CN115154476A - 青钱柳的提取物及其抗痛风和降尿酸应用 - Google Patents
青钱柳的提取物及其抗痛风和降尿酸应用 Download PDFInfo
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- CN115154476A CN115154476A CN202210609872.2A CN202210609872A CN115154476A CN 115154476 A CN115154476 A CN 115154476A CN 202210609872 A CN202210609872 A CN 202210609872A CN 115154476 A CN115154476 A CN 115154476A
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- rhamnose
- glucose
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- cyclocarya paliurus
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Abstract
本发明涉及一种从青钱柳提取的异戊烯基黄酮类化合物,并具体公开其提取方法及应用,所述青钱柳异戊烯基黄酮类化合物,其结构如式Ⅰ所示:
Description
技术领域
本发明涉及青钱柳的提取物,尤其涉及青钱柳的正丁醇活性部位和异戊烯基黄酮类化合物,及其提取方法以及应用。
背景技术
青钱柳[Cyclocaryapaliurus(Bata1)Iljinsk]系胡桃科(Juglaruiaceae)青钱柳属植物,是中国特有的单种属植物,广泛分布于安徽、江苏、浙江等地。20世纪80年代以来,国内外专家学者主要针对青钱柳的资源培育、化学成分、生物活性和产品开发研究等方面进行了大量研究。结果表明,青钱柳具有多种对人体有益的生理活性和药理功能。
异戊烯基黄酮是在黄酮母核上连有异戊烯基的一类化合物,相比于黄酮类化合物,显示了更加突出的生物活性,主要包括抗炎和免疫调节、心血管保护、改善代谢性疾病、改善骨质疏松、促进干细胞分化、神经保护、抗肿瘤、抗衰老及生殖作用等方面,具有广阔的应用前景。异戊烯基黄酮类代表性成分淫羊藿苷主要可通过钠通道阻滞阻断β受体和中枢降压作用的机制发挥降压作用。淫羊藿抑制血管平滑肌Ca 2+内流,直接扩张血管平滑肌而降低血管阻力。也发现淫羊藿苷可显著改善痛风性关节炎损关节的肿胀度、降低步态评分、改善滑膜组织损伤,在80mg/kg-1剂量时与秋水仙碱作用相当,并发现在淫羊藿苷治疗组关节积液中的白血病数,IL-1β,IL-6,TNF-α和PGE2均显著降低,提示淫羊藿苷改善痛风与其抗炎作用有关。淫羊藿总黄酮还可以通过选择性地阻断β1受体和降低血浆内皮素含量,直接扩张血管来降低血压。
青钱柳叶含有多种药用化学成分,包括胡萝卜素、蛋白质、黄酮类、多糖类、三萜类等化合物,其中异戊烯基黄酮因其结构和药理活性的多样性而受到广泛关注。目前关于青钱柳异戊烯基黄酮药理活性多集中于降糖和炎症的研究,关于其他方面的活性以及机制研究较少,因此具体阐明青钱柳异戊烯基黄酮其他应用活性及作用机制对广泛的临床应用和创新药物研发具有重大意义。
发明内容
针对现有技术的不足,本发明目的是提供青钱柳正丁醇活性部位和异戊烯基黄酮类化合物的提取方法及改善痛风活性成分和药效物质基础进行系统研究。
为了解决上述技术问题,本发明的技术方案如下:
一种异戊烯基黄酮类化合物化合物,结构通式如下:
其中,R7选自L-鼠李糖-(2→1)-L-鼠李糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R8选自氢、D-葡萄糖、L-鼠李糖-(2→1)-D-葡萄糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R9选自羟基,甲氧基、乙氧基、丙氧基;
优选的,所述异戊烯基黄酮类化合物化合物,其结构式如下:
本发明还提供一种从青钱柳提取上述异戊烯基黄酮类化合物的方法,包括以下步骤:
S1、将青钱柳叶用乙醇/水加热回流提取,浓缩得浸膏;
S2、将浸膏用水分散,用正丁醇萃取,并将萃取液浓缩,得正丁醇萃取浓缩液;
S3、采用HPLC-DAD、TLC和UPLC-MS/MS方法对正丁醇萃取浓缩液进行分析及分离纯化。
优选的,S1中,青钱柳叶经过干燥粉碎处理。
优选的,S1中,乙醇的浓度为70%,青钱柳叶质量与乙醇的比值为1:10,加热的温度为120℃,加热的时间为2h,浓缩的温度为60℃,浓缩的时间为2-3天。
优选的,S2中,利用正丁醇萃取三次,青钱柳叶质量与每次使用的正丁醇体积的比值为1:10,浓缩的温度为65℃,浓缩的时间为72-96小时。
优选的,S3中,正丁醇萃取部位经大孔树脂EtOH:H2O(0:100-0:95)梯度洗脱,HPLC-DAD对样品进行分析,浓缩合并得到5个部位(a-e);
