KR20230164451A - Composition for preventing, ameliorating or treating bone disease comprising 1,3-dibenzyl-5-fluorouracil as effective component - Google Patents
Composition for preventing, ameliorating or treating bone disease comprising 1,3-dibenzyl-5-fluorouracil as effective component Download PDFInfo
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- KR20230164451A KR20230164451A KR1020220064214A KR20220064214A KR20230164451A KR 20230164451 A KR20230164451 A KR 20230164451A KR 1020220064214 A KR1020220064214 A KR 1020220064214A KR 20220064214 A KR20220064214 A KR 20220064214A KR 20230164451 A KR20230164451 A KR 20230164451A
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- bone
- fluorouracil
- dibenzyl
- preventing
- bone disease
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Abstract
본 발명은 1,3-디벤질-5-플루오로우라실을 유효성분으로 함유하는 골질환의 예방, 개선 또는 치료용 조성물에 관한 것으로, 상세하게는 1,3-디벤질-5-플루오로우라실은 세포독성이 없으며, 파골세포의 생성 및 분화 억제 활성이 우수하고, 난소를 절제한 마우스에서 감소된 골밀도, 해면골과 피지골의 체적비 및 해면골 수를 증가시키고, 증가된 해면골 분리 수치를 감소시키는 효과가 우수하므로, 골질환에 대한 의약품, 건강기능식품 등에 유용하게 사용할 수 있다.The present invention relates to a composition for preventing, improving or treating bone disease containing 1,3-dibenzyl-5-fluorouracil as an active ingredient, and specifically, 1,3-dibenzyl-5-fluorouracil. It has no cytotoxicity, has excellent activity in suppressing the generation and differentiation of osteoclasts, and has the effect of increasing the reduced bone density, volume ratio of cancellous bone and sebaceous bone, and number of cancellous bones in ovariectomized mice, and reducing the increased number of cancellous bone separations. Because it is excellent, it can be usefully used in medicines for bone diseases, health functional foods, etc.
Description
본 발명은 1,3-디벤질-5-플루오로우라실을 유효성분으로 함유하는 골질환의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, improving or treating bone disease containing 1,3-dibenzyl-5-fluorouracil as an active ingredient.
뼈(bone)는 인체의 연조직과 체중을 지탱해주고 내부기관을 둘러싸서 내부 장기를 외부의 충격으로부터 보호한다. 또한, 근육이나 장기를 구조적으로 지탱할 뿐만 아니라 체내의 칼슘이나 다른 필수 무기질 즉 인이나 마그네슘과 같은 물질을 저장하는 인체의 중요한 부분 중 하나이다.Bone supports the body's soft tissues and body weight, surrounds internal organs, and protects them from external shock. In addition, it is one of the important parts of the human body that not only structurally supports muscles and organs, but also stores substances such as calcium and other essential minerals, such as phosphorus and magnesium.
뼈는 세포, 콜라겐성 기질 및 무기질 성분으로 구성된 매우 복잡한 조직이다. 이들은 장기의 보호뿐만 아니라, 조혈화에 필요한 미세 환경제공과 같은 기본적이며 다양한 기능을 제공하여 준다. 또한, 근육이나 장기를 구조적으로 지탱할 뿐만 아니라 체내의 칼슘이나 다른 필수 무기질 즉, 인이나 마그네슘과 같은 물질을 저장하는 인체의 중요한 부분 중 하나이다.Bone is a very complex tissue composed of cells, collagenous matrix and mineral components. They provide basic and diverse functions such as protecting organs as well as providing the microenvironment necessary for hematopoiesis. In addition, it is one of the important parts of the human body that not only structurally supports muscles and organs, but also stores substances such as calcium and other essential minerals, such as phosphorus and magnesium.
성장이 끝난 성인의 뼈는 멈추지 않고 죽는 날까지 오래된 뼈는 제거하고 새로운 뼈로 대체하는 생성과 흡수 과정을 매우 역동적이고, 지속적으로 반복 재생하면서 균형을 유지하게 된다. 이를 골재형성(bone remodeling)이라고 한다.Adult bones that have completed growth do not stop, but until the day of death, the process of creation and resorption, in which old bone is removed and replaced with new bone, is very dynamic and continuously regenerates, maintaining balance. This is called bone remodeling.
오래된 뼈는 제거하고 새로운 뼈로 대체하는 순환(turnover)은 성장과 스트레스에 의해서 일어나는 뼈의 미세한 손상을 회복시키고 적절히 뼈의 기능을 유지하는데 필수적이다. 골재형성은 크게 두 종류의 세포가 관여하는 것으로 알려졌다. 두 세포 중 하나는 뼈를 생성하는 조골세포(osteoblast)이고, 다른 하나는 뼈를 파괴하는 파골세포(osteoclast)이다. 조골세포는 RANKL(receptor activator of nuclear factor-κB ligand)과 이것의 유도 수용체(decoy receptor)인 OPG(osteoprotegerin)를 생성한다. RANKL이 파골 전구세포(osteoclast progenitor cells) 표면에 있는 수용체인 RANK(receptor activator of nuclear factor-κB)에 결합하면 파골 전구세포가 거대 다핵 파골세포로 성숙화되어 골 흡수(bone resorption)가 일어난다. 그러나 OPG가 RANKL과 결합하면 RANKL과 RANK 사이의 결합이 차단되어 파골세포의 형성이 억제되고 필요 이상의 골 흡수가 일어나지 않게 된다. 이러한 파골세포의 활성으로 오래된 뼈의 흡수 또는 파괴가 이루어지며 이는 뼈에 구멍을 내어 적은 양의 칼슘이 혈류로 방출되어 신체기능을 유지하는데 사용된다.The cycle of removing old bone and replacing it with new bone (turnover) is essential for recovering microscopic damage to bone caused by growth and stress and maintaining proper bone function. It is known that two types of cells are largely involved in bone remodeling. One of the two cells is an osteoblast, which creates bone, and the other is an osteoclast, which destroys bone. Osteoblasts produce RANKL (receptor activator of nuclear factor-κB ligand) and its decoy receptor, OPG (osteoprotegerin). When RANKL binds to RANK (receptor activator of nuclear factor-κB), a receptor on the surface of osteoclast progenitor cells, the osteoclast progenitor cells mature into giant multinucleated osteoclasts and bone resorption occurs. However, when OPG binds to RANKL, the bond between RANKL and RANK is blocked, inhibiting the formation of osteoclasts and preventing unnecessary bone resorption. The activity of these osteoclasts causes resorption or destruction of old bone, which creates holes in the bone and releases a small amount of calcium into the bloodstream, which is used to maintain body functions.
