WO2015169121A1 - 槲皮素-o-糖苷衍生物在治疗脂质代谢紊乱疾病中的应用 - Google Patents

槲皮素-o-糖苷衍生物在治疗脂质代谢紊乱疾病中的应用 Download PDF

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WO2015169121A1
WO2015169121A1 PCT/CN2015/073814 CN2015073814W WO2015169121A1 WO 2015169121 A1 WO2015169121 A1 WO 2015169121A1 CN 2015073814 W CN2015073814 W CN 2015073814W WO 2015169121 A1 WO2015169121 A1 WO 2015169121A1
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quercetin
group
compound
lipid metabolism
liver
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French (fr)
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尚靖
李妤
金�雨
吕金鹏
王路路
张志超
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南京睿鹰润泽生物医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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  • the invention relates to the field of medicine, in particular to the application of a class of quercetin-O-glycoside derivatives in the treatment of disorders of lipid metabolism.
  • Lipid metabolism disorders refer to energy metabolism-related diseases characterized by abnormal lipid metabolism in the body, including fatty liver, obesity, atherosclerosis, and hyperlipoproteinemia.
  • the main feature of lipid metabolism disorders is the abnormality of lipids (lipids) and their metabolic products and amounts in the blood and other tissues and organs, which can show the accumulation of triglycerides and cholesterol, liver lobule inflammation and The increase in the content of alanine transaminase (ALT) and the change in the secretion of adipocytokines.
  • ALT alanine transaminase
  • the pathogenesis of lipid metabolism disorders is complicated and it is difficult to treat at present.
  • Quercetin-O-glycoside compounds are widely distributed in various fruits, vegetables and Chinese herbal medicines, and are abundant in saffron, saffron, chicory, and mango. In recent years, a large number of domestic and foreign literature reports have found that chicory has obvious effects of lowering blood sugar and blood lipids (Xinjiang Traditional Chinese Medicine, 2006, 24: 80-83).
  • the present invention uses quercetin as a raw material to synthesize a class of quercetin-O-glycoside derivatives, and its pharmacological and chemical studies show that the derivatives and pharmaceutical compositions of the present invention have potential application value in the treatment of lipid metabolism disorders .
  • R 1 represents a hydrogen atom, monosaccharide group, glucuronic acid or galacturonic acid
  • R 2 represents a hydrogen atom, a monosaccharide group, glucuronic acid or galacturonic acid
  • R 3 represents a hydrogen atom, a methyl group, a methanol group, an ethyl group, an ethanol group, an acetate group or a benzyl group;
  • R 4 represents a hydrogen atom, a methyl group, a methanol group, an ethyl group, an ethanol group, an acetate group or a benzyl group;
  • R 1 , R 2 , R 3 , and R 4 do not simultaneously represent a hydrogen atom.
  • the monosaccharide in the monosaccharide group is preferably glucose, galactose, rhamnose, xylose, arabinose or fructose.
  • the pharmaceutically acceptable salt, solvate or polymorph of the compound of the present invention has the same pharmacological activity as the compound of the present invention.
  • the present invention also discloses a pharmaceutical composition, which contains the compound (I) of the present invention or a pharmaceutically acceptable salt, solvate or polymorph thereof, and a pharmaceutically acceptable carrier.
  • the composition can be prepared into a variety of conventional preparations in the pharmaceutical field, such as tablets, granules, injections, dripping pills, capsules, aerosols, suppositories, plasters, etc., orally or intravenously, intramuscularly, subcutaneously or otherwise.
  • the composition can be administered in different doses.
  • the compounds of the present invention can also be used to treat other diseases related to lipid metabolism disorders.
  • the clinically used dose of the compound of the present invention is 0.01 mg to 1000 mg/day, and it can also deviate from this range according to the severity of the disease or the different dosage forms.
  • the compounds of the present invention can be prepared by the following methods:
  • Rat hepatocytes were cultured normally for 24 hours (6-well plate), and FFA was used to induce the establishment of a high-fat model of hepatocytes. After that, they were given different kinds of quercetin-O-glycoside derivatives (20 ⁇ M) and cultured for 24 hours. Remove the culture medium, wash twice with PBS, then add 100 ⁇ L of lysate to each well, scrape the cells, place on ice for 20min, centrifuge at 12000rpm/min for 10min, take the supernatant, operate according to the instructions of the TG and TC kits, and determine TG respectively , TC content.
  • Table 1 The effect of the quercetin-O-glycoside derivative of the present invention (20 ⁇ M) on the content of triglyceride (TG) in primary rat liver cells
  • Table 2 The effect of the quercetin-O-glycoside derivative of the present invention (20 ⁇ M) on the content of cholesterol (TC) in primary rat liver cells
  • quercetin-O-glycoside derivatives of the present invention can reduce the deposition of triglycerides (TG) and cholesterol (TC) in primary rat liver cells.
