WO2017076332A1 - 具有acc1蛋白调控作用的五环三萜类化合物及其用途 - Google Patents

具有acc1蛋白调控作用的五环三萜类化合物及其用途 Download PDF

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WO2017076332A1
WO2017076332A1 PCT/CN2016/104607 CN2016104607W WO2017076332A1 WO 2017076332 A1 WO2017076332 A1 WO 2017076332A1 CN 2016104607 W CN2016104607 W CN 2016104607W WO 2017076332 A1 WO2017076332 A1 WO 2017076332A1
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compound
independently selected
formula
tumor
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王宏林
白晶
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苏州博创园生物医药科技有限公司
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms

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  • the present invention belongs to the field of pharmacy; more specifically, the present invention relates to pentacyclic triterpenoids having a regulation of acetyl-CoA carboxylase 1 (ACC1) protein, and uses thereof.
  • ACC1 acetyl-CoA carboxylase 1
  • colorectal cancer mainly colon cancer
  • the incidence of colorectal cancer has increased in most countries in the world.
  • the number of cases of colorectal cancer and the number of deaths in China have also increased.
  • the number of new cases in China has exceeded 170,000 per year, which is the fourth most common malignant tumor disease in China.
  • the median age of onset of colorectal cancer is about ten years ahead of Europe and the United States. Younger patients are more common than Europe and the United States. This is a feature of colorectal cancer in China.
  • the etiology of colorectal cancer is not fully understood, and it is currently believed to be the result of a combination of genetic factors, environmental factors, and immune factors.
  • Acetyl-11-keto- ⁇ -boswellic acid is: Acetyl-11-keto- ⁇ -boswellic acid, abbreviated as Ak ⁇ BA or AKBA, which has the structural formula of Figure 1A. It is one of the important ingredients contained in the jelly-like resin of the plant-type mastic tree.
  • AKBA AKBA
  • the enrichment and purification of AKBA from natural Boswellia extracts is described in International Patent Application No. WO 03/0746, U.S. Patent No. 2,030, 997, 081, and International Patent Application No. WO 03/077860. Higher purity products can be obtained by chromatographic separation and recrystallization.
  • Boswellia extract has been used as an anti-inflammatory agent in traditional medicine, such as in the treatment of arthritis and patients with ulcerative colitis.
  • boswellic acid has attracted attention due to its anti-proliferative effect.
  • Boswellic acid can inhibit the growth of several leukemia cell lines, melanoma and promote apoptosis in vitro.
  • the target of boswellic acid has not been elucidated, the anti-tumor mechanism is still unclear, and the specific sensitive tumor and anti-proliferative activity of the existing boswellic acid anti-tumor remains to be discovered and improved.
  • ACC1 acetyl-CoA carboxylase 1
  • a compound of formula (I), or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a tumor;
  • R is independently selected from: AcO- or
  • R is AcO-.
  • R is Preferably, the compound is a compound of formula (II);
  • R is R' is independently selected from the group consisting of hydrogen, hydroxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen.
  • R is R' is independently selected from the group consisting of: hydroxy, C1-C2 alkyl.
  • R is R' is hydrogen
  • the compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof modulates the function of the ACC1 protein by targeting the ACC1 protein. , inhibit the growth of tumors.
  • the tumor is a tumor that is overexpressed or overactivated by ACC1.
  • the tumor comprises colon cancer, lymphoma, pancreatic cancer, liver cancer, ovarian cancer.
  • a pharmaceutical composition for treating a tumor comprising: a compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is a suspension obtained by mixing sodium carboxymethylcellulose and water.
  • a method of treating a tumor comprising: administering to a subject in need of treatment an effective amount of a compound of formula (I) or an isomer, solvate or precursor thereof, or Their pharmaceutically acceptable salts.
  • Figure 1 AKBA and CKBA structural formulas.
  • Figure 2 Growth inhibition effects of CKBA and AKBA on various human colon cancer cell lines.
  • Figure 3 Growth inhibition of CKBA and AKBA on human lymphoma HH cell line, human pancreatic cancer BxPC3 cell line, human liver cancer HepG2 cell line, and human ovarian cell line skov3.
  • A is the inhibitory effect of AKBA on human lymphoma cell line HH
  • B is the inhibitory effect of CKBA on human lymphoma cell line HH
  • C is the inhibitory effect of AKBA on human pancreatic cancer cell line BxPC3
  • D is CKBA on human pancreas
  • E is the inhibitory effect of AKBA on human hepatoma cell line HepG2
  • F is the inhibitory effect of CKBA on human hepatoma cell line HepG2
  • G is the inhibitory effect of AKBA on human ovarian cancer cell line skov3
  • Figure 4 CKBA significantly inhibits the growth of colon tumors in a model of colonitis-associated colon cancer.
  • Figure 5 CKBA significantly inhibits the growth of subcutaneous xenografts of colon cancer.
  • Figure 6 Biotin labeling of AKBA and CKBA.
  • Figure 7 Identification of AKBA and CKBA co-targeting ACC1 (the coding gene is ACACA).
  • Figure 8 Western blotting experiments show that AKBA and CKBA act on ACC1.
  • the inventors have intensively studied for the first time to reveal a novel pentacyclic triterpene structural modification compound which can effectively treat tumors such as colon cancer and exert anti-tumor effects by targeting and binding to ACC1 protein.
  • the present invention has been completed on this basis.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group containing from 1 to 4 carbon atoms, preferably from 1 to 2 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl.
  • alkenyl as used herein, includes straight-chain and branched hydrocarbon groups containing at least one carbon-carbon double bond and 2 to 4 carbon atoms, preferably 2 to 3 carbon atoms.
