KR102661950B1 - Composition for preventing or treating of osteoclast differentiation comprising Broussonetia kazinoki extracts or prenylated compounds isolated therefrom - Google Patents
Composition for preventing or treating of osteoclast differentiation comprising Broussonetia kazinoki extracts or prenylated compounds isolated therefrom Download PDFInfo
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- KR102661950B1 KR102661950B1 KR1020210046507A KR20210046507A KR102661950B1 KR 102661950 B1 KR102661950 B1 KR 102661950B1 KR 1020210046507 A KR1020210046507 A KR 1020210046507A KR 20210046507 A KR20210046507 A KR 20210046507A KR 102661950 B1 KR102661950 B1 KR 102661950B1
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Abstract
본 발명은 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물을 포함하는 파골세포 분화 억제용 조성물에 관한 것으로, 구체적으로는 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물이 파골 세포 형성을 억제하고 골 재흡수를 억제하는 것을 확인하였으며, 이를 이용하여 골 용해성 골 질환의 예방 또는 치료에 기여할 것으로 기대된다.The present invention relates to a composition for inhibiting osteoclast differentiation comprising a mulberry extract or a prenylated compound isolated therefrom. Specifically, the mulberry extract or a prenylated compound isolated therefrom inhibits osteoclast formation and promotes bone resorption. It has been confirmed that it inhibits osteolytic bone disease, and it is expected to contribute to the prevention or treatment of osteolytic bone disease.
Description
본 발명은 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물을 포함하는 파골세포 분화 억제용 조성물에 관한 것이다.The present invention relates to a composition for inhibiting osteoclast differentiation comprising a mulberry extract or a prenylated compound isolated therefrom.
파골 세포는 골수에 있는 골수 조혈 줄기 세포와 구별되는 골 재흡수세포이다(Xu & Teitelbaum, 2013). 핵인자-κB 리간드 수용체 활성화제(RANKL)/RANK 신호 증가로 인한 과도한 파골 세포 형성 및/또는 활성은 골다공증 및 류마티스 관절염과 같은 골용해성 골질환을 유발한다 (Kearns 등, 2008). 따라서 골용해성 골질환을 치료하고 예방하기 위한 전략으로, RANKL/RANK 신호 전달 경로를 억제하여 상승된 파골세포 형성 및/또는 활성을 억제할 수 있다. 최근에는 천연물을 이용한 골용해성골 질환의 치료 및 예방에 대한 관심이 높아지고 있다 (An 등, 2016; Kim 등, 2018; Sethi 등, 2007).Osteoclasts are bone resorption cells that are distinct from bone marrow hematopoietic stem cells in the bone marrow (Xu & Teitelbaum, 2013). Excessive osteoclast formation and/or activity due to increased receptor activator of nuclear factor-κB ligand (RANKL)/RANK signaling causes osteolytic bone diseases such as osteoporosis and rheumatoid arthritis (Kearns et al., 2008). Therefore, as a strategy to treat and prevent osteolytic bone disease, elevated osteoclast formation and/or activity can be suppressed by inhibiting the RANKL/RANK signaling pathway. Recently, there has been increasing interest in the treatment and prevention of osteolytic bone disease using natural products (An et al., 2016; Kim et al., 2018; Sethi et al., 2007).
한편, 닥나무 (Broussonetia kazinoki)는 뽕나무과에 속하는 낙엽관목으로 한국, 일본, 중국 전역에 분포한다. 옛날에는 저포라고 불리는 일종의 피륙을 짜는 데 사용되었고, 고려시대 이후에는 제지원료로 사용되기 시작하여 조선시대에 이르러서는 닥나무를 원료로 하여 종이를 만드는 것이 본격화되었다. 이와 함께 닥나무의 잎, 열매 및 가지는 부종에 대한 강장제, 이뇨제 및 억제제 치료를 위한 일반적인 약용 식물로 민간 의학에서 사용되었다 (Zhang et al., 2001). 닥나무 추출물은 이 외에도 항염증 효과, 아토피성 피부염 유사 반응 억제, 탈색 효과, 혈관 신생 억제 등을 통한 항암 효과, 근모세포 분화 자극 등 다양한 약리 활성을 가지고 있는 것으로 알려졌다 (Lee et al., 2016). 이러한 효과를 갖는 닥나무의 주요 생리 활성 분자에는 알칼로이드, 플라보노이드 및 1,3-디페닐프로판 등이 있다 (Wang et al., 2012). 그러나, 닥나무 뿌리의 생리학적 활성물질에 관한 연구는 아직 충분히 이루어지지 않았으며, 항파골형성과 관련된 보고도 미미한 실정이다.Meanwhile, mulberry tree ( Broussonetia kazinoki ) is a deciduous shrub belonging to the Moraceae family and is distributed throughout Korea, Japan, and China. In the past, it was used to weave a type of cloth called Jeopo, and after the Goryeo Dynasty, it began to be used as a raw material for papermaking, and by the Joseon Dynasty, the production of paper using mulberry trees as a raw material began in earnest. Along with this, the leaves, fruits and branches of mulberry have been used in folk medicine as a common medicinal plant for tonic, diuretic and depressant treatment of edema (Zhang et al., 2001). In addition, mulberry extract is known to have various pharmacological activities, including anti-inflammatory effects, inhibition of atopic dermatitis-like reactions, depigmentation effects, anticancer effects through inhibition of angiogenesis, and stimulation of myoblast differentiation (Lee et al., 2016). The main bioactive molecules of mulberry tree that have these effects include alkaloids, flavonoids, and 1,3-diphenylpropane (Wang et al., 2012). However, research on the physiologically active substances of mulberry roots has not yet been sufficiently conducted, and reports related to anti-osteoclastogenesis are minimal.
종래선행기술인 한국등록특허 제1914202호에는 삼지닥나무 추출물을 함유하는 골 질환 치료, 예방 또는 개선용 조성물이 기재되어 있으나, 본 발명의 닥나무 (Broussonetia kazinoki) 활성물질과는 차이가 있다. 한국등록특허 제1693725호에는 닥나무 추출물을 유효성분으로 함유하는 혈관신생 억제용 조성물이 기재되어 있으나, 역시 본 발명의 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물을 포함하는 파골세포 분화 억제용 조성물은 기재되어 있지 않다.Korean Patent No. 1914202, which is a prior art, describes a composition for treating, preventing or improving bone disease containing an extract of paper mulberry ( Broussonetia ) of the present invention. kazinoki ) It is different from the active substance. Korean Patent No. 1693725 describes a composition for inhibiting angiogenesis containing a mulberry extract as an active ingredient, but also describes a composition for inhibiting osteoclast differentiation containing the mulberry extract of the present invention or a prenylated compound isolated therefrom. It is not done.
본 발명의 목적은 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물을 포함하는 파골세포 분화 억제용 조성물을 제공하는 데 있다.The purpose of the present invention is to provide a composition for inhibiting osteoclast differentiation comprising a mulberry extract or a prenylated compound isolated therefrom.
본 발명은 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물을 포함하는 파골세포 분화 억제용 조성물을 제공한다.The present invention provides a composition for inhibiting osteoclast differentiation comprising a mulberry extract or a prenylated compound isolated therefrom.
상기 닥나무 추출물은, 닥나무(Broussonetia kazinoki)의 잎, 줄기, 뿌리, 꽃, 열매, 씨를 포함할 수 있으며, 바람직하게는 줄기 또는 뿌리이며, 더욱 바람직하게는 뿌리이다.The mulberry extract is a mulberry tree ( Broussonetia kazinoki ) leaves, stems, roots, flowers, fruits, and seeds, preferably stems or roots, and more preferably roots.
