등의 미네랄을 포함할 수 있다. 또한, 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다.In addition, the composition may include additional ingredients that are commonly used in food and can improve smell, taste, and sight. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like may be included. In addition, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chrome (Cr) may be included. In addition, amino acids such as lysine, tryptophan, cysteine, and valine may be included.
또한, 상기 조성물은 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(foodadditives)을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.In addition, the composition contains preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), disinfectants (bleaching powder and high bleaching powder, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisole (BHA), butylhydroxy toluene (BHT), etc.), coloring agents (tar colorant, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG, etc.), sweeteners (dulcin, cyclemate, saccharin, sodium, etc.) ), flavoring (vanillin, lactones, etc.), leavening agent (alum, D-potassium hydrogentartrate, etc.), strengthening agent, emulsifier, thickener (thickener), coating agent, gum base agent, foam inhibitor, solvent, food additives such as improver ) may be included. The additive may be selected according to the type of food and used in an appropriate amount.
본 발명의 Pleosporales sp. 추출물과 함께 식품학적으로 허용가능한 식품 보조 첨가제를 더 포함할 수 있으며, 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. Pleosporeles sp. of the present invention. Along with the extract, it may further include food additives acceptable for food science, may be used together with other foods or food ingredients, and may be appropriately used according to conventional methods. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (prevention, health or therapeutic treatment).
본 발명에서 용어 "개선", "예방" 및 "치료"는 최광의의 개념으로 해석되어야 하며, "개선"이란 질환 또는 하나 이상의 임상적 증상을 일시적/지속적으로 완화시키는 모든 행위를 의미한다. "예방"이란, 질환에 노출되거나 질환에 걸리기 쉬울 수 있으나 질환의 증상을 아직 경험하거나 드러내지 아니한 환자에게서 질환의 임상적 증상 중 하나 이상이 진행되지 아니하도록 하는 것을 의미한다. "치료"란, 질환 또는 이의 하나 이상의 임상적 증상의 발달을 저지 또는 감소시키는 모든 행위를 의미한다.In the present invention, the terms "improvement", "prevention" and "treatment" should be interpreted in the broadest sense, and "improvement" refers to any action that temporarily/continuously alleviates a disease or one or more clinical symptoms. "Prevention" means preventing one or more of the clinical symptoms of a disease from progressing in a patient who may be exposed to or predisposed to a disease, but who has not yet experienced or manifested symptoms of the disease. "Treatment" means any action that prevents or reduces the development of a disease or one or more clinical symptoms thereof.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for exemplifying the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.
실시예Example
실시예 1: 분리된 대사화합물의 구조 결정Example 1: Structure Determination of Isolated Metabolites
배양된 진균 균주 Pleosporales sp. SF-7343의 건조 추출물은 여러 크로마토그래피 단계를 거쳐 alternate C (R1이 CH3인 화합물 1), altenusin(R1이 H인 화합물 1), alternariol(화합물 2), altenuene(화합물 3)을 수득하였다. 그들의 구조는 1D 및 2D NMR, MS 분석을 기반으로 하고 문헌에 보고된 데이터와 비교하여 결정되었다.The cultured fungal strain Pleosporeles sp. The dried extract of SF-7343 went through several chromatographic steps to obtain alternate C (
실시예 2: 세포 생존율에 대한 화합물 1 내지 화합물 3의 효과Example 2: Effect of
MTT 분석을 사용하여 HaCaT 세포에 대한 화합물 1 내지 화합물 3의 세포독성을 평가했다. 그 결과는 도 1에 도시되어 있으며, 후속 실험을 위해 세포에 이 4가지 화합물을 안전한 농도 범위로 처리했다: R1이 CH3인 화합물 1(20-60μM), R1이 H인 화합물 1(5-20μM), 화합물 2(2.5-10μM) 및 화합물 3(20-80μM).The cytotoxicity of
실시예 3: TNF-α/IFN-γ로 자극된 HaCaT 세포에서 IL-6 분비에 대한 화합물 1 내지 화합물 3의 효과Example 3: Effects of
