WO2008040208A1 - (2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one in manufacture of medicaments for treating cancers - Google Patents

(2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one in manufacture of medicaments for treating cancers Download PDF

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WO2008040208A1
WO2008040208A1 PCT/CN2007/070651 CN2007070651W WO2008040208A1 WO 2008040208 A1 WO2008040208 A1 WO 2008040208A1 CN 2007070651 W CN2007070651 W CN 2007070651W WO 2008040208 A1 WO2008040208 A1 WO 2008040208A1
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cancer
compound
cancer cells
dihydroxybenzylidene
benzofuran
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PCT/CN2007/070651
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French (fr)
Chinese (zh)
Inventor
Long Yu
Haoxing Zhang
Qingyu Lang
Lisha Tang
Jia Li
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Fudan University
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Priority to CN2007800330141A priority Critical patent/CN101511355B/en
Publication of WO2008040208A1 publication Critical patent/WO2008040208A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the field of cell biology, and provides the use of the compound s6 for the preparation of an anticancer drug. Background technique
  • Tumors are diseases that seriously endanger human health.
  • the incidence of cancer has increased in recent years. At present, more than 6 million people worldwide die of cancer every year, and the number of new cases is 8 million. This number is increasing year by year.
  • Malignant tumors commonly known as cancer, are unrestricted and diffuse masses caused by the mutating of organs and tissue cells of the human body. It can destroy the organs and tissues of the human body, consumes limited energy in the body, and damages human life and even causes death.
  • Mitosis is a very important stage in the cell cycle process.
  • the difference between a tumor and a normal cell is infinite hyperplasia, that is, mitosis loses its normal regulation.
  • Most tumors occur due to genomic instability caused by mitosis.
  • Genomic instability is caused by chromosome instability.
  • Chromosomal instability is a characteristic marker of cancer.
  • Abnormal chromosome segregation, central granule replication and segregation can lead to abnormalities in the number of chromosomes per cell, ie aneuploidy, increased chance of heterozygous deletion, loss of tumor suppressor gene or increased number of proto-oncogenes Disrupts cell life metabolism and signaling, increasing the chance of cancer.
  • Kinase plays an important role in the completion of mitosis and cell cycle regulation, and thus has become a research hotspot in molecular biology.
  • a compound of formula I namely (2Z)-2-(3,4-dihydroxybenzylidene;)-1-benzofuran-3 (2H ketone, Or the use of a pharmaceutically acceptable salt or ester thereof in the preparation of an anti-cancer composition, such as an anti-cancer drug;
  • the composition is a pharmaceutical composition, a nutraceutical composition or a dietary supplement combination.
  • the medicament is for killing cancer cells or inhibiting the growth of cancer cells.
  • the anticancer drug contains 0.001 to 99% by weight (; preferably 0.01 to 90% by weight;) a compound of the formula I and a pharmaceutically acceptable carrier or excipient.
  • the medicament is also for inhibiting phosphokinase Aurora-B.
  • the anticancer drug is an injection, granule, capsule, solution or tablet.
  • the cancer is selected from the group consisting of liver cancer, colon cancer, gastric cancer, and lung cancer.
  • a method for inhibiting tumor cell growth in vitro comprising the steps of: adding a compound (2 ⁇ )-2- ⁇ ; 3,4-dihydroxybenzylidene to a culture system of the tumor cell Base 1-benzofuran-3(2 ⁇ )-one.
  • the tumor cells are selected from the group consisting of liver cancer cells, colon cancer cells, gastric cancer cells, and lung cancer cells.
  • a method of treating cancer comprising the steps of: administering (2 ⁇ )-2-(3,4-dihydroxybenzylidene)-1-benzene to a mammalian subject in need of treatment Furan-3(2 ⁇ )-one or a pharmaceutically acceptable salt thereof.
  • the application amount is from 0.1 mg/kg to 20 mg/kg of body weight per day.
  • Figure 1 is a graph showing the inhibition results of s6 against SW 620 cells. It can be seen that the IC50 (half lethal) of the s6 of the present invention against the human colon cancer cell line (sw620) is about 1 ⁇ Mo.
  • Figure 2 is a graph showing the anti-tumor effect of s6. It can be seen that the tumor weight of mice decreased significantly after s6 administration. detailed description
  • the name of the compound is -2-(3,4-dihydroxybenzylidene) -1 - benzofuran-3 (2 ⁇ -one [(2 -2- (3, 4-dihydroxybenzylidene)-1-benzene) Furan-3(2-ketone), abbreviated as s6, having a molecular weight of 254, can be obtained by commercially available or conventional methods.
  • the present invention also includes compounds obtained by subjecting the compound to conventional substitution.
  • the s6 compound of the present invention can be used in the form of a salt or an ester derived from a pharmaceutically or physiologically acceptable acid or base.
  • These salts include, but are not limited to, salts or esters formed with: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, oxalic acid, fumaric acid, Maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or isethionic acid.
  • the salts of halides are also suitable.