상기 닥나무 추출물은 닥나무를 물, C1~4의 저급 알코올, 아세톤(acetone), 에틸아세테이트(ethyl acetate), 디에틸아세테이트(diethyl acetate), 디에틸에테르(diethyl ether), 벤젠(benzene), 클로로포름(chloroform) 및 헥산(hexane)으로 이루어진 군에서 선택되는 1종 또는 이들의 혼합용매로 추출한 추출물 일 수 있다.The mulberry tree extract is obtained by mixing mulberry tree with water, C1-4 lower alcohol, acetone, ethyl acetate, diethyl acetate, diethyl ether, benzene, and chloroform ( It may be an extract extracted with one solvent selected from the group consisting of chloroform and hexane, or a mixed solvent thereof.
상기 닥나무 추출물의 추출 방법으로는 열수추출법, 냉침추출법, 환류냉각추출법, 용매추출법, 수증기증류법, 초음파추출법, 용출법, 압착법 등의 방법 중 어느 하나를 선택하여 사용할 수 있다. 또한, 목적하는 추출물은 추가로 통상의 분획 공정을 수행할 수도 있으며, 통상의 정제 방법을 이용하여 정제될 수도 있다. 상기한 용매 추출법으로 추출된 닥나무 추출물은 원심분리, 여과, 농축 후 동결 건조하여 냉장실에 보관하면서 그대로 사용할 수도 있다. 또한, 상기 닥나무 추출물을 실리카 겔 컬럼 크로마토그래피(silica gel columnchromatography), 박층 크로마토그래피(thin layer chromatography), 고성능 액체 크로마토그래피(high performance liquid chromatography) 등과 같은 다양한 크로마토그래피를 이용하여 추가로 정제된 분획을 얻고, 이를 정제하여 하기 화학식 [1]로 표현되는 프레닐화 화합물을 얻을 수 있다.As an extraction method for the mulberry extract, any one of the following methods can be selected and used: hot water extraction, cold needle extraction, reflux cooling extraction, solvent extraction, steam distillation, ultrasonic extraction, dissolution, and compression. In addition, the desired extract may be further subjected to a conventional fractionation process or may be purified using a conventional purification method. The mulberry extract extracted by the solvent extraction method described above can be centrifuged, filtered, concentrated, freeze-dried, and stored in a refrigerator for use as is. In addition, the mulberry extract was further purified into fractions using various chromatographies such as silica gel column chromatography, thin layer chromatography, and high performance liquid chromatography. and purifying it to obtain a prenylated compound represented by the following formula [1].
본 발명은 닥나무 추출물로부터 분리한 하기 화학식 [1]로 표현되는 프레닐화 화합물인 화합물 1~19로 이루어진 군으로부터 선택되는 1 이상을 포함하는 파골세포 분화 억제용 조성물을 제공한다.The present invention provides a composition for inhibiting osteoclast differentiation comprising at least one selected from the group consisting of compounds 1 to 19, which are prenylated compounds isolated from mulberry extract and represented by the following formula [1].
화학식 [1]Chemical formula [1]
본 발명은 또한 하기 화학식 [2]로 표현되는 화합물 2, 3, 5 및 6 로 이루어진 군으로부터 선택되는 1 이상을 포함하는 것을 특징으로 하는 파골세포 분화 억제용 조성물을 제공한다.The present invention also provides a composition for inhibiting osteoclast differentiation, characterized in that it contains at least one selected from the group consisting of compounds 2, 3, 5 and 6 represented by the following formula [2].
화학식 [2]Chemical formula [2]
본 발명의 파골세포 분화 억제용 조성물은 약학적 조성물로 제조될 수 있다. 상기 파골세포 분화 억제용 조성물의 약학적 조성물은 전체 약학적 조성물 총 중량에 대하여 바람직하게는 0.001~50중량%, 더 바람직하게는 0.001~40중량%, 가장 바람직하게는 0.001~30중량%로 하여 첨가될 수 있다.The composition for inhibiting osteoclast differentiation of the present invention may be prepared as a pharmaceutical composition. The pharmaceutical composition of the composition for inhibiting osteoclast differentiation is preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight, and most preferably 0.001 to 30% by weight, based on the total weight of the entire pharmaceutical composition. may be added.
상기 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 액제, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균주사용액의 형태로 제형화하여 사용될 수 있다. 상기 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제, 감미제, 산미제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토즈, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제, 산미제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween)-61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, solutions, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. You can. Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants, sweeteners, and acidulants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the mulberry extract of the present invention or a prenylated compound isolated therefrom and at least one excipient, such as starch. It is prepared by mixing calcium carbonate, sucrose or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, syrups, etc. In addition to the commonly used simple diluents such as water and liquid paraffin, they contain various excipients such as wetting agents, sweeteners, fragrances, preservatives, and acidulants. may be included. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable esters such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween-61, cacao, laurin, glycerogeratin, etc. can be used.
본 발명의 약학적 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중과, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여 경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 500㎎/㎏/일의 범위이다. 바람직한 투여량은 0.1㎎/㎏/일 내지 200㎎/㎏/일이며, 더 바람직한 투여량은 1㎎/㎏/일 내지 200㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition of the present invention will vary depending on the age, gender, and weight of the subject to be treated, the specific disease or pathological state to be treated, the severity of the disease or pathological state, the route of administration, and the judgment of the prescriber. Dosage determinations based on these factors are within the level of one skilled in the art, and dosages generally range from 0.01 mg/kg/day to approximately 500 mg/kg/day. A preferred dosage is 0.1 mg/kg/day to 200 mg/kg/day, and a more preferred dosage is 1 mg/kg/day to 200 mg/kg/day. Administration may be administered once a day, or may be administered several times. The above dosage does not limit the scope of the present invention in any way.
본 발명의 약학적 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 주사 및 피부 도포에 의해 투여될 수 있다. 본 발명의 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있는 약제이다.The pharmaceutical composition of the present invention can be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection and dermal application. The mulberry extract of the present invention or the prenylated compound isolated therefrom has little toxicity and side effects, so it is a drug that can be safely used even when taken for a long period of time for preventive purposes.
본 발명은 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물을 포함하는 파골세포 분화 억제용 건강기능식품을 제공한다.The present invention provides a health functional food for inhibiting osteoclast differentiation comprising a mulberry extract or a prenylated compound isolated therefrom.
상기 닥나무 추출물은, 닥나무를 물, C1~4의 저급 알코올, 아세톤(acetone), 에틸아세테이트(ethyl acetate), 디에틸아세테이트(diethyl acetate), 디에틸에테르(diethyl ether), 벤젠(benzene), 클로로포름(chloroform) 및 헥산(hexane)으로 이루어진 군에서 선택되는 1종 또는 이들의 혼합용매로 추출한 추출물 일 수 있다.The mulberry tree extract is obtained by mixing mulberry tree with water, C1-4 lower alcohol, acetone, ethyl acetate, diethyl acetate, diethyl ether, benzene, and chloroform. It may be an extract selected from the group consisting of (chloroform) and hexane, or a mixed solvent thereof.
또한 상기 프레닐화 화합물은 상기 화학식 [1]로 표현되는 화합물 1 내지 19 중 선택되는 1 이상을 포함할 수 있다. 또한 상기 프레닐화 화합물은 상기 화학식 [2]로 표현되는 화합물 2, 3, 5 및 6 중 선택되는 1 이상을 포함할 수 있다.Additionally, the prenylated compound may include one or more selected from compounds 1 to 19 represented by the formula [1]. Additionally, the prenylated compound may include one or more selected from compounds 2, 3, 5, and 6 represented by the formula [2].