골질환 관련 선행기술로는 한국등록특허 제2376512호에 '4-헥실레소르시놀을 유효성분으로 포함하는 골질환 예방 또는 치료용 약학조성물'이 개시되어 있으며, 한국등록특허 제2015488호에 '트리메틸피라진을 유효성분으로 함유하는 골다공증의 예방 또는 치료용 약학적 조성물'이 개시되어 있다. 하지만, 본 발명의 '1,3-디벤질-5-플루오로우라실을 유효성분으로 함유하는 골질환의 예방, 개선 또는 치료용 조성물'에 대해서는 아직까지 개시된 바가 없다.As prior art related to bone disease, Korean Patent No. 2376512 discloses ‘Pharmaceutical composition for preventing or treating bone disease containing 4-hexylresorcinol as an active ingredient’, and Korean Patent No. 2015488 discloses ‘Pharmaceutical composition for preventing or treating bone disease. A pharmaceutical composition for preventing or treating osteoporosis containing trimethylpyrazine as an active ingredient is disclosed. However, the 'composition for preventing, improving or treating bone disease containing 1,3-dibenzyl-5-fluorouracil as an active ingredient' of the present invention has not yet been disclosed.
본 발명은 상기와 같은 요구에 의해 도출된 것으로서, 본 발명은 1,3-디벤질-5-플루오로우라실(1,3-dibenzyl-5-fluorouracil)을 유효성분으로 함유하는 골질환의 예방, 개선 또는 치료용 조성물을 제공하고, 1,3-디벤질-5-플루오로우라실은 세포독성이 없으며, 파골세포의 생성 및 분화 억제 활성이 우수하고, 난소를 절제한 마우스에서 감소된 골밀도, 해면골과 피지골의 체적비 및 해면골 수를 증가시키고, 증가된 해면골 분리 수치를 감소시키는 것을 확인함으로써, 본 발명을 완성하였다.The present invention was developed in response to the above-mentioned needs, and the present invention is directed to preventing bone diseases containing 1,3-dibenzyl-5-fluorouracil as an active ingredient, A composition for improvement or treatment is provided, and 1,3-dibenzyl-5-fluorouracil has no cytotoxicity, has excellent activity in suppressing the generation and differentiation of osteoclasts, and has reduced bone density and cancellous bone in ovariectomized mice. The present invention was completed by confirming that the volume ratio of sebaceous bone and the number of cancellous bones were increased, and the increased number of cancellous bone separations was reduced.
상기 과제를 해결하기 위하여, 본 발명은 화학식 1의 1,3-디벤질-5-플루오로우라실(1,3-dibenzyl-5-fluorouracil) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 골질환의 예방 또는 치료용 약학 조성물을 제공한다.In order to solve the above problem, the present invention provides a method containing 1,3-dibenzyl-5-fluorouracil of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for preventing or treating bone disease is provided.
또한, 본 발명은 화학식 1의 1,3-디벤질-5-플루오로우라실(1,3-dibenzyl-5-fluorouracil) 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 함유하는 골질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a method for preventing or treating bone disease containing 1,3-dibenzyl-5-fluorouracil of Formula 1 or a foodologically acceptable salt thereof as an active ingredient. Provides a health functional food composition for improvement.
또한, 본 발명은 화학식 1의 1,3-디벤질-5-플루오로우라실(1,3-dibenzyl-5-fluorouracil) 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 함유하는 골질환의 예방 또는 개선용 사료 첨가제를 제공한다.In addition, the present invention provides a method for preventing or treating bone disease containing 1,3-dibenzyl-5-fluorouracil of Formula 1 or a foodologically acceptable salt thereof as an active ingredient. Provides feed additives for improvement.
본 발명의 1,3-디벤질-5-플루오로우라실은 세포독성이 없으며, 파골세포의 생성 및 분화 억제 활성이 우수하고, 난소를 절제한 마우스에서 감소된 골밀도, 해면골과 피지골의 체적비 및 해면골 수를 증가시키고, 증가된 해면골 분리 수치를 감소시키는 효과가 있다.1,3-dibenzyl-5-fluorouracil of the present invention has no cytotoxicity, has excellent activity in suppressing osteoclast production and differentiation, and has reduced bone density, volume ratio of cancellous bone and sebaceous bone, and reduced bone density in ovariectomized mice. It has the effect of increasing the number of cancellous bones and reducing the increased number of cancellous bone separations.
도 1은 본 발명의 1,3-디벤질-5-플루오로우라실의 처리 농도에 따른 골수 유래 대식세포(BMMs; bone marrow-derived macrophages)의 세포 생존율을 확인한 결과이다. mock는 1,3-디벤질-5-플루오로우라실을 처리하지 않은 대조군이고, n.s.는 대조군(mock)과 1,3-디벤질-5-플루오로우라실을 처리한 실험군간에 통계적으로 유의한 차이가 없다는 것을 의미한다.
도 2는 골수 유래 대식세포에 본 발명의 1,3-디벤질-5-플루오로우라실을 처리하고 TRAP(Tartrate-resistant acid phosphatase) 염색 후, 촬영한 사진(A), TRAP 양성 다핵 파골세포 수(B) 및 TRAP 활성을 나타낸 그래프(C)이다. mock는 M-CSF 및 RANKL을 처리한 대조군이다. *은 M-CSF 및 RANKL을 처리한 대조군(mock) 대비 M-CSF 및 RANKL과 함께 1,3-디벤질-5-플루오로우라실을 농도별로 처리한 실험군(25, 50 및 100μM)의 TRAP 양성 다핵 파골세포 수 및 TRAP 활성이 통계적으로 유의미하게 감소하였다는 것으로, *은 p<0.05이다.