  • salts include: salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, as well as esters, carbamates or other conventional "prodrugs" (when given in this form) In the case of medicine, it can be converted into an active part in the body).
  • the compound s6 can be used for the preparation of an anticancer drug.
  • the present invention detects the action of the compound s6 on tumor cells and cancer cells according to a standard MTS assay, and the results show that the s6 of the present invention acts on various tumor cells and cancer cells, such as liver cancer cells, colon cancer cells, gastric cancer cells, lung cancer cells, and the like. , have a killing or inhibition effect.
  • the compound s6 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This further confirmed that the compound s6 of the present invention has an effect of inhibiting malignant tumors.
  • Aik2 mainly plays a role in the mitosis of cells.
  • Aik2 acts as a chromosomal concomitant protein involved in the regulation of the interaction between the centromere and the spindle microtubule.
  • Aik2 migrates from the centromere to the middle zone of the cell, and is distributed at the end of the cell plate and the posterior mitotic bridge. Post-mitotic events are associated with chromosome segregation and cytokinesis. Mutations in Aik2 inhibit the formation of dividing sulcus and lead to the formation of multinucleated cells.
  • Aik2 is localized to 17ql3, an area that is abnormal in a variety of human cancer cells, and Aik2 is highly expressed in abnormally ploidy colon cancer cell lines. Therefore, researchers are looking for molecules that interact with Aik2 and use them as antitumor drugs.
  • the present invention also establishes a mouse model of transplanted tumor for detecting the effect of s6 on tumors and cancer cells in vivo. The results also show that s6 can inhibit tumor growth in vivo.
  • the anticancer drug prepared from the compound s6 is a pharmaceutical composition comprising a therapeutically effective amount of the compound s6 and a pharmaceutically acceptable carrier or excipient.
  • the effective application amount is 0.1 mg / kg to 20 mg / kg body weight per day.
  • the antitumor drug prepared may be an injection or a tablet or the like.
  • the present invention can provide different effects when administered (administered) therapeutically.
  • these materials can be formulated in a non-toxic, inert, andpharmaceutically acceptable aqueous carrier medium, wherein the pH is usually from about 5 to about 8, preferably from about 6 to about 8, although the pH may be The nature of the formulation and the condition to be treated vary.
  • the formulated pharmaceutical compositions can be administered by conventional routes including, but not limited to, intramuscular, intraperitoneal, subcutaneous, intradermal, intratumoral, or topical administration.
  • s6 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carrier include, but are not limited to, saline, buffer, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical preparation should be matched to the mode of administration.
  • the s6 of the present invention can be prepared in the form of an injection, for example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • compositions such as injections, solutions, tablets and capsules are preferably prepared under sterile conditions.
  • the amount of active ingredient administered is a therapeutically effective amount, for example from about 1 microgram per kilogram body weight to about 5 milligrams per kilogram body weight per day.
  • the s6 of the present invention can also be used with other therapeutic agents.
  • a therapeutically effective dose of s6 can be administered to a mammal
  • the therapeutically effective dose is usually at least about 10 micrograms per kilogram of body weight, and in most cases does not exceed about 80 milligrams per kilogram of body weight, preferably the dosage is from about 500 micrograms per kilogram of body weight to about 2 milligrams per kilogram of body weight.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician. Cancer has become the first cause of death, and the substances that kill tumors and cancer cells have become the research hotspots in the biomedical field.
  • the s6 of the present invention has a killing or inhibiting effect on various tumor cells and cancer cells; meanwhile, the compound s6 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This all proves that the compound s6 of the present invention has an effect of inhibiting malignant tumors.
  • the compound s6 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier to prepare an anticancer drug to inhibit the continued growth of the tumor.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the human Aurora-B protein kinase (NCBI accession number NP-004208) was cloned, expressed and purified using E. coli expression system for high-throughput screening experiments.
  • AUR0RAB pity acidified substrate MBP (UPSTATE, CAT#13-110, lot#27845), covalently binds ⁇ - 33 [ on [ ⁇ - 33 ⁇ ]- ⁇ in solution to the substrate. Its Ser is phosphorylated to produce the substrate 33 P-MBP with isotopic labeling.
  • the activity of the enzyme was detected by counting the scintillation liquid by counting with a liquid scintillation counter, and the inhibition of the activity of the different compounds was observed to initially evaluate the activity of the compound.
  • Seed plate 1000 cells/well Compound: s6
  • Cell line human colon cancer cell line (sw620)
  • the drug was administered from the next day after the inoculation, and the administration volume was 0.5 ml/20 g body weight, and the intraperitoneal injection was continued for 7 days.
  • the animals were sacrificed by cervical dislocation, and the tumor mass was dissected and weighed. The results were determined. The results are shown in Figure 2. After inoculation of s6, the tumor weight of the mice decreased significantly, and the more s6 inoculated, the tumor weight decreased. The more obvious.