  • TG triglycerides
  • TC cholesterol
  • compound 2 quercetin-3-O- ⁇ -D-glucuronide
  • compound 4 quercetin-3-O- ⁇ -D-glucuronide
  • Quercetin-O-glycoside derivatives of the present invention (quercetin, quercetin-3-O- ⁇ -D-glucoside, quercetin-3-O- ⁇ -D-glucuronide) Pharmacodynamic Study on Rat Lipid Metabolism Disturbance Model Induced by High Fat Feed
  • the experimental groups are as follows: 1Normal group: normal feed + 0.5% CMC-Na; 2 High fat model group: high fat feed + 0.5% CMC-Na; 3 Simvastatin group (10 mg/kg): high fat feed + simvastatin 10mg/kg; 4 bezafibrate To Group (10mg/kg): high-fat diet + bezafibrate 10mg/kg; 5 Quercetin-3-O- ⁇ -D-glucoside group (25mg/kg): high-fat diet + quercetin-3 -O- ⁇ -D-glucoside 25mg/kg; 6Quercetin-3-O- ⁇ -D-glucuronide group (25mg/kg): high-fat feed + quercetin-3-O- ⁇ -D-Glucuronide 25mg/kg; 7Quercetin (25mg/kg): high-fat feed + quercetin 25mg/kg. While feeding the feed, the corresponding drugs were given by gavage every morning, and the
  • the rats were sacrificed, the liver was taken out, the miscellaneous tissues were removed, the blood was removed by rinsing with pre-cooled physiological saline, the filter paper was blotted dry, and it was immersed in 10% formaldehyde solution for fixation, dehydrated, immersed in wax, sliced, displayed, attached, baked slices Dye afterwards.
  • the acidic nucleus is stained blue by alkaline hematoxylin, and the alkaline cytoplasm is stained red by acidic eosin. As a result, the nucleus is blue and the cytoplasm is red.
  • liver index liver weight/body weight.
  • the blood was collected from the femoral artery and placed at room temperature for 2 hours, then centrifuged at 3500 r/min for 15 minutes. The upper clear transparent liquid was the collected serum, which was aliquoted and stored in a refrigerator at -70°C. Determine the content of TC, TG, LDL-C and HDL-C according to the method described in the kit instructions. Enzymatic endpoint method was used to determine the content of TC and TG, and chemical inhibition method was used to determine the content of LDL-C and HDL-C.
  • Preparation of protein sample Take the liver of each group of animals and extract the total protein in the tissue.
  • BCA protein quantification Take 1.2 mL of protein standard preparation solution and add it to a tube of protein standard (30 mg BSA), and make a 25 mg/mL protein standard solution after fully dissolving. Take an appropriate amount of 25mg/mL protein standard and dilute with PBS to the final concentration To It is 0.5mg/mL. According to the number of samples, prepare an appropriate amount of BCA working solution according to 50 volumes of BCA reagent A plus 1 volume of BCA reagent B (50:1), and mix thoroughly. Add 0,1,2,4,8,12,16,20 ⁇ l of standards to the standard wells of a 96-well plate, and add PBS to make up to 20 ⁇ l.
  • the protein sample is mixed with 5 ⁇ standard SDS-PAGE loading buffer to make the final concentration of SDS-PAGE loading buffer 1 ⁇ , and then boiled in a boiling water bath for 5 minutes, and the protein sample is stored at -20°C for later use.
  • ECL luminescent liquid A liquid + B liquid is mixed in equal volume (do not prepare under strong light). After 1 minute, fully contact the membrane protein face down with the mixed liquid, and after reacting for 5 minutes, transfer the film to another plastic wrap Top, remove the remaining liquid; gel image analysis: put the above-mentioned colored film into a gel imager, expose and analyze it with a fully automatic gel image analyzer.
  • Table 3 shows that the weight, liver index, cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) of the model group were significantly different from the normal group (p ⁇ 0.01). Simvastatin and bezafibrate can significantly reduce the content of TC, TG and LDL-C in the serum of rats, and increase the content of HDL-C, which is significantly different from the model group (p ⁇ 0.05 or p ⁇ 0.01).
  • simvastatin, quercetin-3-O- ⁇ -D-glucoside and quercetin-3-O- ⁇ -D-glucuronide can significantly improve the high-fat diet to a certain extent. Obesity and lipid metabolism disorders caused by feeding.
  • PPAR- ⁇ is the main target of bezafibrate to lower triglycerides.
  • the experimental results are shown in Fig. 3, compared with the blank control group, the expression of PPAR- ⁇ in the high-fat model group was down-regulated, indicating that high-fat diet feeding can cause disorder of triglyceride metabolism pathway in the liver and produce lipid accumulation.
  • the bezafibrate, quercetin-3-O- ⁇ -D-glucoside, and quercetin-3-O- ⁇ -D-glucuronide administration group showed significant expression of PPAR- ⁇ Activation; compared with the model group, the expression of PPAR- ⁇ in the quercetin administration group was not significantly activated. It is suggested that quercetin-3-O- ⁇ -D-glucoside and quercetin-3-O- ⁇ -D-glucuronide play a role in lowering triglycerides by acting on PPAR- ⁇ .