도 3은 본 발명의 1,3-디벤질-5-플루오로우라실의 처리 시간에 따른 RANKL(receptor activator of NF-kappaB ligand)로 유도된 신호전달 관련 단백질(p-IκBα, p-p65, p-p38, p-ERK, p-JNK)의 발현량 변화를 확인한 결과이다. mock는 1,3-디벤질-5-플루오로우라실을 처리하지 않은 대조군이다.
도 4는 난소를 절제한 마우스에 본 발명의 1,3-디벤질-5-플루오로우라실(10mg/kg)을 처리하고, TRAP 염색 및 헤마톡실린 염색을 통해 대퇴골의 소주 영역에서 골 조직학적 형태(A) 및 파골세포 형성(B)을 촬영한 사진이고, TRAP 양성 다핵 파골세포(TRAP+ MNC) 수를 계수하여 나타낸 그래프(C)이다. Sham은 난소를 절제하지 않은 정상군이고, OVX는 난소를 절제한 대조군이다. *는 난소를 절제한 대조군(OVX) 대비 난소를 절제하고 1,3-디벤질-5-플루오로우라실을 처리한 실험군(10mg/kg)의 TRAP 양성 다핵 파골세포 수가 통계적으로 유의미하게 감소하였다는 것으로, p<0.05이다.
도 5는 난소를 절제한 마우스에 1,3-디벤질-5-플루오로우라실(10mg/kg)을 처리하고 마이크로 CT 분석을 통해 골구조 변화를 촬영한 사진(A)이고, 해면질 부위의 골밀도(BMD), 해면골과 피지골의 체적비(BV/TV), 해면골 수(Tb.N) 및 해면골 분리(Tb.Sp.) 수치를 나타낸 그래프(B)이다. Sham은 난소를 절제하지 않은 정상군이고, OVX는 난소를 절제한 대조군이다. ###는 난소를 절제하지 않은 정상군(Sham) 대비 난소를 절제한 대조군(OVX)의 해면질 부위의 골밀도(BMD), 해면골과 피지골의 체적비(BV/TV), 해면골 수(Tb.N) 및 해면골 분리(Tb.Sp.) 수치가 통계적으로 유의미하게 감소 또는 증가하였다는 것으로, p<0.001이다. *** 및 **는 난소를 절제한 정상군(OVX) 대비 난소를 절제하고 1,3-디벤질-5-플루오로우라실을 처리한 실험군(10mg/kg)의 골밀도(BMD), 해면골과 피지골의 체적비(BV/TV) 및 해면골 수(Tb.N)가 통계적으로 유의미하게 증가하였다는 것으로, ***은 p<0.001이고, **는 p<0.01이다. *는 난소를 절제한 정상군(OVX) 대비 난소를 절제하고 1,3-디벤질-5-플루오로우라실을 처리한 실험군(10mg/kg)의 해면골 분리(Tb.Sp.) 수치가 통계적으로 유의미하게 감소하였다는 것으로, p<0.05이다. Figure 1 shows the results of confirming the cell survival rate of bone marrow-derived macrophages (BMMs) according to the treatment concentration of 1,3-dibenzyl-5-fluorouracil of the present invention. mock is the control group not treated with 1,3-dibenzyl-5-fluorouracil, and ns is the statistically significant difference between the control group (mock) and the experimental group treated with 1,3-dibenzyl-5-fluorouracil. It means that there is no.
Figure 2 is a photograph (A) taken after treating bone marrow-derived macrophages with 1,3-dibenzyl-5-fluorouracil of the present invention and staining with TRAP (Tartrate-resistant acid phosphatase), showing the number of TRAP-positive multinucleated osteoclasts. (B) and a graph showing TRAP activity (C). mock is the control group treated with M-CSF and RANKL. * indicates TRAP positivity in the experimental group (25, 50, and 100 μM) treated with 1,3-dibenzyl-5-fluorouracil at different concentrations along with M-CSF and RANKL compared to the control group (mock) treated with M-CSF and RANKL. The number of multinucleated osteoclasts and TRAP activity were statistically significantly reduced, * means p<0.05.
Figure 3 shows the signal transduction-related proteins (p-IκBα, p-p65, p) induced by RANKL (receptor activator of NF-kappaB ligand) according to the treatment time of 1,3-dibenzyl-5-fluorouracil of the present invention. This is the result of confirming changes in the expression level of -p38, p-ERK, p-JNK). mock is a control group that was not treated with 1,3-dibenzyl-5-fluorouracil.
Figure 4 shows ovariectomized mice treated with 1,3-dibenzyl-5-fluorouracil (10 mg/kg) of the present invention, and bone histology in the trabecular region of the femur through TRAP staining and hematoxylin staining. This is a photograph of the morphology (A) and osteoclast formation (B), and a graph (C) showing the number of TRAP-positive multinucleated osteoclasts (TRAP + MNC) counted. Sham is the normal group without ovaries removed, and OVX is the control group with ovaries removed. * indicates a statistically significant decrease in the number of TRAP-positive multinucleated osteoclasts in the experimental group (10 mg/kg) in which the ovaries were removed and treated with 1,3-dibenzyl-5-fluorouracil compared to the control group (OVX) in which the ovaries were removed. That is, p<0.05.
Figure 5 is a photograph (A) of ovariectomized mice treated with 1,3-dibenzyl-5-fluorouracil (10 mg/kg) and bone structure changes taken through micro-CT analysis, and bone density in the spongy area. This is a graph (B) showing the values of (BMD), volume ratio of cancellous bone and sebaceous bone (BV/TV), cancellous bone number (Tb.N), and cancellous bone separation (Tb.Sp.). Sham is the normal group without ovaries removed, and OVX is the control group with ovaries removed. ### represents bone mineral density (BMD), cancellous bone to sebaceous bone volume ratio (BV/TV), and cancellous bone count (Tb.N) in the cancellous area of the control group (OVX) with ovariectomy compared to the normal group without ovariectomy (Sham). ) and trabecular bone separation (Tb.Sp.) values were statistically significantly decreased or increased, p<0.001. *** and ** represent bone mineral density (BMD), cancellous bone and This means that the volume ratio of sebaceous bone (BV/TV) and cancellous bone number (Tb.N) increased statistically significantly, where *** indicates p<0.001 and ** indicates p<0.01. * indicates the trabecular bone separation (Tb.Sp.) value of the experimental group (10 mg/kg) with ovaries removed and treated with 1,3-dibenzyl-5-fluorouracil compared to the normal group (OVX) with ovaries removed. There was a significant decrease, which means p<0.05.
