WO2018223851A1 - 阿替匹林c及其类似物在制备肝再生药物中的应用 - Google Patents

阿替匹林c及其类似物在制备肝再生药物中的应用 Download PDF

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WO2018223851A1
WO2018223851A1 PCT/CN2018/088410 CN2018088410W WO2018223851A1 WO 2018223851 A1 WO2018223851 A1 WO 2018223851A1 CN 2018088410 W CN2018088410 W CN 2018088410W WO 2018223851 A1 WO2018223851 A1 WO 2018223851A1
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liver
drug
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吴亮
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中国药科大学
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

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  • the invention relates to the application of atripiline C and its analogues in the preparation of liver regenerative medicine, and belongs to the technical field of biomedicine.
  • liver is an important metabolic and detoxifying organ and plays an important role in maintaining the body's dynamic balance.
  • liver tissue most liver cells do not undergo mitosis and are in a relatively static state.
  • many chemicals, drugs, viruses, etc. cause liver damage, which eventually leads to a variety of acute and chronic liver damage.
  • Liver cancer is one of the most common malignant tumors with high mortality in China, and it is also one of the most serious liver diseases.
  • the main treatment for various hepatobiliary tumors and acute and chronic end-stage liver disease is partial hepatectomy. In clinical applications, hepatectomy and living donor liver transplantation are currently the most effective treatments for liver cancer and end-stage liver disease worldwide.
  • liver transplantation The reason why hepatectomy and living donor liver transplantation are feasible is the unique and powerful regenerative capacity of hepatocytes; after partial resection of the liver, hepatocytes are rapidly activated, and hepatocyte proliferation is achieved through DNA synthesis and mitosis, when proliferating to a certain number The division stops and the nascent cells re-differentiate into mature hepatocytes, a process that is liver regeneration. After the patient undergoes surgery, if the remaining liver lacks regenerative capacity, delays regenerative capacity or has weak regenerative capacity, it may cause various adverse syndromes such as acute liver failure, septic infection, ascites, hemorrhage, renal failure or hepatic encephalopathy after surgery. .
  • liver failure after surgery is still the main cause of postoperative death, and is directly related to the prognosis of patients. Therefore, finding safe and effective drugs for regulating liver regeneration has important theoretical significance and clinical application value in reducing the risk of hepatectomy and shortening the recovery time of patients.
  • liver cells are the basic unit of the structure and function of the body. Regardless of the cause of liver disease, hepatocyte injury is the basis of common pathology and pathophysiology.
  • the liver is an important organ that integrates many functions such as metabolism, synthesis, detoxification, bile secretion, endocrine and immunity. It is highly vulnerable to various harmful factors such as viruses, drugs and poisons, alcohol and excessive fat. .
  • the rate, extent and number of hepatocyte damage, as well as the status of regeneration and repair are intrinsic determinants of the progression and severity of liver disease. Controlling or eliminating the cause of liver damage, blocking the continued damage of liver cells, promoting liver cell regeneration and repair, is a common treatment principle for various liver diseases.
  • liver cell regeneration not only helps protect liver cells themselves, but also helps to delay or block liver fibrosis, hepatitis, cirrhosis, liver failure, and reduce the risk of hepatocellular carcinoma.
  • acitrillin C has been widely used as a tumor suppressor component, and it can exert anticancer effects by inducing apoptosis of human cancer cells, inhibiting tumor angiogenesis, and inducing cell cycle arrest. This strengthens the risk of hepatocellular carcinoma in the reduction of adipillin C
  • the invention provides an application of atripiline C and its analog (Artepillin C, ARC) in preparing liver regeneration medicine.
  • Atripiline C and its analogs have the following structure of formula (I):
  • R 1 is selected from H or isopentenyl
  • R 2 is OH
  • R 3 is selected from H or isopentenyl
  • R 4 is selected from H or CH 2 Ph or Or CH 2 CHPh.
  • Formula I is preferably atripiline C, and the chemical formula of atripiline C is: 3-[4-hydroxy-3,5-bis(3-methyl-2-butenyl)phenyl]-2-(E )-Acrylic acid with a molecular weight of 300.40 and its chemical structure is as follows:
  • the above-mentioned drugs also include a pharmaceutically acceptable salt of ethipirin C and an analog thereof, which refers to a salt formed by reacting a compound with an inorganic acid, an organic acid, an alkali metal or an alkaline earth metal.
