CN109438536A - 一种异槲皮素及其衍生物的应用与制备方法 - Google Patents
一种异槲皮素及其衍生物的应用与制备方法 Download PDFInfo
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- CN109438536A CN109438536A CN201811269583.2A CN201811269583A CN109438536A CN 109438536 A CN109438536 A CN 109438536A CN 201811269583 A CN201811269583 A CN 201811269583A CN 109438536 A CN109438536 A CN 109438536A
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- Prior art keywords
- isoquercitin
- derivative
- rutin
- group
- glycosylation
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- OVSQVDMCBVZWGM-LQSBFMDOSA-N 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2r,3s,4r,5r,6s)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OVSQVDMCBVZWGM-LQSBFMDOSA-N 0.000 title claims abstract description 114
- 238000002360 preparation method Methods 0.000 title claims description 12
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 claims abstract description 31
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 claims abstract description 24
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 claims abstract description 24
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 claims abstract description 24
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- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 claims abstract description 15
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- IKGXIBQEEMLURG-UHFFFAOYSA-N Rutin Chemical compound OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本公开提供了一种异槲皮素及其衍生物,其结构式如式I所示的化合物
Description
技术领域
本发明涉及一种异槲皮素及其衍生物的应用与制备方法。
背景技术
芦丁又称芸香苷,是一类黄酮类化合物,是我国医药工业中中草药原料之一。异槲皮苷(Isoquercitrin,Quercetin-3-glucose)是芦丁的衍生物,其在结构上只比芦丁少一个上的鼠李糖基,也称作槲皮素葡萄糖苷。尽管芦丁在植物资源中的分布广泛(如在槐花中芦丁含量最高可达28%),异槲皮苷在自然界中的分布较少,其含量仅有几万分之一甚至是十万分之几(大连轻工业学院学报,2007,26(2): 112~115)。由于本身结构式的多个活泼酚羟基,采用传统方式化学合成异槲皮苷的成本高,因而以芦丁为原料采用水解法制备在工艺可行性方面具有相对优势。