  • alkynyl as used herein includes both straight-chain and branched hydrocarbon groups containing at least one carbon-carbon triple bond and from 2 to 4 carbon atoms, preferably from 2 to 3 carbon atoms.
  • halogen refers to F, Cl, Br, or I.
  • isomer as used herein includes: geometric isomers, enantiomers, diastereomers (eg, cis and trans isomers, conformational isomers).
  • solvate denotes a compound carrying a solvent molecule, for example, the solvate may be a hydrate.
  • the term "containing” means that the various ingredients can be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
  • a "pharmaceutically acceptable" ingredient is a substance which is suitable for use in humans and/or animals without excessive adverse side effects (e.g., toxicity, irritation, and allergy), i.e., has a reasonable benefit/risk ratio.
  • a "pharmaceutically acceptable carrier” is a method for delivering a compound, an isomer, a solvate, a precursor, or a pharmaceutically acceptable salt thereof of the formula (I) of the present invention to an animal or a human.
  • the carrier can be a liquid or a solid.
  • a tumor associated with expression or overexpression of ACC1 refers to a type of tumor whose growth must rely on ACC1 expression or overexpression to inhibit the expression or activity of ACC1 in such tumors. The growth is inhibited and even apoptosis.
  • R is independently selected from: AcO- or
  • R is AcO-, which is 11 carbonyl- ⁇ -acetyl succinic acid (AKBA);
  • R is independently selected from the group consisting of hydrogen, hydroxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogen.
  • R' is independently selected from the group consisting of hydrogen, hydroxy, C1-C2 alkyl. More preferably, R' is hydrogen.
  • the present invention also includes isomers, solvates, precursors, or pharmaceutically acceptable salts thereof of the above compounds of the formula (I), as long as they also have the same or substantially the same functions as the compounds of the formula (I).
  • pharmaceutically acceptable salt means a salt formed by reacting a compound with an inorganic acid, an organic acid, an alkali metal or an alkaline earth metal.
  • salts include, but are not limited to, (1) salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; (2) salts with the following organic acids, such as acetic acid, oxalic acid, succinic acid, tartaric acid , methanesulfonic acid, maleic acid, or arginine.
  • Other salts include those formed with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, in the form of esters, carbamates, or other conventional "prodrugs".
  • the compound has one or more asymmetric centers. Therefore, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, diastereomeric mixtures, cis or trans isomers.
  • precursor of a compound means a compound which is converted into a structural formula (I) by a metabolic or chemical reaction of a precursor of the compound in a patient after administration by an appropriate method, or a chemical structural formula (I). a salt or solution of a compound.
  • the compound has a structure represented by the formula (III).
  • the English name of the compound of formula (III) is 3-o- ⁇ -cyclohexanoyl-11-keto- ⁇ -boswellic acid, abbreviated as CKBA.
  • the compounds of the present invention can be obtained by a variety of methods well known in the art, using known starting materials, such as the reference CN201310623314.2 or the examples of the present invention. The method.
  • AKBA acetyl-CoA carboxylase 1
  • Acetyl CoA carboxylase is divided into two subtypes, ACC1 (ACC- ⁇ ) and ACC2 (ACC- ⁇ ), with molecular weights of 265kD and 280kD, respectively, which are widely present in the biological world.
  • ACC1 is mainly expressed in tissues that produce fat, such as liver and fat cells
  • ACC2 is mainly expressed in adipose tissue or cells, such as heart and muscle cells. Since ACC1 regulates the metabolism of fatty acids, it is considered to be a target for the treatment of metabolic syndrome and various tumors. Studies have shown that targeting ACC1 can inhibit the growth of a variety of cancer stem cells.
  • ACC1 is a rate-limiting step catalytic enzyme in the long-chain fatty acid biosynthesis reaction. Its deletion can lead to inhibition or even apoptosis of some tumor cell lines.
  • the inhibition of ACC1 by chemical inhibitors can also inhibit the self-renewal of cancer stem cells. Therefore, the compound of the present invention inhibits the growth of tumor by regulating the binding of ACC1 protein, regulating the function of ACC1 protein.
  • the present inventors have found in the study that the compound of the formula (III) of the present invention has a more pronounced effect of inhibiting the division and proliferation of colon cancer cells compared to 11 carbonyl- ⁇ -acetyl succinic acid (AKBA).
  • AKBA 11 carbonyl- ⁇ -acetyl succinic acid
  • the present invention provides the use of a compound of the formula (I) or an isomer, a solvate thereof, a precursor thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a treatment Tumor drugs.
  • the tumor is preferably an ACC1 overexpressed or overactivated (or caused) tumor, such as colon cancer, lymphoma, pancreatic cancer, liver cancer, ovarian cancer, and the like.
  • the effects of the four human colon cancer cell lines: HCT116, Lovo, HT29 and SW480 were verified by the in vitro test using the compound of the formula (I) according to the present invention, and the present invention was obtained.
  • the compound showed a better inhibition of tumor cell growth than AKBA.
  • the compound of the formula (I) according to the present invention is used for human lymphoma HH cell line, human pancreatic cancer BxPC3 cell line, human liver cancer HepG2 cell line, human by in vitro assay.
  • the ovarian cell line skov3 cell line was subjected to cell proliferation activity study, and it was found that the compounds CKBA and AKBA of the present invention have a good inhibitory effect on the growth of the above tumor cells, and the inhibitory activity of CKBA is more significant than that of AKBA.
  • the compound of formula (I) is also tested in vivo to verify its effect on colon tumor formation in an enteritis-associated intestinal cancer model.
  • the compound of the formula (I) of the present invention showed a more remarkable inhibitory effect than the solvent control group.
  • the compound of formula (I) is also tested in vivo for verification of the growth of subcutaneous xenografts of HCT116 colon cancer cells.