  • HMGR is the rate-limiting enzyme for liver cholesterol synthesis
  • ABCA1 is an important protein that mediates liver cholesterol efflux. It can be seen from Figure 4 that compared with the control group, quercetin-3-O- ⁇ -D-glucoside (2) and quercetin-3-O- ⁇ -D-glucuronide (4) are extremely Significantly up-regulate the increase in rat liver ABCA1 protein expression, and further significantly down-regulate the decrease in rat liver HMGR protein expression (P ⁇ 0.01), but quercetin (1) cannot significantly up-regulate the increase in rat liver ABCA1 protein expression .
  • quercetin-3-O- ⁇ -D-glucuronide (2) and quercetin-3-O- ⁇ -D-glucuronide (4) can directly regulate the synthesis of cholesterol in liver cells And efflux; Quercetin (1) cannot directly regulate the efflux of liver cell cholesterol.
  • Figure 1 shows the effects of quercetin-3-O- ⁇ -D-glucoside and quercetin-3-O- ⁇ -D-glucuronide on liver tissue structure in rats
  • Figure 2 shows the effects of quercetin-3-O- ⁇ -D-glucoside and quercetin-3-O- ⁇ -D-glucuronide on lipid deposition in the liver of rats
  • Figure 3 shows the effects of quercetin (1), quercetin-3-O- ⁇ -D-glucoside (2), and quercetin-3-O- ⁇ -D-glucuronide (4) on rats The expression of PPAR- ⁇ in the liver
  • Figure 4 shows the effects of quercetin (1), quercetin-3-O- ⁇ -D-glucuronide (2), and quercetin-3-O- ⁇ -D-glucuronide (4) on rats The influence of liver HMGR and ABCA1 protein expression
  • the first two steps were the same as in Example 1.
  • the obtained light yellow syrup (6.18g, 10mmol), bromomethanol (1.09g, 10mmol), potassium carbonate (1.38g, 10mmol) were dissolved in 50ml of tetrahydrofuran solution and heated.
  • the reaction was refluxed for 7 hours, and then purified by silica gel column chromatography to obtain a pale yellow solid.
  • the preparation process is the same as in Example 1.
  • the acetyl bromide- ⁇ -D-glucose used in the second step reaction is replaced with acetyl bromide- ⁇ -D-glucuronic acid methyl ester.
  • the reaction yield is 46.7%, mp245-248°C.
  • the preparation process is the same as in Example 2.
  • the acetyl bromide- ⁇ -D-glucose used in the second step reaction is replaced with acetyl bromide- ⁇ -D-glucuronic acid methyl ester.
  • the reaction yield is 50.2%, mp224-227°C.
  • the preparation process is the same as in Example 1.
  • the difference between the acidity of the 3 and 7 positions of the compound is used to control the reaction temperature between 10 °C and 15 °C, and the 7 position is successfully obtained.
  • the quercetin-7-O- ⁇ -D-glucoside (6), the product of the glycosylation reaction of the hydroxyl group, has a reaction yield of 34.7%, mp 202-206°C.
  • the preparation process is the same as that in Example 3.
  • the difference between the acidity of the 3-position and the 7-position hydroxyl group of the compound is used to control the reaction temperature between 14°C and 20°C.
  • the quercetin-7-O- ⁇ -D-glucuronide (7), the product of the glycosylation reaction of the hydroxyl group has a reaction yield of 46.2%, and mp213-215°C.
  • the preparation method is the same as that in Example 1.
  • the acetyl bromide- ⁇ -D-glucose is replaced with acetyl bromide- ⁇ -D-galactose to obtain quercetin-3-O- ⁇ -D-galactoside (8).
  • the rate is 49.1%, mp234 ⁇ 237°C.
  • the preparation method is the same as in Example 3.
  • the acetyl bromide- ⁇ -D-glucuronic acid methyl ester is replaced with acetyl bromide- ⁇ -D-galacturonic acid methyl ester to obtain quercetin-3-O- ⁇ -D -Galacturonic acid glycoside (9), the yield is 41.9%, mp 219 ⁇ 223°C.

