WO2023025296A1 - 仙鹤草内酯在制备预防和/或治疗宫颈癌的药物中的用途 - Google Patents

仙鹤草内酯在制备预防和/或治疗宫颈癌的药物中的用途 Download PDF

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WO2023025296A1
WO2023025296A1 PCT/CN2022/115207 CN2022115207W WO2023025296A1 WO 2023025296 A1 WO2023025296 A1 WO 2023025296A1 CN 2022115207 W CN2022115207 W CN 2022115207W WO 2023025296 A1 WO2023025296 A1 WO 2023025296A1
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cervical cancer
drug
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    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
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  • the invention belongs to the field of medicine, and in particular relates to the use of agrilide in the preparation of medicines for preventing and/or treating cervical cancer.
  • Cervical cancer is the most common gynecological malignancy.
  • the high-incidence age of carcinoma in situ is 30-35 years old, and that of invasive carcinoma is 45-55 years old. In recent years, the onset tends to be younger.
  • the treatment options for cervical cancer mainly include surgery, radiotherapy, chemotherapy and traditional Chinese medicine.
  • Agrimony as one of the Chinese herbal medicines with anti-tumor effects, has the effects of tonifying deficiency, strengthening the body, eliminating accumulation and dispelling stagnation in the treatment of tumors.
  • Modern cytological studies have confirmed that the water body fluid of Agrimony has anti-tumor effects, such as the document "Research Progress in Chemical Components and Pharmacology of Agrimony” (Zhao Ying et al. Specialty Research, 2001, Phase 1) which discloses that Agrimony extract has anti-tumor effects on cervical cancer, liver cancer, etc.
  • Agrimide is one of the active components of Agrimony, and its structure is as follows:
  • Agrimony lactone is a colorless columnar crystal, easily soluble in ethanol, ether and pyrobenzene, and its pharmacological effects mainly include anti-inflammatory, anti-oxidative stress, hypoglycemic and anti-tumor. But studies have shown (Teng H et al. Inhibition of cell proliferation and triggering of apoptosis by agrimonolide through MAP kinase (ERK and p38) pathways in human gastric cancer AGS cells. Food Funct, 2016, 7(11): 4605-4613.) It is only sensitive to human gastric adenocarcinoma AGS cell line and can treat gastric cancer; it has no anticancer activity against liver cancer, breast cancer, and colon cancer cell lines. There is no report in the prior art that acrimony lactone can inhibit cervical cancer cells and treat cervical cancer.
  • the object of the present invention is to provide the use of agrilide in the preparation of medicines for preventing and/or treating cervical cancer.
  • the present invention provides compounds represented by formula I, or stereoisomers thereof, or salts thereof, or solvates thereof, or hydrates thereof, or prodrugs thereof in the preparation of drugs for preventing and/or treating cervical cancer use:
  • R 1 , R 2 , and R 3 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyl, amino, and carboxyl.
  • R 1 , R 2 , and R 3 are independently selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and hydroxyl.
  • R 3 is selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, and hydroxyl.
  • R 3 is selected from C 1 -C 3 alkoxy groups.
  • the drug is a drug that inhibits the proliferation of cervical cancer cells; and/or, the drug is a drug that promotes apoptosis of cervical cancer cells.
  • the cervical cancer cells are Hela cells.
  • the drug uses the aforementioned compound, or its stereoisomer, or its salt, or its solvate, or its hydrate, or its prodrug as the active ingredient, plus pharmaceutically acceptable excipients or preparations prepared from auxiliary ingredients.
  • the present invention also provides a medicine, which uses the aforementioned compound, or its stereoisomer, or its salt, or its solvate, or its hydrate, or its prodrug as the active ingredient, plus pharmaceutically Preparations prepared with acceptable excipients or auxiliary ingredients.
  • the present invention finds that the acrimony lactone has a significant inhibitory effect on the growth of cervical cancer cells, and can further inhibit the formation of tumors by cervical cancer cells.
