KR20190014715A - Pharmaceutical composition for preventing or treating cancer comprising receptor tyrosine kinases inhibitor - Google Patents
Pharmaceutical composition for preventing or treating cancer comprising receptor tyrosine kinases inhibitor Download PDFInfo
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- KR20190014715A KR20190014715A KR1020170098524A KR20170098524A KR20190014715A KR 20190014715 A KR20190014715 A KR 20190014715A KR 1020170098524 A KR1020170098524 A KR 1020170098524A KR 20170098524 A KR20170098524 A KR 20170098524A KR 20190014715 A KR20190014715 A KR 20190014715A
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Abstract
Description
본 발명은 수용체 티로신 키나아제 활성 억제 화합물을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물, 항암 효과 증진용 조성물 또는 암 예방 또는 개선용 건강식품에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating cancer, a composition for enhancing anticancer activity, or a health food for cancer prevention or improvement, which comprises a receptor tyrosine kinase activity inhibitory compound as an active ingredient.
수용체 티로신 키나아제(receptor tyrosine kinases, RTKs)는 세포막을 관통하는 막관통단백질(transmembrane protein)로 세포 증식, 세포 이동, 세포 주기 및 세포 분화를 조절하는 세포신호전달계를 담당하는 아주 중요한 수용체 그룹 중 하나이며, 인체 RTKs는 약 20개로 분류된다. 그 중 혈소판 유도 성장인자 수용체(Platelet Derived Growth Factor Receptor, PDGFR)는 리간드 혈소판 유래 생장인자(PDGF)에 의해 활성화될 수 있으며, 유사 분열물질-활성화 단백질인산화효소(Mitogen-activated protein kinases, MAPK), 포스파티딜이노시톨 3-인산화효소(phosphotidyl inositol 3-kinase, PI3K) 및 STAT3(signal transducer and activator of transcription 3)으로 하위 신호전달 경로를 활성화시킬 수 있다. 돌연변이를 포함한 PDGFR의 활성화는 위장관 기질 종양(Gastrointestinal stromal tumor, GIST), 다형성 신경교아세포종(Glioblastoma multiforme), 만성 골수 백혈병에서 관찰된다. 약 30%의 급성 골수 백혈병(Acute myeloid leukemia, AML)환자의 FLT3(FMS-like tyrosine kinase 3) 유전자 내 막근접 도메인(juxtamembrane domain)에서 내부 순차 중복(internal tandem duplication, IDT) 돌연변이가, 급성 림프성 백혈병(Acute lymphoblastic leukemia, ALL)환자 중 약 3%에서 발견되며, 이러한 돌연변이를 가진 환자는 예후가 좋지 않다고 알려짐에 따라, FLT3 억제는 급성 골수 백혈병 및 급성 림프성 백혈병 치료에 도움을 줄 수 있다. Receptor tyrosine kinases (RTKs) are transmembrane proteins that penetrate cell membranes and are one of the most important receptor groups responsible for cell signaling systems that regulate cell proliferation, cell migration, cell cycle and cell differentiation , And human RTKs are classified into about 20. Platelet Derived Growth Factor Receptor (PDGFR) can be activated by ligand platelet-derived growth factor (PDGF), mitogen-activated protein kinases (MAPK) The phosphotidyl inositol 3-kinase (PI3K) and STAT3 (signal transducer and activator of transcription 3) can activate the downstream signaling pathway. Activation of PDGFR, including mutations, is observed in GISTs, Glioblastoma multiforme, and chronic myeloid leukemia. An internal tandem duplication (IDT) mutation in the juxtamembrane domain of FLT3 (FMS-like tyrosine kinase 3) gene in approximately 30% of patients with acute myeloid leukemia (AML) FLT3 inhibition may be helpful in the treatment of acute myelogenous leukemia and acute lymphoblastic leukemia as it is known in about 3% of patients with acute lymphoblastic leukemia (ALL), and those with these mutations are known to have poor prognosis .
c-Kit은 리간드 줄기세포성장인자(stem cell factor, SCF)에 의해 활성화될 수 있으며 D816V 또는 V560G과 같은 포인트 돌연변이형은 리간드 없이 끊임없이 활성화되어 세포 증식, 세포 생존 및 세포사멸(apoptosis)에 저항성을 가질 수 있다. 특히, c-Kit의 경우 비만세포를 활성화하여 비만세포증(mastocytosis) 유발하고, 다양한 기관(피부, 간, 위장관(gastrointestinal tract), 생식기 등)에서 발현을 증가시켜 자가 면역 질환, 백혈병, 위장관 기질종양(gastrointestinal stromal tumor, GIST), 소세포폐암, 고환암, 다형성 신경교아세포종 등을 유발한다. 약 70 내지 80% GISTs 환자는 c-Kit의 기능획득변이(gain-of-function) 돌연변이를 가지고 있다. 니코틴에 의해 SCF가 증가되면 비소세포폐암의 c-Kit가 활성화됨으로써 비소세포폐암의 빠른 성장과 전이가능성이 있는 것이 보고된 바 있다.c-Kit can be activated by ligand stem cell factor (SCF), and point mutants such as D816V or V560G are constantly activated without ligand to resist cell proliferation, cell survival and apoptosis Lt; / RTI > In particular, c-Kit induces mastocytosis by activating mast cells and increases expression in various organs (skin, liver, gastrointestinal tract, reproductive tract, etc.) to induce autoimmune diseases, leukemia, gastrointestinal stromal tumors gastrointestinal stromal tumor (GIST), small cell lung cancer, testicular cancer, and polymorphic glioblastoma. Patients with about 70-80% GISTs have a gain-of-function mutation in c-Kit. It has been reported that the increase of SCF by nicotine leads to the rapid growth and metastasis of non-small cell lung cancer due to activation of c-Kit of non-small cell lung cancer.
사이클린-의존성 키나아제(cyclin-depedent kinase, CDK)는 세포 주기에 매우 중요한 세린/트레오닌 단백질 키나아제이다. 이러한 복합체는 촉매성 소분자인 사이클린의존성 인산화효소(cyclin-dependent kinase, CDK)와 조절성 소분자인 사이클린(Cyclin) 2가지로 구성되어 있으며, 각 CDK는 특이적인 사이클린과 복합체를 이루어 활성화된다. 각 세포 주기의 진행은 특정 CDK/사이클린 복합체에 의해 조절될 수 있으며 특히, CDK1/사이클린 B1, CDK2/사이클E, CDK2/사이클린 A는 세포주기 진행에 중요한 인자이다.Cyclin-depenedent kinase (CDK) is a serine / threonine protein kinase that is crucial to the cell cycle. These complexes consist of two catalytic small molecules, cyclin-dependent kinase (CDK) and regulatory small molecule, cyclin. Each CDK is complexed with a specific cyclin to activate it. The progression of each cell cycle can be controlled by specific CDK / cyclin complexes. In particular, CDK1 / cyclin B1, CDK2 / cycle E, and CDK2 / cyclin A are important factors in cell cycle progression.