상기 건강기능식품은 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물이 전체 식품 총 중량에 대하여 바람직하게는 0.001~50중량%, 더 바람직하게는 0.001~30중량%, 가장 바람직하게는 0.001~10중량%로 하여 첨가될 수 있다.The health functional food contains preferably 0.001 to 50% by weight, more preferably 0.001 to 30% by weight, and most preferably 0.001 to 10% by weight of mulberry extract or prenylated compounds isolated therefrom, based on the total weight of the entire food. It can be added as .
상기 건강기능식품은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 추출물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강기능성식품류 등이 있다.The health functional food includes the form of tablets, capsules, pills, or liquid, and foods to which the extract of the present invention can be added include, for example, various foods, beverages, gum, tea, vitamin complexes, and health products. There are functional foods, etc.
본 발명은 하기 화학식 [3]으로 표현되는 화합물 1-4, 6-8 로 이루어진 군으로부터 선택되는 하나의 신규 화합물을 제공한다.The present invention provides a novel compound selected from the group consisting of compounds 1-4 and 6-8 represented by the following formula [3].
화학식 [3]Chemical formula [3]
상기 신규화합물 화합물 1-4, 6-8 은 닥나무 추출물로부터 분리한 것일 수 있다.The new compounds 1-4 and 6-8 may be isolated from mulberry extract.
본 발명은 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물을 포함하는 파골세포 분화 억제용 조성물에 관한 것으로, 구체적으로는 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물이 파골 세포 형성을 억제하고 뼈 손실을 억제하는 것을 확인하였으며, 이를 이용하여 골 용해성 골 질환의 예방 또는 치료에 기여할 것으로 기대된다.The present invention relates to a composition for inhibiting osteoclast differentiation comprising a mulberry extract or a prenylated compound isolated therefrom. Specifically, the mulberry extract or a prenylated compound isolated therefrom inhibits osteoclast formation and bone loss. It has been confirmed that this will contribute to the prevention or treatment of osteolytic bone disease.
도 1은 본 발명의 닥나무 추출물로부터 분리한 화합물 1-19의 화학 구조이다.
도 2는 본 발명에 따른 화합물 1-3 및 5-8에 대한 주요 HMBC (파란색 화살표) 및 COZY (검은색 굵은 글꼴) 상관 관계를 나타낸 것이다.
도 3은 MeOH에서 화합물 1 (왼쪽)의 계산치 및 실험 ECD 스펙트럼과 화합물 2-7 (오른쪽)의 실험치 ECD 스펙트럼를 나타낸 것이다.
도 4는 RAW264.7 세포에서 닥나무 추출물로부터 분리한 화합물의 RANKL 유도 파골세포 형성에 미치는 효과 (A) 및 세포 생존률을 나타낸 그래프이다 (평균 ± SE, P <0.01, 용매 대조군 대비, n = 3).
도 5는 BMM에서 RANKL 유도 파골 세포 형성에 대한 농도에 따른 화합물 2 (A), 3 (B) 및 6 (C)의 효과를 나타낸 TRAP 양성 다핵 (> 5 핵) 파골 세포 사진(× 40) 및 그래프 (평균 ± SE, P <0.05)이다.
도 6은 M-CSF 및 RANKL 유도 BMM에서 본 발명의 화합물 6의 농도별 재흡수 피트 형성에 미치는 효과를 나타낸 사진 및 상기 피트 영역을 정량화하여 나타낸 그래프이다.Figure 1 shows the chemical structure of compound 1-19 isolated from the mulberry extract of the present invention.
Figure 2 shows the main HMBC (blue arrows) and COZY (black bold font) correlations for compounds 1-3 and 5-8 according to the invention.
Figure 3 shows the calculated and experimental ECD spectra of compound 1 (left) and the experimental ECD spectrum of compounds 2-7 (right) in MeOH.
Figure 4 is a graph showing the effect (A) and cell survival rate of compounds isolated from mulberry extract on RANKL-induced osteoclast formation in RAW264.7 cells (mean ± SE, P < 0.01, compared to solvent control, n = 3). .
Figure 5 is a photograph (×40) of TRAP-positive multinucleated (>5 nuclei) osteoclasts showing the effect of compounds 2 (A), 3 (B), and 6 (C) on RANKL-induced osteoclast formation in BMM. Graph (mean ± SE, P < 0.05).
Figure 6 is a photograph showing the effect of compound 6 of the present invention on the formation of resorption pits at each concentration in M-CSF and RANKL-induced BMM and a graph showing the quantification of the pit area.
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the content introduced herein is provided to be thorough and complete, and to fully convey the spirit of the present invention to those skilled in the art.
<< 실시예Example 1. 닥나무 추출물 제조 및 이로부터 분리한 화합물 수득> 1. Preparation of mulberry extract and obtaining compounds isolated from it>
닥나무 (Broussonetia kazinoki)의 뿌리는 2018 년 5 월 대한민국 대전 노은동에서 수집되어 민병선 교수(저자 중 한 명)가 확인하였으며, 바우처 표본 (CUD-0814-1)은 대구 가톨릭 대학교 약학 대학 식물 표본실에 기탁되었다.Mulberry ( Broussonetia) kazinoki ) roots were collected from Noeun-dong, Daejeon, South Korea in May 2018 and identified by Professor Byeong-seon Min (one of the authors), and the voucher specimen (CUD-0814-1) was deposited in the herbarium of the College of Pharmacy, Daegu Catholic University.
닥나무 (7 kg)의 공기 건조된 뿌리를 MeOH (15 L × 3)를 사용하여 추출하고, 이를 취합, 농축하여 닥나무 추출물 (330g)을 얻었다.The air-dried roots of mulberry tree (7 kg) were extracted using MeOH (15 L × 3), and the extracts were collected and concentrated to obtain mulberry extract (330 g).
기초실험으로 상기 닥나무 추출물을 RANKL 유도 RAW264.7 세포에 투여한 결과 농도 의존적으로 TRAP 양성 파골세포의 수가 감소하는 것을 확인하고, 상기 닥나무 추출물로부터 파골세포 형성 억제 활성을 갖는 화합물을 분리하기 위한 실험을 수행하였다.As a basic experiment, it was confirmed that the number of TRAP-positive osteoclasts decreased in a concentration-dependent manner when the mulberry extract was administered to RANKL-induced RAW264.7 cells, and an experiment was conducted to isolate a compound with osteoclast formation inhibitory activity from the mulberry extract. carried out.