  • the pharmaceutical composition in the form of a tablet is prepared by a conventional technique by mixing the following components and then directly compressing the tablet, and the formulation is as follows:

Abstract

The use of (2Z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2H)-one in manufacture of medicaments for treating cancers. The compound demonstrates inhibition towards liver, colon, lung and stomach cancer cells and phosphokinase Aurora-B. The compound of the present invention can be formulated into anticancer pharmaceutical compositions with pharmaceutically acceptable carriers to suppress the continuous growth of tumors.

Description

(2Z) -2- (3， 4-二羟基亚苄基) -1-苯并呋喃 -3 (2H) -酮  (2Z) -2- (3, 4-dihydroxybenzylidene)-1-benzofuran-3(2H)-one
在制备抗癌药物中的应用  Application in the preparation of anticancer drugs
技术领域  Technical field
本发明涉及细胞生物学领域， 提供了化合物 s6在制备抗癌药物中的应用。 背景技术  The present invention relates to the field of cell biology, and provides the use of the compound s6 for the preparation of an anticancer drug. Background technique
肿瘤是严重危害人类健康的疾病。 近年来肿瘤的发病率日见增长， 目前全世界 每年有 600多万人死于癌症， 新发病例 800万， 这数字还在逐年增加。 我国 13亿人 口中每年有百万新发癌症病人， 待治疗病人约 200万， 死亡约 130万。 预计到 2006 年年底， 我国将有 170万人死于癌症， 癌症已成为第一位死因。  Tumors are diseases that seriously endanger human health. The incidence of cancer has increased in recent years. At present, more than 6 million people worldwide die of cancer every year, and the number of new cases is 8 million. This number is increasing year by year. There are millions of new cancer patients in China each year, with about 2 million patients to be treated and about 1.3 million deaths. It is estimated that by the end of 2006, 1.7 million people will die of cancer in China, and cancer has become the first cause of death.
恶性肿瘤俗称癌症，是人体的器官和组织细胞发生变异后引起的无限制生长的 和扩散的肿块。 它可以破坏人体的器官和组织功能， 消耗体内有限能量， 而使人的生 命活动受到损害， 甚至导致死亡。  Malignant tumors, commonly known as cancer, are unrestricted and diffuse masses caused by the mutating of organs and tissue cells of the human body. It can destroy the organs and tissues of the human body, consumes limited energy in the body, and damages human life and even causes death.
有丝***是细胞周期过程中很重要的一个阶段。肿瘤与正常细胞的区别就是无限 制增生， 即有丝***失去正常调控。 大多数的肿瘤其发生原因是有丝***所致的基因 组的不稳定性， 基因组的不稳定又来源于染色体的不稳定， 染色体的不稳定是癌症的 特征性标志。 染色体的分离、 中心粒的复制和分离发生异常， 会导致每个细胞染色体 数目的异常， 即非整倍体， 增加杂合性缺失的机会， 抑癌基因的缺失或原癌基因的数 目增加都会使细胞生命代谢和信号传导发生紊乱， 增加癌变的机会。激酶在完成有丝 ***和细胞周期调控中起着重要作用， 从而成为目前分子生物学的研究热点。  Mitosis is a very important stage in the cell cycle process. The difference between a tumor and a normal cell is infinite hyperplasia, that is, mitosis loses its normal regulation. Most tumors occur due to genomic instability caused by mitosis. Genomic instability is caused by chromosome instability. Chromosomal instability is a characteristic marker of cancer. Abnormal chromosome segregation, central granule replication and segregation can lead to abnormalities in the number of chromosomes per cell, ie aneuploidy, increased chance of heterozygous deletion, loss of tumor suppressor gene or increased number of proto-oncogenes Disrupts cell life metabolism and signaling, increasing the chance of cancer. Kinase plays an important role in the completion of mitosis and cell cycle regulation, and thus has become a research hotspot in molecular biology.
为了***， 本领域迫切需要开发能够有效抑制肿瘤细胞生长的化合物。 发明内容  In order to treat tumors, there is an urgent need in the art to develop compounds capable of effectively inhibiting the growth of tumor cells. Summary of the invention
本发明的目的是提供化合物 s6在制备抗癌药物中的应用。 在本发明的第一方面， 提供了一种式 I所示的化合物， 即 (2Z)-2-(3,4-二羟基亚苄 基;) -1-苯并呋喃 -3(2H 酮， 或其药学上可接受的盐或酯在制备抗癌的组合物 (如抗癌药 物;)中的应用。
Figure imgf000003_0001
It is an object of the present invention to provide the use of the compound s6 for the preparation of an anticancer drug. In a first aspect of the invention, there is provided a compound of formula I, namely (2Z)-2-(3,4-dihydroxybenzylidene;)-1-benzofuran-3 (2H ketone, Or the use of a pharmaceutically acceptable salt or ester thereof in the preparation of an anti-cancer composition, such as an anti-cancer drug;
Figure imgf000003_0001
在另一优选例中， 所述的组合物为药物组合物， 保健品组合物或饮食补充剂组合 在另一优选例中， 所述的药物用于杀伤癌细胞或抑制癌细胞的生长。  In another preferred embodiment, the composition is a pharmaceutical composition, a nutraceutical composition or a dietary supplement combination. In another preferred embodiment, the medicament is for killing cancer cells or inhibiting the growth of cancer cells.