  • the agrilactone can be used for preventing or treating cervical cancer, and can be used for preparing medicines for preventing or treating cervical cancer, and has a good application prospect.
  • Fig. 1 is a picture (100X) of Hela cells in the normal control group and the Agrimidine lactone treatment group for 24h.
  • Fig. 2 is a picture (100X) of Hela cells in the normal control group and the Agrimidine lactone treatment group for 48 hours.
  • Fig. 3 is a picture (100X) of Hela cells in the normal control group and the Agrimidine lactone treatment group for 72h.
  • Fig. 4 is a statistical chart of the cell survival rate after treatment with agrilactone for 24 hours.
  • Fig. 5 is a statistical graph of the cell survival rate after treatment with agrilactone for 48 hours.
  • Fig. 6 is a statistical chart of the cell survival rate after treatment with agrilactone for 72 hours.
  • the raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.
  • Example 1 CCK8 detects the effect of agrimones on the proliferation of Hela cells
  • 1.1 Cell line Hela cell line, purchased from the Cell Bank of the Chinese Academy of Sciences.
  • DMEM medium store at -20°C, prepare a complete culture solution containing 10% FBS and 1% penicillin-streptomycin double antibody by volume before use;
  • Penicillin-streptomycin solution 100-fold dilution is added to the culture medium
  • PBS phosphate buffer PBS powder was adjusted to 1000 mL with ddH 2 O, adjusted to pH 7.2, autoclaved at 121°C for 30 minutes, and stored at 4°C for later use.
  • Agrimonolide solution 5mg/tube, add 0.5ml DMSO, dissolve to obtain 10mg/ml mother solution.
  • Agrimony lactone was purchased from Chengdu Croma Biotechnology Co., Ltd., product number CHB-X-111, batch number CHB180406.
  • 24h 1Normal control group (normally cultured Hela cells, without adding drugs); 250 ⁇ g/ml Agrimony lactone treatment group;
  • 48h 1Normal control group (normally cultured Hela cells, without adding drugs); 250 ⁇ g/ml Agrimony lactone treatment group;
  • 72h 1Normal control group (normally cultured Hela cells, without adding drugs); 250 ⁇ g/ml Agrimony lactone treatment group.
  • Hela cells were cultured in DMEM medium containing penicillin, streptomycin (each 1U/mL, 0.1mg/mL) and 10% FBS, placed in a cell culture incubator at 37°C, 5% CO 2 , and relative humidity of 100%. The cells were cultured in medium, adhered to the wall, and subcultured for subsequent experiments.
  • a blank well (medium+CCK-8, blank group) and a normal control group (Hela cells without agrimilide treatment+medium+CCK8) were set at the same time.
  • A normal control group: absorbance value of Hela cells not treated with agrilide.
  • Statistical software is SPSS16.0. P ⁇ 0.05, the difference between the two groups was considered statistically significant.
  • agrilactone has a significant inhibitory effect on the growth of cervical cancer cells, and can further inhibit the formation of tumors by cervical cancer cells.
  • the agrilactone can be used for preventing or treating cervical cancer, and can be used for preparing medicines for preventing or treating cervical cancer, and has a good application prospect.