  • the compound of the formula (I) according to the invention is More significant inhibition was shown compared to the solvent control group.
  • the present invention also provides a method of treating a tumor, such as a tumor associated with overexpression or overactivation of ACC1, such as colon cancer, the method comprising: administering an effective amount of said subject to a subject in need of treatment A compound of the formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition for treating a tumor comprising: (a) an effective amount of the compound of the formula (I), or an isomer, a solvate thereof, a precursor thereof, or a pharmaceutically thereof thereof An acceptable salt; and (b) a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition contains the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof in an amount of from 0.01 to 5% by weight.
  • the pharmaceutical composition contains 0.03-3% by weight of the compound of the formula (I) or a pharmaceutically acceptable salt thereof; more preferably, the pharmaceutical composition contains by weight
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is in a ratio of 0.05 to 1%.
  • the pharmaceutical composition of the present invention may be in a variety of dosage forms as long as it is a dosage form capable of efficiently reaching the mammalian body.
  • it may be selected from the group consisting of: solutions, suspensions, tablets, capsules, powders, granules or syrups. Based on the type of disease to which the compounds of the present invention are treated, one skilled in the art can select a dosage form that is convenient to use.
  • the effective administration dose of the compound of the formula (I) as an active ingredient may vary depending on the mode of administration and the severity of the disease to be treated. However, generally, when the compound of the present invention is administered at a dose of about 0.05 to 500 mg/kg, preferably 0.1 to 300 mg/kg, more preferably 1 to 200 mg/kg of animal body weight per day, a satisfactory effect can be obtained. Preferably, it is administered in divided doses of 1-3 times per day or in sustained release form. This dosage regimen can be adjusted to provide an optimal therapeutic response. For example, several separate doses may be administered per day, or the dose may be proportionally reduced, as is critical to the condition of the treatment.
  • acetyl-11-keto- ⁇ -boswellic acid (abbreviated as AKBA) and 2.63 g of potassium hydroxide (KOH) were placed, and 50 ml of isopropanol was added as a solvent under a nitrogen atmosphere. Heating reflux reaction After about 6 hours, the reaction system was cooled to room temperature, and the solvent was evaporated to dryness using a rotary evaporator to give a white solid. After adding 30 ml of dichloromethane, dilute hydrochloric acid was added to adjust the pH of the mixture to be acidic. The aqueous phase was extracted with dichloromethane (3 ⁇ 15 mL).
  • EtOAc EtOAc
  • CMC-Na sodium carboxymethylcellulose
  • CMC-Na sodium carboxymethylcellulose
  • Example 3 Inhibition of growth of human colon cancer cells in vitro
  • Human colon cancer cell lines HCT116, Lovo, HT29 and SW480 purchased from ATCC
  • HCT116, Lovo, HT29 and SW480 purchased from ATCC
  • 25, 30, 35, 50, 100 ⁇ M) CKBA and AKBA the total volume is 100 ⁇ l
  • the control group is added with a final concentration of 0.5% DMSO
  • the blank control well is only added to 100 ⁇ l of medium, each set is set to three Multiple holes.
  • the compound of the formula (III) (CKBA) and AKBA were able to inhibit the division and proliferation of colon cancer cells.
  • the compound of formula (III) (CKBA) inhibited colon cancer cells more effectively than AKBA.
  • CKBA completely inhibited the growth of human colon cancer cells at a lower concentration (20-25 ⁇ M), while AKBA required a concentration of 100 ⁇ M to achieve the same effect, so CKBA inhibited the growth of colon cancer cells in vitro significantly better than AKBA.
  • Example 4 Inhibition of growth of human lymphoma, human pancreatic cancer, human liver cancer, and human ovarian cancer cells in vitro
  • the present invention tested the growth inhibitory effects of CKBA and AKBA on human lymphoma HH cell line, human pancreatic cancer BxPC3 cell line, human liver cancer HepG2 cell line, and human ovarian cell line skov3 in vitro.
  • Example 5 Inhibition of growth of colonitis-associated colon cancer tumors in vivo
  • An animal model of AOM/DSS colon cancer was established. 10 C57BL/6 mice of 6-8 weeks old were taken. On the first day, each mouse was intraperitoneally injected with AOM 1 mg/ml 200 ⁇ l, and on days 6-10, water containing 2.5% DSS was continuously fed for 5 days, 11-26 The day was changed to ordinary water, and the water containing 2.5% DSS was continuously fed for 5 days on the 27th to 31st days, the ordinary water was fed on the 32nd to 47th days, and the second was fed with 2.5% DSS on the 48th to 49th days. Water for 2 days, then change to ordinary water for the first 50-56 days.
  • mice of the treatment group were intraperitoneally injected with 200 ⁇ l of a CMC-Na suspension of 5 mg/ml CKBA per day, and 5 mice of the control group were intraperitoneally injected with a blank suspension of 200 ⁇ l per day. Mice were sacrificed on day 57 and colons were photographed to record the number and size of tumors in the colon.
  • Example 6 Inhibition of subcutaneous xenografts of colon cancer cells in vivo
  • HCT116 cells were cultured, digested with 0.5% trypsin, centrifuged, resuspended in sterile PBS, cells were counted, and the cells were diluted to a concentration of 2.8 ⁇ 10 8 /ml.
  • Each nude mouse of 12 nude mice was subcutaneously injected with 100 ul of the cell suspension under the armpit, and the first day of the experiment was recorded.
  • On day 5-16 6 nude mice in the experimental group were intraperitoneally injected with 200 ⁇ l of CMC-Na suspension of 5 mg/ml CKBA, and 6 nude mice of the control group were intraperitoneally injected with 200 ⁇ l of blank suspension per day. The nude mice used vernier calipers. Tumor size was measured and recorded. On the 17th day, the nude mice were sacrificed, photographed, tumors and spleens were taken and the records were weighed.