임상시험에서 다수의 RTK 억제제가 초기 임상 반응을 보였지만, 일시적인 반응으로 확인되었으며, 내성이 빠르게 나타나는 문제점이 확인되었다. 또한, RTK 억제제에 의해 KIT은 D816V 돌연변이가 발생할 수 있고, PDGFR은 D842V 돌연변이가, FLT3의 경우 D835V 돌연변이가 발생할 수 있으며, 이러한 돌연변이들은 표적에 대한 RTK 억제제의 결합을 간섭할 수 있다. In clinical trials, a number of RTK inhibitors showed initial clinical responses, but were identified as transient responses and identified problems with rapid resistance. In addition, the RTK inhibitor may cause a D816V mutation in the KIT, a D842V mutation in the PDGFR, and a D835V mutation in the FLT3, and these mutations may interfere with the binding of the RTK inhibitor to the target.
따라서, 다양한 암 종에서 RTK의 활성화와 빠른 세포주기 진행은 비정상세포 조절에 관여하고 있기 때문에 RTK 활성과 함께 CDK1/사이클린B와 CDK2/사이클린A, CDK5/p35 복합체 키나아제 활성을 표적으로 하는 억제제 개발이 요구된다.Therefore, RTK activation and rapid cell cycle progression are involved in the regulation of abnormal cells in various cancer species. Therefore, the development of inhibitors targeting RTK activity and CDK1 / cyclin B and CDK2 / cyclin A and CDK5 / p35 complex kinase activity Is required.
본 발명은 다양한 암 종에서 수용체 티로신 키나아제(RTK)의 활성을 효과적으로 억제시킬 수 있는 화합물을 유효성분으로 함유하는 조성물을 항암치료제로 제공하며, 다른 항암제 또는 방사선과 병용하여 치료 효과를 향상시킬 수 있는 항암 치료 효과 증진용 조성물로 제공하고자 한다.The present invention provides a composition containing, as an active ingredient, a compound capable of effectively inhibiting the activity of a receptor tyrosine kinase (RTK) in various cancer species as an anticancer therapeutic agent, and can be used in combination with other anticancer agents or radiotherapy, And to provide a composition for promoting therapeutic effect.
본 발명은 하기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating cancer, which comprises, as an active ingredient, a compound represented by Formula 1 below or a pharmaceutically usable salt thereof.
[화학식 1][Chemical Formula 1]
상기 화학식 1에서, In Formula 1,
X는 질소 및 탄소에서 선택된 어느 하나일 수 있다.X may be any one selected from nitrogen and carbon.
본 발명은 상기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 항암 효과 증진용 조성물을 제공한다.The present invention provides a composition for promoting an anti-cancer effect comprising a compound represented by Formula 1 or a pharmaceutically usable salt thereof as an active ingredient.
또한, 본 발명은 상기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 개선용 건강식품을 제공한다.The present invention also provides a health food for preventing or ameliorating cancer, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따르면, 상기 화학식 1과 같이 표시되는 화합물은 키나아제 활성 억제를 통하여 암세포의 성장을 억제하는 것을 확인하였으며, 종래의 항암제 또는 방사선 치료와 병용처리할 경우, 암세포의 아팝토시스 사멸효과가 향상되는 것으로 확인됨에 따라, 상기 화학식 1과 같이 표시되는 화합물은 암 예방 또는 치료용 약학조성물 또는 항암치료 및 방사선 치료의 항암 치료 효과 증진용 조성물로 제공될 수 있다.According to the present invention, it has been confirmed that the compound represented by Formula 1 inhibits the growth of cancer cells through inhibition of kinase activity, and when cancer treatment is combined with conventional anticancer drugs or radiation therapy, apoptosis killing effect of cancer cells is improved The compound represented by Formula 1 can be provided as a pharmaceutical composition for preventing or treating cancer or as a composition for enhancing the effect of chemotherapy of chemotherapy and radiation therapy.
도 1은 인체백혈병 MV4-11 세포주에 화합물 1 및 화합물 2를 10μM 처리하였을 때 FLT3의 하위 신호전달계 기질 단백질인 STAT5(Signal Transducer and Activator of Transcription 5)의 인산화가 억제되는 것을 확인한 결과이다.
도 2는 인체백혈병 MV4-11 세포주에 화합물 1 및 화합물 2를 10μM 처리하였을 때 아폽토시스(apoptosis)에 의한 세포사멸이 발생하는 것을 확인한 결과이다.
도 3은 인체백혈병 MV4-11 세포주에 화합물 1 및 화합물 2를 2μM과 항암제 시스플라틴 5 μM을 병용 적용하였을 때, 세포 증식이 억제되는 것을 확인한 결과이다.
도 4는 인체백혈병 MV4-11 세포주에 화합물 1 및 화합물 2를 10μM 방사선 1Gy 조사를 병용 적용하였을 때, 세포 사멸이 증가되는 것을 확인한 결과이다.FIG. 1 shows that phosphorylation of STAT5 (signal transducer and activator of transcription 5), a low-level signal transduction system protein of FLT3, was inhibited when 10 μM of
FIG. 2 shows the results of apoptosis-induced apoptosis when 10 μM of
FIG. 3 shows the result of confirming that cell proliferation is inhibited when 2 μM of
FIG. 4 shows the results of confirming that cell death was increased when Compound 1 and Compound 2 were applied to a human leukemia MV4-11 cell line in combination with 10 μM irradiation and 1 Gy irradiation.
본 발명은 하기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물을 제공할 수 있다.The present invention can provide a pharmaceutical composition for preventing or treating cancer, which comprises, as an active ingredient, a compound represented by Formula 1 below or a pharmaceutically usable salt thereof.
[화학식 1][Chemical Formula 1]
상기 화학식 1에서, X는 질소 및 탄소에서 선택된 어느 하나일 수 있다.In Formula 1, X may be any one selected from nitrogen and carbon.
보다 상세하게는 상기 화학식 1과 같이 표시되는 화합물은 수용체 티로신 키나아제 활성을 저해할 수 있다.More specifically, the compound represented by Formula 1 may inhibit receptor tyrosine kinase activity.
상기 암은 폐암, 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나일 수 있으며, 상기 백혈병은 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병 및 만성 림프구성 백혈병으로 이루어진 군에서 선택될 수 있다.Said cancer is selected from the group consisting of lung cancer, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, breast cancer, gastric cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, Cancer, cancer of the bladder, cancer of the esophagus, cancer of the thyroid, cancer of the bladder, kidney cancer, blood cancer and rectal cancer, and the leukemia is selected from the group consisting of acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia Can be selected from the group.