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Abstract

本发明涉及药物合成及药理学领域，具体涉及一类槲皮素-O-糖苷衍生物的制备方法及其在治疗脂质代谢紊乱疾病中的应用。所述衍生物如式I的化合物，包括式I化合物的盐和式I化合物的光学异构体和外消旋体。本发明要解决的技术问题是设计并合成一类槲皮素-O-糖苷衍生物，通过体外、体内的药理活性研究发现，槲皮素-O-糖苷衍生物在体内外实验中均可发挥降脂的作用。另外本发明还提供了一种治疗脂质代谢紊乱疾病的药物组合物。

Description

槲皮素-O-糖苷衍生物在治疗脂质代谢紊乱疾病中的应用 技术领域
本发明涉及医药领域，具体涉及一类槲皮素-O-糖苷衍生物在治疗脂质代谢紊乱疾病中的应用。
背景技术
随着经济水平的发展，国民生活方式的改变，一系列脂代谢紊乱的疾病的发生率日趋上升。脂质代谢紊乱疾病(lipid metabolism disorders)是指以机体脂质代谢异常为主要特征的能量代谢相关疾病，包括脂肪肝、肥胖、动脉粥样硬化和高脂蛋白血症等。在临床上，脂质代谢紊乱疾病的主要特征是血液及其他组织器官中脂质(脂类)及其代谢产物质和量的异常，可表现出甘油三酯和胆固醇的蓄积，肝脏小叶炎症和谷丙转氨酶(alanine transaminase, ALT)含量的增加以及脂肪细胞因子分泌量的改变。脂质代谢紊乱疾病的发病机制复杂，目前治疗比较困难。
槲皮素-O-糖苷类化合物在各种水果、蔬菜和中草药中分布广泛，其在藏红花、茵陈、菊苣、芒果中含量丰富。近年来，国内外大量文献报道发现，菊苣具有明显的降血糖、降血脂作用(新疆中医药,2006,24:80-83)。
发明内容
我们研究发现菊苣中的一类槲皮素-O-糖苷化合物是其发挥降脂作用的主要药效成分，在此基础上，我们运用化学的方法合成一类槲皮素-O-糖苷衍生物，对其进行体内外的药理活性筛选，研究其发挥降脂作用的机制，对于脂质代谢紊乱疾病的治疗具有重要的价值。
本发明用槲皮素为原料合成一类槲皮素-O-糖苷衍生物，其药理和化学研究表明本发明的衍生物及其药物组合物在治疗脂质代谢紊乱疾病中具有潜在的应用价值。
本发明的槲皮素-O-糖苷衍生物(I)结构式如下：
Figure PCTCN2015073814-appb-000001
其中R1代表氢原子、单糖基、葡萄糖醛酸或半乳糖醛酸；
R2代表氢原子、单糖基、葡萄糖醛酸或半乳糖醛酸；
R3代表氢原子、甲基、甲醇基、乙基、乙醇基、乙酸基或苄基；
R4代表氢原子、甲基、甲醇基、乙基、乙醇基、乙酸基或苄基；
且R1、R2、R3、R4不同时代表氢原子。
其中单糖基中的单糖优选葡萄糖、半乳糖、鼠李糖、木糖、***糖或果糖。
最优选的化合物如下：
Figure PCTCN2015073814-appb-000002
本发明化合物的药学上可接受的盐、溶剂合物或多晶型物具有同本发明化合物同样的药理活性。
本发明还公开了一种药物组合物，其中含有本发明的化合物(I)或其药学上可接受的盐、溶剂合物或多晶型物及药学上可接受的载体。所述组合物可以制备成多种药学领域的常规制剂，如片剂、颗粒剂、注射剂、滴丸、胶囊、气雾剂、栓剂、膏药等，经口服或者经静脉、肌肉、皮下或以其他的注射方式注射，经口腔、直肠、***、皮肤吸收或者经鼻腔吸入，以含有活性成分的药物制剂形式，以药学上可接受的制剂形式给予。根据所述疾病，和待治疗的患者以及给药途径，可以以不同的剂量给予组合物。本发明的化合物，也可以用于治疗其他与脂质代谢紊乱有关的疾病。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
本发明的化合物可用下列方法制备：
Figure PCTCN2015073814-appb-000003
下面是本发明部分化合物的药效学试验及结果：
一、槲皮素-O-糖苷衍生物对肝细胞甘油三酯(TG)代谢的调控作用
大鼠肝细胞正常培养24h后(6孔板)，用FFA诱导肝细胞高脂模型的建立，之后给予含有不同种类的槲皮素-O-糖苷衍生物(20μM)的培养基培养24h后，去除培养液，用PBS洗2次，之后每孔加100μL裂解液，刮下细胞，冰上放置20min，12000rpm/min离心10min，取上清，分别按TG、TC试剂盒说明书操作，分别测定TG、TC的含量。
实验结果见表1、表2：
表1 本发明槲皮素-O-糖苷衍生物(20μM)对大鼠原代肝细胞中甘油三酯(TG)含量的影响
Figure PCTCN2015073814-appb-000004
Figure PCTCN2015073814-appb-000005
与模型组比较：*p<0.05,**p<0.01
表2 本发明槲皮素-O-糖苷衍生物(20μM)对大鼠原代肝细胞中胆固醇(TC)含量的影响
Figure PCTCN2015073814-appb-000006
Figure PCTCN2015073814-appb-000007