  • Example 7 Test for capturing protein targets in cells
  • Human colon cancer cells HCT116 were first incubated with AKBA and CKBA for 1 hour, followed by biotin-labeled AKBA and CKBA (structure shown in Figure 6) for an additional 1.5 hours. The cells were washed twice with PBS, and the cells were lysed by RIPA and centrifuged to obtain a protein supernatant. Pre-washed agarose microspheres were added and incubated on a shaker for 1 hour. After washing the microspheres for 6 times, add protein loading buffer at 95 ° C for 10 minutes. The samples were separated by SDS-PAGE, silver stained (Fig. 7A), and the differential bands were cut out, and analyzed by LC/MS/MS ESI-MicroTOF-QII mass spectrometry (Fig. 7B).
  • Example 8 Western blotting experiments verify that AKBA and CKBA act on ACC1
  • the denatured grouped protein samples were added to the same volume in the SDS-PAGE gel. After running the gel, the protein bands on the polyacrylamide gel were transferred to the PVDF membrane by wet transfer, and the membrane was blocked at room temperature for 2 hours, and then with ACC1. Incubate overnight at 4 ° C, wash 3 times with TBST, incubate for 2 hours at room temperature with the corresponding secondary antibody, wash TBST for 3 more times, and add ECL coloring solution to take a photo.

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Abstract

本发明涉及具有乙酰辅酶A羧化酶1(ACC1)蛋白调控作用的五环三萜类化合物及其用途。本发明的化合物能直接作用于ACC1蛋白，发挥抑制肿瘤生长的作用，且抑制作用非常显著。

Description

具有ACC1蛋白调控作用的五环三萜类化合物及其用途 技术领域
本发明属于药学领域；更具体地，本发明涉及具有乙酰辅酶A羧化酶1(ACC1)蛋白调控作用的五环三萜类化合物、及其用途。
背景技术
近20多年来，世界上多数国家结直肠癌(主要是结肠癌)发病率呈上升趋势。随着人们生活水平的提高，饮食习惯与结构的改变，加之人口老龄化趋势影响，我国结直肠癌发病人数和死亡人数也呈增长态势。据统计，我国每年新发病例已超过17万，是我国发病率排第四位的恶性肿瘤性疾病。结直肠癌的中位发病年龄在中国比欧美提前约十年，青年患者比欧美多见，这是结直肠癌在中国的一个特点。结直肠癌的病因尚未完全清楚，目前认为主要是遗传因素、环境因素、免疫因素等综合作用的结果。
11羰基-β-乙酰乳香酸的英文全名是：Acetyl-11-keto-β-boswellic acid，简称AkβBA或AKBA，其具有如图1A的结构式。是植物卡式乳香树的胶状树脂-乳香含有的重要成份之一。从天然乳香树提取物中富集纯化AKBA已经描述于国际专利申请WO 03/0746，美国专利20030199581以及国际专利申请WO 03/077860中。更高纯度的产品可以通过色谱分离以及重结晶的方法而获得。
乳香提取物已经在传统的医药中被用作抗炎剂，如对关节炎以及溃疡性结肠炎患者的治疗。另外乳香酸由于其抗增殖作用而受到关注，乳香酸在体外可以抑制几种白血病细胞株，黑素瘤的生长并促进细胞凋亡。但是，由于乳香酸作用靶点尚未阐明，抗肿瘤机制尚不明确，现有乳香酸抗肿瘤的具体敏感性瘤种和抗增殖活性仍有待发现和提高。
发明内容
本发明的目的在于提供具有乙酰辅酶A羧化酶1(ACC1)蛋白调控作用的五环三萜类化合物及其用途。
在本发明的第一方面，提供式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备治疗肿瘤的药物；
Figure PCTCN2016104607-appb-000001
其中，R独立地选自：AcO-或
Figure PCTCN2016104607-appb-000002
在一个优选例中，式(I)所示化合物中，R为AcO-。
在另一个优选例中，式(I)所示化合物中，R为
Figure PCTCN2016104607-appb-000003
较佳地，所述化合物为式(II)化合物；
Figure PCTCN2016104607-appb-000004
在另一优选例中，式(I)所示化合物中，R为
Figure PCTCN2016104607-appb-000005
R’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素。