본 발명의 일실시예에 따르면, 상기 화학식 1과 같이 표시되는 화합물인 화합물 1 및 화합물 2는 표 2와 같이 23종의 키나아제 활성을 억제하는 효과를 나타냈으며 특히, 0.1 μM 농도에도 불구하고 cKit(V560G), FLT1, FLT3, FLT3(D835Y), FLT3(ITD), FLT4 키나아제에 대하여 매우 우수한 억제 효과를 나타내것이 확인되었다.According to one embodiment of the present invention,
또한, 상기 화합물 1 및 화합물 2의 항암 효과를 다양한 암질환 세포에서 확인한 결과, 표 4와 같이 화합물 1 및 화합물 2 모두 폐암, 유방암, 대장암과 백혈병 세포에서 우수한 증식 억제 효과를 보인 반면, CCD18-Co 정상세포의 세포 생존율은 같은 농도에서 억제되지 않았으므로 선택적인 암세포 증식 억제효과가 확인되었다.As shown in Table 4,
본 발명의 한 구체예에서, 상기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 치료용 약학조성물은 통상적인 방법에 따라 주사제, 과립제, 산제, 정제, 환제, 캡슐제, 좌제, 겔, 현탁제, 유제, 점적제 또는 액제로 이루어진 군에서 선택된 어느 하나의 제형을 사용할 수 있다.In one embodiment of the present invention, the pharmaceutical composition for preventing or treating cancer, which comprises the compound represented by Formula 1 or a pharmaceutically utilizable salt thereof as an active ingredient, may be administered orally, parenterally, , Pills, capsules, suppositories, gels, suspensions, emulsions, drops, or liquid preparations can be used.
본 발명의 다른 구체예에서, 상기 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In another embodiment of the present invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, disintegrant, sweetener, coating, swelling agent, lubricant, lubricant, flavoring agent, antioxidant, buffer, A dispersant, a surfactant, a binder, and a lubricant.
구체적으로 담체, 부형제 및 희석제는 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 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 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, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
본 발명의 일실시예에 따르면 상기 약학조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.
상기 화학식 1과 같이 표시되는 화합물의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The preferred dosage of the compound represented by Formula 1 may vary depending on the condition and body weight of the subject, the type and degree of disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.
본 발명은 하기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 항암 효과 증진용 조성물을 제공할 수 있다.The present invention can provide a composition for promoting an anti-cancer effect comprising, as an active ingredient, a compound represented by Formula 1 below or a pharmaceutically usable salt thereof.
[화학식 1][Chemical Formula 1]
상기 화학식 1에서, X는 질소 및 탄소에서 선택된 어느 하나일 수 있다.In Formula 1, X may be any one selected from nitrogen and carbon.
상기 항암 효과 증진용 조성물은 항암제 또는 방사선과 병용 처리될 수 있다.The anticancer effect enhancing composition may be treated with an anticancer agent or radiation.
상기 항암제는 시스플라틴(Cisplatin), 5-플루오로우라실(5-fluorouracil), 파클리탁셀(Paclitaxel), 독소루비신(Doxorubicin), 도노루비신(Daunorubicin), 빈블라스틴(Vinblastine), 빈크리스틴(Vincristine), 액티노마이신 D(Actinomycin D), 테니포사이드(Teniposide), 에토포사이드(Etoposide), 시클로포스파미드 (cyclophosphamide), 에피루비신(epirubicin), 아드리아마이신(adriamycin), 다우노마이신(daunomycin) 및 미토마이신-C(mitomycin-C)으로 이루어진 군에서 선택된 어느 하나 이상일 수 있다.The anticancer agent is selected from the group consisting of cisplatin, 5-fluorouracil, Paclitaxel, Doxorubicin, Daunorubicin, Vinblastine, Vincristine, Actinomycin D, Teniposide, Etoposide, cyclophosphamide, epirubicin, adriamycin, daunomycin, and mitomycin, And C (mitomycin-C).
상기 조성물은 조성물 총 100 중량부에 대하여, 항암제 1 내지 99 중량부 및 화학식 1과 같이 표시되는 화합물 1 내지 99 중량부를 포함할 수 있다.The composition may comprise 1 to 99 parts by weight of an anticancer agent and 1 to 99 parts by weight of a compound represented by the general formula (1), based on 100 parts by weight of the total composition.
상기 조성물은 폐암, 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나의 암 질환에 대한 항암 효과를 증진시킬 수 있다.The composition may be used for the treatment and / or prophylaxis of lung cancer, leukemia, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, breast cancer, larynx cancer, prostate cancer, bladder cancer, And rectal cancer, the anticancer effect of the present invention can be enhanced.
상기 백혈병은 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병 및 만성 림프구성 백혈병으로 이루어진 군에서 선택될 수 있다.The leukemia may be selected from the group consisting of acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
본 발명의 다른 일실시예에 따르면, MV4-11 백혈병 세포에 2 μM의 화합물 1 및 2와 5 μM의 공지된 항암제인 시스플라틴(Cisplatin; 5 μM)을 48시간 동안 병용 처리하고 MTT 시험법을 통하여 세포 생존율을 분석한 결과, 도 3과 같이 항암제인 시스플라틴이 단독 처리된 대조군보다 시스플라틴과 화합물 1을 병용 투여한 실험군의 세포 증식 억제 효과가 40% 이상나타났으며, 시스플라틴과 화합물 2를 병용 투여한 실험군에서는 60% 이상 증가된 것을 확인할 수 있었다.According to another embodiment of the present invention, MV4-11 leukemia cells were treated with 2 μM of
또한, 배양된 인체 혈액암세포 MV4-11 세포주에 10 μM의 화합물 1 및 화합물 2와 방사선 1Gy 조사를 병용 처리한 후 48시간 배양하고 FACSort 유세포분석기(Becton dickinson, 미국)를 사용하여 아폽토시스가 유도된 세포를 확인한 결과, 도 4와 같이 MV4-11 인체혈액암 세포주에서 아폽토시스에 의한 세포사멸이 방사선 단독 조사군과 비교하여 각각 2.1 배, 1.8 배 이상 유도되는 것을 확인할 수 있었다. In addition, the cultured human blood cancer cell MV4-11 cell line was treated with 10 μM of
상기 결과들로부터 본 발명의 화합물 1 및 화합물 2는 종래의 항암제 치료 또는 방사선 치료시 병용처리되어 항암 효과를 상승시킬 수 있는 것이 확인되었다.From the results, it was confirmed that the
또한, 본 발명은 하기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염을 유효성분으로 함유하는 암 예방 또는 개선용 건강식품을 제공할 수 있다.The present invention also provides a health food for preventing or ameliorating cancer, which comprises, as an active ingredient, a compound represented by
[화학식 1][Chemical Formula 1]
상기 화학식 1에서, X는 질소 및 탄소에서 선택된 어느 하나일 수 있다.In
상기 암은 폐암, 백혈병, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 유방암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 혈액암 및 직장암으로 이루어진 군에서 선택된 어느 하나인 것일 수 있다.Wherein the cancer is selected from the group consisting of lung cancer, leukemia, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, breast cancer, brain cancer, larynx cancer, prostate cancer, bladder cancer, And rectal cancer.