异槲皮苷在抗氧化、降血压、抗炎、抗癌和抑制血小板聚集等方面具有与芦丁(Rutin)和槲皮素(Quercetin)类似甚至更高效的生物活性和生物利用度,在延缓人体老化和防治疾病方面具有重要作用。相关药理实验结果表明,异槲皮苷具有生津止渴、清热解暑、降压强心及延年益寿的作用,还可有效地用于防治糖尿病、高血压、冠心病、抑郁症及神经衰弱等疾病(CN101152201;CN101103121;Phytomedicine,2009,16:761~767;Phytotherapy Research,2008,22: 1552~1556;European Journal of Pharmacology,2005,522:108~115;中草药,2009,40(4):618~620)。因此,异槲皮苷是目前药学界的热点新药化合物,一直也是国际上各大医药食品公司竞相开发的高级食品添加剂、辅助药物或药物有效成分。
异槲皮素在植物体内广泛的存在,但是含量极低,在芦丁上存在 4个活泼的羟基,羟基是芦丁、异槲皮素和槲皮素的药效基团,用化学法来制备异槲皮素的时候,羟基容易收到酸碱等环境的影响发生结构改变,异槲皮素的产率和质量就会大大降低,而且用化学法来制备异槲皮素不仅成本高,对环境破坏极大。
发明内容
本发明应用糖苷酶催化水解芦丁为异槲皮素和糖苷转移酶催化槲皮素和异槲皮素为多糖基槲皮素,不仅解决了化学法制备异槲皮素和多糖基异槲皮素时纯度低,生产规模小,环境污染严重,成本高的问题,而且能够实现工业化生产。
技术方案如下:
一种异槲皮素及其衍生物,其结构式如式I所示的化合物
其中,n=1~9;R选自Glu、Rha、Gal、Xyl或All。
进一步,n=1~5;R选自Glu、Rha或Gal。
上述化合物的制备方法,包括使用三叶苷、根皮苷、根皮素、柚皮苷、柚皮素、山茶苷A、山茶苷B、橙皮苷、橙皮素、新橙皮苷、新橙皮素、芹菜素、木犀草素、木犀草苷、芦丁、槲皮素、黄芪苷、黄芪素、芸香苷、金丝桃苷或甘草素为原料,通过酶解原料制备,所述酶由糖苷酶和糖基转移酶组成。所述糖基转移酶包括葡萄糖基转移酶、木糖基转移酶、半乳糖基转移酶中的一种或组合;糖基为葡萄糖、 UDP-葡萄糖、木糖、UDP-木糖、半乳糖、UDP-半乳糖或赤藓糖。制备方法的反应条件:反应缓冲液质量分数为0.05~1%的磷酸氢二钠——柠檬酸钠缓冲液或质量分数为0.9%的NaCl缓冲液;缓冲液的 pH2~10,反应缓冲液质量分数为0.1%的磷酸氢二钠——柠檬酸钠缓冲液;缓冲液的pH3.1~6.6,反应温度控制35~75℃,反应时间控制1~24小时。
一种药物组合物,包含上述异槲皮素或其衍生物,以及药学上可接受的盐、载体、赋形剂、稀释剂、媒介物或它们的组合。
上述异槲皮素或其衍生物可应用于食品、保健品、化妆品和药品上。
上述异槲皮素或其衍生物可应用于控制和治疗骨质疏松症、清除自由基、抗炎、抗癌、抑菌、降压、心血管保护、降血脂、降血压方面。
本发明的异槲皮素及其衍生物既解决了芦丁和槲皮素溶解度差的问题,又解决了芦丁在人体内的分解吸收的问题,提高了异槲皮素和多糖基异槲皮素的生物利用度,且在预防和治疗骨质疏松和降血脂方面具有显著的疗效。
附图说明
图1是实施例9所述糖基化异槲皮素溶解度的曲线图;
图2是实施例9所述糖基化异槲皮素清除自由基能力的柱状图。
具体实施方式
实施例1:
以芦丁为原料,反应缓冲液为质量分数为0.5%的磷酸氢二钠——柠檬酸钠缓冲液,缓冲液的pH 6,反应温度45℃,反应时间控制24小时。在反应体系中加入鼠李糖苷酶,酶的质量分数为投入芦丁的25%。在该反应体系中,异槲皮素的摩尔收率98.8%。
实施例2:
以芦丁为原料,反应缓冲液为质量分数为0.5%的磷酸氢二钠——柠檬酸钠缓冲液,缓冲液的pH 6.1,反应温度55℃,反应时间控制12~15小时。在反应体系中加入鼠李糖苷酶和葡萄糖苷酶或者柚苷酶,总酶的质量分数为投入芦丁的20~30%。在该反应体系中,槲皮素的摩尔收率101.6%。