与空白组比较：###p<0.001；与模型组比较：*p<0.05,**p<0.01，***p<0.001
由表1、表2的结果可知，以上本发明的槲皮素-O-糖苷衍生物均可降低甘油三酯(TG)、胆固醇(TC)在原代大鼠肝细胞中的沉积。其中化合物2(槲皮素-3-O-β-D-葡萄糖苷)、化合物4(槲皮素-3-O-β-D-葡萄糖醛酸苷)的作用较为显著。
二、本发明槲皮素-O-糖苷衍生物(槲皮素、槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷)对高脂饲料喂养导致的大鼠脂质代谢紊乱模型的药效学研究
取健康雄性大鼠30只，重量200±20g/只，分笼饲养，自由饮水，室温20℃-25℃，光照12小时/天。普通饲料喂养一周后，除正常组大鼠6只喂以普通饲料，其余喂以高脂饲料(2％胆固醇、10％猪油和88％基础饲料)。4周后，喂以高脂饲料的大鼠按血清TC水平随机分为4组，每组6只。实验分组如下①正常组：普通饲料+0.5％CMC-Na；②高脂模型组：高脂饲料+0.5％CMC-Na；③辛伐他汀组(10mg/kg)：高脂饲料+辛伐他汀10mg/kg；④苯扎贝特 组(10mg/kg)：高脂饲料+苯扎贝特10mg/kg；⑤槲皮素-3-O-β-D-葡萄糖苷组(25mg/kg)：高脂饲料+槲皮素-3-O-β-D-葡萄糖苷25mg/kg；⑥槲皮素-3-O-β-D-葡萄糖醛酸苷组(25mg/kg)：高脂饲料+槲皮素-3-O-β-D-葡萄糖醛酸苷25mg/kg；⑦槲皮素(25mg/kg)：高脂饲料+槲皮素25mg/kg。在喂以饲料的同时，每天上午分别灌胃给予相应药物，正常组和模型组给予等量的0.5％CMC-Na溶液。每周按体重调整给药剂量，给药4周。
在饲养过程中注意对动物精神状态、饮食、活动、粪便颜色及性状等一般情况的观察，并每周称量动物体重，检查饲喂高脂饲料及药物灌胃对动物身体状况的影响。槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷对大鼠肝组织结构影响的考察：采集样本进行分组及给药，末次给药后，禁食(不禁水)16h，处死大鼠，迅速摘取肝，用生理盐水洗净，放入10％甲醛中固化，进行病理切片HE染色。
病理切片HE染色：
大鼠处死，取出肝，除去杂组织，用预冷生理盐水漂洗除去血液，滤纸吸干，浸入10％甲醛溶液中固定，经过脱水、浸蜡包埋、切片、展片、附贴、烤片后进行染色。通过对HE的吸附、吸收，酸性细胞核被碱性苏木素染成蓝色，碱性胞浆被酸性伊红染成红色，结果使胞核呈蓝色，胞浆呈红色。
油红O染色考察大鼠肝脏脂质沉积状况：
取新鲜大鼠肝脏组织少许，OTC包埋后冰冻切片机切片，切片厚度为8-10μm，贴附到载玻片上；将冰冻切片用油红O染液染色10-15min后，用60％异丙醇快速漂洗后，流水洗5min；苏木素复染30s，酸酒精酸化；流水冲洗5min；用滤纸吸干后，50％甘油封片，镜下拍照观察。
血清中生化指标的测定：
末次给药后，禁食(不禁水)16h，称量体重，处死大鼠，取出肝脏，用生理盐水冲洗血液以滤纸吸干。肝脏称重并计算肝脏指数，肝脏指数＝肝脏重量/体重。经股动脉取血，置于室温2h后，3500r/min离心15min，上层澄清透明液为所取血清，分装于-70℃冰箱保存。按剂盒说明书中所述方法，测定TC、TG、LDL-C和HDL-C含量。采用酶学终点法测定TC和TG含量，化学抑制法测定LDL-C和HDL-C含量。
WesternBlot测定肝脏中PPAR-α、HMGR和ABCA1蛋白：
蛋白样品的制备：取各组动物的肝脏，提取组织内总蛋白。
BCA蛋白定量：取1.2mL蛋白标准配制液加入到一管蛋白标准(30mgBSA)中，充分溶解后配制成25mg/mL的蛋白标准溶液。取适量25mg/mL蛋白标准，用PBS稀释至终浓度 为0.5mg/mL。根据样品数量，按50体积BCA试剂A加1体积BCA试剂B(50:1)配制适量BCA工作液，充分混匀。将标准品按0,1,2,4,8,12,16,20μl加到96孔板的标准品孔中，加PBS补足到20μl。加适当体积样品到96孔板的样品孔中，加标准品稀释液到20μl。各孔加入200μlBCA工作液，37℃放置20-30min。注:也可以室温放置2小时，或60℃放置30分钟。BCA法测定蛋白浓度时，颜色会随着时间的延长不断加深。并且显色反应会因温度升高而加快。如果浓度较低，适合在较高温度孵育，或适当延长孵育时间。测定A562，540-595nm之间的波长也可接受。根据标准曲线计算出样品的蛋白浓度。
蛋白样品与5×标准SDS-PAGE loading buffer混合使SDS-PAGEloading buffer的终浓度为1×，然后放在沸水浴中煮沸5min，蛋白样品放于-20℃保存备用。