상기 백혈병은 급성 골수성 백혈병, 만성 골수성 백혈병, 급성 림프구성 백혈병 및 만성 림프구성 백혈병으로 이루어진 군에서 선택될 수 있다.The leukemia may be selected from the group consisting of acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia.
상기 건강식품은 상기 화학식 1과 같이 표시되는 화합물 또는 이의 약제학적으로 이용가능한 염 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.The health food is used together with food or food additives in addition to the compound represented by
상기 건강식품에 함유된 화합물의 유효용량은 상기 치료제의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the compound contained in the above-mentioned health food may be used in accordance with the effective dose of the therapeutic agent, but may be less than the above range for health and hygiene purposes or for long-term intake for health control purposes, It is clear that the component can be used in an amount of more than the above range since there is no problem in terms of safety.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제등을 들 수 있다.There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
<< 참고예Reference example > 물질 > Substance 및 기구And apparatus
합성한 화합물의 녹는점은 크뢰스 M5000 녹는 점 측정기기(Kruess M5000 Melting Point apparatus)를 사용하여 결정하였으며, 그 값은 보정하지 않았다. 양성자 NMR 스펙트라(Proton NMR specta)는 300 MHz에서 아반스-300(Avance-300, Bruker)에 기록하였다. 화학적 이동은 ppm 단위로 기록하였고, Me4Si를 대비 표준(reference standard)로 사용하였다.The melting point of the synthesized compound was determined using a Kruess M5000 Melting Point apparatus and the value was not corrected. Proton NMR spectra were recorded on an Avance-300 (Bruker) at 300 MHz. Chemical shifts were recorded in ppm and Me4Si was used as a reference standard.
질량 스펙트라(mass spectra)는 JEOL, JMS-600W VG Trio-2 GC-MS에 기록하였다.The mass spectra were recorded on a JEOL, JMS-600W VG Trio-2 GC-MS.
반응 생성물은 실리카겔 60(silica gel 60, 230-400 mesh, Merck)를 이용한 깨끗한 컬럼 크로마토그래피를 사용하여 정제하였고, 사전 코팅된 실리카 겔 60 F254(precoated silica gel 60 F254, E.Merch, Mumbai, India)를 이용한 박층크로마토그래피(thin layer chromatography)를 이용하여 추적 관찰하였다. 스팟(spots)은 인몰리브덴산(phosphomolybdic acid, PMA) 또는 하네시안 용액(Hanessian's solution)을 이용하여 염색한 후, UV light(254 nm)에서 가시화하였다.The reaction products were purified using clean column chromatography on silica gel 60 (230-400 mesh, Merck), precoated silica gel 60 F254 (precoated silica gel 60 F254, E. Merch, Mumbai, India ) Using thin layer chromatography. The spots were stained with phosphomolybdic acid (PMA) or Hanessian's solution and visualized with UV light (254 nm).
<< 실시예Example 1> 화합물 합성 1> Compound Synthesis
하기 반응식 1과 같은 과정으로 표 1과 같은 화합물을 합성하였다.The compound shown in Table 1 was synthesized by following the procedure of
[반응식 1][Reaction Scheme 1]
R 1
R 2
(3a)(3a)
(3b)(3b)
(3c)(3c)
(3d)(3d)
(3e)(3e)
(3f)(3f)
(3g)(3g)
(3h)(3h)
(3i)(3i)
(3j)(3j)
(3k)(3k)
(3l)(3l)
1. One. 아자이드Azide (( AzideAzide ) 합성) synthesis
0.2M의 아세톤에 4'-브로모페나실 브로마이드(4'-Bromophenacyl bromide; 1.0 eq) 또는 2-브로모-4'-플루오로아세토페논(2-Bromo-4'-fluoroacetophenone)을 용해시키고 아지드화나트륨(sodium azide; 3.0 eq)를 첨가하였다. 실온에서 16시간 동안 교반하며 반응시킨 후, 혼합물을 여과하고 진공 하에서 농축하여 아자이드 화합물(1a-b)을 얻었다(93% 수율).Bromophenacyl bromide (1.0 eq) or 2-bromo-4'-fluoroacetophenone was dissolved in acetone of 0.2 M, Sodium azide (3.0 eq) was added. After stirring and reaction at room temperature for 16 hours, the mixture was filtered and concentrated in vacuo to afford the azide compound (1a-b) (93% yield).
2. 이소티오시아네이트(2. Isothiocyanate ( IsothiocyanateIsothiocyanate ) 합성) synthesis
다이클로로메테인(dichloromethane, DCM)에 아민 용액인 아닐린(Aniline), p-아니시딘(p-Anisidine), 2,5-디메톡시아닐린(2,5-Dimethoxyaniline), 1-나프틸아민(1-Naphtylamine) 또는 3-아미노-4-메톡시 페닐 에틸 술폰(3-Amino-4-methoxyphenyl ethyl sulfone)을 각각 1.0 eq 용해시키고, 티오포스겐(thiophosgene) 1.2 eq을 처리하여 4시간 동안 교반하였다. 반응이 완전히 끝난 후, 혼합물을 K2CO3 포화 용액으로 희석하고, DCM으로 각각의 시간에 추출하였다.Dichloromethane (dichloromethane, DCM) in the amine solution of aniline (Aniline), p - anisidine (p -Anisidine), 2,5- dimethoxy aniline (2,5-Dimethoxyaniline), 1- naphthylamine (1 Amino-4-methoxyphenyl ethyl sulfone) was dissolved in 1.0 eq each, 1.2 eq of thiophosgene was treated, and the mixture was stirred for 4 hours. After the reaction was complete, the mixture was diluted with K 2 CO 3 saturated solution and extracted with DCM at each time.
결합된 유기층(organic layers)은 무수 MgSO4 하에서 건조하고, 여과한 후 진공에서 농축하여 이소티오시아네이트 화합물(2a-l)을 수득하였다.The combined organic layers (organic layers) is over anhydrous MgSO 4 , Filtered, and concentrated in vacuo to give isothiocyanate compound (2a-1).
3. 3. 이소옥사졸Isoxazole (( IsooxazoleIsooxazole ) 합성) synthesis
상기 방법으로 합성된 아자이드 화합물(1a-b) 1.0 eq과 0.2M 디옥산(dioxane)에 용해시킨 이소티오시아네이트 화합물(2a-l; 1.0 eq)을 혼합하여 교반한 용액에 트리페닐포스핀(triphenylphosphine, PPh3; 1.0 eq)을 첨가하였다.1.0 eq of the azide compound (1a-b) synthesized in the above manner and an isothiocyanate compound (2a-1; 1.0 eq) dissolved in 0.2M dioxane were mixed and stirred. Then, triphenylphosphine a; (triphenylphosphine, PPh 3 1.0 eq ) was added.