상기 닥나무 추출물을 물 (0.5L)에 용해시키고 n-헥산, CH2Cl2, EtOAc 및 n-BuOH로 연속적으로 분배하였다. 이 때 수득한 CH2Cl2-용해성 분획 (90g)을 실리카겔 크로마토 그래피 (MeOH:CH2Cl2, 1:20, v/v)에 적용하여 8 개의 분획 (B1-B8)을 수득하였으며, 이 중, 분획 B3 (15 g)을 실리카 겔 컬럼 (MeOH:CH2Cl2, 1:15, v/v)에서 용출하여 9 개의 하위 분획 (B3.1-B3.9)을 수득하였다. 상기 하위분획 B3.2 (900 mg)를 실리카겔 CC (아세톤:n-헥산, 1:1, v/v)로 분획하여 화합물 10 (15 mg) 및 19 (4 mg)를 수득하였다. 또한 하위분획 B3.4 (3 g)를 RP-18 실리카겔 CC (H2O:MeOH, 1:1, v/v)를 사용하여 정제하여 화합물 9 (4 mg), 13 (25 mg), 14 (4 mg),16 (2 mg), 및 17 (20 mg) 을 수득하였다. 하위분획 B3.6 (100 mg)을 실리카 겔 컬럼 (MeOH : CH2Cl2, 1:12, v/v)로 용리하여 화합물 1 (4 mg) 및 12 (10 mg)를 수득하였다. 분획 B5 (16 g)는 실리카겔 CC (MeOH:EtOAc, 1:30, v/v)로 분획하여 12 개의 하위 분획 (B5.1-B5.12)을 얻었고, 이 중, 하위분획 B5.5 (600 mg)를 RP-18 실리카겔 컬럼 (H2O:MeOH, 3:2, v/v)을 사용하여 분리하여 화합물 6 (5 mg), 7 (3 mg), 및 15 (9 mg)를 얻었다. 또 다른 하위분획 B5.5.9 (60 mg)를 HPLC (MeOH:H2O, 55:45, v/v, 유속 : 5 mL/min)로 정제하여 화합물 3 (20 mg, tR 21.3 분) 및 4 (50 mg, tR 22.5 분)를 수득하였으며, 분획 B5.9 (2 g)를 RP-18 실리카겔 컬럼 (H2O:MeOH, 1:2, v/v)을 사용하여 분리하여 화합물 8 (4 mg) 및 18 (3 mg)을 얻었다. The mulberry extract was dissolved in water (0.5 L) and successively partitioned between n-hexane, CH 2 Cl 2 , EtOAc and n-BuOH. The CH 2 Cl 2 -soluble fraction (90g) obtained at this time was applied to silica gel chromatography (MeOH:CH 2 Cl 2 , 1:20, v/v) to obtain 8 fractions (B1-B8), which Among them, fraction B3 (15 g) was eluted on a silica gel column (MeOH:CH 2 Cl 2 , 1:15, v/v) to obtain 9 subfractions (B3.1-B3.9). The subfraction B3.2 (900 mg) was fractionated with silica gel CC (acetone:n-hexane, 1:1, v/v) to obtain compounds 10 (15 mg) and 19 (4 mg). Additionally, subfraction B3.4 (3 g) was purified using RP-18 silica gel CC (H 2 O:MeOH, 1:1, v/v) to obtain compounds 9 (4 mg), 13 (25 mg), and 14. (4 mg), 16 (2 mg), and 17 (20 mg) were obtained. Subfraction B3.6 (100 mg) was eluted with a silica gel column (MeOH: CH 2 Cl 2 , 1:12, v/v) to give compounds 1 (4 mg) and 12 (10 mg). Fraction B5 (16 g) was fractionated with silica gel CC (MeOH:EtOAc, 1:30, v/v) to obtain 12 subfractions (B5.1-B5.12), of which subfraction B5.5 ( 600 mg) was separated using an RP-18 silica gel column (H 2 O:MeOH, 3:2, v/v) to obtain compounds 6 (5 mg), 7 (3 mg), and 15 (9 mg). . Another subfraction B5.5.9 (60 mg) was purified by HPLC (MeOH:H 2 O, 55:45, v/v, flow rate: 5 mL/min) to obtain compound 3 (20 mg, t R 21.3 min) and 4 (50 mg, t R 22.5 min) was obtained, and fraction B5.9 (2 g) was separated using an RP-18 silica gel column (H 2 O:MeOH, 1:2, v/v) to obtain compound 8. (4 mg) and 18 (3 mg) were obtained.
화합물 2 (5mg, tR 18.4 분), 5 (5mg, tR 20.2 분) 및 11 (6mg, tR 23.5 분)은 하위분획 B5.9.8 (680 mg)을 HPLC (MeOH: H2O, 60:40, v/v, 유속 : 5 mL/분)로 분리하여 얻었다. Compounds 2 (5 mg, t R 18.4 min), 5 (5 mg, t R 20.2 min) and 11 (6 mg, t R 23.5 min) were purified from subfraction B5.9.8 (680 mg) by HPLC (MeOH: H 2 O, 60: 40, v/v, flow rate: 5 mL/min).
<< 실시예Example 2. 닥나무 추출물로부터 분리한 화합물의 구조 확인> 2. Confirmation of the structure of compounds isolated from mulberry extract>
상기 실시예 1로부터 분리한 화합물의 구조를 확인하였다. JASCO P-2000 디지털 편광계 (JASCO Corporation, Tokyo, Japan)를 사용하여 광학 회전을 측정하였으며, IR 스펙트럼은 JASCO FT / IR-4100 분광계 (JASCO Corporation, Tokyo, Japan)로 측정하였다. 전자 원형 이색성 (ECD) 및 UV 스펙트럼은 J-1500 원형 이색성 분광 광도계 (JASCO Corporation, Tokyo, Japan)를 사용하여 얻었다. NMR 스펙트럼은 Bruker Ascend™ 500 MHz (Buker Corporation, Massachusetts, USA) 분광계로 측정하였고, 고해상도 고속 원자 충격 질량 분광법 (HRFABMS) 및 고해상도 전자 분무 이온화 질량 분광법 (HRESIMS)은 JEOL JMS-AX 300L 분광기 (JEOL, Akishima, Tokyo, Japan) 및 AB SCIEX TripleTOF™5600 분광계 (AB Sciex Pte. Ltd., 캐나다 온타리오)에서 수행하였다.The structure of the compound isolated from Example 1 was confirmed. Optical rotation was measured using a JASCO P-2000 digital polarimeter (JASCO Corporation, Tokyo, Japan), and IR spectra were measured with a JASCO FT/IR-4100 spectrometer (JASCO Corporation, Tokyo, Japan). Electronic circular dichroism (ECD) and UV spectra were obtained using a J-1500 circular dichroism spectrophotometer (JASCO Corporation, Tokyo, Japan). NMR spectra were measured on a Bruker Ascend ™ 500 MHz (Buker Corporation, Massachusetts, USA) spectrometer, and high-resolution fast atomic bombardment mass spectrometry (HRFABMS) and high-resolution electrospray ionization mass spectrometry (HRESIMS) were performed on a JEOL JMS-AX 300L spectrometer (JEOL, Akishima, Tokyo, Japan) and an AB SCIEX TripleTOF ™ 5600 spectrometer (AB Sciex Pte. Ltd., Ontario, Canada).
이 연구에 사용된 화합물 1의 모든 컨포머는 MMFF 역장에서 "혼합 비틀림 / 저 모드 샘플링"이있는 Macromodel (버전 2019-2, Schrdinger LLC) 모듈을 사용하여 발견하였다. 검색은 모든 잠재적 컨포머를 탐색하기 위해 1 kJ/mol 에너지 창 한계와 10,000 개의 최대 단계 수로 기체상에서 구현하였다. Polak-Ribiere Conjugate Gradient (PRCG) 방법은 RMS (Root Mean Square) 기울기에서 10,000 회 반복 및 0.001 kJ (mol Å) -1 수렴 임계 값으로 컨포머를 최소화하는 데 사용하였다. 12 개의 모든 컨포머는 B3LYP/6-31+G(d,p) 수준의 기체 상태에서 Gaussian 16 패키지 (Gaussian Inc.)를 사용하여 기하학적 최적화를 수행하였다. 중복 컨포머를 제외하고 생성된 11 개의 컨포머는 모두 편광성 연속체 모델 (PCM, 메탄올)의 B3LYP/6-31+G(d,p) 수준에서 여기 에너지, 발진기 강도 및 회전 강도를 계산하였다. ECD 스펙트럼은 각 컨 포머의 계산 된 Gibbs 자유 에너지를 기반으로 볼츠만 평균화되었으며 σ/γ 값이 0.25 eV인 SpecDis 소프트웨어 (버전 1.71)로 시각화하였다.All conformers of compound 1 used in this study were analyzed using Macromodel with “mixed torsion/low-mode sampling” in the MMFF force field (version 2019-2, Schr dinger LLC) module. The search was implemented in the gas phase with an energy window limit of 1 kJ/mol and a maximum number of steps of 10,000 to explore all potential conformers. The Polak-Ribiere Conjugate Gradient (PRCG) method was used to minimize the conformer with 10,000 iterations and a convergence threshold of 0.001 kJ (mol Å)-1 in root mean square (RMS) gradient. All 12 conformers were geometrically optimized using the Gaussian 16 package (Gaussian Inc.) in the gas phase at the B3LYP/6-31+G(d,p) level. Excluding redundant conformers, the excitation energy, oscillator strength, and rotation strength of all 11 generated conformers were calculated at the B3LYP/6-31+G(d,p) level of the polarizability continuum model (PCM, methanol). The ECD spectra were Boltzmann averaged based on the calculated Gibbs free energy of each conformer and visualized with SpecDis software (version 1.71) with a σ/γ value of 0.25 eV.