TNF-α/IFN-γ로 자극된 HaCaT 세포에서 화합물 1-3의 항염증 효과를 확인하기 위해, 먼저 IL-6의 분비를 분석했다. 도 2에 나타낸 바와 같이, R1이 CH3인 화합물 1 및 화합물 2는 IL-6의 분비를 유의하게 억제하였고, R1이 H인 화합물 1은 고농도에서 IL-6 분비의 억제 효과를 나타내었다. 화합물 3은 IL-6 분비에 유의한 영향을 미치지 않았다. 4가지 화합물 중 R1이 CH3인 화합물 1과 화합물 2가 HaCaT 세포에서 IL-6 분비를 억제하는 효과가 가장 현저하게 나타났다. 따라서, 다음의 추가 실험에서는 가장 효과적인 두 가지 화합물로 실험하였다.In order to confirm the anti-inflammatory effect of compounds 1-3 in HaCaT cells stimulated with TNF-α/IFN-γ, IL-6 secretion was analyzed first. As shown in FIG. 2,
실시예 4: TNF-α/IFN-γ로 자극된 HaCaT 세포에서 IL-8, MDC 및 RANTES 분비에 대한 화합물 1 및 화합물 2의 효과Example 4: Effect of
표피는 물리적인 장벽일 뿐만 아니라 다양한 사이토카인과 케모카인을 생성하는 화학적, 면역학적 장벽이기도 하다. 다음의 염증성 사이토카인 및 케모카인에 대한 R1이 CH3인 화합물 1 및 화합물 2의 효과는 도 3에 도시되어 있다. IL-8, 대식세포 유래 케모카인(macrophage-derived chemokine, MDC) 및 RANTES(regulated upon activation, normal T cell expressed and presumably secreted) 수준은 ELISA를 사용하여 세포 배양 상등액으로부터 결정되었다. IL-8, MDC, RANTES의 분비는 TNF-α/IFN-γ 자극군에서 대조군에 비해 유의하게 증가하였고, R1이 CH3인 화합물 1과 화합물 2로 전처리한 군에서 용량 의존적으로 감소하였다.The epidermis is not only a physical barrier, but also a chemical and immunological barrier that produces various cytokines and chemokines. The effects of
실시예 5: HaCaT 세포에서 TNF-α/IFN-γ 유도된 ICAM-1 발현에 대한 화합물 1 및 화합물 2의 효과Example 5: Effect of
염증 상태에서 각질형성세포는 ICAM-1과 같은 접착 분자도 발현할 수 있다. ICAM-1의 발현은 주변 피부 조직으로의 백혈구의 흡착을 촉진한다. TNF-α/IFN-γ로 유도된 ICAM-1 발현에 대한 화합물 1과 화합물 2의 효과를 실험하였다. 도 4에 나타낸 바와 같이, R1이 CH3인 화합물 1 및 화합물 2는 모두 용량 의존적 방식으로 ICAM-1 발현을 현저하게 감소시켰다.In inflammatory conditions, keratinocytes can also express adhesion molecules such as ICAM-1. Expression of ICAM-1 promotes the adsorption of leukocytes to the surrounding skin tissue. The effects of
실시예 6: HaCaT 세포에서 FLG 및 IVL 발현에 대한 화합물 1 및 화합물 2의 효과Example 6: Effect of
필라그린(FLG)과 인볼큐린(IVL)은 표피의 최상층에 존재하는 유전자를 암호화하는 두 개의 단백질로서, 각질세포 분화와 피부장벽 기능에 중요한 역할을 한다. 염증성 각질형성세포에서는 이 두 단백질의 발현이 감소하고 피부 장벽 기능이 약해진다. R1이 CH3인 화합물 1을 처리 시, TNF-α/IFN-γ 그룹과 비교하여 FLG 및 IVL 발현의 감소를 회복한다는 것을 확인하였다(도 5A-C). TNF-α/IFN-γ군과 비교하여, 화합물 2는 HaCaT 세포에서 TNF-α/IFN-γ에 의해 유도된 IVL 발현의 감소를 억제하였다(도 5D 및 F). Filaggrin (FLG) and involcurin (IVL) are two proteins that encode genes present in the uppermost layer of the epidermis, and play an important role in keratinocyte differentiation and skin barrier function. In inflammatory keratinocytes, the expression of these two proteins is reduced and the skin barrier function is weakened. It was confirmed that when
실시예 7: HaCaT 세포에서 NF- κB, p-STAT1 및 p-STAT3 신호 전달 경로에 대한 화합물 1 및 화합물 2의 효과 Example 7: NF- in HaCaT cells Effect of
케라티노사이트에서 TNF-α 및 IFN-γ의 동시 자극은 사이토카인과 케모카인의 방출로 이어지고, 이 과정은 NF-κB, p-STAT1 및 p-STAT3 신호 전달 경로에 의해 조절된다. 도 6A-D에 나타난 바와 같이, 세포에 TNF-α/IFN-γ를 처리한 경우, 대조군에 비해 p-IκBα 및 p65가 유의하게 증가하였다. R1이 CH3인 화합물 1과 화합물 2로 전처리하면 IκBα의 인산화와 p65의 활성화가 감소하였다. p-IκBα/IκBα의 비율도 감소하였다. 또한, 도 6E-H에 나타난 바와 같이, R1이 CH3인 화합물 1과 화합물 2는 STAT1과 STAT3의 인산화를 현저하게 하향 조절하였다. 이러한 결과로부터, R1이 CH3인 화합물 1과 화합물 2가 TNF-α/IFN-γ 처리된 HaCaT 세포에서 NF-κB, p-STAT1 및 p-STAT3 신호 전달 경로를 조절할 수 있음을 알 수 있다.Simultaneous stimulation of TNF-α and IFN-γ in keratinocytes leads to the release of cytokines and chemokines, a process regulated by the NF-κB, p-STAT1 and p-STAT3 signaling pathways. As shown in Fig. 6A-D, when cells were treated with TNF-α/IFN-γ, p-IκBα and p65 were significantly increased compared to the control group. IκBα phosphorylation and p65 activation were decreased when pretreatment with
실시예 8: HO-1 발현 및 Nrf2 전좌에 대한 화합물 1 및 화합물 2의 효과Example 8: Effects of
화합물이 헴 옥시게나제(HO)-1의 발현을 유도하는지 여부를 조사하기 위해, HaCaT 세포를 R1이 CH3인 화합물 1(20-60μM)과 화합물 2(2.5-10μM)로 처리하였고, HO-1 유도제인 코발트 프로토포르피린(cobalt protoporphyrin, CoPP)은 20μM에서 HO-1 발현을 증가시켰으며, 이를 양성 대조군으로 사용하였다. 결과는 도 7 A-D에 도시되어 있다. R1이 CH3인 화합물 1은 용량-(도 7A 및 B) 및 시간 의존적 방식(도 7E 및 F)으로 HO-1 발현을 유도하였다. To investigate whether the compounds induce expression of heme oxygenase (HO)-1, HaCaT cells were treated with Compound 1 (20-60 μM) and Compound 2 (2.5-10 μM), where R 1 is CH 3 , Cobalt protoporphyrin (CoPP), an HO-1 inducer, increased HO-1 expression at 20 μM, which was used as a positive control. The results are shown in Figure 7 AD.