Western Blot过程：灌注分离胶：制备10％分离胶，混匀，注入玻璃槽，然后胶上加一层水液封；灌注浓缩胶：待分离胶聚合后，倾出覆盖水层，加入4％浓缩胶，将梳子***浓缩胶中；上样：安装电泳装置，加入电泳缓冲液。上样量为含30μg蛋白的样品体积；电泳：连接好电泳装置后，以浓缩胶80V约30分钟，待溴酚蓝到达分离胶后将电压调整为120V，约60分钟。待溴酚蓝距分离胶底部1cm时停止电泳，根据Marker条带裁剪凝胶；转膜：裁剪大小合适的硝酸纤维素膜(NC膜)，按照滤纸-凝胶-NC膜-滤纸顺序安放，赶走气泡，连接好转膜装置，10V转膜(根据蛋白分子量调整，按每1kD转膜1分钟计算)，转膜结束后，取出NC膜；封闭：2.5％BSA室温封闭1小时；孵育一抗：将一抗用TBST稀释至适宜浓度，在反应板上加1mL一抗稀释液，将NC膜正面朝下反贴在一抗稀释液中，4℃孵育过夜；洗膜：室温摇床TBST洗涤10分钟，共3次；孵育二抗：将二抗用TBST稀释至适宜浓度，在反应板上加1mL二抗稀释液，将NC膜正面朝下反贴在二抗稀释液中，室温孵育1小时；洗膜：室温摇床TBST洗涤10分钟，共3次；显色：新鲜配制ECL发光液。ECL发光液A液+B液等体积混匀(勿在强光下配制)，1分钟后，将膜蛋白面朝下与此混合液充分接触，反应5分钟后将膜转移至另一保鲜膜上，去尽残液；凝胶图像分析：将上述显色后的膜放入凝胶成像仪中，利用全自动凝胶成像分析仪曝光并进行分析。
实验结果
1、槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷对大鼠肝脏组织结构的影响
实验结果如图1所示，与正常组相比，模型组肝索排列紊乱，肝细胞内出现明显的空泡，局部可见炎细胞浸润。辛伐他汀和槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷均可明显改善上述病理状况。
2、槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷对大鼠肝脏脂质沉积的影响
实验结果如图2所示，与正常组相比，模型组胞浆内充满大小不等的红色脂滴，显示高脂饲料喂养可引起肝脏中脂滴的蓄积。辛伐他汀和槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷给药组与模型组相比，胞浆内脂滴含量明显减少，且槲皮素-3-O-β-D-葡萄糖醛酸苷组对大鼠肝脏脂质沉积的改善程度较槲皮素-3-O-β-D-葡萄糖苷组为优。
3、槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷对大鼠体重及血清生化指标的影响
表3显示，模型组体重、肝指数、胆固醇(TC)、甘油三酯(TG)和低密度脂蛋白胆固醇(LDL-C)与正常组相比均有极显著差异(p<0.01)。辛伐他汀与苯扎贝特都能明显降低大鼠血清中TC、TG和LDL-C含量，升高HDL-C含量，与模型组比较具有显著性差异(p<0.05或p<0.01)。槲皮素(25mg/kg)、槲皮素-3-O-β-D-葡萄糖苷(25mg/kg)、槲皮素-3-O-β-D-葡萄糖醛酸苷(25mg/kg)均能在一定程度上的降低大鼠体重、肝指数以及血清中TC、TG和LDL-C含量，升高HDL-C含量，部分与模型组相比具有显著性差异(p<0.05或p<0.01)，但是相同给药浓度条件下，槲皮素的药理作用要低于槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷的药理作用。实验结果提示，辛伐他汀与槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷均可以在一定程度上明显改善高脂饲料喂养导致的肥胖与脂质代谢紊乱。
表3 槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷对大鼠体重及血清生化指标的影响(n＝6)
Figure PCTCN2015073814-appb-000008
与空白组比较，*p<0.05,**p<0.01；与模型组比较，#p<0.05,##p<0.01
4、槲皮素(1)、槲皮素-3-O-β-D-葡萄糖苷(2)、槲皮素-3-O-β-D-葡萄糖醛酸苷(4)对大鼠 肝脏PPAR-α的表达影响
PPAR-α是苯扎贝特降甘油三酯的主要靶点。实验结果如附图3所示，与空白对照组相比高脂模型组PPAR-α表达下调，显示高脂饲料喂养可引起肝脏中甘油三酯代谢途径紊乱并产生脂质的蓄积。苯扎贝特和槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷给药组与模型组相比，PPAR-α表达显著激活；而槲皮素给药组与模型组相比，PPAR-α的表达未见显著激活。提示槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷是通过作用于PPAR-α而发挥降甘油三酯的作用。
5、槲皮素(1)、槲皮素-3-O-β-D-葡萄糖苷(2)、槲皮素-3-O-β-D-葡萄糖醛酸苷(4)对大鼠肝脏HMGR和ABCA1蛋白表达的影响