  • ethipirin C and an analog thereof refers to a salt formed by reacting a compound with an inorganic acid, an organic acid, an alkali metal or an alkaline earth metal.
  • These salts include (but are not limited to):
  • a salt formed with the following inorganic acid hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or the like.
  • a salt formed with an organic acid such as acetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, maleic acid, arginine or the like.
  • a salt formed with an alkali metal or an alkaline earth metal sodium, potassium, calcium, magnesium, or the like.
  • Atripiline C and its analogs or pharmaceutically acceptable salts are capable of promoting liver regeneration in liver damage.
  • Liver damage includes liver physical damage or liver chemical damage, liver physical damage is liver resection, liver rupture or liver puncture, and liver chemical damage is hepatotoxic damage.
  • Acitrillin C and its analogs or pharmaceutically acceptable salts are capable of improving liver function following liver injury.
  • Atripiline C and its analogs or pharmaceutically acceptable salts are capable of stimulating hepatocyte proliferation in liver damage.
  • Acitrillin C and its analogs or pharmaceutically acceptable salts are capable of stimulating normal hepatocyte proliferation in cirrhosis, hepatitis, liver cancer, liver fibrosis, fatty liver disease, and liver failure.
  • Atropin C and its analogs or pharmaceutically acceptable salts are capable of improving liver/body weight recovery.
  • Figure 1 is a liver weight ratio test result of liver regeneration test in the examples
  • Figure 2 is a bar graph of the liver tissue biochemical index AST in the examples.
  • Figure 3 is a bar graph of the liver biochemical indicator ALT in the examples.
  • Figure 4 is a bar graph of the liver tissue biochemical index Albumin in the examples.
  • Figure 5 is a graph showing the effect of different doses of ARC on liver histopathology of hepatectomy models in the examples (HE, 200 ⁇ );
  • the animal model is a 70% hepatectomy model.
  • the mice were divided into three groups, the solvent group and the drug-administered group.
  • the doses of the drug-administered group were 8 mg/kg and 12 mg/kg, respectively.
  • 4% chloral hydrate was used for intraperitoneal injection.
  • the abdomen of the mice was disinfected with alcohol.
  • the skin and meat were cut from the xiphoid 1-2 cm width to expose the liver.
  • the middle leaves were pressed with a cotton swab and the middle leaves were cut.
  • the sacral ligament on the upper.
  • the left lobe of the liver was ligated with a thread, and the left lobe of the liver was cut slightly near the ligation site; the middle lobe was ligated, and the ligated site was 2-3 cm under the fork of the middle lobe, and the middle lobe was cut off.
  • intraperitoneal injection of 0.4 ml of normal saline and place the mouse in a warm environment. The drug was administered at regular intervals every day, and after three days of administration, the mice were sacrificed on the fourth day of the experiment.
  • mice On the fourth day, the mice were sacrificed, and the liver weight and body weight of the mice were weighed, and the liver regeneration index was calculated by the ratio of the two.
  • ARC significantly accelerated the recovery of liver/body weight ratio in hepatectomized mice compared to the solvent group.
  • liver/body weight ratio regenerative liver weight / postoperative weight *100%, where *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001)
  • mice On the 4th day, the mice were sacrificed and blood samples were taken for determination of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin (Albumin) in serum.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • Albumin albumin
  • liver tissue was fixed with 4% paraformaldehyde, tissue repair, distilled water rinse, dehydrated, paraffin embedded, and conventionally sectioned to obtain 4 ⁇ m sections.
  • the sections were dewaxed, stained, dehydrated, transparent, and mounted for light microscopy to observe hepatic inflammatory infiltration and edema. The result is shown in Figure 5:
  • hepatocytes In the solvent group, hepatocytes degenerated significantly, showing varying degrees of swelling and vacuolar degeneration, and the lesions were diffusely distributed ("*"); a small number of mitotic figures (shown by "arrows") with nuclear enlargement and binuclear cells were seen.
  • the degree of hepatocyte degeneration was improved, and nuclear enlargement and binuclear cells were observed, and mitotic figures were significantly increased.
  • the degree of hepatocyte degeneration was improved, and nuclear enlargement was also observed. Large and binuclear cells, nuclear fission has increased.