또한, R1이 CH3인 화합물 1이 Nrf2의 핵 전좌에 미치는 영향을 실험하였다. 도 7G 및 H에 도시된 바와 같이, R1이 CH3인 화합물 1은 세포질에서 핵으로의 Nrf2의 전좌를 유의하게 촉진시켰다. 이러한 결과로부터, R1이 CH3인 화합물 1이 HO-1의 발현을 촉진하고 Nrf2/HO-1 경로를 조절할 수 있음을 알 수 있다.In addition, the effect of
실시예 9: TNF-α/IFN-γ 자극된 HaCaT 세포에서 화합물 1(RExample 9: Compound 1 (R) in TNF-α/IFN-γ Stimulated HaCaT Cells 1One =CH=CH 33 )의 효과) effect
R1이 CH3인 화합물 1이 HO-1의 발현을 유도할 수 있다는 결과를 바탕으로, 화합물 1(R1=CH3)의 항염증 효과가 HO-1과 관련이 있는지 실험하였다. 선택적 HO-1 억제제인 tin protoporphyrin IX(Snpp)를 사용하였고, 세포를 3시간 동안 Snpp(40μM)를 처리 또는 미처리하고, R1이 CH3인 화합물 1(60μM)을 처리 또는 미처리한 후, 24시간 동안 TNF-α/IFN-γ로 처리하였다. IL-6, IL-8 및 RANTES의 수준은 ELISA에 의해 결정되었다. 도 8A-C에 나타난 바와 같이, R1이 CH3인 화합물 1을 처리시 TNF-α/IFN-γ에 의해 유도된 IL-6, IL-8 및 RANTES의 분비를 유의하게 감소시켰다. 그러나 TNF-α/IFN-γ+화합물 1군에 비해, IL-6, IL-8 및 RANTES의 분비는 화합물 1+Snpp군에 의해 역전되었다. 또한, NF-κB 결합 활성도 유사한 결과를 보였다. SnPP 단독 처리 또는 TNF-α/IFN-γ+SnPP 그룹은 세포 생존율, IL-6, IL-8, RANTES 및 NF-κB 결합 활성에 영향을 미치지 않았다. 이러한 결과로부터, R1이 CH3인 화합물 1의 항염증 효과가 HO-1 발현에 의해 매개됨을 알 수 있다.Based on the result that
실시예 10: 물질 및 방법Example 10: Materials and Methods
실시예 10-1: 일반적인 실험 절차Example 10-1: General Experimental Procedure
Jasco P-2000 디지털 편광계(JASCO Corp., Tokyo, Japan)를 사용하여 광학 회전을 기록했다. 핵 자기 공명(NMR) 스펙트럼(1D 및 2D)은 JEOL JNM ECP-400 분광계(JEOL Ltd., Tokyo, Japan)를 사용하여 DMSO-d 6 (δH/δC = 2.50/39.52) 에 기록되었으며, 화학적 이동은 잔류 용매 피크와 관련하여 참조되었다. 이핵 다중 양자 일관성(HMQC) 및 이핵 다중 결합 상관 관계(HMBC) 실험은 각각 1 J CH = 140 Hz 및 n J CH = 8 Hz 에 대해 최적화되었다. HRESIMS 데이터는 AB Sciex Triple TOF 4600 기기(AB Sciex Pte. Ltd., Framingham, MA, USA)를 사용하여 수득하였다. 박막 크로마토그래피(TLC)는 Kieselgel 60 F254 (1.05715; Merck, Darmstadt, Germany) 또는 RP-18 F254s (Merck)플레이트에서 수행되었다. 플레이트에 10% 황산 수용액(H2SO4)을 분사한 후 가열하여 스팟을 시각화했다. 컬럼 크로마토그래피는 실리카겔(Kieselgel 60, 70-230 mesh 및 230-400 mesh, Merck) 및 YMC octadecyl-functionalized 실리카겔(C18)에서 수행되었다. 고성능 액체 크로마토그래피(HPLC)는 분취 C18 컬럼(10 Х 250 mm; 5 μm 입자 크기)에서 5 mL/min의 유속으로 수행되었으며 화합물은 210 및 254nm 에서 자외선(UV) 흡수로 검출되었다. Optical rotations were recorded using a Jasco P-2000 digital polarimeter (JASCO Corp., Tokyo, Japan). Nuclear magnetic resonance (NMR) spectra (1D and 2D) were recorded in DMSO- d 6 ( δH / δC = 2.50/39.52) using a JEOL JNM ECP-400 spectrometer (JEOL Ltd., Tokyo, Japan); Chemical shifts were referenced relative to residual solvent peaks. The binuclear multiple quantum coherence (HMQC) and binuclear multiple coupling correlation (HMBC) experiments were optimized for 1 J CH = 140 Hz and n J CH = 8 Hz, respectively. HRESIMS data were obtained using an AB Sciex Triple TOF 4600 instrument (AB Sciex Pte. Ltd., Framingham, MA, USA). Thin layer chromatography (TLC) was performed on Kieselgel 60 F 254 (1.05715; Merck, Darmstadt, Germany) or RP-18 F 254s (Merck) plates. After spraying 10% sulfuric acid aqueous solution (H 2 SO 4 ) on the plate, the spot was visualized by heating. Column chromatography was performed on silica gel (
실시예 10-2: 진균 물질 및 발효Example 10-2: Fungal substances and fermentation
진균 균주 SF-7343은 2017년 1월 남극 킹 조지 섬의 마리안 코브(Marian Cove, 62°13′16.5''S, 58°46′29.6''W)에서 채취한 이끼에서 분리되었다. 샘플 1g을 막자사발과 유봉으로 갈아서 멸균 해수(10mL)와 혼합했다. 샘플의 일부(0.1mL)를 해수가 포함된 PDA 배지에서 스프레드 플레이트 방법을 사용하여 처리하고 25°C에서 14일 동안 배양했다. 분리물을 여러 번 계대 배양한 후, 최종 순수 배양물을 선택하여 -70°C에서 보관했다. 진균 균주 SF-7343은 ITS 유전자 서열 분석에 기초하여 동정되었다. SF-7343(GenBank accession number MK785420)의 ITS 유전자를 사용한 GenBank 검색은 Pleosporales sp. Di61-4(KC514877), Pleosporales sp. AM282-P9T2T(KT264548) 및 Lophodermium pini-excelsae(EU520183)는 각각 100%, 99.58% 및 99.37%의 서열 동일성을 나타내면서 가장 근접하게 일치하였다. 따라서 진균 균주 SF-7343은 Pleosporales sp.로 특정되었다.Fungal strain SF-7343 was isolated in January 2017 from moss collected from Marian Cove (62°13′16.5''S, 58°46′29.6''W) on King George Island, Antarctica. 