实施例3:
以槲皮素为原料,反应缓冲液为质量分数为1%的磷酸氢二钠——柠檬酸钠缓冲液,缓冲液的pH 3.5,反应温度40~45℃,反应时间控制10~12小时。在反应体系中加入葡萄糖苷酶:葡萄糖基转移酶=10:90,总酶的质量分数为投入芦丁的35~40%。在该反应体系中,异槲皮素的摩尔收率97.2%。
实施例4:
以槲皮素为原料,反应缓冲液为质量分数为0.05%的磷酸氢二钠——柠檬酸钠缓冲液,缓冲液的pH 8,反应温度65~70℃,反应时间控制18~24小时。在反应体系中加入葡萄糖基转移酶,酶的质量分数为投入槲皮素的25~30%。在该反应体系中,多糖基异槲皮素的摩尔收率101.8%。
实施例5:
以异槲皮素为原料,反应缓冲液为质量分数为0.05%的磷酸氢二钠——柠檬酸钠缓冲液,缓冲液的pH10,反应温度85℃,反应时间控制72小时。在反应体系中加入葡萄糖苷酶:葡萄糖基转移酶=10: 90,总酶的质量分数为投入异槲皮素的20%。在该反应体系中,低多糖基异槲皮素(1≦n≦3)的摩尔收率98.1%。
实施例6:
以异槲皮素为原料,反应缓冲液为质量分数为0.05%的磷酸氢二钠——柠檬酸钠缓冲液,缓冲液的pH 10,反应温度55~60℃,反应时间控制8~12小时。在反应体系中加入葡萄糖苷酶:葡萄糖基转移酶=90:10,总酶的质量分数为投入异槲皮素的20~35%。在该反应体系中,高多糖基异槲皮素(4≦n≦9)的摩尔收率96.9%。
实施例7:
以槲皮素为原料,反应缓冲液为质量分数为0.5%的磷酸氢二钠——柠檬酸钠缓冲液,缓冲液的pH 6,反应温度65℃,反应时间控制36小时。在反应体系中加入糖基转移酶,酶的质量分数为投入槲皮素的20%,然后在该反应体系中,再加入葡萄糖苷酶,低多糖基异槲皮素(1≦n≦3)的摩尔收率98.4%。
实施例8:
以异槲皮素为原料,反应缓冲液为质量分数为1%的磷酸氢二钠——柠檬酸钠缓冲液,缓冲液的pH 10,反应温度75~85℃,反应时间控制24~36小时。在反应体系中加入葡萄糖苷酶:葡萄糖基转移酶=90:10,总酶的质量分数为投入异槲皮素的20~35%。在该反应体系中,高多糖基异槲皮素(4≦n≦9)的摩尔收率98.5%。
实施例9:糖基化异槲皮素的溶解度和溶出速率测定
1、溶解度的测定
将高糖基化异槲皮素和低糖基化异槲皮素按质量比1:1混匀得到糖基化异槲皮素。
化合物溶解能力的大小直接影响到药物在溶液体系和细胞体系的应用。因为糖基化异槲皮素在水溶液中稳定,所以我们利用紫外分光光度法对饱和状态的糖基化异槲皮素的水溶液进行溶解度值的测定。本实验中,分别精密量取10mg、50mg、100mg、200mg、1000 mg的根皮素,置于100mL容量瓶中,加DMSO稀释至刻度,摇匀,得到一系列的浓度分别为0.1mg/mL,0.5mg/mL,1mg/mL,2mg/mL, 10mg/mL的根皮素标准溶液,用HPLC分析,对283nm区间的特征峰进行积分,记录峰面积。以根皮素的浓度为纵坐标,峰面积为横坐标作图,并进行线性回归,测定曲线如图1所示。
标准曲线方程1:y=0.00151A+0.00966,R2=0.9999为根皮素拟合曲线。
然后将过量的糖基化异槲皮素和异槲皮素分别加入到2mL水相中,置于25±1℃恒温振荡器上连续振荡72h,取出后转移到离心管中, 8000r/min离心15min,取上清液用0.45μm微孔滤膜过滤,并用甲醇稀释至线性范围之内,采用HPLC法测定糖基化异槲皮素和异槲皮素在水中的溶解度。结果如图2。
标准曲线方程为y=5354.3957A-126.64,R2=0.9950。饱和溶液经100倍稀释后,吸光度积分值为335.18,浓度为1.294g/L,则糖基化异槲皮素的溶解度是36.51g/L。
结果表明:糖基化的三叶苷的溶解度是三叶苷的60倍左右。
2、溶出速率的测定
1)分析方法学的建立