a-e部位TLC薄层分析,10%浓硫酸/乙醇加热显色,其中Fr.C薄层板显示黄色条带。
首先对Fr.C采用聚酰胺柱色谱,去除色素,鞣质等干扰性成分,HPLC-DAD分析合并,得到6个部位Fr.C1-C6,Fr.C1主要为黄酮类吸收,初步确定Fr.C1部位为黄酮类富集部位;接着采用HW-40C和反向ODS柱层析,整个分离过程用UPLC-MS/MS方法对异戊烯基黄酮进行追踪,通过紫外特征吸收峰对异戊烯基黄酮类化合物有效分离;最后采用半制备高效液相对目标化合物进行纯化。
本发明还要求保护一种活性部位,所述活性部位为如上述的正丁醇萃取浓缩液,所述活性部位的主要成分是上述的异戊烯基黄酮。
本发明还要求保护如上述的活性部位在制备改善痛风和降尿酸的药物中的应用。
进一步的,所述异戊烯基黄酮分离纯化具体过程为:
本发明采用HPLC-DAD、TLC和UPLC-MS/MS方法对正丁醇萃取浓缩液进行追踪、分析及分离纯化。正丁醇部位445g经大孔树脂层析柱,采用乙醇-水系统(0:100,30:70,50:50,70:30,95:5)等度洗脱,综合HPLC-DAD分析结果,将青钱柳正丁醇部位初步划分位五个部位(Fr.a-e)。Fr.b(106g)经聚酰胺层析柱,采用乙醇-水系统(0:100-95:5)洗脱,根据HPLC-DAD分析结果分为六个部分(Fr.b1-b6)。
Fr.c(107g)经聚酰胺层析柱,采用乙醇-水系统(0:100-95:5)洗脱,根据HPLC-DAD分析结果分为六个部分(Fr.c1-c6),Fr.c1(22.9g)经HW-40C柱层析采用甲醇-水系统(0:100-75:5)洗脱,经HPLC-DAD分析,合并相同馏分后得到Fr.c1.1-Fr.c1.12。Fr.c1.2经ODS-AA中压柱,采用甲醇-水系统(5:95-75:5)洗脱,经HPLC-DAD分析,得到Fr.c1.2.1-Fr.c1.2.45。Fr.c1.2.23-Fr.c1.2.25经半制备液相(ACN-H2O 21%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物28(8.6mg),29(5.9mg)and 30(7.4mg)。Fr.c1.2.29-Fr.c1.2.30经半制备液相(ACN-H2O 24%,v/v,220nm,3mL/min)得到化合物27(13.6mg),35(11.7mg)and 40(15.7mg).Fr.c1.2.35-Fr.c1.2.36经半制备液相(ACN-H2O 31%,v/v,220nm,3mL/min)分离得到32(13.6mg)and 33(6.4mg)。Fr.c1.3经ODS-AA中压柱,采用甲醇-水系统(5:95-75:5)洗脱,经HPLC-DAD分析,得到Fr.c1.3.1-Fr.c1.3.28。Fr.c1.3.13经半制备液相(ACN-H2O 18%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物36(10.8mg),37(4.9mg)。Fr.c1.3.15经半制备液相(ACN-H2O 22%,v/v,220nm,3mL/min)得到化合物38(7.4mg),39(11.3mg)。Fr.c1.8经半制备液相(ACN-H2O 29%,v/v,220nm,3mL/min)得到化合物43(750.6mg),44(107.5mg),45(59.3mg)。
Fr.c2(20.5g)经HW-40C柱层析采用甲醇-水系统(0:100-75:5)洗脱,经HPLC-DAD分析,合并相同馏分后得到Fr.c2.1-Fr.c2.10。Fr.c2.4经ODS-AA中压柱,采用甲醇-水系统(5:95-75:5)洗脱,经HPLC-DAD分析,得到Fr.c2.4.1-Fr.c2.4.40。Fr.c2.4.18经半制备液相(ACN-H2O 20%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物53(33.7mg);Fr.c2.4.24-Fr.c2.4.25经半制备液相(ACN-H2O 22%,v/v,220nm,3mL/min)得到化合物34和化合物51的混合物,混合物经薄层制备层析(展开剂:水饱和正丁醇)分离得到化合物34(7.6mg),化合物51(28.5mg);Fr.c2.4.26经半制备液相(ACN-H2O 25%,v/v,220nm,3mL/min)得到化合物50(26.4mg),化合物51(76.2mg);Fr.c2.4.28经半制备液相(ACN-H2O25%,v/v,220nm,3mL/min)得到化合物49(13.1mg)。Fr.c2.6经ODS-AA中压柱,采用甲醇-水系统(15:85-75:5)洗脱,经HPLC-DAD分析,合并相同馏分后得到Fr.c2.6.1-Fr.c2.6.35。