HMGR是肝脏胆固醇合成的限速酶，ABCA1是介导肝脏胆固醇外排的重要蛋白。由附图4可知，与对照组比较，槲皮素-3-O-β-D-葡萄糖苷(2)、槲皮素-3-O-β-D-葡萄糖醛酸苷(4)可极显著上调大鼠肝脏ABCA1蛋白表达量的上升，进一步极显著下调大鼠肝脏HMGR蛋白表达量的下降(P<0.01)，但是槲皮素(1)不能显著上调大鼠肝脏ABCA1蛋白表达量的上升。实验结果提示，槲皮素-3-O-β-D-葡萄糖苷(2)、槲皮素-3-O-β-D-葡萄糖醛酸苷(4)可直接调控肝细胞的胆固醇的合成与外排；槲皮素(1)并不能够直接调控肝细胞胆固醇的外排。
附图说明
图1是槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷对大鼠肝脏组织结构的影响
图2是槲皮素-3-O-β-D-葡萄糖苷、槲皮素-3-O-β-D-葡萄糖醛酸苷对大鼠肝脏脂质沉积的影响
图3是槲皮素(1)、槲皮素-3-O-β-D-葡萄糖苷(2)、槲皮素-3-O-β-D-葡萄糖醛酸苷(4)对大鼠肝脏PPAR-α的表达影响
图4是槲皮素(1)、槲皮素-3-O-β-D-葡萄糖苷(2)、槲皮素-3-O-β-D-葡萄糖醛酸苷(4)对大鼠肝脏HMGR和ABCA1蛋白表达的影响
具体实施方式
实施例1
槲皮素-3-O-β-D-葡萄糖苷(化合物2)的合成
将槲皮素50g(150mmol),二苯二氯甲烷50mL(256mmol),二乙二醇二甲醚100mL投 入200mL的单口烧瓶中,加热回流10分钟。减压蒸去溶剂得到黄色浆状物,经硅胶柱色谱纯化,得淡黄色固体(35.67g，46.32％),将上步制得的化合物23.3g(50mmol)同碳酸钾13.8g(100mmol)先后溶于四氢呋喃溶液中(100mL)，搅拌下向缓慢向其中加入乙酰溴-α-D-葡萄糖19.85g(50mmol)，控制反应液的温度在0-5℃,在此温度条件下继续搅拌反应8小时。反应液用二氯甲烷40mL稀释,过滤去除剩余的碳酸钾,将滤液水次,有机层用无水硫酸钠干燥,经硅胶柱色谱纯化，得固体11.84g,收率32.17％。将上步制得的化合物11.84g(15mmol)溶于四氢呋喃100mL中,加入10％Pd/C10.65g,常压氢解,室温反应24h后,过滤去除10％Pd/C。减压去除溶剂得到糖浆物,经硅胶柱色谱纯化,得淡黄色糖浆物。向其中加入甲醇钠溶液15mL，室温条件下反应3小时,经聚酰胺柱色谱分离(氯仿：甲醇＝5：1),得淡黄色固体(3.01，45.6％)，mp214～217℃。
1H-NMR(400MHz,DMSO-d6)：δ3.30–3.60(m,6H),5.15(d,J＝7.6Hz,1H),6.10(d,J＝1.6Hz,1H),6.30(d,J＝2.0Hz,1H),6.71(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),7.61(d,J＝2.0Hz,1H).ESI-MS(m/z):Calcd.464.1；found:463.2[M-H]-.
实施例2
3',4'-二羟甲基槲皮素-3-O-β-D-葡萄糖苷(化合物3)的合成
前两步反应同实施例1，将得到的淡黄色糖浆物(6.18g，10mmol)，溴甲醇(1.09g，10mmol)，碳酸钾(1.38g，10mmol)先后溶于50ml四氢呋喃溶液中，加热条加下回流反应7小时，之后经硅胶柱色谱纯化,得淡黄色固体，向其中加入甲醇钠溶液15mL，室温条件下反应3小时,经聚酰胺柱色谱分离(氯仿：甲醇＝7：1),得淡黄色固体(3.23g，67.2％)，mp231～235℃。
1H-NMR(400MHz,DMSO-d6)：δ3.34–3.67(m,6H),4.27-4.31(m,4H),5.25(d,J＝7.6Hz,1H),6.16(d,J＝1.6Hz,1H),6.38(d,J＝2.0Hz,1H),6.54(s,2H),6.56(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,2.0Hz,1H),7.75(d,J＝2.0Hz,1H).MS(m/z):525.3[M+H]+.
实施例3
槲皮素-3-O-β-D-葡萄糖醛酸苷(化合物4)的合成
制备过程同实施例1，将第二步反应所用的乙酰溴-α-D-葡萄糖换为乙酰溴-α-D-葡萄糖醛酸甲酯，反应收率为46.7％，mp245～248℃。
1H-NMR(400MHz,DMSO-d6)：δ3.30–3.60(m,6H),5.15(d,J＝7.6Hz,1H),6.10(d,J＝1.6Hz,1H),6.30(d,J＝2.0Hz,1H),6.71(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),8.27(d,J＝2.4Hz,1H).MS(m/z):479.1[M+H]+.