1 g of the sample was ground in a mortar and pestle and mixed with sterile seawater (10 mL). An aliquot (0.1 mL) of the sample was processed using the spread plate method in PDA medium containing seawater and incubated at 25 °C for 14 days. After passage of the isolate several times, the final pure culture was selected and stored at -70 °C. Fungal strain SF-7343 was identified based on ITS gene sequencing. A GenBank search using the ITS gene of SF-7343 (GenBank accession number MK785420) identified Pleosporeles sp. Di61-4 (KC514877), Pleosporeles sp. AM282-P9T2T (KT264548) and Lophodermium pini-excelsae (EU520183) were the closest matches, exhibiting 100%, 99.58% and 99.37% sequence identity, respectively. The fungal strain SF-7343 was therefore characterized as Pleosporeles sp.
실시예 10-3: 대사화합물의 추출 및 분리Example 10-3: Extraction and Separation of Metabolites
진균 균주 Pleosporales sp. SF-7343은 각각 300mL의 PDB 배지와 75g의 질석과 3% NaCl을 포함하는 20개의 Fernbach 플라스크에서 배양되었다. 플라스크에 진균 균주의 종자 배양물 5mL를 개별적으로 접종하고 25°C에서 14일 동안 배양했다. 배양된 진균을 EtOAc(20L)로 직접 추출하여 유기상을 제공한 다음, 이를 진공에서 증발시켜 잔류물 SF-7343V(3.91g)를 얻었다. 조추출물(crude extract)을 H2O (각각 500mL) 중 20, 40, 60, 80 및 100%(v/v) MeOH의 단계적 구배로 용리하는 RP C18 플래시 컬럼 크로마토그래피를 사용하여 분획화하여, 6개의 분획인 SF-7343V-1 내지 SF-7343V-6을 수득하였다. R1이 H인 화합물 1(9.0 mg)를 40분에 걸쳐 0.01% 산을 포함하는 H2O 중 30-100% MeOH의 구배 용매 시스템의 용출과 함께 C18 분취 HPLC에 의해 분획 SF-7343V-3 30 mg으로부터 정제했다(tR = 27 min). 그 다음, 분획 SF-7343V-4(1.6249g)를 CH2Cl2-MeOH (100:1-0:100)로 용리된 실리카겔 컬럼(32 x 3 cm)에 적용하여 11개의 하위 분획(SF-7343V-4.1 내지 SF-7343V-4.11)을 수득하였다. 이 하위 분획 중에서 하위 분획 SF7343-4.8(280.8 mg)을 CH2Cl2-MeOH (125:1)로 용리된 실리카겔 컬럼(20 x 2 cm)으로 추가 분리하여 하위 분획 SF7343-4.8.1 내지 SF7343-4.8.5를 수득하였다. 하위 분획 SF7343-4.8.5(49.5mg)를 C18 분취 HPLC(30분에 걸쳐 H2O 중 50-75% 메탄올)에 적용하여 화합물 3(3.2 mg, tR = 18.2 min)를 수득하였다. 마지막으로, 하위 분획 SF-7343V-4.9(45.0 mg)를 C18 분취 HPLC(30분에 걸쳐 H2O 중 50-100% MeOH의 구배 용매 시스템으로 용리)로 정제하여 R1이 CH3인 화합물 1(4.2 mg, tR = 19 min) 및 화합물 2(6.4 mg, tR = 22 min)을 수득하였다.The fungal strain Pleosporeles sp. SF-7343 was cultured in 20 Fernbach flasks each containing 300 mL of PDB medium, 75 g of vermiculite and 3% NaCl. Flasks were individually inoculated with 5 mL of seed cultures of fungal strains and incubated at 25 °C for 14 days. Direct extraction of the cultured fungi with EtOAc (20 L) provided an organic phase which was then evaporated in vacuo to give a residue of SF-7343V (3.91 g). The crude extract was fractionated using RP C 18 flash column chromatography eluting with a stepwise gradient of 20, 40, 60, 80 and 100% (v/v) MeOH in H 2 O (500 mL each) , 6 fractions SF-7343V-1 to SF-7343V-6 were obtained. Compound 1 (9.0 mg) where R 1 is H was fractionated by C 18 preparative HPLC with elution with a gradient solvent system of 30-100% MeOH in H 2 O containing 0.01% acid over 40 min. SF-7343V- 3 was purified from 30 mg (t R = 27 min). Then, fraction SF-7343V-4 (1.6249 g) was applied to a silica gel column (32 x 3 cm) eluted with CH 2 Cl 2 -MeOH (100:1-0:100) to obtain 11 sub-fractions (SF- 7343V-4.1 to SF-7343V-4.11) were obtained. Of these sub-fractions, sub-fraction SF7343-4.8 (280.8 mg) was further separated with a silica gel column (20 x 2 cm) eluted with CH 2 Cl 2 -MeOH (125:1) to obtain sub-fractions SF7343-4.8.1 to SF7343- 4.8.5 was obtained. Sub-fraction SF7343-4.8.5 (49.5 mg) was subjected to C 18 preparative HPLC (50-75% methanol in H 2 O over 30 min) to give compound 3 (3.2 mg, t R = 18.2 min). Finally, sub-fraction SF-7343V-4.9 (45.0 mg) was purified by C 18 preparative HPLC (eluting with a gradient solvent system of 50-100% MeOH in H 2 O over 30 min) to obtain compounds where R 1 is CH 3 1 (4.2 mg, t R = 19 min) and compound 2 (6.4 mg, t R = 22 min) were obtained.