Fr.c2.6.16经半制备液相(ACN-H2O 28%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物31(10.6mg);Fr.c2.6.20经半制备液相(ACN-H2O 27%,v/v,220nm,3mL/min)得到化合物46(33.7mg),47(21.9mg),48(9.4mg);Fr.c2.6.22经半制备液相(ACN-H2O 32%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物41(104.2mg);Fr.c2.6.25经半制备液相(ACN-H2O 39%,v/v,220nm,3mL/min)得到化合物52(7.5mg);Fr.c2.6.28经半制备液相(ACN-H2O44%,v/v,220nm,3mL/min)得到化合物42(7.5mg)。
所述化合物27-53的结构式为:
本发明还提供上述异戊烯基黄酮类化合物27-53在制备改善痛风和降尿酸的药物中的应用。
与现有技术相比,本发明的有益效果如下:
1、本发明提供了一种全新的从青钱柳中提取异戊烯基黄酮类化合物27-53的方法,该方法简单可重复。
2、本发明为青钱柳正丁醇活性部位和异戊烯基黄酮类化合物27-53提供了新的应用,并研究了其药物机理,为青钱柳正丁醇活性部位和异戊烯基黄酮类化合物27-53提供了新的降尿酸和抗痛风的应用前景。
附图说明
图1为化合物27的HSQC谱
图2为化合物27的HMBC谱
图3为化合物28的1H-1H COSY谱
图4为化合物28的HSQC谱
图5为化合物28的HMBC谱
图6为化合物28的1H-1H COSY谱
图7为化合物29的HSQC谱
图8为化合物29的HMBC谱
图9为化合物29的1H-1H COSY谱
图10为化合物30的HSQC谱
图11为化合物30的HMBC谱
图12为化合物30的1H-1H COSY谱
图13为化合物31的HSQC谱
图14为化合物31的HMBC谱
图15为化合物31的1H-1H COSY谱
图16为化合物32的HSQC谱
图17为化合物32的HMBC谱
图18为化合物32的1H-1H COSY谱
图19为化合物33的HSQC谱
图20为化合物33的HMBC谱
图21为化合物33的1H-1H COSY谱
图22为化合物34的HSQC谱
图23为化合物34的HMBC谱
图24为化合物34的1H-1H COSY谱
图25为化合物35的HSQC谱
图26为化合物35的HMBC谱
图27为化合物35的1H-1H COSY谱
图28为化合物36的HSQC谱
图29为化合物36的HMBC谱
图30为化合物36的1H-1H COSY谱
图31为化合物37的HSQC谱
图32为化合物37的HMBC谱
图33为化合物37的1H-1H COSY谱
图34为化合物38的HSQC谱
图35为化合物38的HMBC谱
图36为化合物38的1H-1H COSY谱
图37为化合物39的HSQC谱
图38为化合物39的HMBC谱
图39为化合物39的1H-1H COSY谱
图40为QQL-HT对大鼠痛风性关节炎模型的关节滑膜的影响。
具体实施方式
以下将结合实施例来详细说明本发明。需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
实施例1
1.1青钱柳药材处理:青钱柳干燥叶(10Kg),粉碎后用70%乙醇120℃加热回流提取(100L;2×2h),60℃浓缩得浸膏,浓缩时间为2天。浸膏进一步用水分散,依次用二氯甲烷、乙酸乙酯、正丁醇萃取,每次10L,萃取3次,萃取液60℃浓缩,浓缩时间为24小时,分别得不同极性部位的萃取浓缩液。
正丁醇部位中主要为黄酮类化合物,标注为QQL-HT。
1.2生物活性导向筛选青钱柳活性部位:采用尿酸钠诱导大鼠建立急性痛风模型对青钱柳正丁醇活性部位改善痛风作用的活性部位进行追踪和筛选:
1.3活性部位成分研究
1.3.1异戊烯基黄酮提取分离与纯化:本发明采用HPLC-DAD、TLC和UPLC-MS/MS方法对正丁醇萃取浓缩液进行追踪、分析及分离纯化。正丁醇部位445g经大孔树脂层析柱,采用乙醇-水系统(0:100,30:70,50:50,70:30,95:5)等度洗脱,综合HPLC-DAD分析结果,将青钱柳正丁醇部位初步划分位五个部位(Fr.a-e)。Fr.b(106g)经聚酰胺层析柱,采用乙醇-水系统(0:100-95:5)洗脱,根据HPLC-DAD分析结果分为六个部分(Fr.b1-b6)。