在另一优选例中， 所述的抗癌药物含有 0.001-99wt% (；较佳地 0.01-90wt%；)式 I 化合物和药学上的载体或者赋形剂。  In another preferred embodiment, the anticancer drug contains 0.001 to 99% by weight (; preferably 0.01 to 90% by weight;) a compound of the formula I and a pharmaceutically acceptable carrier or excipient.
在另一优选例中， 所述的药物还用于抑制磷酸激酶 Aurora-B。  In another preferred embodiment, the medicament is also for inhibiting phosphokinase Aurora-B.
在另一优选例中， 该抗癌药物是针剂、 颗粒剂、 胶囊、 溶液或片剂。  In another preferred embodiment, the anticancer drug is an injection, granule, capsule, solution or tablet.
在另一优选例中， 所述的癌症选自： 肝癌、 结肠癌、 胃癌和肺癌。  In another preferred embodiment, the cancer is selected from the group consisting of liver cancer, colon cancer, gastric cancer, and lung cancer.
在本发明的第二方面， 提供了一种体外抑制肿瘤细胞生长的方法， 包括步骤： 在所述肿瘤细胞的培养体系中添加化合物 (2Ζ)-2-<;3,4-二羟基亚苄基 1-苯并呋喃 -3(2Η)-酮。  In a second aspect of the invention, a method for inhibiting tumor cell growth in vitro is provided, comprising the steps of: adding a compound (2Ζ)-2-<; 3,4-dihydroxybenzylidene to a culture system of the tumor cell Base 1-benzofuran-3(2Η)-one.
在另一优选例中， 所述的肿瘤细胞选自： 肝癌细胞、 结肠癌细胞、 胃癌细胞和 肺癌细胞。  In another preferred embodiment, the tumor cells are selected from the group consisting of liver cancer cells, colon cancer cells, gastric cancer cells, and lung cancer cells.
在本发明的第三方面， 提供了一种治疗癌症的方法， 包括步骤： 给需要治疗 的哺乳动物对象施用 (2Ζ)-2-(3,4-二羟基亚苄基 )-1-苯并呋喃 -3(2Η)-酮或其药学上 可接受的盐。  In a third aspect of the invention, a method of treating cancer comprising the steps of: administering (2Ζ)-2-(3,4-dihydroxybenzylidene)-1-benzene to a mammalian subject in need of treatment Furan-3(2Η)-one or a pharmaceutically acceptable salt thereof.
在另一优选例中， 所述的施用量为每天 0.1毫克 /千克至 20毫克 /千克体重。 附图说明  In another preferred embodiment, the application amount is from 0.1 mg/kg to 20 mg/kg of body weight per day. DRAWINGS
图 1为 s6对 SW620细胞抑制结果图。 可见， 本发明的 s6对人类结肠癌细胞株 (sw620)的 IC50 (半数致死）为约 1 μ Mo Figure 1 is a graph showing the inhibition results of s6 against SW 620 cells. It can be seen that the IC50 (half lethal) of the s6 of the present invention against the human colon cancer cell line (sw620) is about 1 μ Mo.
图 2为 s6抑瘤效果图。 可见， s6给药后， 小鼠瘤重明显下降。 具体实施方式 Figure 2 is a graph showing the anti-tumor effect of s6. It can be seen that the tumor weight of mice decreased significantly after s6 administration. detailed description
Figure imgf000004_0001
Figure imgf000004_0001
所 述 化 合 物 的 名 称 为 -2- (3, 4-dihydroxybenzyl idene) -1 - benzofuran-3 (2^ -one [ (2 -2- (3， 4-二羟基亚苄基） -1-苯并呋喃- 3 (2 -酮]， 简 称为 s6， 分子量为 254， 可通过市售获得或常规方法制备。 本发明还包括对该化合 物进行常规替代所得到的化合物。  The name of the compound is -2-(3,4-dihydroxybenzylidene) -1 - benzofuran-3 (2^-one [(2 -2- (3, 4-dihydroxybenzylidene)-1-benzene) Furan-3(2-ketone), abbreviated as s6, having a molecular weight of 254, can be obtained by commercially available or conventional methods. The present invention also includes compounds obtained by subjecting the compound to conventional substitution.