상기 혼합물을 90℃까지 가열하면서 4시간 동안 교반하고, 반응이 종료된 후 실온까지 온도를 식히고 압력을 가하여 용매를 제거하였다.The mixture was stirred for 4 hours while heating to 90 DEG C, and after the reaction was completed, the temperature was cooled to room temperature, and the solvent was removed by applying pressure.
용매 제거 후 잔여물을 에틸 아세테이트(Ethyl Acetate, EtOAc)/헥산(hexane) (1:10)을 이동상으로 사용한 실리카겔 상의 깨끗한 컬럼 크로마토 그래피로 정제하여 용리액으로 수득하였다(3a-j, 32% 수율).After removal of the solvent, the residue was purified by flash column chromatography on silica gel using ethylacetate (EtOAc) / hexane (1:10) as the mobile phase to give the title compound as an eluent (3a-j, 32% yield) .
4. 교차 결합(Cross coupling)4. Cross coupling
상기 합성된 3e 화합물, 3-피리디닐보론산(3-Pyridinylboronic acid; 1.5 eq) 또는 페닐보론산(Phenylboronic acid; 1.5 eq) 및 K2CO3 를 용해시킨 0.2M DMF을 혼합한 용액에 Pd(dppf)Cl2(0.5 mol%)를 첨가하고, 상기 혼합용액을 90℃에서 10시간 동안 교반한 후 아세트산에틸ethyl acetate) 및 물로 각각의 시간에 추출하였다. The synthesized 3e compound, 3-pyridinylboronic acid (1.5 eq) or phenylboronic acid (1.5 eq) and K 2 CO 3 Dissolved Pd (dppf) Cl 2 (0.5 mol%) was added to a mixed solution of 0.2M DMF and the mixture was stirred at 90 ° C for 10 hours and then extracted with ethyl acetate (ethyl acetate) and water for each hour.
결합된 유기층(organic layers)을 무수 MgSO4하에서 건조하고, 여과한 후, 진공하에서 농축하였다. 잔여물은 EtOAc/헥산(1:5) 이동상을 사용하여 실리카겔 상의 깨끗한 컬럼 크로마토 그래피로 정제하여, 하기 화합물 11(3k) 및 화합물 12(3l)를 용리액으로 수득하였다(3k 및 3l 각각 35% 수율).The combined organic layers were dried under anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by clean column chromatography on silica gel using an EtOAc / hexane (1: 5) mobile phase to give the following compounds 11 (3k) and 12 (3l) as eluants (3k and 3l, ).
[화합물 11][Compound 11]
N-(5-(N- (5- ( 에틸설포닐Ethylsulfonyl )-2-)-2- 메톡시페닐Methoxyphenyl )-5-(4-(피리딘-3-일)페닐)) -5- (4- (pyridin-3-yl) phenyl) 옥사졸Oxazole -2--2- 아민Amine [N-(5-(ethylsulfonyl)-2-methoxyphenyl)-5-(4-(pyridin-3-yl)phenyl)oxazol-2-amine; 화합물 (3k)] [N- (5- (ethylsulfonyl) -2-methoxyphenyl) -5- (4- (pyridin-3-yl) phenyl) oxazol-2-amine; Compound (3k)]
하얀색 고체, mp = 183-185℃, 1H NMR (300 MHz, DMSO-d6)δ 10.52 (s, 1H), 9.86 (br s, 1H), 8.68-9.02 (m, 1H), 7.41-7.88 (m, 9H), 7.08-7.38 (m, 1H), 3.83-4.20 (m, 3H), 3.24 (br d, J=7.70 Hz, 2H), 1.15 (br t, J=7.34 Hz, 3H); MS (FAB) m/z 436 (MH+)White solid, mp = 183-185 ℃, 1 H NMR (300 MHz, DMSO-d 6) δ 10.52 (s, 1H), 9.86 (br s, 1H), 8.68-9.02 (m, 1H), 7.41-7.88 (m, 9H), 7.08-7.38 (m, 1H), 3.83-4.20 (m, 3H), 3.24 (br d, J = 7.70 Hz, 2H), 1.15 (br t, J = 7.34 Hz, 3H); MS (FAB) m / z 436 (MH < + & gt ; ).
[화합물 12][Compound 12]
5-(비페닐-4-일)-N-(5-(5- (biphenyl-4-yl) -N- (5- ( 에틸설포닐Ethylsulfonyl )-2-)-2- 메톡시페닐Methoxyphenyl )) 옥사졸Oxazole -2--2- 아민Amine [5-(biphenyl-4-yl)-N-(5-(ethylsulfonyl)-2-methoxyphenyl)oxazol-2-amine; [5- (biphenyl-4-yl) -N- (5- (ethylsulfonyl) -2-methoxyphenyl) oxazol-2-amine; 화합물 (Compound ( 3l)]3l)]
노란색 고체, mp = 203.0-203.2℃, 1H NMR (300 MHz, DMSO-d6)δ 10.52 (s, 1H), 9.81 (s, 1H), 8.70-8.84 (m, 1H), 7.18-7.85 (m, 11H), 3.90-4.06 (m, 3H), 3.14-3.28 (m, 2H), 1.05-1.18 (m, 3H); MS (FAB) m/z 435 (MH+).Yellow solid, mp = 203.0-203.2 ℃, 1 H NMR (300 MHz, DMSO-d 6) δ 10.52 (s, 1H), 9.81 (s, 1H), 8.70-8.84 (m, 1H), 7.18-7.85 ( m, 11H), 3.90-4.06 (m, 3H), 3.14-3.28 (m, 2H), 1.05-1.18 (m, 3H); MS (FAB) m / z 435 (MH < + & gt ; ).
<< 실시예Example 2> 키나아제 활성 억제 효과 확인 2> Confirmation of inhibition of kinase activity
상기 실시예 1과 같이 합성된 화합물 11 및 화합물 12의 RTK 키나아제 활성 억제 효과를 확인하였다.Compound 11 and compound 12 synthesized in the same manner as in Example 1 were confirmed to have an inhibitory effect on RTK kinase activity.
유로핀스(Eurofins, 영국) 및 Reaction Biology사 (미국)의 키나아제 프로파일링 서비스를 이용하여 0.1 μM 농도의 화합물 11 및 화합물 12의 다양한 키나아제 활성 억제 효과를 측정하여 하기 표 2에 나타내었다.Various kinase activity inhibitory effects of Compound 11 and Compound 12 at 0.1 μM concentrations were measured using the kinase profiling service of Eurofins (UK) and Reaction Biology (USA), and are shown in Table 2 below.