Fr.c(107g)经聚酰胺层析柱,采用乙醇-水系统(0:100-95:5)洗脱,根据HPLC-DAD分析结果分为六个部分(Fr.c1-c6),Fr.c1(22.9g)经HW-40C柱层析采用甲醇-水系统(0:100-75:5)洗脱,经HPLC-DAD分析,合并相同馏分后得到Fr.c1.1-Fr.c1.12。Fr.c1.2经ODS-AA中压柱,采用甲醇-水系统(5:95-75:5)洗脱,经HPLC-DAD分析,得到Fr.c1.2.1-Fr.c1.2.45。Fr.c1.2.23-Fr.c1.2.25经半制备液相(ACN-H2O 21%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物28(8.6mg),29(5.9mg)and 30(7.4mg)。Fr.c1.2.29-Fr.c1.2.30经半制备液相(ACN-H2O 24%,v/v,220nm,3mL/min)得到化合物27(13.6mg),35(11.7mg)and 40(15.7mg).Fr.c1.2.35-Fr.c1.2.36经半制备液相(ACN-H2O 31%,v/v,220nm,3mL/min)分离得到32(13.6mg)and 33(6.4mg)。Fr.c1.3经ODS-AA中压柱,采用甲醇-水系统(5:95-75:5)洗脱,经HPLC-DAD分析,得到Fr.c1.3.1-Fr.c1.3.28。Fr.c1.3.13经半制备液相(ACN-H2O 18%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物36(10.8mg),37(4.9mg)。Fr.c1.3.15经半制备液相(ACN-H2O 22%,v/v,220nm,3mL/min)得到化合物38(7.4mg),39(11.3mg)。Fr.c1.8经半制备液相(ACN-H2O 29%,v/v,220nm,3mL/min)得到化合物43(750.6mg),44(107.5mg),45(59.3mg)。
Fr.c2(20.5g)经HW-40C柱层析采用甲醇-水系统(0:100-75:5)洗脱,经HPLC-DAD分析,合并相同馏分后得到Fr.c2.1-Fr.c2.10。Fr.c2.4经ODS-AA中压柱,采用甲醇-水系统(5:95-75:5)洗脱,经HPLC-DAD分析,得到Fr.c2.4.1-Fr.c2.4.40。Fr.c2.4.18经半制备液相(ACN-H2O 20%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物53(33.7mg);Fr.c2.4.24-Fr.c2.4.25经半制备液相(ACN-H2O 22%,v/v,220nm,3mL/min)得到化合物34和化合物51的混合物,混合物经薄层制备层析(展开剂:水饱和正丁醇)分离得到化合物34(7.6mg),化合物51(28.5mg);Fr.c2.4.26经半制备液相(ACN-H2O 25%,v/v,220nm,3mL/min)得到化合物50(26.4mg),化合物51(76.2mg);Fr.c2.4.28经半制备液相(ACN-H2O25%,v/v,220nm,3mL/min)得到化合物49(13.1mg)。Fr.c2.6经ODS-AA中压柱,采用甲醇-水系统(15:85-75:5)洗脱,经HPLC-DAD分析,合并相同馏分后得到Fr.c2.6.1-Fr.c2.6.35。Fr.c2.6.16经半制备液相(ACN-H2O 28%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物31(10.6mg);Fr.c2.6.20经半制备液相(ACN-H2O 27%,v/v,220nm,3mL/min)得到化合物46(33.7mg),47(21.9mg),48(9.4mg);Fr.c2.6.22经半制备液相(ACN-H2O 32%,0.1%CH3COOH,v/v,220nm,3mL/min)得到化合物41(104.2mg);Fr.c2.6.25经半制备液相(ACN-H2O 39%,v/v,220nm,3mL/min)得到化合物52(7.5mg);Fr.c2.6.28经半制备液相(ACN-H2O44%,v/v,220nm,3mL/min)得到化合物42(7.5mg)。
1.3.2结构确证:运用UV、IR、NMR、MS、CD、ORD、ECD及单晶X-rays等现代光谱技术确证各化合物的平面结构和立体构型,进行谱学表征和光谱数据的系统归属。
首先通过紫外吸收确认化合物的吸收类型以及其是否存在共轭片段。接着采用1D/2D NMR对化合物的平面结构进行确定,并通过质谱对其分子量进行确认。对于化合物的绝对构型采用NOESY,ROESY以及CD、ECD等确认。
1.4化学结构
分离到异戊烯基黄酮27个(27-53),具体见表1。
表1.化合物27-53分子信息
结构表征数据为:
化合物27:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:204(3.88),270(1.42),320(0.77),and 349(0.71)nm。HRESIMS,m/z:841.3125[M+H]+(calculated for 841.3130)。