R1이 CH3인 화합물 1은 다음과 같은 특징을 갖는다:
갈색 무정형 분말(Brown amorphous powder); HR-ESI-MS m/z: 327.0848 [M + Na]+ (calcd. for [C16H16O6Na]+, 327.0839). 1H NMR (DMSO-d 6, 400 MHz): 10.22 (s, OH-3), 8.73 (s, OH-11), 8.70 (s, OH-10), 6.55 (s, H-12), 6.42 (d, J = 2.4 Hz, H-4), 6.40 (s, H-9), 6.13 (d, J = 2.4 Hz, H-6), 3.72 (s, OCH 3-5), 3.41 (s, OCH 3-1), 1.87 (s, H-14); 13C NMR (DMSO-d 6, 100 MHz): 168.4 (C-1), 160.8 (C-5), 157.4 (C-3), 144.2 (C-10), 143.0 (C-7), 142.2 (C-11), 130.9 (C-8), 125.2 (C-13), 116.9 (C-12), 116.1 (C-9), 113.0 (C-2), 107.3 (C-6), 99.7 (C-4), 55.2 (OCH3-5), 51.4 (OCH3-1), 18.9 (C-14).Brown amorphous powder; HR-ESI-MS m/z : 327.0848 [M + Na] + (calcd. for [C 16 H 16 O 6 Na] + , 327.0839). 1 H NMR (DMSO- d 6 , 400 MHz): 10.22 (s, O H -3), 8.73 (s, O H -11), 8.70 (s, O H -10), 6.55 (s, H -12 ), 6.42 (d, J = 2.4 Hz, H-4), 6.40 (s, H-9), 6.13 (d, J = 2.4 Hz, H-6), 3.72 (s, OCH 3 -5), 3.41 (s, OCH 3 -1 ), 1.87 (s, H -14); 13 C NMR (DMSO- d 6 , 100 MHz): 168.4 (C-1), 160.8 (C-5), 157.4 (C-3), 144.2 (C-10), 143.0 (C-7), 142.2 ( C-11), 130.9 (C-8), 125.2 (C-13), 116.9 (C-12), 116.1 (C-9), 113.0 (C-2), 107.3 (C-6), 99.7 (C -4), 55.2 ( OCH 3 -5), 51.4 ( OCH 3 -1), 18.9 (C-14).
R1이 H인 화합물 1은 다음과 같은 특징을 갖는다:
황색 분말(Yellowish powder); HR-ESI-MS m/z: 291.0878 [M + H]+ (calcd. for [C15H15O6]+, 291.0863). 1H NMR (DMSO-d 6, 400 MHz): 8.67 (brs, OH-11), 8.63 (brs, OH-10), 6.54, (s, H-12), 6.43 (d, J = 2.7 Hz, H-4), 6.42 (s, H-9), 6.10 (d, J = 2.7 Hz, H-6), 3.76 (s, OCH 3-5), 1.86 (s, H-14); 13C NMR (DMSO-d 6, 100 MHz): 171.6 (C-1), 162.0 (C-5), 161.5 (C-3), 145.0 (C-7), 144.0 (C-10), 142.2 (C-11), 132.4 (C-8), 125.0 (C-13), 116.7 (C-12), 116.0 (C-9), 108.9 (C-6), 108.8 (C-2), 99.6 (C-4), 55.3 (OCH3-5), 18.9 (C-14).Yellowish powder; HR-ESI-MS m/z : 291.0878 [M + H] + (calcd. for [C 15 H 15 O 6 ] + , 291.0863). 1 H NMR (DMSO- d 6 , 400 MHz): 8.67 (brs, O H -11), 8.63 (brs, O H -10), 6.54, (s, H -12), 6.43 (d, J = 2.7 Hz, H-4), 6.42 (s, H-9), 6.10 (d, J = 2.7 Hz, H-6), 3.76 (s, OCH 3-5 ), 1.86 (s, H-14); 13 C NMR (DMSO- d 6 , 100 MHz): 171.6 (C-1), 162.0 (C-5), 161.5 (C-3), 145.0 (C-7), 144.0 (C-10), 142.2 ( C-11), 132.4 (C-8), 125.0 (C-13), 116.7 (C-12), 116.0 (C-9), 108.9 (C-6), 108.8 (C-2), 99.6 (C -4), 55.3 ( OCH 3 -5), 18.9 (C-14).