本发明的 s6化合物可以以由药学上或生理学可接受的酸或碱衍生的盐或酯形 式使用。 这些盐包括（但不限于）与如下酸形成的盐或酯： 氢氯酸、 氢溴酸、 硫酸、 柠檬酸、 酒石酸、 磷酸、 乳酸、 丙酮酸、 乙酸、 琥珀酸、 草酸、 富马酸、 马来酸、 草酰乙酸、 甲磺酸、 乙磺酸、 苯磺酸、 或羟乙磺酸。 卤化物的盐同样适用。 其他盐 包括： 与碱金属或碱土金属（如钠、 钾、 钙或镁）形成的盐， 以及以酯、 氨基甲酸酯 或其他常规的 "前体药物" 的形式（当以这种形式给药时， 在体内可转化成活性部 分）。 本发明中， 化合物 s6可用于制备抗癌药物。  The s6 compound of the present invention can be used in the form of a salt or an ester derived from a pharmaceutically or physiologically acceptable acid or base. These salts include, but are not limited to, salts or esters formed with: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, oxalic acid, fumaric acid, Maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or isethionic acid. The salts of halides are also suitable. Other salts include: salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, as well as esters, carbamates or other conventional "prodrugs" (when given in this form) In the case of medicine, it can be converted into an active part in the body). In the present invention, the compound s6 can be used for the preparation of an anticancer drug.
本发明按标准 MTS实验检测了化合物 s6对于肿瘤细胞和癌细胞的作用情况， 结 果显示， 本发明的 s6对多种肿瘤细胞和癌细胞， 例如肝癌细胞、 结肠癌细胞、 胃癌 细胞和肺癌细胞等， 都有杀伤或者抑制效果。  The present invention detects the action of the compound s6 on tumor cells and cancer cells according to a standard MTS assay, and the results show that the s6 of the present invention acts on various tumor cells and cancer cells, such as liver cancer cells, colon cancer cells, gastric cancer cells, lung cancer cells, and the like. , have a killing or inhibition effect.
进一步研究显示， 本发明的化合物 s6对磷酸激酶 Aurora-B 有抑制作用。 这 进一步证实了本发明的化合物 s6具有抑制恶性肿瘤的作用。  Further studies have shown that the compound s6 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This further confirmed that the compound s6 of the present invention has an effect of inhibiting malignant tumors.
恶性肿瘤俗称癌症， 是人体的器官和组织细胞发生变异后引起的无限制生长 的和扩散的肿块。 激酶在完成有丝***和细胞周期调控中起着重要作用， 从而成为 目前分子生物学的研究热点。 AIK (Aur0ra/Ipl l Kinase )是目前已知的五大调节性激 酶家族之一。 到目前为止， 人类 Aiks家族共发现三个成员： Aikl、 Aik2 (Aurora-B) 和 Aik3。 其中， Aik2主要在细胞有丝***期起作用。 它作为染色体伴随蛋白参与调 节着丝粒与纺锤体微管的相互作用， 在中期至后期这一瞬时， Aik2 由着丝粒迁移至 细胞中间区带， 末期分布于细胞盘和后有丝***桥， 参与后有丝***事件， 故与染色 体的分离和胞质***有关。 Aik2 的突变使***沟的形成被抑制， 并导致形成多核细 胞。 Aik2定位于 17ql3， 这一区域在人类多种癌细胞中出现异常， 而在异常倍性的结 肠癌细胞株中 Aik2高表达。 因此， 科研人员纷纷寻找与 Aik2作用的分子， 并将其作 为抗肿瘤药物来研究。 Malignant tumors, commonly known as cancer, are unrestricted and diffuse masses caused by the mutating of organs and tissue cells of the human body. Kinase plays an important role in the completion of mitosis and cell cycle regulation, and thus has become a research hotspot in molecular biology. AIK (Aur 0 ra/Ipl l Kinase ) is currently known as the five major regulatory One of the enzyme families. So far, the human Aiks family has found three members: Aikl, Aik2 (Aurora-B) and Aik3. Among them, Aik2 mainly plays a role in the mitosis of cells. It acts as a chromosomal concomitant protein involved in the regulation of the interaction between the centromere and the spindle microtubule. At the metaphase to the late stage, Aik2 migrates from the centromere to the middle zone of the cell, and is distributed at the end of the cell plate and the posterior mitotic bridge. Post-mitotic events are associated with chromosome segregation and cytokinesis. Mutations in Aik2 inhibit the formation of dividing sulcus and lead to the formation of multinucleated cells. Aik2 is localized to 17ql3, an area that is abnormal in a variety of human cancer cells, and Aik2 is highly expressed in abnormally ploidy colon cancer cell lines. Therefore, researchers are looking for molecules that interact with Aik2 and use them as antitumor drugs.
本发明还建立了移植瘤小鼠模型， 用于检测 s6对体内肿瘤和癌细胞的作用。 结果也显示 s6可以抑制体内肿瘤生长。 本发明中， 由化合物 s6制备的抗癌药物是由含有效治疗量的化合物 s6和药学 上的载体或者赋形剂组成的药物组合物。  The present invention also establishes a mouse model of transplanted tumor for detecting the effect of s6 on tumors and cancer cells in vivo. The results also show that s6 can inhibit tumor growth in vivo. In the present invention, the anticancer drug prepared from the compound s6 is a pharmaceutical composition comprising a therapeutically effective amount of the compound s6 and a pharmaceutically acceptable carrier or excipient.