化合物28:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:204(3.87),270(1.39),320(0.76)and 349(0.70)nm。HRESIMS,m/z 827.2974[M+H]+(calculated for 827.2974)。
化合物29:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:204(4.00),271(1.66),316(0.91),and 350(0.83)nm。HRESIMS,m/z 857.3074[M+H]+(calculated for 857.3079)。
化合物30:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:204(4.15),271(2.44),316(1.37),and 350(1.12)nm。HRESIMS,m/z 857.3074[M+H]+(calculated for 857.3079)。
化合物31:黄色无定型粉末,,UV(MeOH)λmax(logε)nm:204(3.95),270(1.52),320(0.83),and 349(0.76)nm。HRESIMS,m/z:807.2701[M+H]+(calculated for 807.2712)。
化合物32:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:204(4.10),271(2.30),316(1.29),and 350(1.05)nm。HRESIMS,m/z:823.3011[M+H]+(calculated for 823.3025)。
化合物33:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:204(3.95),270(1.52),321(0.65),and 349(0.76)nm。HRESIMS,m/z:955.3442[M+H]+(calculated for 955.3447)。
化合物34:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:203(3.86),270(1.20),321(0.65),and 349(0.60)nm。HRESIMS,m/z:825.2827[M+H]+(calculated for 825.2817)。
化合物35:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:204(4.10),271(2.30),316(1.29),and 350(1.05)nm。HRESIMS,m/z:711.2500[M+H]+(calculated for 711.2500)。
化合物36:黄色无定型粉末;,UV(MeOH)λmax(logε)nm:200(3.70),271(1.05),316(0.59),and 350(0.48)nm。HRESIMS,m/z:711.2505[M+H]+(calculated for 711.2500)。
化合物37:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:199(3.75),271(1.13),316(0.63),and 350(0.52)nm。HRESIMS,m/z 857.3083[M+H]+(calcd for C39H53O21,857.3079)。
化合物38:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:199(3.75),271(1.13),316(0.63),and 350(0.52)nm。HRESIMS,m/z:825.2822[M+H]+(calcd for C38H49O20,825.2817)。
化合物39:黄色无定型粉末;;UV(MeOH)λmax(logε)nm:199(3.75),271(1.13),316(0.63),and 350(0.52)nm。HRESIMS,m/z:839.2982[M+H]+(calcd for 839.2974)。
表2化合物27-30的1H NMR和13C NMR信号归属
aMeasured in DMSO-d6 at 400MHz;bMeasured in DMSO-d6 at 500MHz;Overlapped signals indicated by(o)表3化合物31-34的1H NMR和13C NMR信号归属
aMeasured in DMSO-d6 at 400MHz;bMeasured in DMSO-d6 at 500MHz;Overlapped signals indicated by(o)
表4化合物35-37的1H NMR和13C NMR信号归属
aMeasured in DMSO-d6 at 400MHz;Overlapped signals indicated by(o).