본 발명의 목적을 달성하기 위하여, 본 발명은 하기 화학식 1의 1,3-디벤질-5-플루오로우라실(1,3-dibenzyl-5-fluorouracil) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 골질환의 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the purpose of the present invention, the present invention uses 1,3-dibenzyl-5-fluorouracil of the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. Provided is a pharmaceutical composition for preventing or treating bone disease containing.
상기 1,3-디벤질-5-플루오로우라실은 파골세포의 분화 및 생성을 억제하고, 상기 골질환은 골소실에 의해 야기될 수 있으며, 상기 골질환은 골다공증, 골다공증성 골절, 골소실증, 골결손, 불유합골절, 골형성 부전증, 골연화증, 골연화증성 골절, 골형성 장애, 종양에 의한 골파괴(Neoplastic bone destruction), 치주질환(Periodontal disease)에 의한 골파괴 및 퇴행성 골질환 중에서 선택된 어느 하나인 것이 바람직하지만 이에 제한하는 것은 아니다. The 1,3-dibenzyl-5-fluorouracil inhibits the differentiation and production of osteoclasts, and the bone disease can be caused by bone loss, and the bone disease includes osteoporosis, osteoporotic fractures, bone loss, Any one selected from bone defects, nonunion fractures, osteogenesis imperfecta, osteomalacia, osteomalacia fractures, osteogenesis imperfecta, neoplastic bone destruction due to tumors, bone destruction due to periodontal disease, and degenerative bone disease. It is desirable, but not limited to this.
상기 약학적으로 허용 가능한 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 아세트산, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 다이하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.As the pharmaceutically acceptable salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and nitrate. Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube. Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, Includes glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.
본 발명의 약학 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The pharmaceutical composition of the present invention may further include appropriate carriers, excipients, or diluents commonly used in the preparation of pharmaceutical compositions.
본 발명에 따른 조성물의 약학적 투여 형태는 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다.The pharmaceutical dosage form of the composition according to the present invention can be used alone or in combination with other pharmaceutically active compounds, as well as in appropriate combinations.
본 발명에 따른 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화 하여 사용될 수 있으나 이에 한정되는 것은 아니다. 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(Calcium carbonate), 수크로스(Sucrose) 또는 락토오스(Lactose), 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 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 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(Witepsol), 마크로골, 트윈(Tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical composition according to the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods. However, it is not limited to this. Carriers, excipients, and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, and methyl. Examples include 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, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the extract with at least one excipient, such as starch, calcium carbonate, and sucrose. ) or prepared by mixing lactose, gelatin, etc. Additionally, 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, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. there is. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, Witepsol, Macrogol, Tween 61, cacao, laurin, glycerogeratin, etc. can be used.
본 발명의 약학 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 약학 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장, 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내(intracerebroventricular) 주사에 의해 투여될 수 있다.The preferred dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, degree of disease, drug form, administration route and period, but can be appropriately selected by a person skilled in the art. The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans through various routes. All modes of administration are contemplated, for example, oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebroventricular injection.
또한, 본 발명은 화학식 1의 1,3-디벤질-5-플루오로우라실(1,3-dibenzyl-5-fluorouracil) 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 함유하는 골질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a method for preventing or treating bone disease containing 1,3-dibenzyl-5-fluorouracil of Formula 1 or a foodologically acceptable salt thereof as an active ingredient. Provides a health functional food composition for improvement.
상기 골질환의 예방 또는 개선용 건강기능식품 조성물은 분말, 과립, 환, 정제, 캡슐, 캔디, 시럽, 발포정 및 음료 중에서 선택된 어느 하나의 제형으로 제조될 수 있으나, 이에 제한되지 않는다.The health functional food composition for preventing or improving bone disease may be manufactured in any one formulation selected from powder, granule, pill, tablet, capsule, candy, syrup, effervescent tablet, and beverage, but is not limited thereto.
본 발명의 건강기능식품 조성물을 식품첨가물로 사용하는 경우, 상기 건강기능식품 조성물을 그대로 첨가하거나 다른 식품 또는 식품성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 양은 그의 사용 목적(예방 또는 개선)에 따라 적절하게 사용될 수 있다. 일반적으로, 식품 또는 음료의 제조시 본 발명의 건강기능식품 조성물은 원료에 대하여 15 중량부 이하, 바람직하게는 10 중량부 이하의 양으로 첨가된다. 그러나 건강을 목적으로 하는 장기간의 섭취인 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로 사용될 수 있다.When using the health functional food composition of the present invention as a food additive, the health functional food composition may be added as is or used together with other foods or food ingredients, and may be used appropriately according to conventional methods. The amount of active ingredient can be appropriately used depending on the purpose of use (prevention or improvement). Generally, when manufacturing a food or beverage, the health functional food composition of the present invention is added in an amount of 15 parts by weight or less, preferably 10 parts by weight or less, based on the raw materials. However, in the case of long-term intake for health purposes, the amount may be below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
상기 건강기능식품의 종류에 특별한 제한은 없다. 상기 건강기능식품 조성물을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There are no particular restrictions on the types of health functional foods. Examples of foods to which the health functional food composition can be added include meat, sausages, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, and tea. There are drinks, alcoholic beverages, and vitamin complexes, and it includes all health foods in the conventional sense.
또한, 본 발명의 건강기능식품 조성물은 식품, 특히 기능성 식품으로 제조될 수 있다. 본 발명의 기능성 식품은 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 유효성분 이외에 천연 탄수화물 또는 향미제를 추가 성분으로서 포함할 수 있다. 상기 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등), 디사카라이드(예컨대, 말토스, 수크로오스 등), 올리고당, 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등) 또는 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)인 것이 바람직하다. 상기 향미제는 천연 향미제(예컨대, 타우마틴, 스테비아 추출물 등)와 합성 향미제(예컨대, 사카린, 아스파르탐 등)를 이용할 수 있다.Additionally, the health functional food composition of the present invention can be manufactured into food, especially functional food. The functional food of the present invention includes ingredients commonly added during food production, and includes, for example, proteins, carbohydrates, fats, nutrients and seasonings. For example, when manufactured as a drink, natural carbohydrates or flavoring agents may be included as additional ingredients in addition to the active ingredient. The natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.), oligosaccharides, polysaccharides (e.g., dextrins, cyclodextrins, etc.), or sugar alcohols (e.g., , xylitol, sorbitol, erythritol, etc.) are preferred. The flavoring agent may be a natural flavoring agent (e.g., thaumatin, stevia extract, etc.) or a synthetic flavoring agent (e.g., saccharin, aspartame, etc.).