상기 방법에 따라 구조 결정된 화합물 1-19의 분자구조를 도 1에 나타내었다. 화합물 1-8는 아래와 같으며, 그 구조특성을 도 2, 3 및 표 1-3에 나타내었다.The molecular structure of compound 1-19, whose structure was determined according to the above method, is shown in Figure 1. Compound 1-8 is as follows, and its structural characteristics are shown in Figures 2 and 3 and Table 1-3.
Kazinol V (화합물 1) : 유성 물질; +27.6 (c 0.06, MeOH); ECD (MeOH) λmax (Δε) 212 (2.32); UV (MeOH) λmax (log ε) 214 (1.01), 258 (0.11), 287 (0.23) nm; IR (KBr) vmax 3309, 3005; 1H (500MHz, 메탄올-d 4) 및 13C NMR (125MHz, 메탄올-d 4) 데이터, 표 1 참조; HRESIMS m/z 585.3553 ([M + Na]+, C36H50O5Na, 585.3556). Kazinol V (Compound 1) : Oily substance; +27.6 ( c 0.06, MeOH); ECD (MeOH) λ max (Δε) 212 (2.32); UV (MeOH) λ max (log ε) 214 (1.01), 258 (0.11), 287 (0.23) nm; IR (KBr) v max 3309, 3005; 1 H (500 MHz, methanol- d 4 ) and 13 C NMR (125 MHz, methanol- d 4 ) data, see Table 1; HRESIMS m/z 585.3553 ([M + Na] + , C 36 H 50 O 5 Na, 585.3556).
Broussonol F (화합물 2) : 노란색 무정형 분말; +81.9 (c 0.09, MeOH); ECD (MeOH) λmax (Δε) 297 (-5.8), 330 (1.8); UV (MeOH) λmax (log ε) 252 (0.17), 290 (0.61) nm; IR (KBr) vmax 3370, 2910, 1682; 1H (500MHz, 메탄올-d 4) 및 13C NMR (125MHz, 메탄올-d 4) 데이터, 표 2 및 3 참조; HREIMS m/z 395.1107 [M + Na]+, C20H20O7Na, 395.1107). Broussonol F (Compound 2) : Yellow amorphous powder; +81.9 ( c 0.09, MeOH); ECD (MeOH) λ max (Δε) 297 (-5.8), 330 (1.8); UV (MeOH) λ max (log ε) 252 (0.17), 290 (0.61) nm; IR (KBr) v max 3370, 2910, 1682; 1 H (500 MHz, methanol- d 4 ) and 13 C NMR (125 MHz, methanol- d 4 ) data, see Tables 2 and 3; HREIMS m/z 395.1107 [M + Na] + , C 20 H 20 O 7 Na, 395.1107).
Broussonol G (화합물 3) : 노란색 무정형 분말; +57.4 (c 0.09, MeOH); ECD (MeOH) λmax (Δε) 266 (2.36), 295 (-0.26), 318 (0.84); UV (MeOH) λmax (log ε) 252 (0.13), 290 (0.48) nm; IR (KBr) vmax 3386, 2885, 1644; 1H (500MHz, 메탄올-d 4) 및 13C NMR (125MHz, 메탄올-d 4) 데이터, 표 2 및 3 참조; HRESIMS m/z 463.1734 ([M + Na]+, C25H28O7Na, 463.1733). Broussonol G (Compound 3) : Yellow amorphous powder; +57.4 ( c 0.09, MeOH); ECD (MeOH) λ max (Δε) 266 (2.36), 295 (-0.26), 318 (0.84); UV (MeOH) λ max (log ε) 252 (0.13), 290 (0.48) nm; IR (KBr) v max 3386, 2885, 1644; 1 H (500 MHz, methanol- d 4 ) and 13 C NMR (125 MHz, methanol- d 4 ) data, see Tables 2 and 3; HRESIMS m/z 463.1734 ([M + Na] + , C 25 H 28 O 7 Na, 463.1733).
Broussonol H ( 화합물 4) : 노란색 무정형 분말; +90.7 (c 0.08, MeOH); ECD (MeOH) λmax (Δε) 263 (4.15), 300 (-3.05), 330 (2.17); UV (MeOH) λmax (log ε) 254 (0.16), 290 (0.52) nm; IR (KBr) vmax 3395, 2904, 1652; 1H (500MHz, 메탄올-d 4) 및 13C NMR (125MHz, 메탄올-d 4) 데이터, 표 2 및 3 참조; HRESIMS m/z463.1732 ([M + Na]+, C25H28O7Na, 463.1733). Broussonol H ( compound 4) : yellow amorphous powder; +90.7 (c 0.08, MeOH); ECD (MeOH) λ max (Δε) 263 (4.15), 300 (-3.05), 330 (2.17); UV (MeOH) λ max (log ε) 254 (0.16), 290 (0.52) nm; IR (KBr) v max 3395, 2904, 1652; 1 H (500 MHz, methanol- d 4 ) and 13 C NMR (125 MHz, methanol- d 4 ) data, see Tables 2 and 3; HRESIMS m/z463.1732 ([M + Na] + , C 25 H 28 O 7 Na, 463.1733).
Broussonol I (화합물 5) : 노란색 무정형 분말; +12.1 (c 0.10, MeOH); ECD (MeOH) λmax (Δε) 257 (0.12), 293 (-0.33); UV (MeOH) λmax (log ε) 254 (0.13), 281 (0.27) nm; IR (KBr) vmax 3398, 2966, 1656; 1H (500MHz, 메탄올-d 4) 및 13C NMR (125MHz, 메탄올-d 4) 데이터, 표 2 및 3 참조; HRESIMS m/z 363.1207 ([M + Na]+, C20H20O5Na, 363.1208). Broussonol I (Compound 5) : Yellow amorphous powder; +12.1 ( c 0.10, MeOH); ECD (MeOH) λ max (Δε) 257 (0.12), 293 (-0.33); UV (MeOH) λ max (log ε) 254 (0.13), 281 (0.27) nm; IR (KBr) v max 3398, 2966, 1656; 1 H (500 MHz, methanol- d 4 ) and 13 C NMR (125 MHz, methanol- d 4 ) data, see Tables 2 and 3; HRESIMS m/z 363.1207 ([M + Na] + , C 20 H 20 O 5 Na, 363.1208).
Broussonol K (화합물 6) : 노란색 무정형 분말; +38.8 (c 0.10, MeOH); ECD (MeOH) λmax (Δε) 289 (-1.32); UV (MeOH) λmax (log ε) 254 (0.16), 284 (0.26) nm; IR (KBr) vmax 3335, 2980; 1H (500MHz, 메탄올-d 4) 및 13C NMR (125MHz, 메탄올-d 4) 데이터, 표 2 및 3 참조; HRFABMS m/z 410.2097 ([M]+, C25H30O5, 410.2093). Broussonol K (Compound 6) : Yellow amorphous powder; +38.8 ( c 0.10, MeOH); ECD (MeOH) λ max (Δε) 289 (-1.32); UV (MeOH) λ max (log ε) 254 (0.16), 284 (0.26) nm; IR (KBr) v max 3335, 2980; 1 H (500 MHz, methanol- d 4 ) and 13 C NMR (125 MHz, methanol- d 4 ) data, see Tables 2 and 3; HRFABMS m/z 410.2097 ([M] + , C 25 H 30 O 5 , 410.2093).