表5化合物38-39的1H NMR和13C NMR信号归属
aMeasured in DMSO-d6 at 400MHz;bMeasured in DMSO-d6 at 500MHz;Overlapped signals indicated by(o)
具体表征图标如图1-39所示。
实施例2
2.1青钱柳正丁醇活性部位和异戊烯基黄酮类化合物抗痛风性关节炎作用
2.1.1实验方法:
QQL-HT抗痛风性关节炎作用研究:选取检疫合格实SD大鼠40只,雄性,按体重随机分为4组,分别为正常对照组、模型对照组、青钱柳正丁醇活性部位组、痛风定胶囊组,每组10只动物。各组灌胃给予相应药液,正常对照组和模型对照组灌胃给予等体积纯水。每天1次,连续给药8天。除正常对照组外,其余各组给药后30min造模,将SD大鼠用异氟烷(诱导1%~4%,维持0.25%~2%)吸入麻醉后,将双侧后腿膝关节周围剃毛,医用酒精消毒皮肤,轻弯曲膝关节,经关节侧面进针,用注射器6号针头将尿酸钠溶液(25mg/mL)0.5mL通过骸上韧带注入大鼠膝关节腔,复制急性痛风性关节炎模型。
候选化合物抗炎作用研究:取大鼠巨噬细胞样细胞系(RAW.264.7)细胞,以1×106/mL浓度接种在96孔板板中,在37℃下培养12h。然后将供试样品(1、3、10、30μM)加入到细胞培养液中培养1h后加入LPS(1μg/mL),共同在37℃下培养24h.将细胞培养液上清液50μL置于新的96孔板中,在每孔中先后分别各加入50μLGriessⅠ液和GriessⅡ液。室温下放置10min后,用酶标仪在540nm测定反应产物的吸光度(A)值。同时用MTT法测定各组药物细胞毒作用。
2.1.2实验结果:
(1)对膝关节肿胀度的影响
分别于造模前及造模后1h、2h、4h、6h、12h采用线敷法测量各组大鼠右侧膝关节周长,,并计算肿胀指数,肿胀指数=(造模后膝关节周长-造模前膝关节周长)/造模前膝关节周长*100%。
如表6所示,与正常对照组比较,模型对照组大鼠关节肿胀百分率显著增大(P<0.01),提示痛风性关节炎模型复制成功;与模型对照组比较,QQL-HT组大鼠造模后1、2、4、6、12h的关节肿胀率显著减小(P<0.05或P<0.01),提示QQL-HT能显著抑制尿酸钠所致大鼠痛风性关节炎模型的肿胀;QQL-HT对痛风性关节炎肿胀的抑制药效作用更持久,且较痛风定胶囊的药效作用更佳。
注:与正常对照组比较+P<0.01;与模型对照组比较*P<0.05,**P<0.01
(2)对关节炎症因子的影响
如表7所示,与正常对照组比较,模型对照组大鼠关节腔冲洗液中炎症因子IL-1β和TNF-α的含量均显著升高(P<0.01);与模型对照组比较,QQL-HT组大鼠关节腔冲洗液中IL-1β和TNF-α均显著降低(P<0.01),提示QQL-HT能显著抑制尿酸钠所致大鼠痛风性关节炎模型的炎症因子分泌,同时QQL-HT对IL-1β和TNF-α分泌的抑制作用明显强于痛风定胶囊。
注:与正常对照组比较+P<0.01;与模型对照组比较*P<0.05
(3)对膝关节滑膜组织病理学检查
造模后24h后,将各组大鼠异氟烷(诱导1%~4%,维持0.25%~2%)吸入麻醉后腹主动脉放血安乐死,取关节滑膜组织置于10%中性福尔马林溶液固定,石蜡包埋,HE染色,进行关节滑膜组织病理学检查,并将膝关节病变按病变程度分为4级别,其中1级为未见异常,2-4级分别按滑膜组织增生,间质水肿、出血,炎症细胞及成纤维细胞浸润的程度分为轻、中、重度病变。
如表8和图40所示,与正常对照组比较,模型对照组大鼠关节病变等级显著增大(P<0.01),病变类型主要为2~3级的滑膜组织增生,并伴有间质水肿、血管充血、炎症细胞及成纤维细胞浸润,提示痛风性关节炎模型复制成功;与模型对照组比较,QQL-HT组大鼠关节病变程度显著减小,各程度病变动物数显著减少(P<0.01),提示QQL-HT能显著改善尿酸钠所致大鼠痛风性关节炎模型的关节病理变化,QQL-HT强于痛风定胶囊。
注:与正常对照组比较+P<0.01;与模型对照组比较*P<0.05。
(4)异戊烯基黄酮类化合物抗炎活性评价
NO与痛风性关节炎密切相关,体内NO水平升高可从多个途径影响病理进程,如启动核因子NF-κB,诱导促炎症细胞因子TNF-α、IL-1等的产生,最终刺激滑膜细胞增生,造成软骨不可逆破坏。以LPS诱导的小鼠单核巨噬细胞(RAW.264.7)为模型,吲哚美辛(Indo)为阳性对照可以进行抗炎活性初筛。本实验采用采用Griess试剂对RAW264.7细胞培养上清中的NO进行检测;用MTT法检测细胞活力,考察化合物对LPS诱导的RAW.264.7细胞模型产生NO的影响,以上清液中NO含量为检测指标。结果见表9。
与模型组对比,#p<0.05,##p<0.01
2.2青钱柳正丁醇活性部位和异戊烯基黄酮类化合物降尿酸作用