상기 건강기능식품 조성물 이외에 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 더 함유할 수 있다. 이러한 상기 첨가되는 성분의 비율은 크게 중요하진 않지만 본 발명의 건강기능식품 조성물 100 중량부에 대하여, 0.01 내지 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above health functional food composition, various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonic acid. It may further contain carbonating agents used in beverages. The ratio of the ingredients added is not very important, but is generally selected in the range of 0.01 to 0.1 parts by weight based on 100 parts by weight of the health functional food composition of the present invention.
또한, 본 발명은 화학식 1의 1,3-디벤질-5-플루오로우라실(1,3-dibenzyl-5-fluorouracil) 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 함유하는 골질환의 예방 또는 개선용 사료 첨가제를 제공한다.In addition, the present invention provides a method for preventing or treating bone disease containing 1,3-dibenzyl-5-fluorouracil of Formula 1 or a foodologically acceptable salt thereof as an active ingredient. Provides feed additives for improvement.
본 발명의 사료 첨가제는 사료관리법상의 보조사료에 해당한다. 본 발명에서 용어 '사료'는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미할 수 있다. 상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The feed additive of the present invention corresponds to supplementary feed under the Feed Management Act. In the present invention, the term 'feed' may mean any natural or artificial diet, meal, etc., or a component of the meal, for or suitable for eating, ingestion, and digestion by animals. The type of feed is not particularly limited, and feed commonly used in the art can be used. Non-limiting examples of the feed include plant feeds such as grains, roots and fruits, food processing by-products, algae, fiber, pharmaceutical by-products, oils and fats, starches, cucurbits or grain by-products; Examples include animal feeds such as proteins, inorganic substances, fats and oils, minerals, oils and fats, single-cell proteins, zooplanktons or food. These may be used alone or in combination of two or more types.
이하, 본 발명의 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail through examples. However, the following examples only illustrate the present invention, and the content of the present invention is not limited to the following examples.
[재료 및 방법][Materials and Methods]
1. 시약, 항체 및 마우스1. Reagents, Antibodies, and Mice
1,3-디벤질-5-플루오로우라실(1,3-dibenzyl-5-fluorouracil)은 SCBT(Santa Cruz Biotechnology, USA)로부터 구매하였고, 재조합 인간 가용성 RANKL(Receptor activator of nuclear factor kappa-B ligand) 및 인간 M-CSF(macrophage colony stimulating factor)는 참고문헌(Shin, B., et al., 2014, J Biol Chem., 289(52): p.35868-81)에 따라 준비하였다. phospho-IκBα, IκBα, phospho-p65, p65, phospho-p38, p38, phospho-ERK, ERK, phospho-JNK, JNK 및 β-actin에 특이적 항체는 Cell Signaling(USA)사에서 구매하였으며, 동물실험은 충남대학교 동물실험윤리위원회(승인번호 CNU-00326 및 CNU-00114)의 승인하에 진행하였다.1,3-dibenzyl-5-fluorouracil was purchased from SCBT (Santa Cruz Biotechnology, USA), and recombinant human soluble RANKL (Receptor activator of nuclear factor kappa-B ligand) ) and human macrophage colony stimulating factor (M-CSF) were prepared according to reference (Shin, B., et al., 2014, J Biol Chem., 289(52): p.35868-81). Antibodies specific for phospho-IκBα, IκBα, phospho-p65, p65, phospho-p38, p38, phospho-ERK, ERK, phospho-JNK, JNK, and β-actin were purchased from Cell Signaling (USA) and were tested on animals. The study was conducted with the approval of the Chungnam National University Animal Experiment Ethics Committee (approval numbers CNU-00326 and CNU-00114).
2. 파골세포 분화, 세포독성 및 면역블롯 분석2. Osteoclast differentiation, cytotoxicity and immunoblot analysis
6주령 C57BL/6J 수컷 마우스의 경골 및 대퇴골에서 수집한 골수 세포를 96웰 플레이트에서 M-CSF(50ng/㎖) 및 RANKL(200ng/㎖) 처리하여 4일 동안 웰당 1×105 세포로 배양하였다. Bone marrow cells collected from the tibia and femur of 6-week-old C57BL/6J male mice were treated with M-CSF (50 ng/ml) and RANKL (200 ng/ml) in a 96-well plate and cultured at 1 × 10 5 cells per well for 4 days. .
골수 유래 파골세포(BMOC; Bone marrow-derived osteoclasts)는 TRAP(Tartrate-resistant acid phosphatase) 염색 및 용액 분석을 통해 추가적으로 분석하였다. TRAP 용액 분석의 경우, 골수 유래 파골세포는 10% 포르말린 및 에탄올/아세톤(50:50 v/v)의 혼합물로 10분 동안 고정시키고 p-니트로페닐 포스페이트(p-nitrophenyl phosphate) 기질과 30분 동안 반응시켰다. 그런 다음, 상층액을 1N NaOH와 혼합하고 마이크로플레이트 리더(Bio-Rad, Hercules, CA, USA)를 사용하여 405nm에서 흡광도를 측정하여 TRAP 활성을 분석하였다. TRAP 염색 분석을 위해, TRAP 용액 상층액을 버리고 세포를 실온에서 20-30분 동안 나프톨 AS 포스페이트(naphthol AS phosphate) 및 패스트 레드 바이올렛(fast red violet)으로 염색하였다. TRAP로 염색된 골수 유래 파골세포의 형태를 현미경으로 촬영하였고, 핵이 3개 이상인 TRAP 양성 다핵 골수 유래 파골세포(TRAP+ MNC, TRAP+ multinucleated bone marrow-derived osteoclasts)는 파골세포로 간주하였다. Bone marrow-derived osteoclasts (BMOC) were further analyzed using tartrate-resistant acid phosphatase (TRAP) staining and solution analysis. For TRAP solution analysis, bone marrow-derived osteoclasts were fixed with a mixture of 10% formalin and ethanol/acetone (50:50 v/v) for 10 min and incubated with p -nitrophenyl phosphate substrate for 30 min. reacted. Then, the supernatant was mixed with 1N NaOH and TRAP activity was analyzed by measuring absorbance at 405 nm using a microplate reader (Bio-Rad, Hercules, CA, USA). For TRAP staining analysis, TRAP solution supernatant was discarded and cells were stained with naphthol AS phosphate and fast red violet for 20-30 minutes at room temperature. The morphology of bone marrow-derived osteoclasts stained with TRAP was photographed under a microscope, and TRAP-positive multinucleated bone marrow-derived osteoclasts (TRAP + MNC, TRAP + multinucleated bone marrow-derived osteoclasts) with three or more nuclei were considered osteoclasts.