Broussonol L (화합물 7) : 노란색 무정형 분말; +49.9 (c 0.1, MeOH); ECD (MeOH) λmax (Δε) 269 (2.24), 293 (-0.24); UV (MeOH) λmax (log ε) 252 (0.14), 275 (0.27) nm; IR (KBr) vmax 3335, 2980; 1H (500MHz, 메탄올-d 4) 및 13C NMR (125MHz, 메탄올-d 4) 데이터, 표 2 및 3 참조; HRESIMS m/z 431.1836 ([M + Na]+, C25H30O5Na, 431.1834). Broussonol L (Compound 7) : Yellow amorphous powder; +49.9 (c 0.1, MeOH); ECD (MeOH) λ max (Δε) 269 (2.24), 293 (-0.24); UV (MeOH) λ max (log ε) 252 (0.14), 275 (0.27) nm; IR (KBr) v max 3335, 2980; 1 H (500 MHz, methanol- d 4 ) and 13 C NMR (125 MHz, methanol- d 4 ) data, see Tables 2 and 3; HRESIMS m/z 431.1836 ([M + Na] + , C 25 H 30 O 5 Na, 431.1834).
Broussonol M (화합물 8) : 노란색 무정형 분말; UV (MeOH) λmax (log ε) 259 (2.5), 349 (1.8) nm; IR (KBr) vmax 3318, 2981, 1650; 1H (500MHz, 메탄올-d 4) 및 13C NMR (125MHz, 메탄올-d 4) 데이터, 표 2 및 3 참조; HRESIMS m/z 393.0950 ([M + Na]+, C20H18O7Na, 393.0947). Broussonol M (Compound 8) : Yellow amorphous powder; UV (MeOH) λ max (log ε) 259 (2.5), 349 (1.8) nm; IR (KBr) v max 3318, 2981, 1650; 1 H (500 MHz, methanol- d 4 ) and 13 C NMR (125 MHz, methanol- d 4 ) data, see Tables 2 and 3; HRESIMS m/z 393.0950 ([M + Na] + , C 20 H 18 O 7 Na, 393.0947).
<< 실시예Example 3. 체외 파골세포 형성에 대한 닥나무 유래 화합물의 효과 확인> 3. Confirmation of the effect of mulberry tree-derived compounds on in vitro osteoclast formation>
RAW264.7 세포는 American Type Culture Collection (Manassas, VA, USA)에서 얻은 다음 스트렙토마이신 (100μg / mL)-페니실린 (100 유닛 / mL) 및 10 % 열 비활성화 FBS를 함유하는 DMEM에서 배양하였다. 상기 RAW264.7 세포 (5 × 104 세포/mL)를 96 웰 플레이트에 시드한 다음, 상기 실시예 1에서 수득한 닥나무 추출물 유래 화합물 1-19를 각각 10 μM의 농도로 처리한 다음, RANKL (100 ng/mL)로 처리하고 배양 배지를 4 일 동안 2 일마다 교체했다. 그 후, 세포를 3.7 % 포르말린으로 15 분 동안 고정한 다음, 0.1 % Triton X-100으로 투과화하고 산성 포스파타제 백혈구 키트 (Sigma-Aldrich; EMD Millipore, Billerica, MA, USA)로 TRAP 염색하여 5 개 이상의 핵을 가진 TRAP 양성 다핵 세포를 파골 세포로 계수하고 도 4A에 나타내었다.RAW264.7 cells were obtained from the American Type Culture Collection (Manassas, VA, USA) and cultured in DMEM containing streptomycin (100 μg/mL)-penicillin (100 units/mL) and 10% heat-inactivated FBS. The RAW264.7 cells (5 × 10 4 cells/mL) were seeded in a 96-well plate, and then treated with mulberry extract-derived compounds 1-19 obtained in Example 1 at a concentration of 10 μM each, followed by RANKL ( 100 ng/mL) and the culture medium was changed every 2 days for 4 days. Afterwards, cells were fixed with 3.7% formalin for 15 min, then permeabilized with 0.1% Triton TRAP-positive multinucleated cells with nuclei were counted as osteoclasts and shown in Figure 4A.
도 4A에서 보는 바와 같이, 화합물 2, 3, 5, 6, 8, 11, 12 및 16은 10 μM에서 RANKL 유도 RAW264.7 세포에서 파골세포의 형성을 억제하는 효과를 나타내었으며, 이 중, 화합물 2, 3, 5 및 6은 파골세포 형성의 억제 효과가 뛰어났다.As shown in Figure 4A, compounds 2, 3, 5, 6, 8, 11, 12, and 16 showed an effect of inhibiting the formation of osteoclasts in RANKL-induced RAW264.7 cells at 10 μM, among which, compounds 2, 3, 5, and 6 had excellent inhibitory effects on osteoclast formation.
특히 화합물 3 및 4는 이성질체로, C-2에서 동일한 절대 배열을 공유하고 있으나, 화합물 3이 4에 비하여 현저한 파골세포 형성 억제 활성을 나타내는 것을 확인하였다. 이는 C-3의 키랄 중심이 항골 세포 형성 활성에 중요한 역할을 하는 것을 시사한다. 또한 화합물 4보다 프레닐기를 하나 더 갖고 있는 화합물 2는 화합물 4와 비교하여 높은 파골세포 형성 억제 활성을 나타내었다. 이를 통해 프레닐기의 추가가 파골세포 형성 억제 활성에 긍적적인 영향을 미친다는 것을 확인할 수 있다. 파골세포 형성 활성과 관련된 -OH 그룹의 영향은 화합물 6과 13을 비교하여 추측할 수 있다. R1 위치에 -OH 그룹을 갖는 화합물 6은 파골세포 형성 억제 활성이 매우 높았으나, 동일 위치에 수소를 갖는 화합물 13의 경우 파골세포 형성 억제 활성은 전혀 나타나지 않았으며, 화합물 13을 처리한 경우, RANKL 유도 RAW264.7 세포는 오히려 파골세포 형성이 증가하였다.In particular, compounds 3 and 4 are isomers and share the same absolute sequence at C-2, but it was confirmed that compound 3 exhibits significant osteoclast formation inhibitory activity compared to 4. This suggests that the chiral center of C-3 plays an important role in anti-osteogenic activity. Additionally, Compound 2, which has one more prenyl group than Compound 4, showed higher osteoclast formation inhibitory activity compared to Compound 4. Through this, it can be confirmed that the addition of a prenyl group has a positive effect on the osteoclast formation inhibitory activity. The influence of the -OH group on osteoclastogenic activity can be inferred by comparing compounds 6 and 13. Compound 6, which has an -OH group at the R1 position, had a very high osteoclast formation inhibitory activity, but Compound 13, which has a hydrogen at the same position, showed no osteoclast formation inhibitory activity at all. When treated with Compound 13, RANKL Induced RAW264.7 cells actually increased osteoclast formation.
<< 실시예Example 4. 닥나무 유래 화합물의 세포 독성 확인> 4. Confirmation of cytotoxicity of mulberry-derived compounds>
닥나무로부터 분리한 화합물의 잠재적인 세포 독성 효과로 인해 RANKL 유도된 파골 세포의 형성을 억제하는지 여부를 확인하기 위해 RAW264.7 세포에 대해 세포 생존력 분석을 수행하였다.Cell viability assay was performed on RAW264.7 cells to determine whether compounds isolated from mulberry tree inhibit the formation of RANKL-induced osteoclasts due to their potential cytotoxic effects.