화합물 2는 다음과 같은 특징을 갖는다:
백색 분말(White powder); HR-ESI-MS m/z: 259.0606 [M + H]+ (calcd. for [C14H11O5]+, 259.0601); 281.0428 [M + Na]+ (Calcd. for [C14H10O5Na]+, 281.0420). 1H NMR (DMSO-d 6, 400 MHz): 7.22 (d, J = 2.0 Hz, H-6), 6.70 (d, J = 2.7 Hz, H-12), 6.62 (d, J = 2.7 Hz, H-10), 6.35 (d, J = 2.0 Hz, H-4), 2.68 (s, H-14); 13C NMR (DMSO-d 6, 100 MHz): 165.6 (C-5), 164.7 (C-1), 164.1 (C-3), 158.4(C-11), 152.6 (C-9), 138.3 (C-13), 138.1 (C-7), 117.5 (C-12), 109.0 (C-8), 104.4 (C-6), 101.6 (C-10), 100.9 (C-4), 97.2 (C-2), 25.2 (C-14).White powder; HR-ESI-MS m/z : 259.0606 [M + H] + (calcd. for [C 14 H 11 O 5 ] + , 259.0601); 281.0428 [M + Na] + (Calcd. for [C 14 H 10 O 5 Na] + , 281.0420). 1 H NMR (DMSO- d 6 , 400 MHz): 7.22 (d, J = 2.0 Hz, H-6), 6.70 (d, J = 2.7 Hz, H-12), 6.62 (d, J = 2.7 Hz, H-10), 6.35 (d, J = 2.0 Hz, H-4), 2.68 (s, H-14); 13 C NMR (DMSO- d 6 , 100 MHz): 165.6 (C-5), 164.7 (C-1), 164.1 (C-3), 158.4 (C-11), 152.6 (C-9), 138.3 ( C-13), 138.1 (C-7), 117.5 (C-12), 109.0 (C-8), 104.4 (C-6), 101.6 (C-10), 100.9 (C-4), 97.2 (C -2), 25.2 (C-14).
화합물 3은 다음과 같은 특징을 갖는다:Compound 3 has the following characteristics:
갈색 무정형 분말(Brown amorphous powder); [α]25 D -25.5 (c 0.22, MeOH). HR-ESI-MS m/z: 293.1028 [M + H]+ (calcd. for [C15H17O6]+, 293.1020); 315.0852 [M + Na]+ (Calcd. for [C15H16O6Na]+, 315.0839). 1H NMR (DMSO-d 6, 400 MHz): 11.28 (s, OH-3), 6.75 (d, J = 2.3 Hz, H-6), 6.51 (d, J = 2.3 Hz, H-4), 6.30 (d, J = 3.2 Hz, H-6'), 5.31 (d, J = 5.6 Hz, OH-5'), 5.13 (brs, OH-4'), 3.95 (m, H-5'), 3.86 (s, OCH 3-5), 3.70 (m, H-4'), 2.26 (dd, J = 3.2, 14.0 Hz, He-3'), 1.95 (dd, J = 7.2, 14.0 Hz, Ha-3'), 1.47 (s, H-7').Brown amorphous powder; [ α ] 25 D −25.5 ( c 0.22, MeOH). HR-ESI-MS m/z : 293.1028 [M + H] + (calcd. for [C 15 H 17 O 6 ] + , 293.1020); 315.0852 [M + Na] + (Calcd. for [C 15 H 16 O 6 Na] + , 315.0839). 1 H NMR (DMSO- d 6 , 400 MHz): 11.28 (s, O H -3), 6.75 (d, J = 2.3 Hz, H-6), 6.51 (d, J = 2.3 Hz, H-4) , 6.30 (d, J = 3.2 Hz, H-6'), 5.31 (d, J = 5.6 Hz, O H -5'), 5.13 (brs, O H -4'), 3.95 (m, H-5 '), 3.86 (s, OC H 3 -5), 3.70 (m, H -4'), 2.26 (dd, J = 3.2, 14.0 Hz, H e -3'), 1.95 (dd, J = 7.2, 14.0 Hz, H a -3'), 1.47 (s, H -7').
실시예 10-4: 세포 배양 및 시약Example 10-4: Cell culture and reagents
HaCaT 세포는 조선대학교 정현숙 교수(광주, 한국)에 의해 기증되었고, 세포를 10% FBS(Gibco, NY, USA) 및 주석 프로토포르피린(Snpp; Calbiochem, Merck, Darmstadt, Germany)이 포함된 DMEM에서 배양하였다. 재조합 인간 TNF-α 및 IFN-γ, IL-8, IL-6 및 RANTES용 ELISA 키트는 Bio-Legend(San Diego, CA, USA)에서 구입했다. ICAM-1, FLG, IVL, 액틴, PCNA, HRP 결합 항마우스 및 항토끼 IgG에 대한 항체는 Santa Cruz Bio-technology(Santa Cruz, CA, USA)에서 구입했다. p-IκBα, IκBα, p65, stat1, p-stat1, stat3, p-stat3, HO-1 및 Nrf2에 대한 항체는 Cell Signaling Technology(Danvers, MA, USA)에서 구입했다. 다른 화학 시약은 Sigma-Aldrich Chemical Company(St. Louis, MO, USA)에서 구입했다.HaCaT cells were donated by Professor Hyeon-Sook Jeong of Chosun University (Gwangju, Korea), and the cells were cultured in DMEM containing 10% FBS (Gibco, NY, USA) and tin protoporphyrin (Snpp; Calbiochem, Merck, Darmstadt, Germany). did ELISA kits for recombinant human TNF-α and IFN-γ, IL-8, IL-6 and RANTES were purchased from Bio-Legend (San Diego, CA, USA). Antibodies against ICAM-1, FLG, IVL, actin, PCNA, and HRP-binding anti-mouse and anti-rabbit IgG were purchased from Santa Cruz Bio-technology (Santa Cruz, CA, USA). Antibodies against p-IκBα, IκBα, p65, stat1, p-stat1, stat3, p-stat3, HO-1 and Nrf2 were purchased from Cell Signaling Technology (Danvers, MA, USA). Other chemical reagents were purchased from Sigma-Aldrich Chemical Company (St. Louis, MO, USA).