检测波长的确定:分别称糖基化异槲皮素、异槲皮素和辅料适量,用甲醇配制成适宜浓度的溶液,并以甲醇为空白对照,于200~700 nm范围内进行扫描。结果表明在263nm处有糖基化异槲皮素和异槲皮素的最大吸收峰;而辅料在此处的测定均无干扰。因此,选定263nm 作为测定波长。标准曲线:精密称糖基化异槲皮素和异槲皮素适量,用甲醇配制成系列浓度的溶液,于263nm处测定吸收度,以浓度(C) 对吸收度(A)进行线性回归。
2)糖基化异槲皮素的溶出度的测定方法
称取含有糖基化异槲皮素83nmol(69mg)和异槲皮素83 nmol(34mg)的固体颗粒样品进行溶出度试验。每组样品平行测定3 份,按中国药典2015版第二法进行。溶出介质为900mL的蒸馏水,温度为37±0.5℃,转速为100±3rpm。分别在3、6、9、12、15min取样5mL并补入相同体积的溶出介质,样品经0.8μm微孔滤膜过滤。取续滤液稀释后于263nm处测定吸收度,计算糖基化异槲皮素和异槲皮素的溶出度。
3)测定结果
标准曲线方程C=16.6913A+0.3480,R2=0.9961,线性范围: 1.051~53.246μg/mL。本发明采用体外溶出度实验以糖基化异槲皮素和异槲皮素原料药为对照,测定糖基化异槲皮素和异槲皮素在体外的溶出情况,结果表明,糖基化异槲皮素在体外溶出情况良好。结果见表1。
表1溶出速率
本发明的糖基化异槲皮素在3~15min内达到标量的83.08%~ 95.16%,药物的体外释放速度良好,能够被生物体很好的利用,异槲皮素的体外释放速度要远远小于糖基化异槲皮素,因此本发明有很好的应用前景。
实施例10:糖基化异槲皮素的防护、处理、治疗骨折和骨质疏松症药物中的用途
原理:单核的破骨前体细胞在分化细胞因子(如RANKL,M-CSF) 诱导下,能够逐渐融合分化为多核的成熟破骨细胞。破骨前体细胞不具备溶骨的能力,只有分化成熟的破骨细胞才具有溶解固执的能力,因此,破骨细胞的分化水平能够反应其溶骨能力。
方法:将破骨前体细胞系或原代分离培养的小鼠破骨前体细胞接种到12孔培养板中,10000细胞/孔。设置对照组,单加药组1(糖基化异槲皮素)、单加药组2(RANKL)和双加药组(糖基化异槲皮素+RANKL)。待细胞贴壁过夜后,加入不同剂量的本发明化合物和 /或50ng/ml的RANKL,持续培养3~5天。等单加RANKL的细胞融合完全后,用37度预热的蒸馏水洗细胞一次,加入甲醇固定 30s,37℃预热的蒸馏水洗细胞三次,然后进行TRAP染色,在显微镜下计数TRAP阳性的多核细胞数。
结果与评价:结果见表2所示。与对照组相比较,加入本发明化合物后,无论在破骨前体细胞系或原代分离培养的小鼠破骨前体细胞中,由RANKL诱导分化的破骨细胞数量明显减少,这个结果证明:本发明化合物能够有效地抑制RANKL诱导的破骨细胞的分化。
表2糖基化异槲皮素对原代培养的骨髓BMMs细胞向破骨细胞分化的影响
化合物 | 浓度 | 增值率(%) |
空白对照 | -/- | 0.00 |
单加药组 | 0.5μM | 27.65% |
单加药组 | 1.0μM | 20.38% |
双加药组 | 1.0μM | 21.67% |
从表2可以看出,与对照组相比较,加入糖基化异槲皮素后,无论在破骨前体细胞系或原代分离培养的小鼠破骨前体细胞中,由 RANKL诱导分化的破骨细胞数量明显减少,这个结果证明:糖基化异槲皮素能够有效地抑制RANKL诱导的破骨细胞的分化。
实施例11:清除自由基能力
分别取0.1ml不同浓度的糖基化异槲皮素,以甲醇为溶剂的样品溶液于试管中,加入2×10-4mol/L的DPPH·溶液(甲醇配制)3.9mL,混合均匀,暗处反应30min后,在263nm处测定其吸光度(Ai),以溶剂代替样品溶液测定空白吸光度(A0),以甲醇代替DPPH·溶液测定吸光度(Aj)。清除率按下式:
计算:清除率(%)=[1-(Ai-Aj)/A0]×100
由图2可知,在10~60μg/ml的糖基化异槲皮素浓度梯度内, DPPH·的清除率呈现出良好的线性关系,并且在达到60μg/ml时,清除率达到稳定状态,高达90.6%左右,与100μg/ml Vc效果基本相同。