在另一优选例中，式(I)所示化合物中，R为
Figure PCTCN2016104607-appb-000006
R’独立地选自：、羟基、C1-C2烷基。
在另一优选例中，式(I)所示化合物中，R为
Figure PCTCN2016104607-appb-000007
R’为氢。
在另一优选例中，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐通过靶向结合ACC1蛋白，调控ACC1蛋白功能，抑制肿瘤的生长。
在另一优选例中，所述的肿瘤是ACC1过表达或过度活化的肿瘤。
在另一优选例中，所述的肿瘤包括：结肠癌，淋巴癌，胰腺癌，肝癌，卵巢癌。
在本发明的另一方面，提供式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备靶向结合ACC1蛋白和调控ACC1蛋白的组合物。
在本发明的另一方面，提供一种用于治疗肿瘤的药物组合物，所述的药物组合物包含：式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐；和药学上可接受的载体。在一个优选例中，所述的药物组合物中，所述的药学上可接受的载体是羧甲基纤维素钠和水混合获得的混悬液。
在本发明的另一方面，提供一种治疗肿瘤的方法，所述方法包括：给予需要治疗的对象有效量的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐。
本发明的其它方面由于本文的公开内容，对本领域的技术人员而言是显而易见的。
附图说明
图1：AKBA和CKBA结构式。
A，AKBA结构式；
B，CKBA结构式(式(III)化合物)。
图2：CKBA及AKBA对多种人结肠癌细胞株生长抑制效果。
A-B，CKBA及AKBA对人结肠癌细胞株HCT116的抑制效果；
C-D，CKBA及AKBA对人结肠癌细胞株Lovo的抑制效果；
E-F，CKBA及AKBA对人结肠癌细胞株HT29的抑制效果；
G-H，CKBA及AKBA对人结肠癌细胞株SW480的抑制效果。
图3：CKBA及AKBA对人淋巴癌HH细胞株、人胰腺癌BxPC3细胞株、人肝癌HepG2细胞株、人卵巢细胞株skov3的生长抑制作用。其中，A为AKBA对人淋巴癌细胞株HH的抑制效果；B为CKBA对人淋巴癌细胞株HH的抑制效果；C为AKBA对人胰腺癌细胞株BxPC3的抑制效果；D为CKBA对人胰腺癌细胞株BxPC3的抑制效果；E为AKBA对人肝癌细胞株HepG2的抑制效果；F为CKBA对人肝癌细胞株HepG2的抑制效果；G为AKBA对人卵巢癌细胞株skov3的抑制效果；H为CKBA对人卵巢癌细胞株skov3的抑制效果。
图4：CKBA显著抑制肠炎相关结肠癌模型中结肠肿瘤的生长。
A，给予CKBA治疗的小鼠的结肠部位照片；
B，给予CMC-Na的小鼠的结肠部位照片；
C，分别给予CKBA及CMC-Na的小鼠结肠中的肿瘤大小；纵坐标是肿瘤大小的评分。
D，分别给予CKBA及CMC-Na的小鼠结肠中的肿瘤负荷(所有肿瘤大小评分相 加后得到的值，为肿瘤大小和个数的综合评分)。
图5：CKBA显著抑制结肠癌皮下移植瘤的生长。
图6：AKBA和CKBA的生物素标记。
图7：AKBA和CKBA共同作用靶点ACC1(其编码基因为ACACA)的鉴定。
A，SDS-PAGE分析和银染结果；
B，银染差异条带质谱打分结果(部分)。
图8:蛋白免疫印迹实验显示AKBA和CKBA作用于ACC1。
具体实施方式
本发明人经过深入的研究，首次揭示一种新的五环三萜结构修饰化合物，其能够有效地治疗肿瘤如结肠癌，通过靶向结合ACC1蛋白来发挥抗肿瘤的作用。在此基础上完成了本发明。
术语
本文所用的术语“烷基”指直链或支链饱和的、含有1-4个碳原子(较佳地1-2个碳原子)的脂族烃类基团。例如，烷基包括但不限于甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基。
本文所用的术语“链烯基”包括含有至少一个碳碳双键和2-4个碳原子(较佳地2-3个碳原子)的直链和支链烃基。
本文所用的术语“链炔基”包括含有至少一个碳碳三键和2-4个碳原子(较佳地2-3个碳原子)的直链和支链烃基。
本文所用的术语“卤素”指F、Cl、Br、或I。
本文所用的术语“异构体”包括：几何异构体、对映异构体、非对映异构体(如顺反异构体，构象异构体)。
本文所用的
Figure PCTCN2016104607-appb-000008
的表示方法是本领域人员熟知的，其表示基团R’可以取代在环上的任意一个或多个可被取代的位置。并且，在不同的取代位置上，R’的选 择可以是不同的。
本文所用的术语“溶剂合物”表示携带有溶剂分子的化合物，例如，所述的溶剂合物可以是水合物。
本发明中，术语“含有”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中，“药学上可接受的”成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应)即有合理的效益/风险比的物质。
本发明中，“药学上可接受的载体”是用于将本发明的式(I)化合物、异构体、溶剂合物、前体，或它们的药学上可接受的盐传送给动物或人的药学上或食品上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体。
如本发明所用，所述的“ACC1表达或过表达相关的肿瘤”是指一类肿瘤，该类肿瘤的生长必需依靠ACC1表达或过表达，抑制该类肿瘤中ACC1的表达或活性可使得肿瘤的生长受到抑制甚至凋亡。
化合物
基于本发明人的新发现，首先提供了一种如结构式(I)所示的化合物：
Figure PCTCN2016104607-appb-000009
其中，R独立地选自：AcO-或
Figure PCTCN2016104607-appb-000010
其中，R为AcO-，即为11羰基-β-乙酰乳香酸(AKBA)；
其中，R为