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Abstract

仙鹤草内酯在制备预防和/或治疗宫颈癌的药物中的用途，具体提供了式(I)所示的化合物、或其立体异构体、或其盐、或其溶剂合物、或其水合物、或其前药在制备预防和/或治疗宫颈癌的药物中的用途，其中，R 1、R 2、R 3分别独立选自C 1-C 6烷基、C 1-C 6烷氧基、羟基、氨基、羧基。仙鹤草内酯对宫颈癌细胞生长具有显著抑制作用，可进一步抑制宫颈癌细胞形成肿瘤，可用于制备预防或治疗宫颈癌的药物。

Description

仙鹤草内酯在制备预防和/或治疗宫颈癌的药物中的用途 技术领域
本发明属于医药领域，具体涉及仙鹤草内酯在制备预防和/或治疗宫颈癌的药物中的用途。
背景技术
宫颈癌是最常见的妇科恶性肿瘤。原位癌高发年龄为30～35岁，浸润癌为45～55岁，近年来其发病有年轻化的趋势。据统计，2020年中国癌症新发457万人，死亡300万人，而宫颈癌的新发率和死亡率分别为2.4％及2％，宫颈癌的新发率和死亡率均居于前十位。目前，宫颈癌的疗方案主要包括手术治疗、放射治疗、化疗及中医药治疗。
中医药治疗因其独到的思维和低毒副作用等特点，在癌症的治疗中有着悠久历史，其与西医治疗联合应用可达“增效减毒”的效应。仙鹤草作为具有抗肿瘤效应的中草药之一，在肿瘤的治疗中具有补虚扶正、消积散结的效应。近代细胞学研究证实仙鹤草水体液具有抗肿瘤效应，如文献《仙鹤草化学成分及药理研究进展》(赵莹等.特产研究2001年第一期)公开了仙鹤草提取液对宫颈癌、肝癌等有明显抑制作用；文献《仙鹤草水提液对多种肺癌细胞的增殖抑制作用实验研究》(蔡田恬等.浙江中西医结合杂志.2017年第27卷第3期)公开了仙鹤草水提液对肺癌细胞有显著的体外增殖抑制作用。
仙鹤内酯是仙鹤草的活性成分之一，结构如下：
Figure PCTCN2022115207-appb-000001
仙鹤草内酯为无色柱状晶体，易溶于乙醇、乙醚和热苯，其药理作用主要包括抗炎、抗氧化应激、降血糖及抗肿瘤。但研究表明(Teng H等.Inhibition of cell proliferation and triggering of apoptosis by agrimonolide through MAP kinase(ERK and p38)pathways in human gastric cancer AGS cells.Food Funct,2016,7(11):4605-4613.)其仅对人源胃腺癌AGS细胞株敏感，可治疗胃癌；而对肝癌、乳腺癌、结肠癌细胞株均无抗癌活性。现有技术中没有报道仙鹤内酯可以抑制宫颈癌细胞，治疗宫颈癌。
发明内容
本发明的目的是提供仙鹤草内酯在制备预防和/或治疗宫颈癌的药物中的用途。
本发明提供了式I所示的化合物、或其立体异构体、或其盐、或其溶剂合物、或其水合物、或其前药在制备预防和/或治疗宫颈癌的药物中的用途：
Figure PCTCN2022115207-appb-000002
其中，R 1、R 2、R 3分别独立选自C 1～C 6烷基、C 1～C 6烷氧基、羟基、氨基、羧基。
进一步地，R 1、R 2、R 3分别独立选自C 1～C 3烷基、C 1～C 3烷氧基、羟基。
进一步地，所述化合物如式II所示：
Figure PCTCN2022115207-appb-000003
其中，R 3选自C 1～C 3烷基、C 1～C 3烷氧基、羟基。
进一步地，R 3选自C 1～C 3烷氧基。
进一步地，所述化合物为如下化合物：
Figure PCTCN2022115207-appb-000004
进一步地，所述药物为抑制宫颈癌细胞增殖的药物；和/或，所述药物为促进宫颈癌细胞凋亡的药物。
进一步地，所述宫颈癌细胞为Hela细胞。
进一步地，所述药物是以前述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其水合物、或其前药为活性成分，加上药学上可接受的辅料 或辅助性成分制备而成的制剂。