상기 표 2와 같이, 화합물 11 및 화합물 12는 23종의 키나아제 활성을 억제하는 효과를 나타냈으며 특히, 0.1 μM 농도에도 불구하고 cKit(V560G), FLT1, FLT3, FLT3(D835Y), FLT3(ITD), FLT4 키나아제에 대하여 매우 우수한 억제 효과를 나타내었다.As shown in Table 2, Compound 11 and Compound 12 showed 23 kinds of kinase activity inhibitory effects. In particular, cKit (V560G), FLT1, FLT3, FLT3 (D835Y) and FLT3 (ITD) , And showed very excellent inhibitory effect on FLT4 kinase.
또한, 상기 유의하게 억제 효과가 나타난 키나아제에 대하여, 화합물 11 및 화합물 12의 50% 억제 농도(the half maximal inhibitory concentration, IC50)를 확인한 결과, 표 3과 같이 확인되었다.In addition, the half-maximal inhibitory concentration (IC 50 ) of the compound 11 and compound 12 was confirmed as shown in Table 3 with respect to the kinase exhibiting the above-mentioned significant inhibitory effect.
((
μMμM
))
((
μMμM
))
상기 표 3과 같이, 화합물 11 및 화합물 12는 FLT3와 FLT3 유전자 내 D835Y, ITD 돌연변이형 FLT3 키나아제에 대하여 50% 저해 농도가 nM 수준으로 뛰어난 억제 효과를 나타내었다.As shown in Table 3, Compound 11 and Compound 12 showed excellent inhibitory effect at 50% inhibition concentration of nM for D835Y and ITD mutant FLT3 kinase in FLT3 and FLT3 genes.
<< 실시예Example 3> 다양한 인체 3> Various human body 암세포주에Cancer cell 대한 효과 확인 Check the effect on
다양한 암 세포주의 세포 증식율에 대하여, 상기 실시예 1에서 합성한 화합물 11 및 화합물 12의 암세포 증식 억제 효과를 확인하였다. The inhibitory effect of the compound 11 and the compound 12 synthesized in Example 1 on the cancer cell proliferation inhibitory effect on the cell growth rate of various cancer cell lines was confirmed.
먼저, ATCC(American Type Culture Collection)에서 구입한 인체 폐암세포주인 H1299, 인체 유방암세포주인 MDA-MB231, 인체 대장암세포주인 HCT116, 인체 급성백혈병세포주인 MV4-11, 인체 정상대장세포주인 CCD18-Co를 10% 소태아혈청(Fetal Bovine Serum, FBS, WELGENE, 한국), 100μg/ml 스트렙토마이신(streptomycin) 및 100 unit/ml 페니실린 (GIBCO, 영국)이 첨가된 DMEM(Dulbecco's modified Eagle's medium, WELGENE), RPMI (WELGENE) 또는 MEM(MV4-11; WELGENE) 배지로 5% CO2 및 37℃ 조건하에서 각각 배양하여 실험에 사용하였다.First, the human lung cancer cell line H1299, the human breast cancer cell line MDA-MB231, the human colorectal cancer cell line HCT116, the human acute leukemia cell line MV4-11, and the human colon cancer cell line CCD18-Co purchased from the American Type Culture Collection (ATCC) (Dulbecco's modified Eagle's medium, WELGENE) supplemented with 10% fetal bovine serum (FBS, WELGENE, Korea), 100 ug / ml streptomycin and 100 unit / ml penicillin (WELGENE) or MEM (MV4-11; WELGENE) medium at 5% CO 2 and 37 ° C, respectively.
1. One. STAT5STAT5 인산화 억제 효과 확인 Identification of inhibition of phosphorylation
배양된 MV4-11 백혈병세포에 화합물 11 및 화합물 12를 처리한 후, FLT3의 하위 신호전달계인 STAT5의 인산화가 억제되는지 웨스턴 블롯을 이용하여 확인하였다. Cultured MV4-11 leukemia cells were treated with Compound 11 and Compound 12 and confirmed by Western blotting to inhibit phosphorylation of STAT5, a lower signaling system of FLT3.
0.1, 1, 2, 5 또는 10 μM 농도의 화합물 11 또는 화합물 12를 1시간 동안 처리한 후, 세포를 수득하고 당 분야에서 통상적으로 이용되는 방법으로 세포 용해액을 얻었다. 상기 세포 용해액을 9% 구배 SDS-PAGE를 이용한 전기영동을 수행하여 분리하고, 니트로셀룰로오즈 막(BioRad, Hercules, CA, USA)으로 옮겼다. 상기 막을 5% 탈지유로 블로킹(blocking)시킨 후, 일차 항체로 항-인산화-STAT5 항체(Anti-phospho-STAT5, Santa Cruz Biotechnology, 미국)과 대조군으로 항-베타 액틴(β-actin, Santa Cruz Biotechnology)를 1시간 동안 반응시켰다. 그 후, 호스래디쉬 퍼옥시다아제(horseradish peroxidase)가 접합된 항-마우스 IgG 항체(Santa Cruz Biotechnology)를 항온 반응시킨 후 ECL 시스템(GE, 미국)을 이용하여 시각화하였다. After treating compound 11 or compound 12 at a concentration of 0.1, 1, 2, 5 or 10 μM for 1 hour, cells were obtained and a cell lysate was obtained by a method commonly used in the art. The cell lysate was separated by performing electrophoresis using 9% gradient SDS-PAGE, and transferred to a nitrocellulose membrane (BioRad, Hercules, CA, USA). The membranes were blocked with 5% skim milk and incubated with anti-phospho-STAT5 antibody (Santa Cruz Biotechnology, USA) as a primary antibody and anti-beta actin (β-actin, Santa Cruz Biotechnology ) Was reacted for 1 hour. Thereafter, horseradish peroxidase-conjugated anti-mouse IgG antibody (Santa Cruz Biotechnology) was incubated and visualized using an ECL system (GE, USA).
그 결과, 도 1과 같이 화합물 11 또는 화합물 12가 처리된 MV4-11 백혈병세포에서 FLT3 키나아제의 기질 단백질인 STAT5의 인산화가 1시간대부터 억제되는 것을 확인할 수 있었다.As a result, it was confirmed that the phosphorylation of STAT5, a substrate protein of FLT3 kinase, was suppressed from 1 hour in MV4-11 leukemia cells treated with Compound 11 or Compound 12 as shown in Fig.