Figure PCTCN2016104607-appb-000011
R’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、 C2-C4链炔基、卤素。较佳地，R’独立地选自：氢、羟基、C1-C2烷基。更佳地，R’为氢。
本发明还包括上述式(I)化合物的异构体、溶剂合物、前体，或它们的药学上可接受的盐，只要它们也具有与式(I)化合物具有相同或基本相同的功能。所述的“药学上可接受的盐”是指化合物与无机酸、有机酸、碱金属或碱土金属等反应生成的盐。这些盐包括(但不限于)：(1)与如下无机酸形成的盐：如盐酸、硫酸、硝酸、磷酸；(2)与如下有机酸形成的盐，如乙酸、草酸、丁二酸、酒石酸、甲磺酸、马来酸、或精氨酸。其它的盐包括与碱金属或碱土金属(如钠、钾、钙或镁)形成的盐，以酯、氨基甲酸酯，或其它常规的“前体药物”的形式。化合物具有一个或多个不对称中心。所以，这些化合物可以作为外消旋的混合物、单独的对映异构体、单独的非对映异构体、非对映异构体混合物、顺式或反式异构体存在。
所述的“化合物的前体”指当用适当的方法服用后，该化合物的前体在病人体内进行代谢或化学反应而转变成结构式(I)的一种化合物，或化学结构式(I)的一个化合物所组成的盐或溶液。
作为本发明的一种优选方式，所述的化合物具有式(III)所示的结构。
Figure PCTCN2016104607-appb-000012
式(III)化合物的英文名为3-o-α-cyclohexanoyl-11-keto-β-boswellic acid，简称CKBA。
本领域人员应理解，在得知了本发明化合物的结构以后，可通过多种本领域熟知的方法、利用公知的原料，来获得本发明的化合物，比如参照专利CN201310623314.2或本发明实施例所述方法。
用途
本发明人发现，本发明的式(III)化合物和AKBA均靶向作用于ACC1蛋白。通过使用生物素(biotin)标记的AKBA和其修饰物，结合使用链霉亲和素(streptavidin)琼脂糖微球从结肠癌细胞株中“钓取”直接作用靶蛋白的方法，本发明人发现AKBA和 其结构修饰物主要通过直接作用于乙酰辅酶A羧化酶1(Acetyl CoA carboxylase 1，简称ACACA或ACC1)基因发挥治疗肿瘤作用。这是首次在肿瘤细胞中明确AKBA和其结构修饰物的共同直接作用靶点。
乙酰辅酶A羧化酶(Acetyl CoA carboxylase)分为ACC1(ACC-α)和ACC2(ACC-β)两亚型，分子量分别为265kD、280kD，广泛存在于生物界。ACC1主要表达在产生脂肪的组织，如肝脏和脂肪细胞，而ACC2主要在耗氧组织或细胞中表达，如心脏和肌肉细胞。由于ACC1调控脂肪酸的代谢，所以被认为是治疗代谢综合症和多种肿瘤的靶点。研究表明：靶向ACC1，可以抑制多种肿瘤干细胞的生长。
ACC1是长链脂肪酸生物合成反应中限速步骤催化酶，其缺失可以导致一些肿瘤细胞系的生长受到抑制甚至凋亡，通过化学抑制剂的方法抑制ACC1的功能还可以抑制肿瘤干细胞的自我更新。因此，本发明的化合物通过靶向结合ACC1蛋白，调控ACC1蛋白功能，抑制肿瘤的生长。
另外，本发明人在研究中发现，相比于11羰基-β-乙酰乳香酸(AKBA)，本发明的式(III)化合物具有更显著的抑制结肠癌细胞分裂、增殖能力的作用，对于肠炎相关结肠癌模型和皮下移植瘤模型有显著的治疗作用。
基于本发明人的上述新发现，本发明提供了式(I)所示的化合物或其异构体、溶剂合物、前体，或它们的药学上可接受的盐的用途，用于制备治疗肿瘤的药物。所述的肿瘤较佳地是ACC1过表达或过度活化的(或导致的)肿瘤，例如结肠癌，淋巴癌，胰腺癌，肝癌，卵巢癌等。
在本发明的具体实施例中，通过体外试验，利用本发明所述的式(I)所示化合物对四种人结肠癌细胞系：HCT116、Lovo、HT29和SW480进行了效果验证，结果本发明的化合物显示出比AKBA更好的抑制肿瘤细胞生长的作用。
在本发明的另一具体实施例中，通过体外试验，利用本发明所述的式(I)所示化合物对人淋巴癌HH细胞株、人胰腺癌BxPC3细胞株、人肝癌HepG2细胞株、人卵巢细胞株skov3细胞株进行了细胞增殖活性研究，结果发现本发明化合物CKBA及AKBA对上述肿瘤细胞生长具有很好的抑制作用，且CKBA的抑制活性比AKBA更为显著。
在本发明的另一具体实施例中，还利用所述的式(I)所示化合物进行了体内试验，验证其对肠炎相关肠癌模型中结肠肿瘤的生成的影响。结果，本发明所述的式(I)化合物显示出与溶剂对照组相比更显著的抑制作用。
在本发明的另一具体实施例中，还利用所述的式(I)所示化合物进行了体内试验，验证其对HCT116结肠癌细胞皮下移植瘤的生长。结果，本发明所述的式(I)化合物显 示出和溶剂对照组相比更显著的抑制作用。
基于本发明人的上述新发现，本发明还提供一种治疗肿瘤(如结肠癌等ACC1过表达或过度活化相关的肿瘤)的方法，所述方法包括：给予需要治疗的对象有效量的所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐。
药物组合物
本发明还提供了一种用于治疗肿瘤的药物组合物，含有：(a)有效量的式(I)所述的化合物、或其异构体、溶剂合物、前体，或它们的药学上可接受的盐；和(b)药学上可接受的载体或赋形剂。
在本发明中，所述的药物组合物含有按照重量比例为0.01-5％的式(I)所示的化合物或其药学上可接受的盐。较佳的，所述的药物组合物含有按照重量比例为0.03-3％的式(I)所示的化合物或其药学上可接受的盐；更佳地，所述的药物组合物含有按照重量比例为0.05-1％的式(I)所示的化合物或其药学上可接受的盐。
本发明所述的药物组合物的剂型可以是多种多样的，只要是能够使活性成分有效地到达哺乳动物机体的剂型都是可以的。比如可选自：溶液、悬浮液、片剂、胶囊、粉末、颗粒或糖浆。根据本发明的化合物所治疗的疾病类型，本领域人员可以选择方便应用的剂型。