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Abstract

阿替匹林C及其类似物在制备肝再生药物中的应用，阿替匹林C能够促进肝损伤中肝再生，改善肝损伤后的肝功能，刺激肝细胞增殖，提高肝/体重比恢复能力。

Description

阿替匹林C及其类似物在制备肝再生药物中的应用 技术领域
本发明涉及一种阿替匹林C及其类似物在制备肝再生药物中的应用，属于生物医药技术领域。
背景技术
肝脏是重要的代谢和解毒器官，在维持机体动态平衡等方面发挥着重要作用。在正常肝组织中，绝大部分肝细胞不会进行有丝分裂，处于相对静止状态，但是，很多化学品、药物、病毒等会引起肝损伤，最终导致多种急慢性肝损伤。肝癌是我国常见的死亡率高的恶性肿瘤之一，也是一种最严重肝疾病。目前，各种肝胆管肿瘤和急慢性终末期肝病主要的治疗手段还是肝部分切除术。在临床应用中，肝切除和活体肝移植是目前世界范围内最有效的治疗肝癌和终末期肝病的方法。肝切除和活体肝移植之所以可行的原因是肝细胞独特的、强大的再生能力；在肝脏被部分切除后，肝细胞迅速被激活，通过DNA合成和有丝分裂进行肝细胞增殖，当增殖到一定数目时即停止分裂，新生细胞再分化为成熟的肝细胞，这一过程为肝再生。患者接受手术后，如果剩余肝脏缺乏再生能力、延缓再生能力或者再生能力弱，会引起多种不良的综合病症，如手术后急性肝衰竭、脓毒性感染、腹水、出血、肾衰竭或肝性脑病。其中，手术后出现的急性肝衰竭仍然是导致术后死亡的主要原因，并直接关系到患者预后的好坏。因此，寻找安全有效的调控肝再生的药物对减低肝切除手术风险、缩短患者术后恢复时间具有重要的理论意义和临床应用价值。
细胞是机体结构和功能的基本单位。无论何种原因引起的肝脏病变，肝细胞损伤是共同的病理学和病理生理学基础。肝脏是人体极为重要的集代谢、合成、解毒、胆汁分泌、内分泌和免疫等诸多功能于一体的重要器官，极易受到病毒、药物和毒物、酒精及过多的脂肪等各种有害因素的攻击。肝细胞损伤的速度、程度和数量以及再生和修 复状态是肝病进展及严重程度的内在决定因素。控制或消除肝损伤的病因，阻断肝细胞的继续损伤，促进肝细胞再生和修复，是各类肝病的共同的治疗原则。所以促进肝细胞再生不仅有利于保护肝细胞本身，也有利于延缓或阻断肝纤维化、肝炎、肝硬化、肝衰竭，并能降低肝细胞癌的发生风险。同时，阿替匹林C最早是作为肿瘤抑制成分而受到广泛关注的，它能通过诱导人体癌细胞发生细胞凋亡、抑制肿瘤血管生成、诱导癌细胞周期阻滞等机制来发挥抗癌作用，这更加强了阿替匹林C降低肝细胞癌的发生风险
发明内容
本发明提供一种阿替匹林C及其类似物(Artepillin C,ARC)在制备肝再生药物中的应用。
阿替匹林C及其类似物具有如下式(Ⅰ)结构：
Figure PCTCN2018088410-appb-000001
其中，R 1选自H或者异戊烯基；
R 2为OH；
R 3选自H或者异戊烯基；
R 4选自H或者CH 2Ph或者
Figure PCTCN2018088410-appb-000002
或者CH 2CHPh。
式Ⅰ优选为阿替匹林C，阿替匹林C化学式为：3-[4-羟基-3，5-二(3-甲基-2-丁烯基)苯基]-2-(E)-丙烯酸，分子量为300.40其化学 结构如下：
Figure PCTCN2018088410-appb-000003
上述药物还包括阿替匹林C及其类似物在药学上可接受的盐，所述药学上可接受的盐是指化合物与无机酸、有机酸、碱金属或碱土金属反应生成的盐。这些盐包括(但不限于)：
与如下无机酸形成的盐：盐酸、硫酸、硝酸、磷酸等。
与如下有机酸形成的盐：乙酸、草酸、丁二酸、酒石酸、甲磺酸、马来酸、精氨酸等。
与如下碱金属或碱土金属形成的盐：钠、钾、钙、镁等。
本发明的研究人员发现如下应用：