세포독성 분석을 위해, 골수 세포(1×105 cell/well)를 1,3-디벤질-5-플루오로우라실(25-100μM)의 처리 또는 무처리에 50ng/㎖의 M-CSF 단독으로 4일 동안 골수 유래 대식세포(BMMs; bone marrow-derived macrophages)로 분화시켰으며, 세포 계수 키트-8(Cell counting Kit-8, Dojindo Lab., Kumamoto, Japan)을 사용하여 제조사의 지침에 따라 세포 생존율(Cell viability)을 측정하였다. RANKL 신호전달 분석은 6웰 플레이트에서 3일 동안 M-CSF(50ng/㎖) 자극으로 골수 유래 대식세포를 제조하고, RANKL 자극 전에 100μM의 1,3-디벤질-5-플루오로우라실과 함께 12시간 동안 전배양하였다. 이후, 세포를 용해 버퍼(250mM Tris-HCl(pH 7.5), 1mM EDTA, 150mM NaCl, 0.5% Triton X-100 및 5% glycerol)로 용해시켰다. 원심분리 후, 세포 용해물을 대상으로 항체를 이용하여 면역블롯 분석을 수행하였다.For cytotoxicity assay, bone marrow cells (1 × 10 5 cells/well) were treated with or without 1,3-dibenzyl-5-fluorouracil (25-100 μM) and treated with 50 ng/ml M-CSF alone. They were differentiated into bone marrow-derived macrophages (BMMs) for 4 days, and cells were counted using Cell counting Kit-8 (Dojindo Lab., Kumamoto, Japan) according to the manufacturer's instructions. Cell viability was measured. For the RANKL signaling assay, bone marrow-derived macrophages were prepared by stimulation with M-CSF (50 ng/ml) for 3 days in 6-well plates, with 100 μM of 1,3-dibenzyl-5-fluorouracil before RANKL stimulation. Pre-cultured for a period of time. Afterwards, cells were lysed with lysis buffer (250mM Tris-HCl (pH 7.5), 1mM EDTA, 150mM NaCl, 0.5% Triton X-100, and 5% glycerol). After centrifugation, immunoblot analysis was performed on the cell lysate using antibodies.
3. 골 분석 및 조직학적 분석3. Bone analysis and histological analysis
8주령 C57BL/6J 마우스를 무작위로 3개 그룹(n=10-11/group)으로 나누었다: 난소를 절제하지 않은 정상군(Sham), 난소를 절제한 대조군(OVX), 난소를 절제하고 1,3-디벤질-5-플루오로우라실을 처리한 실험군(10mg/kg). 난소절제 수술 1주일 후, 마우스에 1,3-디벤질-5-플루오로우라실(10mg/kg)을 매일 3주 동안 복강 내 주사하고 3주 후, 대퇴골을 수집하여 분석하였다. 마이크로-CT 분석을 위해, 대퇴골을 10% 포르말린으로 고정시키고 0.5mm 알루미늄 필터를 사용한 50kV, 200μA 및 6.775μm 이미지 픽셀 해상도에서 CT(SkyScan 1076, Bruker micro-CT, Kontich, Belgium)를 사용하여 원위 대퇴골의 해면골 형태를 측정하였다. 마지막으로 골밀도(BMD), 해면골과 피지골의 체적비(BV/TV), 해면골 수(Tb.N) 및 해면골 분리(Tb.Sp.) 수치를 측정하였고, 조직학적 분석을 위해 대퇴골을 4℃에서 15% EDTA 용액에 3주 동안 탈회시키고 파라핀에 포매하였다. 파라핀 절편을 TRAP 및 헤마톡실린으로 염색하고, TRAP 양성 다핵 파골세포를 현미경으로 가시화하여 계수하였다.8-week-old C57BL/6J mice were randomly divided into 3 groups (n=10-11/group): non-ovariectomized normal group (Sham), ovariectomized control group (OVX), and ovariectomized 1; Experimental group treated with 3-dibenzyl-5-fluorouracil (10 mg/kg). One week after ovariectomy surgery, mice were intraperitoneally injected with 1,3-dibenzyl-5-fluorouracil (10 mg/kg) daily for 3 weeks, and 3 weeks later, femurs were collected and analyzed. For micro-CT analysis, the femur was fixed in 10% formalin and the distal femur was scanned using CT (SkyScan 1076, Bruker micro-CT, Kontich, Belgium) at 50 kV, 200 μA, and 6.775 μm image pixel resolution using a 0.5 mm aluminum filter. The cancellous bone morphology was measured. Finally, bone mineral density (BMD), cancellous bone to sebaceous bone volume ratio (BV/TV), cancellous bone number (Tb.N), and cancellous bone separation (Tb.Sp.) were measured, and femurs were stored at 4°C for histological analysis. It was decalcified in 15% EDTA solution for 3 weeks and embedded in paraffin. Paraffin sections were stained with TRAP and hematoxylin, and TRAP-positive multinucleated osteoclasts were visualized under a microscope and counted.
4. 통계처리4. Statistical processing
모든 결과는 평균±표준편차(SD)로 표시하였고, 통계 분석은 일원분산분석(one-way ANOVA) 또는 양측(two-tailed) Student's 검정을 이용하여 수행하였다. p값이 0.05 미만일 경우, 통계적으로 유의적 차이가 있다고 판정하였다.All results were expressed as mean ± standard deviation (SD), and statistical analysis was performed using one-way ANOVA or two-tailed Student's test. If the p value was less than 0.05, it was determined that there was a statistically significant difference.