式(I)化合物作为活性成分的有效施用剂量可随给药的模式和待治疗的疾病的严重程度而变化。然而，通常当本发明的化合物每天以约0.05-500mg/kg，较佳地0.1-300mg/kg，更佳地1-200mg/kg动物体重的剂量给予时，能得到令人满意的效果，较佳地每天以1-3次分开的剂量给予，或以缓释形式给药。可调节此剂量方案以提供最佳治疗应答。例如，由治疗状况的迫切要求，可每天给予若干次分开的剂量，或将剂量按比例地减少。
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J.萨姆布鲁克等编著，分子克隆实验指南，第三版，科学出版社，2002中所述的条件，或按照制造厂商所建议的条件。
实施例1：式(III)化合物(CKBA)的制备
在100毫升双口瓶中加入8克acetyl-11-keto-β-boswellic acid(简称AKBA)和2.63克氢氧化钾(KOH)，在氮气保护下加入异丙醇50毫升作为溶剂。加热回流反应 约6小时，待反应体系冷却到室温，使用旋转蒸发仪旋干溶剂，得到白色固体，加入30毫升二氯甲烷后加入稀盐酸调节混合体系pH值至酸性。用二氯甲烷萃取水相3次(3*15毫升)，收集二氯甲烷溶剂，用无水硫酸镁干燥，旋干溶剂得到棕色油状产物，使用石油醚：乙酸乙酯(90：10)作为洗脱剂用柱层析法提纯，得到白色固体KBA 5.8g，产率约为78％。将1克KBA溶于10毫升二氯甲烷(含有2mol％4-二甲基吡啶)，加入1.5当量的三乙胺和1.2当量的环己甲酰氯，冰浴过夜。反应完全后，用10％的碳酸氢钠溶液处理，并用二氯甲烷萃取3次(3*10毫升)，收集二氯甲烷溶剂，用无水硫酸镁干燥混合物，旋干溶剂得到白色固体。用石油醚：乙酸乙酯(90：10)作为洗脱剂，用柱层析法提纯，得到酰化产物3-o-α-cyclohexanoyl-11-keto-β-boswellic acid 4g，产率约为55％。
取一定量的式(III)的化合物进行核磁、质谱分析得其分子式为C37H56O5，分子量为581，如图1。
实施例2：式(III)化合物的羧甲基纤维素钠混悬液的制备
(1)混悬液1
取一定量羧甲基纤维素钠(简称CMC-Na)用双蒸水溶解过夜制备成0.3％(g/ml)的CMC-Na溶液。将此溶液加入一定量的CKBA粉末制备成5mg/ml的混悬液，可以简单超声辅助CKBA分散。
(2)空白混悬液
取一定量羧甲基纤维素钠(简称CMC-Na)用双蒸水溶解过夜制备成0.3％(g/ml)的CMC-Na溶液作为空白混悬液。该空白混悬液作为动物实验中的对照。
实施例3：体外抑制人结肠癌细胞生长的实验
取对数生长期的人结肠癌细胞株HCT116、Lovo、HT29和SW480(购自ATCC)种96孔板，每孔1.5×104个细胞，分别加入呈梯度浓度(1，5，10，20，25，30，35，50，100μM)的CKBA和AKBA，总体积为100微升，对照组加入终浓度为0.5％的DMSO，空白对照孔仅加入100微升培养基，每组均设三个复孔。细胞培养箱培养24小时后，每孔加入CCK-8溶液10微升，将培养板放置于培养箱(37℃，5％CO2条件下)避光孵育4小时后取出。酶标仪测定450nm波长处的O.D.值。计算抑制率：抑制率＝【1-(实验组O.D.值/对照组O.D.值)】×100％。
结果如图2，式(III)化合物(CKBA)及AKBA均能够抑制结肠癌细胞分裂、增殖。 两者相比较，式(III)化合物(CKBA)比AKBA能更加有效地抑制结肠癌细胞。CKBA在较低浓度(20-25μM)下完全抑制人结肠癌细胞的生长，而AKBA则需要在100μM浓度下才能达到相同效果，故CKBA体外抑制结肠癌细胞生长的活性显著地优于AKBA。
实施例4：体外抑制人淋巴癌、人胰腺癌、人肝癌、人卵巢癌细胞生长的实验
按照实施例3所述方法，本发明测试了CKBA和AKBA体外对人淋巴癌HH细胞株、人胰腺癌BxPC3细胞株、人肝癌HepG2细胞株、人卵巢细胞株skov3的生长抑制作用。
结果如图3A～H所示，CKBA及AKBA均能够在体外显著抑制上述肿瘤细胞的分裂、增殖，且CKBA对人胰腺癌BxPC3细胞株和人卵巢细胞株skov3的生长抑制作用明显优于AKBA。具体试验结果如表1。
表1
Figure PCTCN2016104607-appb-000013
实施例5：体内抑制肠炎相关结肠癌肿瘤生长的实验
建立AOM/DSS结肠癌肿瘤动物模型。取6-8周龄的C57BL/6小鼠10只，第1天每只小鼠腹腔注射AOM 1mg/ml 200μl，第6-10天连续喂含2.5％DSS的水5天，第11-26天换成普通水喂，第27-31天再次连续喂含2.5％DSS的水5天，第32-47天换成普通水喂，之后第48-49天第三次喂含2.5％DSS的水2天，再换成普通水喂第50-56天。第50-56天给治疗组5只小鼠每只每天腹腔注射5mg/ml CKBA的CMC-Na混悬液200μl，对照组5只小鼠每只每天腹腔注射空白混悬液200μl。第57天处死小鼠，取结肠拍照，记录结肠部位肿瘤的数量和大小。
结果如图4A-D。CKBA治疗组小鼠结肠部位肿瘤的个数明显少于对照组小鼠，并且肿瘤的大小也明显小于对照组。
实施例6：体内抑制结肠癌细胞皮下移植瘤的实验
培养HCT116细胞，用0.5％胰酶消化后离心，重悬于无菌的PBS中，对细胞计数，稀释细胞至浓度为2.8×108个/ml。对12只裸鼠每只裸鼠的腋下通过皮下注射细胞悬液100ul，记为实验开始第一天。第5-16天实验组6只裸鼠腹腔注射5mg/ml CKBA的CMC-Na混悬液200μl，对照组6只裸鼠每只每天腹腔注射空白混悬液200μl，两组裸鼠均使用游标卡尺测量肿瘤大小并记录。第17天处死裸鼠，拍照，取肿瘤和脾脏拍照并称重记录。
结果如图5。CKBA治疗组裸鼠的皮下肿瘤大小明显小于对照组裸鼠，表明CKBA对结肠癌细胞皮下移植瘤具有显著治疗作用。
实施例7：在细胞中钓取蛋白靶点的试验
人结肠癌细胞HCT116先和AKBA和CKBA孵育1小时，再加入biotin标记的AKBA和CKBA(结构如图6)继续孵育1.5小时。细胞用PBS洗两遍，RIPA裂解细胞后离心得到蛋白上清。加入预先洗好的琼脂糖微球，在摇床上孵育1小时。洗微球6遍后加入蛋白上样缓冲液95℃煮10分钟。样品用SDS-PAGE分离，银染显色(如图7A)后割取差异条带，LC/MS/MS ESI-MicroTOF-QII质谱分析(如图7B)。