本发明中， 所述的有效应用量为每天 0. 1毫克 /千克至 20毫克 /千克体重。 本发明中， 所制备的抗肿瘤药物可以是针剂或片剂等。  In the present invention, the effective application amount is 0.1 mg / kg to 20 mg / kg body weight per day. In the present invention, the antitumor drug prepared may be an injection or a tablet or the like.
本发明 s6及其类似物等，当在治疗上进行施用（给药）时，可提供不同的效果。 通常，可将这些物质配制于无毒的、惰性的和药学上可接受的水性载体介质中， 其 中 pH通常约为 5-8， 较佳地 pH约为 6-8， 尽管 pH值可随被配制物质的性质以及 待治疗的病症而有所变化。 配制好的药物组合物可以通过常规途径进行给药， 其 中包括（但并不限于）： 肌内、 腹膜内、 皮下、 皮内、 瘤内、 或局部给药。  The present invention, s6, its analogs and the like, can provide different effects when administered (administered) therapeutically. Generally, these materials can be formulated in a non-toxic, inert, andpharmaceutically acceptable aqueous carrier medium, wherein the pH is usually from about 5 to about 8, preferably from about 6 to about 8, although the pH may be The nature of the formulation and the condition to be treated vary. The formulated pharmaceutical compositions can be administered by conventional routes including, but not limited to, intramuscular, intraperitoneal, subcutaneous, intradermal, intratumoral, or topical administration.
以本发明的 s6为例， 可以将其与合适的药学上可接受的载体联用。这类药物 组合物含有治疗有效量的化合物和药学上可接受的载体或赋形剂。 这类载体包括 (但并不限于）： 盐水、 缓冲液、 葡萄糖、 水、 甘油、 乙醇、 及其组合。 药物制剂 应与给药方式相匹配。本发明的 s6可以被制成针剂形式， 例如用生理盐水或含有 葡萄糖和其他辅剂的水溶液通过常规方法进行制备。 诸如片剂和胶囊之类的药物 组合物， 可通过常规方法进行制备。 药物组合物如针剂、 溶液、 片剂和胶囊宜在 无菌条件下制造。活性成分的给药量是治疗有效量， 例如每天约 1微克 /千克体重 -约 5毫克 /千克体重。 此外， 本发明的 s6还可与其他治疗剂一起使用。  Taking s6 of the present invention as an example, it can be used in combination with a suitable pharmaceutically acceptable carrier. Such pharmaceutical compositions contain a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier or excipient. Such carriers include, but are not limited to, saline, buffer, dextrose, water, glycerol, ethanol, and combinations thereof. The pharmaceutical preparation should be matched to the mode of administration. The s6 of the present invention can be prepared in the form of an injection, for example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants. Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably prepared under sterile conditions. The amount of active ingredient administered is a therapeutically effective amount, for example from about 1 microgram per kilogram body weight to about 5 milligrams per kilogram body weight per day. Furthermore, the s6 of the present invention can also be used with other therapeutic agents.
当本发明的 s6被用作药物时， 可将治疗有效剂量的 s6施用于哺乳动物， 其 中该治疗有效剂量通常至少约 10微克 /千克体重， 而且在大多数情况下不超过约 80毫克 /千克体重， 较佳地该剂量是约 500微克 /千克体重-约 2毫克 /千克体重。 当然， 具体剂量还应考虑给药途径、 病人健康状况等因素， 这些都是熟练医师技 能范围之内的。 癌症已成为第一位死因，杀伤肿瘤和癌细胞生长的物质也由此成为了目前生物医 药界的研究热点。 本发明的 s6对多种肿瘤细胞和癌细胞都有杀伤或者抑制效果； 同 时， 本发明的化合物 s6对磷酸激酶 Aurora-B 有抑制作用。 这都证明了本发明的 化合物 s6具有抑制恶性肿瘤的作用。将本发明的化合物 s6可用于与合适的药学上 可接受的载体联用制备抗癌药物， 以抑制肿瘤继续生长。 下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例仅用于说明本发 明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实验方法， 通常按照 常规条件如 Sambrook等人， 分子克隆： 实验室手册（New York : Cold Spring Harbor Laboratory Press, 1989)中所述的条件， 或按照制造厂商所建议的条件。 实施例 1 体外酶活抑制实验 When the s6 of the present invention is used as a medicament, a therapeutically effective dose of s6 can be administered to a mammal, The therapeutically effective dose is usually at least about 10 micrograms per kilogram of body weight, and in most cases does not exceed about 80 milligrams per kilogram of body weight, preferably the dosage is from about 500 micrograms per kilogram of body weight to about 2 milligrams per kilogram of body weight. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician. Cancer has become the first cause of death, and the substances that kill tumors and cancer cells have become the research hotspots in the biomedical field. The s6 of the present invention has a killing or inhibiting effect on various tumor cells and cancer cells; meanwhile, the compound s6 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This all proves that the compound s6 of the present invention has an effect of inhibiting malignant tumors. The compound s6 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier to prepare an anticancer drug to inhibit the continued growth of the tumor. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to the conditions described in conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer. The suggested conditions. Example 1 In vitro enzyme activity inhibition experiment
应用大肠杆菌表达***， 克隆、 表达并纯化得到了人源 Aurora-B 蛋白激酶 (NCBI登陆号为 NP— 004208)，用于高通量筛选筛选实验。 采用放射性同位素技术， AUR0RAB 憐酸化底物 MBP (UPSTATE 公司， CAT#13- 110， lot#27845)，将溶液中 [γ-33Ρ] -ΑΤΡ上的 γ-33Ρ转移共价结合到底物， 使其 Ser磷酸化， 产生具有同位素标 记的底物 33P-MBP。 最后加入闪烁液通过液体闪烁计数仪计数来检测该酶活性， 可 以观察不同化合物对其活性的抑制情况， 以初步评价化合物的活性。 The human Aurora-B protein kinase (NCBI accession number NP-004208) was cloned, expressed and purified using E. coli expression system for high-throughput screening experiments. Using radioisotope technology, AUR0RAB pity acidified substrate MBP (UPSTATE, CAT#13-110, lot#27845), covalently binds γ- 33 [ on [γ- 33 Ρ]-ΑΤΡ in solution to the substrate. Its Ser is phosphorylated to produce the substrate 33 P-MBP with isotopic labeling. Finally, the activity of the enzyme was detected by counting the scintillation liquid by counting with a liquid scintillation counter, and the inhibition of the activity of the different compounds was observed to initially evaluate the activity of the compound.