实施例12:糖基化异槲皮素对二甲苯所致小鼠耳肿胀的药理学实验
SPF级NIH小鼠,雄性,60只。随机为模型对照组、阳性对照组(阿司匹林)、受试药物低、中、高剂量组,10只/组。各组小鼠按照20ml/kg体重灌胃给药,1次/天,连续2天。末次给药0.5h后,在小鼠右耳涂布二甲苯0.05ml/只,右耳给予蒸馏水。2h后处死小鼠,剪下左右耳片,用直径9mm的打孔器分别在左、右耳同一部位打下圆耳片,测量两耳片重量差为肿胀度。
表3糖基化异槲皮素对小鼠耳肿胀试验影响
组别 | 剂量(mg/kg) | 数量(只) | 耳肿涨(mg) | 抑制(%) |
模型对照组 | - | 10 | 21.65±2.69 | - |
阿司匹林 | 200 | 10 | 14.25±2.13 | 29.56% |
受试样品低剂量组 | 100 | 10 | 15.63±2.52 | 27.81% |
受试样品中剂量组 | 200 | 10 | 13.71±1.94 | 36.67% |
受试样品高剂量组 | 400 | 10 | 12.31±1.81 | 43.16% |
从表3可以看出,阳性药(阿司匹林),糖基化异槲皮素的低、中、高剂量组,对二甲苯引起的耳肿胀有明显的抑制作用(P<0.01~0.05),其中,以糖基化异槲皮素的中、高剂量组效果最明显。该实验表明糖基化异槲皮素具有明显的抗炎活性。
实施例13:糖基化异槲皮素药物的毒理学实验
在28±1℃的温度,70±5%的湿度条件下,选取7~8周龄,健康的清洁级NIH小鼠20只雌雄各半,体重在20~22g。将饲料和水消毒,试验前和试验的观察期内,均按正常饲料条件饲养。
将糖基化异槲皮素溶解在0.5%Tween80中,浓度为300mg/ml,将该液体经口给药小鼠,给药剂量为0.4ml/20g小鼠体重。给药后观察1、4、8、12h,以后每12h观察一次。观察死亡情况,每天记录小鼠体重变化以及其他的症状。第10天,断颈处死小鼠,取各器官进行病理检查。
在第10天,全部小鼠存活,2.0g/kg剂量的糖基化异槲皮素未见毒性反应。小鼠各器官病理检查正常,没有发现病变,10天内小鼠体重未见减轻。因此,说明本发明的糖基化异槲皮素药物在口服给药动物时未见毒性。
实施例14:低糖基化普鲁宁的生物利用度实验
1、样品制备:分别取糖基化异槲皮素编号为①和异槲皮素编号为②两个样品;
2、试验方法:试验动物采用体重约2kg的健康家兔40只(由中山大学实验动物中心提供),动物随机分为四组,预先禁食12h后,分别灌胃给予上述样品,剂量为300mg/kg(相当于70kg成人日服用剂量4g),给予样品后密集测定血浆中糖基化异槲皮素和异槲皮素的含量,至达峰时间后半小时,检测血药峰浓度(Cmax);
试验样品灌胃结束后,停药一段时间,至动物体内样品完全代谢,然后静脉注射给予等剂量样品溶液,并测定血浆中样品含量 (μg/mL),以此作为参比数据;结果见表4:
表4:糖基化异槲皮素宁生物利用度
实验样品 | ① | ② |
给药量(g) | 0.6 | 0.6 |
样品含量(%) | 2.64 | 2.64 |
样品给药剂量(mg) | 15.68 | 15.68 |
静脉给样血浆样品浓度(μg/mL) | 79.68 | 76.89 |
口服给样血浆中样品峰浓度Cmax(μg/mL) | 70.53 | 12.65 |
吸收率(%) | 95.61% | 10.64% |
试验结果表明:本发明所述糖基化异槲皮素(①号样品)中吸收率高,为异槲皮素(②号样品)的8.6倍,其生物利用度大大提高。
实施例15:糖基化异槲皮素对营养性肥胖C57BL/6J小鼠糖脂代谢的影响
1.1实验材料
1.1.1实验动物及饲养环境
C57BL/6J小鼠,雄性,SPF级,4周龄,由中山大学实验动物中心提供。许可证号:SCXK(粤)2009-0004。饲养条件:温度20-25℃, 湿度55±10%,12h/12h光照黑暗循环,24小时自由饮食饮水。
1.1.2主要药物和试剂
辛伐他汀,杭州默沙东制药有限公司,批号:120689;