本发明还提供了一种药物，它是以前述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其水合物、或其前药为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。
本发明发现仙鹤草内酯对宫颈癌细胞生长具有显著抑制作用，可进一步抑制宫颈癌细胞形成肿瘤。仙鹤草内酯可用于预防或治疗宫颈癌，制备预防或治疗宫颈癌的药物，具有良好的应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为正常对照组和仙鹤草内酯处理24h组Hela细胞的图片(100X)。
图2为正常对照组和仙鹤草内酯处理48h组Hela细胞的图片(100X)。
图3为正常对照组和仙鹤草内酯处理72h组Hela细胞的图片(100X)。
图4为仙鹤草内酯处理24h后细胞存活率统计图。
图5为仙鹤草内酯处理48h后细胞存活率统计图。
图6为仙鹤草内酯处理72h后细胞存活率统计图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1、CCK8检测仙鹤草内酯对Hela细胞增殖的影响
1、实验材料
1.1细胞株：Hela细胞株，购买自中国科学院细胞库。
1.2培养条件：将细胞培养于含10％优质胎牛血清和1％青霉素-链霉素双抗的DMEM培养基中，2-3d换液1次，细胞80％融合度时传代，可按照1∶3传代比例进行，于37℃，5％CO2及饱和湿度培养箱中培养。
1.3主要试剂配制：
(1)DMEM培养基：-20℃保存，临用前按体积比配成含10％FBS和1％青霉素-链霉素双抗的完全培养液；
(2)青霉素-链霉素溶液：100倍稀释加入培养基中；
(3)PBS磷酸盐缓冲液：PBS粉剂用ddH 2O定容至1000mL，调pH7.2，121℃、30min高压灭菌，4℃保存备用。
(4)仙鹤草内酯(Agrimonolide)溶液：5mg/管，加入0.5ml DMSO，溶解后得到10mg/ml的母液。仙鹤草内酯购自成都克洛玛生物科技有限公司，货号CHB-X-111，批号CHB180406。
2、细胞模型分组
24h：①正常对照组(正常培养Hela细胞，不加入药物)；②50μg/ml仙鹤草内脂处理组；
48h：①正常对照组(正常培养Hela细胞，不加入药物)；②50μg/ml仙鹤草内脂处理组；
72h：①正常对照组(正常培养Hela细胞，不加入药物)；②50μg/ml仙鹤草内脂处理组。
3、实验步骤
细胞培养：
Hela细胞培养于含青、链霉素(各1U/mL，0.1mg/mL)以及10％FBS的DMEM培养基中，放置在37℃、5％CO 2、相对湿度为100％的细胞培养箱中培养，细胞贴壁生长，经过传代培养用于后续实验。
CCK-8法检测法：
(1)取正常生长的Hela细胞，计数调整细胞浓度至2×10 4/mL。
(2)分别接种于96孔板中，每孔100μL，每组细胞设4个复孔。
(3)将96孔板移入培养箱中培养(37℃，5％CO 2)，用50μg/ml仙鹤草内酯分别处理24h、48h和72h。
(4)培养结束后，各组每孔加入10μL CCK-8溶液(注意不要产生气泡)，于培养箱内孵育1h。
(5)用酶标仪测定在450nm处的吸光度值。
(6)同时设置空白孔(培养基+CCK-8，空白组)，正常对照组(未经仙鹤草内酯处理的Hela细胞+培养基+CCK8)。
细胞存活率计算：
细胞存活率(％)＝[A(实验组)-A(空白组)]/[A(对照组)-A(空白组)]×100％
A(实验组)：实验组为使用仙鹤草内酯处理后的细胞的吸光度值；
A(空白组)：只有培养基和CCK-8溶液而没有细胞的吸光度值；
A(正常对照组)：未使用仙鹤草内酯处理的Hela细胞的吸光度值。
统计方法：
统计方法采用两独立样本均数比较的t检验。统计软件为SPSS16.0。P<0.05，认为两组差异有统计学意义。
4、实验结果
仙鹤草内酯处理24h、48h、72h后Hela细胞的图片如图1～3所示。由图1～3可知：使用仙鹤草内酯处理Hela细胞后，Hela细胞开始凋亡、破碎。仙鹤草内酯处理组较正常对照组，显微镜视野中细胞量大量减少。说明仙鹤草内酯可以导致Hela细胞大量凋亡。