2. 2. 암세포주Cancer cell line 생존 억제 효과 확인 Confirm survival inhibition effect
상기 방법으로 배양된 다양한 세포주를 각각 3 × 103의 갯 수로 96웰 플레이트에 분주 후 24시간 배양한 다음, 상기 실시예 1과 같이 합성된 10 μM 농도의 화합물 11 및 화합물 12를 각각 처리하고 48시간 동안 배양하였다. 그 후 0.5 mg/mL의 MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) 용액을 각각의 웰에 첨가하고 37℃에서 3시간 추가 배양하였다. 배양이 끝난 후 상등액을 제거하고 형성된 포르마잔(formazan) 결정을 DMSO에 용해시킨 후 분광분석계(랩시스템즈, 미국)를 이용하여 590nm에서 측정하였으며, 대조군에는 DMSO를 처리하였다.Various cell lines cultured by the above method were dispensed into 96-well plates at a number of 3 × 10 3 , and then cultured for 24 hours. Then, the compound 11 and compound 12 at a concentration of 10 μM synthesized in the same manner as in Example 1 were treated respectively, Lt; / RTI > 0.5 mg / mL MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) solution was then added to each well and further incubated at 37 ° C for 3 hours. After the culture was completed, the supernatant was removed, and the formazan crystals formed were dissolved in DMSO. The resultant solution was measured at 590 nm using a spectrophotometer (Lab Systems, USA), and the control group was treated with DMSO.
그 결과를 생존율 100%에 대한 상대적인 증식율으로써 하기 표 4에 나타내었다.The results are shown in Table 4 as relative growth rates relative to 100% survival rate.
혈액암세포MV4-11
Blood cancer cells
대장암세포DLD-1
Colon cancer cells
폐암세포H460
Lung cancer cell
유방암세포MDA-MB231
Breast cancer cell
대장 정상세포CCD18-Co
Colonic normal cell
상기 표 4와 같이, 본 발명에 따른 화합물 11 및 화합물 12는 폐암, 유방암, 대장암과 백혈병 세포에서 우수한 증식 억제 효과를 보였으며, CCD18-Co 정상세포의 세포 생존율은 같은 농도에서 억제되지 않았으므로 선택적인 암세포 증식 억제효과가 있음을 확인할 수 있었다.As shown in Table 4, the compounds 11 and 12 according to the present invention showed excellent proliferation inhibitory effects in lung cancer, breast cancer, colon cancer and leukemia cells, and the cell viability of CCD18-Co normal cells was not inhibited at the same concentration It was confirmed that there was a selective cancer cell proliferation inhibiting effect.
또한, 상기 실시예 1에서 합성된 화합물들을 급성백혈병세포인 MV4-11에 상기 실시예 1에서 합성한 유도체 2 내지 유도체 12를 처리한 후, 세포 생존에 대한 억제 효과를 확인하였다.In addition, the compounds synthesized in Example 1 were treated with MV4-11, which is an acute leukemia cell, and derivatives 2 to 12 synthesized in Example 1, and the inhibitory effect on cell survival was confirmed.
세포를 3 × 103의 갯 수로 96-웰 플레이트에 분주한 후 24시간 배양한 다음 10 μM의 상기 실시예 1에서 합성한 화합물 2 내지 화합물 12를 각각 처리하고 48시간 동안 배양하였다. 그 후 0.5 mg/mL의 MTT 용액을 각각의 웰에 첨가하고 37℃에서 3시간 동안 추가 배양하였다. 배양이 끝난 후, 상등액을 제거하고 형성된 포르마잔 결정을 DMSO에 용해시키고 분광분석계를 이용하여 590nm에서 측정하였다. Handle 3 × 10 After 3 Conger channel dispensed in 96-well plates of cultured for 24 hours, and then the compound 2 to compound 12 synthesized in Example 1 of 10 μM and each cell was cultured for 48 hours. A 0.5 mg / mL MTT solution was then added to each well and further incubated at 37 [deg.] C for 3 hours. After incubation, the supernatant was removed and the formazan crystals formed were dissolved in DMSO and measured at 590 nm using a spectrophotometer.
대조군에는 DMSO를 처리하였으며, 하기 표 5와 같이 세포 생존율을 생존율 100%에 대한 상대적 값으로 나타내었다.The control group was treated with DMSO and the cell survival rate was expressed as a relative value to the survival rate of 100% as shown in Table 5 below.
한편, 세포사멸에 관여하는 카스파제-3(caspase-3)와 DNA 복구에 관여하는 PARP(poly-ADP ribose polymerase)의 절단을 웨스턴 블롯으로 확인하였다. 이때 카스파제-3 항체(Cell signaling technology, Inc. 미국)와 PARP-1 항체(PARP-1, Cell signaling technology, Inc. 미국)로 단백질과 절단된 PARP 단백질의 검출하였다. Meanwhile, cleavage of caspase-3 (caspase-3) involved in apoptosis and PARP (poly-ADP ribose polymerase) involved in DNA repair was confirmed by Western blotting. At this time, proteins and cleaved PARP proteins were detected with caspase-3 antibody (Cell signaling technology, Inc. USA) and PARP-1 antibody (PARP-1, Cell signaling technology, Inc. USA).
그 결과, 도 2와 같이 화합물 11 및 화합물 12가 처리된 MV4-11 백혈병 세포에서 아폽토시스에 의한 세포사멸과 관련된 유전자인 카스파제-3(caspase-3) 발현 및 PARP(poly-ADP ribose polymerase)의 절단이 증가되는 것을 확인할 수 있었다.As a result, expression of caspase-3, a gene involved in apoptosis-induced apoptosis in MV4-11 leukemia cells treated with Compound 11 and Compound 12, and expression of PARP (poly-ADP ribose polymerase) It was confirmed that the cutting was increased.
<< 실시예Example 4> 병용처리에 따른 항암 효과 확인 4> Confirmation of anticancer effect by combination treatment
1. 항암제와 병용처리에 따른 항암 효과 확인1. Identification of anticancer effect by combination treatment with anticancer agent
상기 실시예 3과 같이 배양된 MV4-11 백혈병 세포에 2 μM의 화합물 11 또는 화합물 12와 5 μM의 공지된 항암제인 시스플라틴(Cisplatin; 5 μM)을 48시간 동안 병용 처리하고 MTT 시험법을 통하여 세포 생존율을 분석하였다.MV4-11 leukemia cells cultured as in Example 3 were treated with 2 μM of Compound 11 or Cisplatin (5 μM), a known anticancer drug of 12 μM and 5 μM, for 48 hours, Survival rate was analyzed.
그 결과, 도 3과 같이 항암제인 시스플라틴이 단독 처리된 대조군보다 시스플라틴과 화합물 1을 병용 투여한 실험군의 세포 증식 억제 효과가 40% 이상으로 나타났으며, 시스플라틴과 화합물 2를 병용 투여한 실험군에서는 60% 이상 증가한 것을 확인하였다. As a result, as shown in FIG. 3, the cell proliferation inhibitory effect of the test group treated with cisplatin and
상기 결과로부터 본 발명에 따른 화합물 11 및 화합물 12는 항암제 치료 효과를 상승시킬 수 있는 항암제 보조제로 사용 가능한 것이 확인되었다.From the above results, it was confirmed that the compound 11 and the compound 12 according to the present invention can be used as an anticancer agent adjuvant which can enhance the therapeutic effect of the anticancer drug.