阿替匹林C及其类似物或者在药学上可接受的盐能够促进肝损伤中肝再生。
肝损伤包括肝物理损伤或肝化学损伤，肝物理损伤为肝切除、肝破裂或肝穿刺，肝化学损伤为肝毒性损伤。
阿替匹林C及其类似物或者在药学上可接受的盐能够改善肝损伤后的肝功能。
阿替匹林C及其类似物或者在药学上可接受的盐能够刺激肝损伤中的肝细胞增殖。
阿替匹林C及其类似物或者在药学上可接受的盐能够刺激肝硬化、肝炎、肝癌、肝纤维化、脂肪性肝病、肝衰竭中正常肝细胞增殖。
阿替匹林C及其类似物或者在药学上可接受的盐能够提高肝/体重比恢复能力。
附图说明
图1是实施例中的肝再生实验肝重比结果；
图2是实施例中的肝组织生化指标AST的柱状图；
图3是实施例中的肝组织生化指标ALT的柱状图；
图4是实施例中的肝组织生化指标Albumin的柱状图；
图5是实施例中不同剂量的ARC对肝切除模型小鼠肝脏组织病理形态学的影响图(HE，200×)；
具体实施方式
下面结合实施例对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
实施例：
1、动物实验设计
动物模型是70％肝切除模型。实验前，先将小鼠分为三组，分别为溶剂组、给药组，给药组剂量分别为8mg/kg和12mg/kg。给药之后再使用4％水合氯醛腹腔注射麻醉，用酒精将老鼠腹部消毒，从剑突往下1-2cm宽度剪开皮肤和肉，使肝部暴露，用棉签压着中叶，剪掉中叶上的镰状韧带。用线将肝左叶结扎，在靠近结扎部位稍上一点剪掉肝左叶；结扎中叶，结扎部位在中叶分叉下2-3cm，剪掉肝中叶。分别将肉和皮肤缝好，腹腔注射0.4ml生理盐水，将老鼠放置在温暖的环境。每天定时去给药，给药三天后，在实验的第四天处死老鼠。
2、肝重比
第4天处死小鼠，分别称量小鼠的肝重和体重，以两者之比计算肝再生指数。
肝再生实验肝重比结果如图1和表1所示，
Figure PCTCN2018088410-appb-000004
表1
从表1和图1可以看出，与溶剂组相比，ARC能显著加快肝切除小鼠的肝/体重比的恢复。
(按照学术界公认的肝/体重比公式来衡量肝重恢复：肝/体重比＝再生肝重/术后体重*100％，其中*P<0.05、**P<0.01、***P<0.001)
3、肝组织生化指标检测
第4天处死小鼠，取血测定血清中谷草转氨酶(AST)、谷丙转氨酶(ALT)、白蛋白(Albumin)的含量
Figure PCTCN2018088410-appb-000005
跟溶剂组相比＊P<0.05、＊＊P<0.01、＊＊＊P<0.001
表2
结果分析：根据图2-4和表2所示，ARC能显著降低肝脏转氨酶ALT和AST水平。在肝损伤治疗过程中，血清中Albumin水平升高被认为是肝脏功能恢复的经典指征之一，在本试验中，ARC给药组小鼠血清中Albumin水平显著高于溶剂组，提示ARC在肝损伤过程中不仅能起到降低损伤程度的作用，同时在肝脏恢复的过程中也能起到积极作用。
4、肝脏组织学分析
肝脏组织H&E染色观察肝受损情况
肝组织经过4％多聚甲醛固定、组织修切、蒸馏水冲洗、脱水、石蜡包埋、常规切片，得到4μm切片。再将切片脱蜡、染色、脱水、透明、封片进行光学显微镜观察肝细胞炎症浸润和水肿情况。结果如图5所示：
结果分析：
溶剂组，肝细胞变性明显，表现为不同程度的肿胀和空泡变性，病变呈弥漫性分布(“*”所示)；可见少量核分裂像(“箭头”所示)， 伴核增大和双核细胞；ARC(8mg/kg)组，肝细胞变性程度有所改善，同样可见核增大和双核细胞，核分裂像明显增多；ARC(12mg/kg)组，肝细胞变性程度有所改善，同样可见核增大和双核细胞，核分裂像有所增多。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变形，这些改进和变形也应视为本发明的保护范围。