平行实验结果显示，本发明的化合物 s6对 Aurora-B蛋白激酶活性抑制的 IC50 为 15· 59nM。 实施例 2癌细胞抑制实验  The results of the parallel experiments showed that the IC50 of the compound s6 of the present invention inhibiting Aurora-B protein kinase activity was 15.59 nM. Example 2 Cancer cell inhibition experiment
按照标准 MTS实验进行， 其中具体参数如下：  According to the standard MTS experiment, the specific parameters are as follows:
种板： 1000个细胞 /孔 化合物： s6 Seed plate: 1000 cells/well Compound: s6
培养时间： 96h  Cultivation time: 96h
加药品后处理时间： 3h  Adding medicine after treatment time: 3h
化合物浓度梯度： 单位： uM  Compound concentration gradient: Unit: uM
重复实验： 6组  Repeat the experiment: 6 groups
数据给出形式： 平均值士标准差  Data given form: mean standard deviation
细胞株： 人类结肠癌细胞株（sw620)  Cell line: human colon cancer cell line (sw620)
结果显示， 本发明的化合物 s6对 sw620抑制的 IC50约为 1 μ Μ。 具体见下表:  The results showed that the compound s6 of the present invention inhibited sw620 by an IC50 of about 1 μΜ. See the table below for details:
Figure imgf000007_0001
实施例 3 对小鼠肝癌 H22抑瘤效果
Figure imgf000007_0001
Example 3 Antitumor effect on mouse liver cancer H22
试验动物及其品系： 昆明种小鼠  Test animals and their strains: Kunming mice
来源： 上海斯莱克实验动物责任有限公司  Source: Shanghai Slack Laboratory Animals Co., Ltd.
生产许可证号： SCXK (沪） 2003-0003  Production license number: SCXK (Shanghai) 2003-0003
使用许可证号： SYXK (沪） 2004-0015  License number: SYXK (Shanghai) 2004-0015
体重： 19-21g  Weight: 19-21g
性别： 雄性  Gender: Male
每组动物数： 8只（对照组 16只） 移植性肿瘤： 小鼠肝癌 H22 试验方法：  Number of animals per group: 8 (16 in the control group) Transplanted tumor: Liver in mice H22 Test method:
取生长良好的小鼠肝癌 H22腹水，用生理盐水以 1： 4稀释（细胞浓度约 1-2X107 个 /ml)， 每只小鼠右腋皮下接种 0. 2ml， 随机分组， 设： 1) 空白对照组 2ml, Randomly grouped, set: To prepare a mouse liver cancer H22 ascites, which is well-diluted with normal saline, diluted 1:4 (cell concentration: 1-2× 10 7 /ml). 1) Blank control group
2) s6 (12. 5mg/kg， ipx7)  2) s6 (12. 5mg/kg, ipx7)
3) s6 (25mg/kg， ipx7)  3) s6 (25mg/kg, ipx7)
接种后次日起给药， 给药体积为 0. 5ml/20g体重， 连续腹腔注射 7天。 接种 后 10日脱颈处死动物， 解剖取瘤块， 称瘤重， 结果判定. 结果如图 2所示， 接种 s6后， 小鼠的瘤重明显下降， 而且接种的 s6越多， 瘤重 下降越明显。 实施例 4  The drug was administered from the next day after the inoculation, and the administration volume was 0.5 ml/20 g body weight, and the intraperitoneal injection was continued for 7 days. On the 10th day after inoculation, the animals were sacrificed by cervical dislocation, and the tumor mass was dissected and weighed. The results were determined. The results are shown in Figure 2. After inoculation of s6, the tumor weight of the mice decreased significantly, and the more s6 inoculated, the tumor weight decreased. The more obvious. Example 4
药物组合物 (片剂）的制备  Preparation of pharmaceutical composition (tablet)
利用常规技术， 混合以下组分， 然后直接压片， 制备片剂形式的药物组合物， 其配方如下：  The pharmaceutical composition in the form of a tablet is prepared by a conventional technique by mixing the following components and then directly compressing the tablet, and the formulation is as follows:
Figure imgf000008_0001
在本发明提及的所有文献都在本申请中引用作为参考， 就如同每一篇文献被 单独引用作为参考那样。 此外应理解， 在阅读了本发明的上述讲授内容之后， 本 领域技术人员可以对本发明作各种改动或修改， 这些等价形式同样落于本申请所 附权利要求书所限定的范围。
Figure imgf000008_0001
All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it is to be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims

权 利 要 求 Rights request
1. 一种式 I所示的化合物 (2Ζ 2-(3,4-二羟基亚苄基 1-苯并呋喃 -3(2H 酮或其药 学上可接受的盐或酯在制备抗癌药物中的应用。 A compound of the formula I (2Ζ2-(3,4-dihydroxybenzylidene 1-benzofuran-3 (2H ketone or a pharmaceutically acceptable salt or ester thereof) for the preparation of an anticancer drug Applications.