糖基化异槲皮素,由佛山市金骏康健康科技有限公司提供;
异槲皮素,由佛山市金骏康健康科技有限公司提供;
标准饲料和高脂饲料,由广东省动物中心提供;
甘油三酯(TG)试剂盒,中生北控生物科技股份有限公司提供,批号:143412;
总胆固醇(TC)试剂盒,中生北控生物科技股份有限公司提供,批号:143628;
直接高密度脂蛋白胆固醇(HDL-C)测定试剂盒,中生北控生物科技股份有限公司,批号140430;
直接低密度脂蛋白胆固醇(LDL-C)测定试剂盒,中生北控生物科技股份有限公司,批号140711;
游离脂肪酸微量测定试剂盒,普利莱基因技术有限公司,批号: El000;
罗康全优越型血糖试纸,瑞士罗氏制药公司提供。
1.2实验方法
1.2.l动物模型的制备、分组与给药
C57BL/6J雄性小鼠,随机选取10只为正常对照组,喂以普通标准饲料(饲料配方:粗蛋白18.5%,粗脂肪4.5%,碳水化合物61%。能量比:粗蛋白21%,粗脂肪11%,碳水化合物68%,总能最3.5 Kcal/g),其余小鼠给予高糖高脂饲料(饲料配方:粗蛋白27%,粗脂肪24%,碳水化合物37%;能量比:蛋白23%,脂肪46%,碳水化合物31%,总能量4.7Kcal/g)。喂养12周后,参考体重大于正常组的平均体重±1.78倍标准差和大于正常体重的20%的标准,选取合格的肥胖小鼠,按照体质量均一的原则分为模型组,阳性药辛伐他汀组,糖基化异槲皮素剂量组,异槲皮素剂量组,每组10只,组间及组内动物分别作标记。正常对照组给予普通饲料,其余各组仍继续给予高糖高脂饲料喂养。糖基化异槲皮素的给药剂量:糖基化异槲皮素剂量组150mg/kg体重,异槲皮素剂量组100mg/kg,用蒸馏水配制成所需浓度,现用现配,每天给药1次,连续给药14周。
辛伐他汀药物剂量3mg/kg体重,用研钵研细,蒸馏水配制成所需浓度,现用现配,每天给药1次,连续给药14周。
模型对照组与正常对照组每天灌服等体积的生理盐水,每天给药 1次,连续给药14周。
1.2.2血糖血脂的测定
给药14周后,动物禁食12h,尾静脉取血一滴,用血糖仪测定空腹血糖;然后眼眶静脉丛取血,室温静置30min以上,以3000rpm 离心15min,分离血清,采用试剂盒测定血清总胆固醇、甘油三酯、高、低密度脂蛋白、游离脂肪酸水平。
1.3实验结果
1.3.1各组小鼠给药期间体重变化
表5给药期间各组小鼠体重变化
表5结果表明:与正常组比较,模型组小鼠体重显著增加 (P<0.01)。从给药第9周开始,辛伐他汀、糖基化异槲皮素和异槲皮素剂量组小鼠体重均开始下降,给药结束后辛伐他汀、糖基化异槲皮素和异槲皮素剂量组小鼠体重,与模型组比较均有显著性降低 (P<0.01)。其中糖基化异槲皮素剂量组对小鼠体重下降最多,有降血脂的作用。
Claims (7)
1.一种异槲皮素及其衍生物,其特征在于:其结构式如式I所示的化合物
其中,n=1~9;R选自Glu、Rha、Gal、Xyl或All。
2.根据权利要求1所述的异槲皮素及其衍生物,其特征在于:n=1~5;R选自Glu、Rha或Gal。
3.一种异槲皮素或其衍生物的制备方法,其特征在于,使用三叶苷、根皮苷、根皮素、柚皮苷、柚皮素、山茶苷A、山茶苷B、橙皮苷、橙皮素、新橙皮苷、新橙皮素、芹菜素、木犀草素、木犀草苷、芦丁、槲皮素、黄芪苷、黄芪素、芸香苷、金丝桃苷或甘草素为原料制备如权利要求1或2所述的异槲皮素或其衍生物。
4.根据权利要求3所述的制备方法,其特征在于,通过酶解原料制备,所述酶由糖苷酶和糖基转移酶组成。
5.一种药物组合物,包含权利要求1~2任意一项所述的化合物及药学上可接受的盐、载体、赋形剂、稀释剂、媒介物或它们的组合。
6.权利要求1或2所述的异槲皮素及其衍生物,在食品、保健品、化妆品和药品上的应用。
7.权利要求1或2所述的异槲皮素及其衍生物,在控制和治疗骨质疏松症、清除自由基、抗炎、抗癌、抑菌、降压、心血管保护、降血脂、降血压方面的应用。
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