实施例4
3',4'-二羟甲基槲皮素-3-O-β-D-葡萄糖醛酸苷(化合物5)的合成
制备过程同实施例2，将第二步反应所用的乙酰溴-α-D-葡萄糖换为乙酰溴-α-D-葡萄糖醛酸甲酯，反应收率为50.2％，mp224～227℃。
1H-NMR(400MHz,DMSO-d6)：δ3.34–3.67(m,6H),4.27-4.31(m,4H),5.25(d,J＝7.6Hz,1H),6.16(d,J＝1.6Hz,1H),6.38(d,J＝2.0Hz,1H),6.54(s,2H),6.56(d,J＝8.4Hz,1H),7.46(dd,J＝8.4,2.0Hz,1H),8.35(d,J＝3.2Hz,1H).MS(m/z):540.3[M+H]+.
实施例5
槲皮素-7-O-β-D-葡萄糖苷(化合物6)的合成
制备过程同实施例1，在对槲皮素进行糖基化的过程中，利用化合物3位和7位羟基酸性的差别，通过控制反应温度在10℃-15℃之间，成功得到在7位羟基发生糖苷化反应的产物槲皮素-7-O-β-D-葡萄糖苷(6)，反应收率为34.7％，mp202～206℃。
1H-NMR(400MHz,DMSO-d6)：δ3.27–3.54(m,6H),5.05(d,J＝7.6Hz,1H),6.17(d,J＝1.6Hz,1H),6.19(d,J＝2.0Hz,1H),6.74(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),7.61(d,J＝2.0Hz,1H).MS(m/z):465.2[M+H]+.
实施例6
槲皮素-7-O-β-D-葡萄糖醛酸苷(化合物7)的合成
制备过程同实施例3，在对槲皮素进行糖基化的过程中，利用化合物3位和7位羟基酸性的差别，通过控制反应温度在14℃-20℃之间，成功得到在7位羟基发生糖苷化反应的产物槲皮素-7-O-β-D-葡萄糖醛酸苷(7)，反应收率为46.2％，mp213～215℃。
1H-NMR(400MHz,DMSO-d6)：δ3.19–3.34(m,6H),5.25(d,J＝7.6Hz,1H),5.76(d,J＝1.6Hz,1H),6.01(d,J＝2.0Hz,1H),6.28(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),8.27(d,J＝2.4Hz,1H).MS(m/z):479.1[M+H]+.
实施例7
槲皮素-3-O-β-D-半乳糖苷(化合物8)的合成
制备方法同实施例1，将乙酰溴-α-D-葡萄糖换为乙酰溴-α-D-半乳糖即可得槲皮素-3-O-β-D-半乳糖苷(8)，收率为49.1％，mp234～237℃。
1H-NMR(400MHz,DMSO-d6)：δ3.23–3.43(m,6H),5.35(d,J＝7.6Hz,1H),6.10(d,J＝1.6Hz,1H),6.30(d,J＝2.0Hz,1H),6.87(d,J＝8.4Hz,1H),7.49(dd,J＝8.4,2.0Hz,1H),7.61(d,J＝2.0Hz,1H).MS(m/z):465.2[M+H]+.
实施例8
槲皮素-3-O-β-D-半乳糖醛酸苷(化合物9)的合成
制备方法同实施例3，将乙酰溴-α-D-葡萄糖醛酸甲酯换为乙酰溴-α-D-半乳糖醛酸甲酯，即可得槲皮素-3-O-β-D-半乳糖醛酸苷(9)，收率为41.9％，mp219～223℃。
1H-NMR(400MHz,DMSO-d6)：δ3.21–3.52(m,6H),5.15(d,J＝7.6Hz,1H),6.19(d,J＝1.6Hz,1H),6.30(d,J＝2.0Hz,1H),6.56(d,J＝8.4Hz,1H),7.56(dd,J＝8.4,2.0Hz,1H),8.27(d,J＝2.4Hz,1H).MS(m/z):479.1[M+H]+.

Claims (6)

  1. 通式(I)所示的化合物或其药学上可接受的盐、溶剂合物或多晶型物：
    Figure PCTCN2015073814-appb-100001
    其中R1代表氢原子、单糖基、葡萄糖醛酸或半乳糖醛酸；
    R2代表氢原子、单糖基、葡萄糖醛酸或半乳糖醛酸；
    R3代表氢原子、甲基、甲醇基、乙基、乙醇基、乙酸基或苄基；
    R4代表氢原子、甲基、甲醇基、乙基、乙醇基、乙酸基或苄基；
    且R1、R2、R3、R4不同时代表氢原子。
  2. 权利要求1的化合物或其药学上可接受的盐、溶剂合物或多晶型物，其中单糖是葡萄糖、半乳糖、鼠李糖、木糖、***糖或果糖。
  3. 权利要求1的化合物或其药学上可接受的盐、溶剂合物或多晶型物，是下列结构化合物：
    Figure PCTCN2015073814-appb-100002
  4. 一种药物组合物，其中含有权利要求1的的化合物或其药学上可接受的盐、溶剂合物或多晶型物及药学上可接受的载体。
  5. 权利要求1、2或3的的化合物或其药学上可接受的盐、溶剂合物或多晶型物用于制备治疗或预防脂质代谢紊乱性疾病的药物的用途。
  6. 权利要求5的用途，其中脂质代谢紊乱性疾病是脂血症、非酒精性脂肪肝或动脉粥样硬化。
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