Figure imgf000009_0001
Figure imgf000009_0001
2. 如权利要求 1所述的应用， 其特征在于， 所述的药物用于杀伤癌细胞或抑制 癌细胞的生长。  2. Use according to claim 1, wherein the medicament is for killing cancer cells or inhibiting the growth of cancer cells.
3.如权利要求 1所述的应用，其特征在于，所述的抗癌药物含有 0.001-99wt% 式 I化合物和药学上的载体或者赋形剂。  3. Use according to claim 1 wherein said anticancer drug comprises from 0.001% to 99% by weight of a compound of formula I and a pharmaceutically acceptable carrier or excipient.
4. 如权利要求 1所述的应用， 其特征在于， 所述的药物还用于抑制磷酸激酶 4. The use according to claim 1, wherein the medicament is further for inhibiting phosphokinase
Aurora-B。 Aurora-B.
5. 如权利要求 1所述的应用， 其特征在于， 该抗癌药物是针剂、 颗粒剂、 胶 囊、 溶液或片剂。  5. Use according to claim 1, characterized in that the anticancer drug is an injection, granule, capsule, solution or tablet.
6. 如权利要求 1所述的应用， 其特征在于， 所述的癌症选自： 肝癌、 结肠癌、 胃癌和肺癌。  6. The use according to claim 1, wherein the cancer is selected from the group consisting of liver cancer, colon cancer, gastric cancer, and lung cancer.
7. 一种体外抑制肿瘤细胞生长的方法， 其特征在于， 包括步骤： 在所述肿瘤 细胞的培养体系中添加化合物 (2Z)-2-(3,4-二羟基亚苄基 )-1-苯并呋喃 -3(2H)-酮。  A method for inhibiting growth of a tumor cell in vitro, comprising the steps of: adding a compound (2Z)-2-(3,4-dihydroxybenzylidene)-1- in the culture system of the tumor cell Benzofuran-3(2H)-one.
8.如权利要求 7所述的方法， 其特征在于， 所述的肿瘤细胞选自： 肝癌细胞、 结肠癌细胞、 胃癌细胞和肺癌细胞。  The method according to claim 7, wherein the tumor cells are selected from the group consisting of liver cancer cells, colon cancer cells, gastric cancer cells, and lung cancer cells.
9. 一种治疗癌症的方法， 其特征在于， 包括步骤： 给需要治疗的哺乳动物对 象施用 (2Z)-2-(3,4-二羟基亚苄基 )-1-苯并呋喃 -3(2H)-酮或其药学上可接受的盐。  A method for treating cancer, comprising the steps of: administering (2Z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3 to a mammalian subject in need of treatment ( 2H)-keto or a pharmaceutically acceptable salt thereof.
10. 如权利要求 9所述方法， 其特征在于， 所述的施用量为每天 0.1毫克 /千 克至 20毫克 /千克体重。  10. The method according to claim 9, wherein the application amount is from 0.1 mg/kg to 20 mg/kg of body weight per day.
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WO1991017749A1 (en) * 1990-05-17 1991-11-28 Baylor College Of Medicine Growth inhibitors and methods of treating cancer and cell proliferative diseases
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WO1991017749A1 (en) * 1990-05-17 1991-11-28 Baylor College Of Medicine Growth inhibitors and methods of treating cancer and cell proliferative diseases
WO2002083123A1 (en) * 2001-04-18 2002-10-24 Pharmacia Italia Spa Aurones as telomerase inhibitors
WO2003105840A2 (en) * 2002-06-17 2003-12-24 The Pennsylvania State Research Foundation Sphingosine kinase inhibitors

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