실시예 1. 1,3-디벤질-5-플루오로우라실의 세포독성Example 1. Cytotoxicity of 1,3-dibenzyl-5-fluorouracil
본 발명의 1,3-디벤질-5-플루오로우라실의 세포독성 여부를 확인하고자 하였다. 골수 유래 대식세포(BMMs; bone marrow-derived macrophages)에 1,3-디벤질-5-플루오로우라실을 농도별로 처리한 결과, 도 1에 개시한 바와 같이 모든 농도의 1,3-디벤질-5-플루오로우라실 처리군에서 세포 생존율이 유지되는 것을 통해 세포독성이 없는 것을 확인하였다.We sought to confirm whether 1,3-dibenzyl-5-fluorouracil of the present invention is cytotoxic. As a result of treating bone marrow-derived macrophages (BMMs) with 1,3-dibenzyl-5-fluorouracil at different concentrations, all concentrations of 1,3-dibenzyl-5-fluorouracil were shown in Figure 1. It was confirmed that there was no cytotoxicity as cell viability was maintained in the 5-fluorouracil treated group.
실시예 2. 1,3-디벤질-5-플루오로우라실의 파골세포 분화 억제 Example 2. Inhibition of osteoclast differentiation by 1,3-dibenzyl-5-fluorouracil
파골세포 분화에 대한 1,3-디벤질-5-플루오로우라실의 효능을 확인하기 위해, 골수 유래 대식세포에 M-CSF(50ng/㎖) 및 RANKL(200ng/㎖)와 1,3-디벤질-5-플루오로우라실을 농도별로 처리하고 4일 후에 세포를 고정시킨 다음, TRAP 염색을 통해 분화된 TRAP 양성 다핵 파골세포(TRAP+ MNC) 수 및 TRAP 활성을 측정하였다. To confirm the efficacy of 1,3-dibenzyl-5-fluorouracil on osteoclast differentiation, bone marrow-derived macrophages were treated with M-CSF (50 ng/ml) and RANKL (200 ng/ml) and 1,3-dibenzyl-5-fluorouracil. Benzyl-5-fluorouracil was treated at various concentrations, the cells were fixed 4 days later, and the number of differentiated TRAP-positive multinucleated osteoclasts (TRAP + MNC) and TRAP activity were measured through TRAP staining.
그 결과, 1,3-디벤질-5-플루오로우라실을 처리한 골수 유래 대식세포는 M-CSF 및 RANKL만을 처리한 대조군(mock)과 비교하여 농도의존적으로 TRAP 양성 다핵 파골세포의 분화를 감소시켰으며(도 2A), 100μM의 1,3-디벤질-5-플루오로우라실 처리군에서 TRAP 양성 다핵 파골세포가 소멸된 것을 확인하였다(도 2B). 또한, 1,3-디벤질-5-플루오로우라실의 처리농도가 증가함에 따라 골수 유래 파골세포의 TRAP 활성도 크게 감소되었다(도 2C).As a result, bone marrow-derived macrophages treated with 1,3-dibenzyl-5-fluorouracil decreased the differentiation of TRAP-positive multinucleated osteoclasts in a concentration-dependent manner compared to the control group (mock) treated only with M-CSF and RANKL. (Figure 2A), and it was confirmed that TRAP-positive multinucleated osteoclasts disappeared in the group treated with 100 μM 1,3-dibenzyl-5-fluorouracil (Figure 2B). In addition, as the treatment concentration of 1,3-dibenzyl-5-fluorouracil increased, TRAP activity of bone marrow-derived osteoclasts was greatly reduced (Figure 2C).
실시예 3. 1,3-디벤질-5-플루오로우라실의 RANK/RANKL 신호전달 경로 억제Example 3. Inhibition of RANK/RANKL signaling pathway by 1,3-dibenzyl-5-fluorouracil
RANK(receptor activator of NF-kappaB)-매개 신호전달 경로에 대한 1,3-디벤질-5-플루오로우라실의 효능을 확인하기 위해, RANKL(receptor activator of NF-kappaB ligand) 처리 없이 2시간 동안 전배양한 골수 유래 파골세포를 RANKL(200ng/㎖)로 자극하여 RANKL 신호전달을 유도하였다. RANK-RANKL 신호전달 경로에서 NF-κB(nuclear factor kappa-light-chain-enhancer of activated B cells) 및 MAP 키나아제(Mitogen-activated protein kinase)의 활성화는 파골세포 생성에 중요하므로, 1,3-디벤질-5-플루오로우라실(100μM)이 처리된 골수 유래 파골세포(BMOC)에서 RANKL 자극에 의한 NF-κB 및 MAP 키나아제의 활성을 측정하였다.To confirm the efficacy of 1,3-dibenzyl-5-fluorouracil on the RANK (receptor activator of NF-kappaB)-mediated signaling pathway, treatment was performed for 2 hours without RANKL (receptor activator of NF-kappaB ligand) treatment. Pre-cultured bone marrow-derived osteoclasts were stimulated with RANKL (200 ng/ml) to induce RANKL signaling. In the RANK-RANKL signaling pathway, activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and MAP kinase (Mitogen-activated protein kinase) is important for osteoclast generation, so 1,3-D The activities of NF-κB and MAP kinase by RANKL stimulation were measured in bone marrow-derived osteoclasts (BMOC) treated with benzyl-5-fluorouracil (100 μM).
그 결과, 도 3에 개시한 바와 같이, 대조군(mock)과 비교하여 1,3-디벤질-5-플루오로우라실을 처리하였을 때 RANKL로 유도된 p-IκBα, p-p65, p-ERK의 발현이 시간 의존적으로 감소되었다.As a result, as shown in Figure 3, compared to the control group (mock), when treated with 1,3-dibenzyl-5-fluorouracil, the levels of p-IκBα, p-p65, and p-ERK induced by RANKL were decreased. Expression was reduced in a time-dependent manner.