실시예 10-5: MTT 분석Example 10-5: MTT assay
세포 생존율을 결정하기 위해, 세포를 48 웰 플레이트에서 2 x 104 세포의 밀도로 유지한 다음, R1이 CH3인 화합물 1(20-80μM), R1이 H인 화합물 1(5-40μM), 화합물 2(12.5-20μM) 및 화합물 3(10-80μM)로 처리하였다. 24시간 동안 배양한 후, 세포 배양 배지를 각 웰에서 제거하고 각 웰에서 500μL의 새로운 배지로 교체했다. 세포를 0.5 mg/mL의 3-(4,5-디메틸티아졸-2-일)-2,5-디페닐테트라졸륨 브로마이드(MTT)와 함께 1시간 동안 인큐베이션하고, 형성된 포르마잔을 디메틸 설폭사이드(DMSO)에 용해시켰다. 용해된 포르마잔의 흡광도는 ELISA 마이크로 플레이트 리더(Molecular Devices, San Jose, CA, USA)를 사용하여 540 nm의 파장에서 측정하였다.To determine cell viability, cells were maintained at a density of 2 x 104 cells in 48 well plates, then compound 1 where R 1 is CH 3 (20-80 μM),
실시예 10-6: 사이토카인 및 케모카인의 측정Example 10-6: Measurement of cytokines and chemokines
HaCaT 세포(5.0 Х 106 cells/mL)를 12웰 플레이트에 접종하였다. ELISA 분석을 위해 세포를 3시간 동안 화합물로 사전 처리한 다음 TNF-α/IFN-γ(각각 5ng/mL)로 자극하여 24시간 동안 공동 처리하였다. 그 후, 세포 배양 상등액을 수집하고 제조사의 지침에 따라 ELISA 키트를 사용하여 IL-6, IL-8, RANTES 및 MDC 수준을 평가하였다. Snpp를 사용한 R1이 CH3인 화합물 1의 실험을 위해 먼저 HaCaT 세포를 Snpp(40μM)로 2시간 동안 처리한 다음, R1이 CH3인 화합물 1을 다시 3시간 동안 배양 배지에 첨가하였다. 마지막으로, 24시간 동안 HaCaT 세포를 TNF-α/IFN-γ로 자극하였다. 그 후 세포 배양 상등액을 채취하여 ELISA 키트를 이용하여 IL-6, IL-8, MDC를 검출하였다.HaCaT cells (5.0 Х 10 6 cells/mL) were seeded in a 12-well plate. For ELISA assays, cells were pre-treated with compounds for 3 hours and then co-treated for 24 hours by stimulation with TNF-α/IFN-γ (5 ng/mL each). Cell culture supernatants were then collected and IL-6, IL-8, RANTES and MDC levels assessed using ELISA kits according to the manufacturer's instructions. For the experiment of
실시예 10-7: 총단백, 핵 및 세포질 단백질의 추출Example 10-7: Extraction of total protein, nuclear and cytoplasmic proteins
총단백(total protein)의 경우, 세포를 긁어 모으고, 수확하고, RIPA 완충액(Thermo Fisher Scientific, MA, USA)으로 용해시켰다. 핵 및 세포질 단백질 분획은 제조사의 지침에 따라 핵 추출 키트(Cayman Chemical, Ann Arbor, MI, USA)를 사용하여 추출하였다. 모든 단백질은 사용할 때까지 -80°C에서 보관되었다. HaCaT 세포는 표시된 농도의 R1이 CH3인 화합물 1 및 화합물 2로 전처리되었다. ICAM-1, FLG 및 IVL의 웨스턴 블롯 분석을 위해 세포를 24시간 동안 TNF-α/IFN-γ(각각 5ng/mL)로 유도하였다. p-IκBα, IκBα, p65, stat1, p-stat1, stat3, 및 p-stat3의 분석을 위해 세포를 15분 동안 TNF-α/IFN-γ로 유도하였다.For total protein, cells were scraped, harvested, and lysed with RIPA buffer (Thermo Fisher Scientific, MA, USA). Nuclear and cytoplasmic protein fractions were extracted using a nuclear extraction kit (Cayman Chemical, Ann Arbor, MI, USA) according to the manufacturer's instructions. All proteins were stored at -80 °C until use. HaCaT cells were pretreated with indicated concentrations of
실시예 10-8: 웨스턴 블랏 분석Example 10-8: Western blot analysis
단백질을 SDS-PAGE 겔에서 전기영동으로 분리하고 니트로셀룰로스 막으로 옮겼다. 막을 실온에서 45-60분 동안 5% 탈지유(TBST에 용해)로 차단하였다. 그 다음 1차 항체(1:1000 희석)와 함께 4°C에서 밤새 인큐베이션하였다. TBST로 3회 세척한 후, 막을 양고추냉이 퍼옥시다제 결합 이차 항체(1:5000 희석)와 함께 실온에서 1시간 동안 인큐베이션하였다. TBST로 세척한 후, ECL 용액을 사용하여 특정 단백질을 검출하였다. 막은 ImageJ 소프트웨어(National Institutes of Health, Rockville, MD, USA)를 사용하여 분석되었다.Proteins were electrophoretically separated on SDS-PAGE gels and transferred to nitrocellulose membranes. Membranes were blocked with 5% skim milk (dissolved in TBST) for 45-60 minutes at room temperature. It was then incubated overnight at 4 °C with primary antibody (1:1000 dilution). After washing three times with TBST, the membrane was incubated with horseradish peroxidase-conjugated secondary antibody (1:5000 dilution) for 1 hour at room temperature. After washing with TBST, specific proteins were detected using the ECL solution. Membranes were analyzed using ImageJ software (National Institutes of Health, Rockville, MD, USA).