2. 방사선 조사 병용처리에 따른 항암 효과 확인2. Confirmation of anticancer effect by radiation irradiation treatment
배양된 인체 혈액암세포 MV4-11 세포주에 10 μM의 화합물 11 및 화합물 12와 방사선 1Gy 조사를 병용 처리한 후 48시간 배양하고 아넥신(annexin) V와 프로피디움 요오드화물(propidium iodide, PI)로 이중염색하고, FACSort 유세포 분석기(Becton dickinson, 미국)를 사용하여 분석한 후, 전체 아폽토시스를 초기 및 말기 아폽토시스 세포를 합산하여 결정하였다. The cultured human blood cancer cell MV4-11 cell line was treated with 10 μM of Compound 11 and
그 결과, 도 4와 같이 MV4-11 인체혈액암 세포주에서 아폽토시스에 의한 세포사멸이 방사선 단독 조사군과 비교하여 각각 2.1 배, 1.8 배 이상 유도되는 것을 확인할 수 있었다.As a result, apoptosis-induced apoptosis in the MV4-11 human blood cancer cell line was induced 2.1-fold and 1.8-fold, respectively, as compared with the radiation alone group, as shown in FIG.
상기 결과로부터 본 발명의 화합물 11 및 화합물 12가 방사선 치료 효과를 상승시킬 수 있는 방사선 치료 보조제로 사용 가능한 것이 확인되었다.From the above results, it was confirmed that the compound 11 and the compound 12 of the present invention can be used as a radiotherapy adjuvant which can enhance the radiation treatment effect.
하기에서는 본 발명에 따른 화합물 11 또는 화합물 12를 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, formulation examples of the composition containing Compound 11 or 12 according to the present invention will be described, but the present invention is not intended to be limited thereto but is specifically described.
<처방예 1> 약학 조성물의 처방예≪ Prescription Example 1 > Prescription Example of Pharmaceutical Composition
1. 산제의 제조1. Manufacturing of powder
화합물 20 mg, 유당 100 mg 및 탈크 10 mg을 혼합하고 기밀포에 충진하여 산제를 제조하였다.20 mg of the compound, 100 mg of lactose and 10 mg of talc were mixed and filled in an airtight container to prepare a powder.
2. 정제의 제조2. Preparation of tablets
화합물 20 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2 mg을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.20 mg of the compound, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate were mixed and tableted according to a conventional preparation method.
3. 캅셀제의 제조3. Preparation of capsules
화합물 10 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2mg을 혼합한 후 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.10 mg of the compound, 100 mg of the corn starch, 100 mg of the lactose and 2 mg of the magnesium stearate were mixed, and the above components were mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
4. 주사제의 제조4. Preparation of injections
화합물 10 mg, 주사용 멸균 증류수 적량 및 pH 조절제 적량을 혼합한 후 통상의 주사제의 제조방법에 따라 1 앰플당(2㎖) 상기의 성분 함량으로 제조하였다.10 mg of the compound, sterile distilled water suitable amount for injection, and pH adjuster were mixed, and the contents were adjusted to the above contents in the amount of 2 ml per ampoule according to the usual injection preparation method.
5. 연고제의 제조5. Manufacture of Ointment
화합물 10 mg, PEG-4000 250 mg, PEG-400 650 mg, 백색바셀린 10 mg, 파라옥시안식향산메칠 1.44 mg, 파라옥시안식향산프로필 0.18 mg 및 잔량의 정제수를 혼합한 후 통상의 연고제의 제조방법에 따라서 연고제를 제조하였다.After mixing 10 mg of the compound, 250 mg of PEG-4000, 650 mg of PEG-400, 10 mg of white petrolatum, 1.44 mg of methyl p-hydroxybenzoate, 0.18 mg of propyl p-hydroxybenzoate and the remaining amount of purified water, An ointment agent was prepared.
<처방예 2> 건강기능식품≪ Prescription Example 2 >
1. 건강식품의 제조1. Manufacture of health food
화합물 1 ㎎, 비타민 혼합물 적량(비타민 A 아세테이트 70 ㎍, 비타민 E 1.0 ㎎, 비타민 B 1 0.13 ㎎, 비타민 B 2 0.15 ㎎, 비타민 B 6 0.5 ㎎, 비타민 B 12 0.2 ㎍, 비타민 C 10 ㎎, 비오틴 10 ㎍, 니코틴산아미드 1.7 ㎎, 엽산 50 ㎍, 판토텐산 칼슘 0.5 ㎎) 및 무기질 혼합물 적량(황산제1철 1.75 ㎎, 산화아연 0.82 ㎎, 탄산마그네슘 25.3 ㎎, 제1인산칼륨 15 ㎎, 제2인산칼슘 55 ㎎, 구연산칼륨 90 ㎎, 탄산칼슘 100 ㎎, 염화마그네슘 24.8 ㎎)을 혼합한 다음 과립을 제조하고 통상의 방법에 따라 건강식품을 제조하였다.
2. 건강음료의 제조2. Manufacture of health drinks
화합물 1 ㎎, 구연산 1000 ㎎, 올리고당 100 g, 매실농축액 2 g, 타우린 1 g 및 정제수를 가하여 전체 900 ㎖가 되도록 하며, 통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관하였다. 1 mg of the compound, 1000 mg of citric acid, 100 g of the oligosaccharide, 2 g of the plum concentrate, 1 g of taurine and purified water were added to make a total of 900 mL, and the above components were mixed according to a conventional health drink manufacturing method, The solution was filtered and sterilized in a sterilized 2 L container, and then refrigerated.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
Claims (13)
[화학식 1]
상기 화학식 1에서,
X는 질소 및 탄소에서 선택된 어느 하나임.1. A pharmaceutical composition for preventing or treating cancer, comprising a compound represented by the following formula (1) or a pharmaceutically usable salt thereof as an active ingredient.
[Chemical Formula 1]
In Formula 1,
X is any one selected from nitrogen and carbon.
[화학식 1]
상기 화학식 1에서,
X는 질소 및 탄소에서 선택된 어느 하나임.1. A composition for enhancing an anticancer effect comprising a compound represented by the following formula (1) or a pharmaceutically usable salt thereof as an active ingredient.
[Chemical Formula 1]
In Formula 1,
X is any one selected from nitrogen and carbon.
[화학식 1]
상기 화학식 1에서,
X는 질소 및 탄소에서 선택된 어느 하나임.A health food for cancer prevention or improvement, comprising a compound represented by the following formula (1) or a pharmaceutically usable salt thereof as an active ingredient.
[Chemical Formula 1]
In Formula 1,
X is any one selected from nitrogen and carbon.
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