RAW264.7 세포를 96 웰 플레이트에 시드한 다음 실시예 3에서 수득한 닥나무 추출물 유래 화합물 1-19를 각각 10 μM의 농도로 처리하고 배양하였다. 72 시간 동안 배양한 후, 각 웰에 MTT (0.5 mg/mL)를 첨가한 다음 플레이트를 3 시간 동안 배양하고 불용성 포르마잔을 DMSO에 용해시켜 마이크로 플레이트 리더에서 540nm에서 측정하여 도 4B에 나타내었다. 도 4B에서 보는 바와 같이, 닥나무 추출물 유래 화합물 1-19는 대부분 세포독성을 나타내지 않았으며, 화합물 1, 9, 12 및 15는 대조군 30~40%의 세포 생존률 저하를 나타냈다. 상기 실시예 4에서 파골세포 형성 억제 활성을 가장 높게 나타낸 화합물 5의 경우, 대조군에 비하여 약 15% 세포 생존률이 저하되는 것이 나타나, 화합물 5의 파골세포 형성 억제 활성이 세포 독성 효과에도 기인할 수 있음을 보여주었다. 그러나 역시 파골세포 형성 억제 활성이 매우 높은 화합물 2, 3 및 6의 경우, 세포 독성은 전혀 나타내지 않았다.RAW264.7 cells were seeded in a 96-well plate, then treated with compounds 1-19 derived from mulberry extract obtained in Example 3 at a concentration of 10 μM and cultured. After incubation for 72 hours, MTT (0.5 mg/mL) was added to each well, then the plate was incubated for 3 hours, and insoluble formazan was dissolved in DMSO, measured at 540 nm in a microplate reader, as shown in Figure 4B. As shown in Figure 4B, most of the compounds 1-19 derived from mulberry extract did not show cytotoxicity, and compounds 1, 9, 12, and 15 showed a decrease in cell viability of 30-40% of the control group. In the case of Compound 5, which showed the highest osteoclast formation inhibitory activity in Example 4, the cell viability decreased by about 15% compared to the control group, suggesting that the osteoclast formation inhibitory activity of Compound 5 may also be due to a cytotoxic effect. showed. However, compounds 2, 3, and 6, which also had very high osteoclast formation inhibitory activity, did not show any cytotoxicity.
<< 실시예Example 5. 닥나무 유래 화합물의 농도별 파골세포 형성 억제 효과 확인> 5. Confirmation of the inhibitory effect of mulberry tree-derived compounds on osteoclast formation at different concentrations>
상기 실시예 4에서 세포 독성 없이 파골세포 형성 억제 효과를 나타내는 것으로 확인한 화합물 2, 3 및 6의 파골세포 형성 억제 활성을 다양한 농도에서 확인하였다.The osteoclast formation inhibitory activity of compounds 2, 3, and 6, which were confirmed to exhibit an osteoclast formation inhibitory effect without cytotoxicity in Example 4, was confirmed at various concentrations.
골수 세포는 ICR 마우스 (6 주령) (DBL, Emseong, Chungbuk, Korea)의 경골과 대퇴골에서 채취한 후 100 U/mL 페니실린이 보충 된 α-MEM (Hyclone, Logan, UT, USA)에서 배양하였다. 10 ng/mL M-CSF, 100 μg/mL 스트렙토마이신 및 10 % FBS (Cambrex, Charles City, IA, USA) 를 37℃에서 5 % CO2 가습 인큐베이터에서 밤새 배양하고 부유 세포를 수집하여 30 ng/mL M-CSF에서 3 일 동안 배양하였다. 이후 배양 접시 바닥에 붙어있는 세포를 BMM으로 분류하여 추가 실험에 사용했다.Bone marrow cells were harvested from the tibia and femur of ICR mice (6 weeks old) (DBL, Emseong, Chungbuk, Korea) and cultured in α-MEM (Hyclone, Logan, UT, USA) supplemented with 100 U/mL penicillin. 10 ng/mL M-CSF, 100 μg/mL streptomycin, and 10% FBS (Cambrex, Charles City, IA, USA) were incubated overnight in a humidified incubator at 37°C with 5% CO 2 and floating cells were collected and incubated at 30 ng/mL. Cultured in mL M-CSF for 3 days. Afterwards, the cells attached to the bottom of the culture dish were classified into BMM and used for further experiments.
상기 BMM (5 × 105 세포/mL)을 시드하고 이후 1 % 스트렙토마이신, 페니실린과 10 % FBS가 함유된 α-MEM에서 BMM을 배양한 후 RANKL (100 ng/mL), M-CSF (30 ng/mL)에서, 화합물 2, 3 및 6의 0, 3, 10, 30 μM로 처리하였다. 이후, 2 일마다 각 화합물이 포함된 배양 배지를 교체하고 7 일 후 TRAP 염색을 통하여 5 개 이상의 핵을 가진 TRAP 양성 다핵 세포를 파골 세포로 계수하고 그 결과를 도 5A(화합물 2), 5B(화합물 3) 및 5C(화합물 6)에 나타내었다.The BMMs ( 5 ng/mL), treated with 0, 3, 10, and 30 μM of compounds 2, 3, and 6. Afterwards, the culture medium containing each compound was replaced every 2 days, and after 7 days, TRAP-positive multinucleated cells with more than 5 nuclei were counted as osteoclasts through TRAP staining, and the results are shown in Figures 5A (compound 2) and 5B ( It is shown in Compound 3) and 5C (Compound 6).
도 5A 내지 5C에서 보는 바와 같이, 화합물 2, 3, 및 6 모두 농도 의존적으로 파골세포 형성 억제 효과를 나타내었다. 화합물 2는 30 μM에서 파골세포 형성 억제 효과가 현저히 나타났으며, 화합물 3 및 6의 경우 10 μM에서 파골세포 형성 억제 효과가 현저히 나타났다.As shown in Figures 5A to 5C, compounds 2, 3, and 6 all showed an inhibitory effect on osteoclast formation in a concentration-dependent manner. Compound 2 showed a significant inhibitory effect on osteoclast formation at 30 μM, and compounds 3 and 6 showed a significant inhibitory effect on osteoclast formation at 10 μM.
<< 실시예Example 6. 닥나무 유래 화합물의 재흡수 피트 형성 억제 효과 확인> 6. Confirmation of the inhibitory effect of mulberry tree-derived compounds on resorption peat formation>
상기 실시예를 통해 세포독성을 나타내지 않으면서 적은 농도에서 파골세포 형성 억제 효과가 뛰어난 화합물 중 하나인 닥나무 유래 화합물 6의 재흡수 피트 형성에 미치는 효과를 확인하였다.Through the above examples, the effect on the formation of resorption pits of paper mulberry-derived compound 6, which is one of the compounds with excellent osteoclast formation inhibition effect at low concentrations without showing cytotoxicity, was confirmed.
OsteoAssay Surface 96-웰 플레이트 (Corning Incorporated, Corning, NY, USA)를 사용하여 BMM (5 × 105 세포/mL)을 시드하고 이후 1 % 스트렙토마이신, 페니실린과 10 % FBS가 함유된 α-MEM에서 BMM을 배양한 후 RANKL (100 ng/mL), M-CSF (30 ng/mL)에서, 0, 1, 3, 10 및 30 μM의 화합물 6을 처리하였다. 이후, 2 일마다 배양 배지를 교체하고 7 일 후, 차아염소산나트륨 용액을 사용하여 웰에서 세포를 완전히 제거하였다. 재흡수 피트는 모델 H550L 현미경 (Nikon Corporation, Tokyo, Japan)으로 캡처하고 ImageJ 소프트웨어 (Java 1.6.0_20 (64bit); NIH, Bethesda, MD, USA)로 정량화하여 도 6에 나타내었다.OsteoAssay Surface 96-well plates (Corning Incorporated, Corning, NY, USA) were used to seed BMM (5 × 105 cells/mL) and then seeded in α-MEM containing 1% streptomycin, penicillin and 10% FBS. After culturing BMMs, they were treated with 0, 1, 3, 10, and 30 μM of Compound 6 in RANKL (100 ng/mL), M-CSF (30 ng/mL). Thereafter, the culture medium was changed every 2 days, and after 7 days, cells were completely removed from the wells using sodium hypochlorite solution. The resorption pits were captured with a model H550L microscope (Nikon Corporation, Tokyo, Japan) and quantified with ImageJ software (Java 1.6.0_20 (64bit); NIH, Bethesda, MD, USA) and shown in Figure 6.