Claims (9)

  1. 阿替匹林C及其类似物在制备肝再生药物中的应用。
  2. 如权利要求1所述的应用，其特征在于：所述肝再生药物是指能够促进肝损伤中肝再生的药物。
  3. 如权利要求2所述的应用，其特征在于：所述肝再生药物是指能够改善肝损伤后肝功能的药物。
  4. 如权利要求1所述的应用，其特征在于：所述肝再生药物是指能够刺激在肝损伤中肝细胞增殖的药物。
  5. 如权利要求1所述的应用，其特征在于：所述肝再生药物是指能够刺激肝硬化、肝炎、肝癌、肝纤维化、脂肪性肝病、肝衰竭中肝细胞增殖的药物。
  6. 如权利要求1所述的应用，其特征在于：所述肝再生药物是指能够提高肝/体重比恢复能力的药物。
  7. 如权利要求1所述的应用，其特征在于，所述阿替匹林C及其类似物具有如下式(Ⅰ)结构：
    Figure PCTCN2018088410-appb-100001
    其中，R 1选自H或者异戊烯基；
    R 2为OH；
    R 3选自H或者异戊烯基；
    R 4选自H或者CH 2Ph或者
    Figure PCTCN2018088410-appb-100002
    或者CH 2CHPh。
  8. 如权利要求7所述的应用，其特征在于，所述式(Ⅰ)结构的优选为阿替匹林C，具体结构式如下：
    Figure PCTCN2018088410-appb-100003
  9. 如权利要求1所述的应用，其特征在于，所述药物还包括阿替匹林C及其类似物在药学上可接受的盐，所述药学上可接受的盐是指化合物与无机酸、有机酸、碱金属或碱土金属反应生成的盐。
PCT/CN2018/088410 2017-06-05 2018-05-25 阿替匹林c及其类似物在制备肝再生药物中的应用 WO2018223851A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1422159A (zh) * 2000-04-10 2003-06-04 宝生物工程株式会社 治疗剂
CN104592188A (zh) * 2015-01-21 2015-05-06 聊城大学 一种从中国蜂胶水提物中分离纯化短叶松素及咖啡酸的衍生物的方法
CN106496023A (zh) * 2015-09-08 2017-03-15 庄明熙 制备、分离与纯化蜂胶中蒿素c活性成分的方法
CN107028927A (zh) * 2017-06-05 2017-08-11 中国药科大学 阿替匹林c及其类似物在制备肝再生药物中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106265620A (zh) * 2015-06-04 2017-01-04 中国科学院上海生命科学研究院 阿特匹灵c及其类似物在制备防治代谢性疾病的药物中的应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1422159A (zh) * 2000-04-10 2003-06-04 宝生物工程株式会社 治疗剂
CN104592188A (zh) * 2015-01-21 2015-05-06 聊城大学 一种从中国蜂胶水提物中分离纯化短叶松素及咖啡酸的衍生物的方法
CN106496023A (zh) * 2015-09-08 2017-03-15 庄明熙 制备、分离与纯化蜂胶中蒿素c活性成分的方法
CN107028927A (zh) * 2017-06-05 2017-08-11 中国药科大学 阿替匹林c及其类似物在制备肝再生药物中的应用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DU, XIA: "Study on Separation of Hepatoprotective Components in Propolis and its Mechanisms of Action", AGRICULTURE, CHINA MASTER S THESES FULL- TEXT DATABASE, 15 February 2014 (2014-02-15) *
HUANG, WENCHENG: "Progress on the Study of Biological Activity and Pharmacological Action of Propolis (Fourth", JOURNAL OF BEE, 31 December 2006 (2006-12-31), pages 27 - 28 *
TÜRKEZ, H. ET AL.: "Propolis Prevents Aluminium-Induced Genetic and Hepatic Damages in Rat Liver", FOOD AND CHEMICAL TOXICOLOGY, vol. 48, no. 10, 31 December 2010 (2010-12-31), pages 2741 - 2746, XP029873926 *
YU , BIN ET AL.: "Progress of Propolis and its Active Components on the Protective Effect of Liver Injury", APICULTURE OF CHINA, vol. 65, 31 December 2014 (2014-12-31), pages 36 - 38 *

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