실시예 4. 1,3-디벤질-5-플루오로우라실의 파골세포 생성 억제Example 4. Inhibition of osteoclastogenesis by 1,3-dibenzyl-5-fluorouracil
난소를 절제한 마우스 모델(OVX)을 대상으로 1,3-디벤질-5-플루오로우라실의 파골세포 생성에 대한 효능을 확인하고자 하였다. 난소를 절제한 C57BL/6 암컷 마우스의 복강 내에 1,3-디벤질-5-플루오로우라실(10mg/kg)을 처리하고 대퇴골을 수집하여 TRAP 염색 및 헤마톡실린 염색을 통해 대퇴골의 소주 영역에서 골 조직학적 형태 및 파골세포 형성을 비교하였다. We aimed to confirm the efficacy of 1,3-dibenzyl-5-fluorouracil on osteoclast formation in an ovariectomized mouse model (OVX). Ovariectomized C57BL/6 female mice were intraperitoneally treated with 1,3-dibenzyl-5-fluorouracil (10 mg/kg), femurs were collected, and TRAP staining and hematoxylin staining were performed in the trabecular region of the femurs. Bone histological morphology and osteoclast formation were compared.
그 결과, 도 4A에 개시한 바와 같이, 난소를 절제한 마우스(OVX)는 난소를 절제하지 않은 마우스(sham)에 비해 해면골이 유의미하게 감소되었고, 이에 대비하여 10mg/kg의 1,3-디벤질-5-플루오로우라실을 처리한 경우 OVX로 유도된 골소실이 유의미하게 억제되었다. 또한, 난소를 절제한 마우스(OVX)에 비해 1,3-디벤질-5-플루오로우라실을 처리한 마우스의 대퇴골의 해면 영역에서 TRAP 양성 다핵 파골세포(TRAP+ MNC) 수가 유의미하게 감소되었다(도 4B 및 도 4C).As a result, as shown in Figure 4A, cancellous bone was significantly reduced in ovariectomized mice (OVX) compared to non-oovariectomized mice (sham), and in contrast, 10 mg/kg of 1,3-D Treatment with benzyl-5-fluorouracil significantly inhibited OVX-induced bone loss. Additionally, the number of TRAP-positive multinucleated osteoclasts (TRAP + MNC) was significantly reduced in the cancellous region of the femur of mice treated with 1,3-dibenzyl-5-fluorouracil compared to ovariectomized mice (OVX) ( Figure 4B and Figure 4C).
실시예 5. 1,3-디벤질-5-플루오로우라실의 골소실 억제Example 5. Inhibition of bone loss by 1,3-dibenzyl-5-fluorouracil
난소를 절제한 마우스(OVX)에 1,3-디벤질-5-플루오로우라실을 처리한 후, 마이크로 CT의 이미지를 BMA(Bone microarchitecture analysis)를 통해 분석하여 골구조 변화를 확인하고, 해면질 부위의 골 매개변수를 측정하였다.After treating ovariectomized mice (OVX) with 1,3-dibenzyl-5-fluorouracil, micro-CT images were analyzed through BMA (Bone microarchitecture analysis) to confirm changes in bone structure, and the spongy area was analyzed. Bone parameters were measured.
이미지 분석 결과, 도 5A에 개시한 바와 같이, 난소를 절제한 마우스(OVX)는 난소를 절제하지 않은 마우스(sham)에 비해 해면골의 골소실이 유의하게 증가되었고, 이에 대비하여 난소를 절제한 마우스(OVX)에 10mg/kg의 1,3-디벤질-5-플루오로우라실을 처리한 경우 증가된 해면골의 골소실이 분명히 억제되었음을 확인하였다. 또한, 골 파라미터 분석에서도 마찬가지로, 난소를 절제한 마우스(OVX)에서 감소된 골밀도(BMD), 해면골과 피지골의 체적비(BV/TV) 및 해면골 수(Tb.N)가 1,3-디벤질-5-플루오로우라실 처리로 인해 유의미하게 증가되고, 해면골 분리(Tb.Sp.) 수치도 10mg/kg의 1,3-디벤질-5-플루오로우라실 처리로 인해 유의미하게 감소되는 것을 확인하였다(도 5B).As a result of image analysis, as shown in FIG. 5A, bone loss in cancellous bone was significantly increased in ovariectomized mice (OVX) compared to non-oophorectomized mice (sham), and in contrast, ovariectomized mice It was confirmed that when (OVX) was treated with 10 mg/kg of 1,3-dibenzyl-5-fluorouracil, the increased bone loss of cancellous bone was clearly suppressed. In addition, in the bone parameter analysis, decreased bone mineral density (BMD), cancellous bone to sebaceous bone volume ratio (BV/TV), and cancellous bone number (Tb.N) were observed in ovariectomized mice (OVX) compared to 1,3-dibenzyl. -It was confirmed that treatment with 5-fluorouracil significantly increased, and the cancellous bone detachment (Tb.Sp.) level was also significantly reduced with treatment with 10 mg/kg of 1,3-dibenzyl-5-fluorouracil. (Figure 5B).
Claims (8)
[화학식 1]
A pharmaceutical composition for the prevention or treatment of bone disease containing 1,3-dibenzyl-5-fluorouracil of the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient: .
[Formula 1]
[화학식 1]
Health function for preventing or improving bone disease containing 1,3-dibenzyl-5-fluorouracil of the following formula (1) or a food-acceptable salt thereof as an active ingredient: Food composition.
[Formula 1]
[화학식 1]
A feed additive for preventing or improving bone disease containing 1,3-dibenzyl-5-fluorouracil of the following formula (1) or a foodologically acceptable salt thereof as an active ingredient: .
[Formula 1]
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220064214A KR20230164451A (en) | 2022-05-25 | 2022-05-25 | Composition for preventing, ameliorating or treating bone disease comprising 1,3-dibenzyl-5-fluorouracil as effective component |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20230164451A true KR20230164451A (en) | 2023-12-04 |
Family
ID=89165138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020220064214A KR20230164451A (en) | 2022-05-25 | 2022-05-25 | Composition for preventing, ameliorating or treating bone disease comprising 1,3-dibenzyl-5-fluorouracil as effective component |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20230164451A (en) |
-
2022
- 2022-05-25 KR KR1020220064214A patent/KR20230164451A/en unknown
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