仙鹤草内酯处理24h后CCK-8检测实验结果如表1、表2和图4所示。
表1.仙鹤草内酯处理24h后CCK-8检测实验结果
Figure PCTCN2022115207-appb-000005
表2.仙鹤草内酯处理24h后统计结果
Figure PCTCN2022115207-appb-000006
P<0.05，两组差异有统计学意义。结果显示仙鹤草内酯干预24h后，Hela细胞存活率与正常对照组相比有显著差异，其存活率明显低于正常对照组，说明仙鹤草内酯对Hela细胞的增殖有显著抑制作用。
仙鹤草内酯处理48h后CCK-8检测实验结果如表3、表4和图5所示。
表3.仙鹤草内酯处理48h后CCK-8检测实验结果
Figure PCTCN2022115207-appb-000007
Figure PCTCN2022115207-appb-000008
表4.仙鹤草内酯处理48h后统计结果
Figure PCTCN2022115207-appb-000009
P<0.05，两组差异有统计学意义。结果显示仙鹤草内酯干预48h后，Hela细胞存活率与正常对照组相比有显著差异，其存活率进一步显著低于正常对照组，进一步说明仙鹤草内酯对Hela细胞的增殖有显著抑制作用。
仙鹤草内酯处理72h后CCK-8检测实验结果如表5、表6和图6所示。
表5.仙鹤草内酯处理72h后CCK-8检测实验结果
Figure PCTCN2022115207-appb-000010
表6.仙鹤草内酯处理72h后统计结果
Figure PCTCN2022115207-appb-000011
P<0.05，两组差异有统计学意义。结果显示仙鹤草内酯干预72h后，Hela细胞存活率与正常对照组相比有显著差异，其存活率显著低于正常对照组，说明仙鹤草内酯对Hela细胞的增殖有十分显著抑制作用。
综上，本发明发现仙鹤草内酯对宫颈癌细胞生长具有显著抑制作用，可进一步抑制宫颈癌细胞形成肿瘤。仙鹤草内酯可用于预防或治疗宫颈癌，制备预防或治疗宫颈癌的药物，具有良好的应用前景。

Claims (9)

  1. 式I所示的化合物、或其立体异构体、或其盐、或其溶剂合物、或其水合物、或其前药在制备预防和/或治疗宫颈癌的药物中的用途：
    Figure PCTCN2022115207-appb-100001
    其中，R 1、R 2、R 3分别独立选自C 1～C 6烷基、C 1～C 6烷氧基、羟基、氨基、羧基。
  2. 根据权利要求1所述的用途，其特征在于：R 1、R 2、R 3分别独立选自C 1～C 3烷基、C 1～C 3烷氧基、羟基。
  3. 根据权利要求2所述的用途，其特征在于：所述化合物如式II所示：
    Figure PCTCN2022115207-appb-100002
    其中，R 3选自C 1～C 3烷基、C 1～C 3烷氧基、羟基。
  4. 根据权利要求3所述的用途，其特征在于：R 3选自C 1～C 3烷氧基。
  5. 根据权利要求4所述的用途，其特征在于：所述化合物为如下化合物：
    Figure PCTCN2022115207-appb-100003
  6. 根据权利要求1～5任一项所述的用途，其特征在于：所述药物为抑制宫颈癌细胞增殖的药物；和/或，所述药物为促进宫颈癌细胞凋亡的药物。
  7. 根据权利要求6所述的用途，其特征在于：所述宫颈癌细胞为Hela细胞。
  8. 根据权利要求1～5任一项所述的用途，其特征在于：所述药物是以 权利要求1～5任一项所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其水合物、或其前药为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。
  9. 一种药物，其特征在于：它是以权利要求1～5任一项所述的化合物、或其立体异构体、或其盐、或其溶剂合物、或其水合物、或其前药为活性成分，加上药学上可接受的辅料或辅助性成分制备而成的制剂。
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