실시예 10-9: NF-κB DNA 결합 분석Example 10-9: NF-κB DNA binding assay
Snpp를 사용한 R1이 CH3인 화합물 1의 실험을 위해 먼저 HaCaT 세포를 Snpp(40μM)로 2시간 동안 처리한 다음, R1이 CH3인 화합물 1을 다시 3시간 동안 배양 배지에 첨가했다. 마지막으로, TNF-α/IFN-γ로 HaCaT 세포를 자극하였다. 그 후, 세포를 채취하고, 핵 추출 키트를 이용하여 핵 단백질 분획을 추출하였다.For the experiment of
NF-κB p65-DNA 결합은 NF-κB p65 전사 인자 분석 키트(10007889, Cayman Chemical)를 사용하여 검출되었다. 핵 분획은 상대적인 핵 NF-κB p65-DNA 결합 활성을 정량화하는 데 사용되었다. 이것은 제조사의 지침에 따라 평가되었다.NF-κB p65-DNA binding was detected using the NF-κB p65 transcription factor assay kit (10007889, Cayman Chemical). Nuclear fractionation was used to quantify relative nuclear NF-κB p65-DNA binding activity. This was evaluated according to the manufacturer's instructions.
실시예 10-10:Examples 10-10: 통계 분석statistical analysis
각 그룹의 결과값은 평균±표준편차(SD)로 표시하였으며, GraphPad Software(San Diego, CA, USA)를 이용하여 일원분산분석(ANOVA)을 수행한 후 Duncan의 다중비교 테스트를 수행하여 유의성을 테스트하였다. 통계적 유의성은 # p < 0.05, ## p < 0.01, ### p < 0.001 vs. 대조군. *p < 0.05, **p < 0.01, ***p < 0.001 vs. TNF-α/IFN-γ-처리군. △ p < 0.05, △△ p < 0.01, △△△ p < 0.001 vs. R1이 CH3인 화합물 1+TNF-α/IFN-γ-처리군으로 설정되었다.The results of each group were expressed as mean ± standard deviation (SD), and after performing one-way analysis of variance (ANOVA) using GraphPad Software (San Diego, CA, USA), Duncan's multiple comparison test was performed to determine significance. tested. Statistical significance was # p < 0.05, ## p < 0.01, ### p < 0.001 vs. control group. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. TNF-α/IFN-γ-treated group. Δp < 0.05, ΔΔp < 0.01 , ΔΔΔ p < 0.001 vs. The
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As above, specific parts of the present invention have been described in detail, and it will be clear to those skilled in the art that these specific descriptions are merely preferred embodiments, and the scope of the present invention is not limited thereby. will be. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (8)
[화학식 1]
[화학식 2]
[화학식 3]
여기서, 상기 R1 내지 R6은 각각 독립적으로 H, 직쇄형 또는 분지쇄형의 C1-10 알킬, C1-10 알콕시, C3-10 사이클로알킬, C2-10 알케닐 또는 C6-10 아릴임.
A pharmaceutical composition for preventing or treating inflammatory diseases comprising at least one compound selected from the group consisting of Formulas 1 to 3 below:
[Formula 1]
[Formula 2]
[Formula 3]
Here, the R 1 to R 6 are each independently H, straight-chain or branched-chain C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 Aryl.
The pharmaceutical composition according to claim 1, wherein R 1 to R 6 are each independently H, CH 3 or CH 2 CH 3 .
The method of claim 1, wherein the compound is an Antarctic fungus Pleosporeles sp. A pharmaceutical composition characterized in that it is isolated from SF-7343 (KCTC 14724BP).
The method of claim 1, wherein the inflammatory disease is arthritis, rhinitis, hepatitis, keratitis, gastritis, enteritis, nephritis, bronchitis, pleurisy, peritonitis, spondylitis, pancreatitis, inflammatory pain, urethritis, cystitis, burn inflammation, dermatitis, periodontitis, gingivitis and A pharmaceutical composition, characterized in that selected from the group consisting of degenerative neuroinflammation.
1) IL-6, IL-8, MDC(macrophage-derived chemokine) 및 RANTES의 분비 억제;
2) ICAM-1의 발현 억제;
3) 필라그린(filaggrin, FLG)과 인볼큐린(involcurin, IVL)의 발현 억제;
4) NF-κB, p-STAT1 및 p-STAT3의 활성화 억제; 및
5) HO-1 발현 및 Nrf2 전좌 촉진.
The pharmaceutical composition according to claim 1, characterized in that it has one or more of the following properties:
1) inhibition of secretion of IL-6, IL-8, MDC (macrophage-derived chemokine) and RANTES;
2) inhibition of expression of ICAM-1;
3) inhibition of expression of filaggrin (FLG) and involcurin (IVL);
4) inhibition of activation of NF-κB, p-STAT1 and p-STAT3; and
5) Promotion of HO-1 expression and Nrf2 translocation.
The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier, excipient or diluent.
[화학식 1]
[화학식 2]
[화학식 3]
여기서, 상기 R1 내지 R6은 각각 독립적으로 H, 직쇄형 또는 분지쇄형의 C1-10 알킬, C1-10 알콕시, C3-10 사이클로알킬, C2-10 알케닐 또는 C6-10 아릴임.
Food for improving inflammation containing at least one compound selected from the group consisting of the following formulas 1 to 3:
[Formula 1]
[Formula 2]
[Formula 3]
Here, the R 1 to R 6 are each independently H, straight-chain or branched-chain C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 2-10 alkenyl or C 6-10 Aryl.
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