分析结果显示，ACC1蛋白评分最高，为AKBA和CKBA在结肠癌细胞中潜在直接作用靶点。
实施例8：蛋白免疫印迹实验验证AKBA和CKBA作用于ACC1
已变性的各组蛋白样品在SDS-PAGE胶中加入相同体积，跑胶后通过湿转将聚丙烯酰胺凝胶上的蛋白条带转移至PVDF膜，膜室温封闭2小时后，和ACC1的一抗4℃孵育过夜，TBST洗3遍后和对应二抗室温孵育2小时，TBST再洗3遍后加入ECL显色液显色拍照。
结果如图8，biotin对照组中没有ACC1蛋白条带，biotin-AKBA和biotin-CKBA组中都显示明显的ACC1蛋白条带，相应的AKBA和CKBA竞争组中ACC1条带明显变弱，说明AKBA和CKBA对biotin标记的化合物结合ACC1有竞争作用。进一步说明AKBA和CKBA作用于ACC1。
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。

Claims (15)

  1. 式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备抑制肿瘤的药物；所述的药物以乙酰辅酶A羧化酶1作为作用靶点；所述的肿瘤是乙酰辅酶A羧化酶1过表达或过度活化的肿瘤；
    Figure PCTCN2016104607-appb-100001
    其中，R独立地选自：AcO-或
    Figure PCTCN2016104607-appb-100002
    R’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素。
  2. 如权利要求1所述的用途，其特征在于，R为
    Figure PCTCN2016104607-appb-100003
  3. 如权利要求2所述的用途，其特征在于，R’独立地选自：氢、羟基、C1-C2烷基。
  4. 如权利要求1所述的用途，其特征在于，R为AcO-。
  5. 如权利要求1所述的用途，其特征在于，所述的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的药物作用靶点为乙酰辅酶A羧化酶1，通过靶向结合乙酰辅酶A羧化酶1蛋白，调控乙酰辅酶A羧化酶1蛋白功能，抑制肿瘤的生长。
  6. 如权利要求1所述的用途，其特征在于，所述的肿瘤包括：结肠癌，淋巴癌，胰腺癌，肝癌，卵巢癌。
  7. 式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐的用途，用于制备靶向结合乙酰辅酶A羧化酶1蛋白和调控乙酰辅酶A羧化酶1蛋白的组合物；
    Figure PCTCN2016104607-appb-100004
    其中，R独立地选自：AcO-或
    Figure PCTCN2016104607-appb-100005
    R’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素。
  8. 如权利要求7所述的用途，其特征在于，R为
    Figure PCTCN2016104607-appb-100006
  9. 如权利要求8所述的用途，其特征在于，R’独立地选自：氢、羟基、C1-C2烷基。
  10. 一种抑制肿瘤的方法，其特征在于，所述方法包括：给予需要治疗的对象有效量的式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐；
    Figure PCTCN2016104607-appb-100007
    其中，R独立地选自：AcO-或
    Figure PCTCN2016104607-appb-100008
    R’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素。
  11. 如权利要求10所述的方法，其特征在于，R为
    Figure PCTCN2016104607-appb-100009
  12. 如权利要求11所述的方法，其特征在于，R’独立地选自：氢、羟基、C1-C2烷基
  13. 一种用于治疗肿瘤的组合物，其特征在于，所述组合物包括：式(I)所示化合物或其异构体、溶剂合物或前体，或它们的药学上可接受的盐；以及药学上可接受的载体；
    Figure PCTCN2016104607-appb-100010
    其中，R独立地选自：AcO-或
    Figure PCTCN2016104607-appb-100011
    R’独立地选自：氢、羟基、C1-C4烷基、C2-C4链烯基、C2-C4链炔基、卤素。
  14. 如权利要求13所述的组合物，其特征在于，R为
    Figure PCTCN2016104607-appb-100012
  15. 如权利要求14所述的组合物，其特征在于，R’独立地选自：氢、羟基、C1-C2烷基。
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CN103193852A (zh) * 2012-01-06 2013-07-10 苏州博创园生物医药科技有限公司 用于治疗结肠癌的化合物及其制备方法
WO2015078321A1 (zh) * 2013-11-30 2015-06-04 苏州博创园生物医药科技有限公司 一种五环三萜结构修饰化合物及其制备方法和应用

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CN103193852A (zh) * 2012-01-06 2013-07-10 苏州博创园生物医药科技有限公司 用于治疗结肠癌的化合物及其制备方法
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