도 6에서 보는 바와 같이, 화합물 6은 RANKL 및 M-CSF 유도 BMM의 골 재흡수를 농도 의존적으로 감소시켰다. 특히 10 μM 이상의 농도에서 골 재흡수를 크게 감소시켜 닥나무 유래 화합물 6이 성숙한 파골 세포 형성을 억제할 수 있음을 나타었다.As shown in Figure 6, compound 6 reduced RANKL- and M-CSF-induced bone resorption of BMM in a concentration-dependent manner. In particular, it was shown that mulberry-derived compound 6 can inhibit the formation of mature osteoclasts by significantly reducing bone resorption at a concentration of 10 μM or higher.
<< 제제예example 1. 약학적 제제> 1. Pharmaceutical preparations>
1.1. 정제의 제조1.1. manufacture of tablets
본 발명의 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물 200㎎을 락토즈 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄하여 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활성 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다. 200 mg of the mulberry extract of the present invention or a prenylated compound isolated therefrom was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silicic acid. A 10% gelatin solution was added to this mixture, then pulverized and passed through a 14 mesh sieve. This was dried and 160 g of potato starch, 50 g of activator, and 5 g of magnesium stearate were added thereto, and the resulting mixture was made into tablets.
1.2. 주사액제의 제조1.2. Manufacturing of injectable solutions
본 발명의 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물 100㎎, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다. 100 mg of the mulberry extract of the present invention or a prenylated compound isolated therefrom, 0.6 g of sodium chloride, and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20°C for 30 minutes.
<< 제제예example 2. 건강기능식품의 제조> 2. Manufacturing of health functional foods>
2.1. 건강기능식품의 제조2.1. Manufacturing of health functional foods
본 발명의 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물 2g, 비타민 혼합물 적량, 비타민 A 아세테이트 70㎍, 비타민 E 1.0㎎, 비타민 B1 0.13㎎, 비타민 B2 0.15㎎, 비타민 B6 0.5㎎, 비타민 B12 0.2㎍, 비타민 C 10㎎, 비오틴 10㎍, 니코틴산아미드 1.7㎎, 엽산 50㎍, 판토텐산 칼슘 0.5㎎, 무기질 혼합물 적량, 황산제1철 1.75㎎, 산화아연 0.82㎎, 탄산 마그네슘 25.3㎎, 제1인산칼륨 15㎎, 제2인산칼슘 55㎎, 구연산칼륨 90㎎, 탄산칼슘 100㎎, 염화마그네슘 24.8㎎을 섞어 과립으로 제조하였으나, 용도에 따라 다양한 제형으로 변형시켜 제조할 수 있다. 또한, 상기의 비타민 및 미네랄 혼합물의 조성비를 임의로 변형 실시하여도 무방하며, 통상의 건강기능식품 제조방법에 따라 상기의 성분을 혼합하여 제조할 수 있다.2 g of mulberry extract of the present invention or a prenylated compound isolated therefrom, appropriate amount of vitamin mixture, 70 μg of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B1, 0.15 mg of vitamin B2, 0.5 mg of vitamin B6, 0.2 μg of vitamin B12, Vitamin C 10㎎, biotin 10㎍, nicotinic acid 1.7㎎, folic acid 50㎍, calcium pantothenate 0.5㎎, mineral mixture, ferrous sulfate 1.75㎎, zinc oxide 0.82㎎, magnesium carbonate 25.3㎎, monobasic potassium phosphate 15㎎ , 55 mg of dicalcium phosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride were mixed to form granules, but it can be manufactured by modifying it into various dosage forms depending on the use. In addition, the composition ratio of the vitamin and mineral mixture may be arbitrarily modified, and the above ingredients may be mixed according to a typical health functional food manufacturing method.
2.2. 건강기능성 음료의 제조2.2. Manufacturing of health functional beverages
본 발명의 닥나무 추출물 또는 이로부터 분리한 프레닐화 화합물 1g, 구연산 0.1g, 프락토올리고당 100g, 정제수 900g을 섞어 통상의 음료 제조방법에 따라 교반, 가열, 여과, 살균, 냉장하여 음료를 제조하였다.A beverage was prepared by mixing 1 g of the mulberry extract of the present invention or a prenylated compound isolated therefrom, 0.1 g of citric acid, 100 g of fructooligosaccharide, and 900 g of purified water and stirring, heating, filtering, sterilizing, and refrigerating according to a typical beverage production method.
Claims (9)
상기 프레닐화 화합물은 하기 화학식 [2]로 표현되는 화합물 2, 3, 5 및 6으로 이루어진 군으로부터 선택되는 1 이상을 포함하며,
상기 골 용해성 골 질환은 류마티스성 관절염 또는 골다공증인 것을 특징으로 하는 골 용해성 골 질환의 예방 또는 치료용 조성물.
화학식 [2]
A composition for preventing or treating osteolytic bone disease comprising a prenylated compound isolated from mulberry extract,
The prenylated compound includes one or more selected from the group consisting of compounds 2, 3, 5, and 6 represented by the following formula [2],
A composition for preventing or treating osteolytic bone disease, wherein the osteolytic bone disease is rheumatoid arthritis or osteoporosis.
Chemical formula [2]
상기 프레닐화 화합물은 하기 화학식 [2]로 표현되는 화합물 2, 3, 5 및 6으로 이루어진 군으로부터 선택되는 1 이상을 포함하며,
상기 골 용해성 골 질환은 류마티스성 관절염 또는 골다공증인 것을 특징으로 하는 골 용해성 골 질환의 예방 또는 개선용 건강기능식품.
화학식 [2]
In the health functional food for preventing or improving osteolytic bone disease containing a prenylated compound isolated from mulberry extract,
The prenylated compound includes one or more selected from the group consisting of compounds 2, 3, 5, and 6 represented by the following formula [2],
A health functional food for preventing or improving osteolytic bone disease, wherein the osteolytic bone disease is rheumatoid arthritis or osteoporosis.
Chemical formula [2]
화학식 [3]
A new compound selected from the group consisting of compounds 1-4 and 6-8 represented by the following formula [3].
Chemical formula [3]
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| KR101165248B1 (en) * | 2010-06-04 | 2012-07-18 | 숙명여자대학교산학협력단 | Pharmaceutical compositions for prevention and treatment of menopausal symptoms or osteoporosis containing the flavan compounds or the pharmaceutically acceptable salts thereof as active ingredient |
| KR101695002B1 (en) * | 2010-08-13 | 2017-01-12 | (주)아모레퍼시픽 | Composition of skin external application containing propanoid derivatives |
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| KR101693725B1 (en) | 2014-10-23 | 2017-01-09 | 단국대학교 천안캠퍼스 산학협력단 | Composition for inhibiting angiogenesis comprising Broussonetia kazinoki extract |
| KR101914202B1 (en) | 2017-06-26 | 2018-11-01 | 재단법인 경기도경제과학진흥원 | Composition for treating, preventing or alleviating bone diseases comprising extract of edgeworthia papyrifera |
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