2.2.1实验方法:
选取检疫合格的雄性ICR小鼠40只,按体重随机分为4组,分别为正常对照组、模型对照组、痛风定胶囊组和QQL-HT组,每组10只动物。各组动物按20mL/kg经口灌胃给予相应浓度药液,正常对照组和模型对照组灌胃给予等体积纯水,每天1次,连续7天。于给药第7天给药前1h按20mL/kg单次腹腔注射OAPS 300mg/kg复制高尿酸症模型,正常对照组和空白给药组给与等体积的0.9%氯化钠注射液。于造模后1h给药,给药后1h采血测血尿酸(采血前一天禁食不禁水)。
2.2.2实验结果
如表10所示,与正常对照组比较,模型对照组小鼠血清UA显著升高(P<0.01),提示高尿酸血症模型复制成功;与模型对照组比较,QQL-HT组小鼠造模后UA均显著降低(P<0.01),提示QQL-HT能显著降低氧氰酸钾所致高尿酸血症模型的尿酸水平,QQL-HT的药效作用明显强于痛风定胶囊。
注:与正常对照组比较+P<0.01;与模型对照组比较*P<0.05
2.3QQL-HT及单体化合物抑制黄嘌呤氧化酶活性
2.3.1实验方法:
黄嘌呤氧化酶(Xanthine oxidase,XOD)作为体内嘌呤分解代谢中关键性的酶,起着维持体内血液中尿酸平衡的重要作用,是降尿酸治疗的作用标靶。黄嘌呤氧化酶通过催化黄嘌呤代谢产生超氧离子和尿酸,因此实验通过测定产生的超氧离子和尿酸含量来评价化合物对黄嘌呤氧化酶的抑制作用。以别嘌醇(Allopurinol)为阳性对照可以进行降尿酸活性初筛。通过测定超氧离子含量评价药物对黄嘌呤氧化酶活性影响采用NBT显色反应,反应体系中加入黄嘌呤(50μM)、黄嘌呤氧化酶(0.1U/ml)、NBT(50μM)和各浓度候选化合物或阳性对照别嘌呤醇(1μg/ml),反应体系中加入磷酸盐缓冲液(50mM,pH=7.5)至终体积100μL。反应以加入黄嘌呤氧化酶为开始,室温反应15min,反应结束后于560nm处测定吸光度值。测定尿酸含量评价药物对黄嘌呤氧化酶活性影响的反应体系中加入黄嘌呤(50μM)、黄嘌呤氧化酶(0.1U/ml)和各浓度候选化合物或阳性对照别嘌呤醇(1μg/ml),反应体系中加入磷酸盐缓冲液(50mM,pH=7.5)至终体积100μL。反应以加入黄嘌呤氧化酶为开始,室温反应15min,反应结束后于295nm处测定吸光度值,计算对黄嘌呤氧化酶的抑制率。
表11体外抑制黄嘌呤氧化酶活性
从上述数据可以看出QQL-HT组和异戊烯基黄酮类化合物表现出较强的抑制痛风性关节炎和降低尿酸的效果,且效果优于阳性药物痛风定胶囊,可以作为一个新型的药物使用。且实验表明,本发明的异戊烯基黄酮类化合物的抑制痛风性关节炎和降低尿酸的效果明显优于现有技术中已经公开的相似的异戊烯基黄酮类化合物,其效果不可预期。
上述实施例阐明的内容应当理解为这些实施例仅用于更清楚地说明本发明,而不用于限制本发明的范围,在阅读了本发明之后,本领域技术人员对本发明的各种等价形式的修改均落入本申请所附权利要求所限定的范围。
Claims (6)
1.一种异戊烯基黄酮类化合物在制备改善痛风的药物中的应用,其特征在于,所述异戊烯基黄酮类化合物的结构通式如下:
其中,R7选自L-鼠李糖-(2→1)-L-鼠李糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R8选自氢、D-葡萄糖、L-鼠李糖-(2→1)-D-葡萄糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R9选自羟基,甲氧基、乙氧基、丙氧基;
3.一种异戊烯基黄酮类化合物在制备降尿酸的药物中的应用,其特征在于,所述异戊烯基黄酮类化合物的结构通式如下:
其中,R7选自L-鼠李糖-(2→1)-L-鼠李糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R8选自氢、D-葡萄糖、L-鼠李糖-(2→1)-D-葡萄糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R9选自羟基,甲氧基、乙氧基、丙氧基;
5.一种活性部位在制备改善痛风的药物中的应用,其特征在于,所述活性部位为青钱柳的正丁醇萃取浓缩液,所述活性部位的主要成分为异戊烯基黄酮类化合物;所述异戊烯基黄酮类化合物的结构通式如下:
其中,R7选自L-鼠李糖-(2→1)-L-鼠李糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R8选自氢、D-葡萄糖、L-鼠李糖-(2→1)-D-葡萄糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R9选自羟基,甲氧基、乙氧基、丙氧基;
6.一种活性部位在制备降尿酸的药物中的应用,其特征在于,所述活性部位为青钱柳的正丁醇萃取浓缩液,所述活性部位的主要成分为异戊烯基黄酮类化合物;所述异戊烯基黄酮类化合物的结构通式如下:
其中,R7选自L-鼠李糖-(2→1)-L-鼠李糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R8选自氢、D-葡萄糖、L-鼠李糖-(2→1)-D-葡萄糖、D-木糖-(2→1)-L-鼠李糖、D-葡萄糖-(4→1)-L-鼠李糖、D-葡萄糖-(2→1)-L-鼠李糖、D-脱氧呋喃糖-(2→1)-L-鼠李糖、D-鸡纳糖-(2→1)-L-鼠李糖、D-葡萄糖-(3→1)-L-鼠李糖、L-鼠李糖;
R9选自羟基,甲氧基、乙氧基、丙氧基;
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102212093A (zh) * | 2010-04-01 | 2011-10-12 | 中国人民解放军第二军医大学 | 黄酮苷类化合物及其制备方法和用途 |
CN102302555A (zh) * | 2011-09-21 | 2012-01-04 | 中国人民解放军第二军医大学 | 一种治疗痛风性关节炎的中药提取物及其制备方法和应用 |
CN105232623A (zh) * | 2015-11-16 | 2016-01-13 | 吴申龙 | 一种青钱柳提取物在制备胃癌药物中的应用 |
CN105560262A (zh) * | 2016-01-04 | 2016-05-11 | 中国科学院昆明植物研究所 | Graveobioside A在制备抗高尿酸血症和抗痛风的药物或保健食品中的应用 |
CN107087697A (zh) * | 2017-03-29 | 2017-08-25 | 广西凌云县盘古生态产业发展有限公司 | 一种可降尿酸的助眠型青钱柳茶及其制备方法 |
CN113150049A (zh) * | 2020-04-20 | 2021-07-23 | 中南大学 | 青钱柳的提取物及其抗痛风和降尿酸应用 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002003996A1 (en) * | 2000-07-12 | 2002-01-17 | RAJKUMAR, Sujatha | Use of dammarane-type tritepenoid saporins |
KR20110055682A (ko) * | 2008-08-22 | 2011-05-25 | 노파르티스 아게 | 간독성과 연관된 hla 대립형질을 보유하지 않은 환자에서 cox-2 의존성 장애의 치료를 위한 cox-2 억제제의 용도 |
JP2011201788A (ja) * | 2010-03-24 | 2011-10-13 | Nippon Menaade Keshohin Kk | 抗炎症剤 |
CN102382092B (zh) * | 2011-07-15 | 2014-04-23 | 北京大学 | 新的异戊烯基黄酮类化合物及其应用 |
CN102935090A (zh) * | 2012-04-28 | 2013-02-20 | 上海中医药大学 | 一种富含三萜类皂苷元的海参提取物的用途 |
EP3108754B1 (en) * | 2015-06-24 | 2019-01-30 | Analyticon Discovery GmbH | Novel triterpene glycosides as sweeteners or sweetener enhancer |
CN104971090A (zh) * | 2015-08-03 | 2015-10-14 | 中国药科大学 | 青钱柳有效部位在制备防治非酒精性脂肪肝药物中的应用 |
CN107080010A (zh) * | 2017-03-29 | 2017-08-22 | 广西凌云县盘古生态产业发展有限公司 | 一种可降尿酸的青钱柳茶及其制备方法 |
CN106977403B (zh) * | 2017-03-31 | 2019-10-01 | 湖南中医药大学 | 一种具有抗癌活性的化合物及其制备方法与应用 |
CN109364119B (zh) * | 2018-12-26 | 2021-10-01 | 浙江大学 | 从青钱柳叶中制备具有降血糖作用的总三萜的方法及应用 |
CN110051726A (zh) * | 2019-04-16 | 2019-07-26 | 浙江大学 | 一种青钱柳叶中总黄酮和总多糖的制备方法及应用 |
CN110746474B (zh) * | 2019-11-14 | 2022-10-04 | 广西师范大学 | 达玛烷型三萜皂苷类化合物及其制备方法和在制备抗炎药物中的应用 |
CN111100175A (zh) * | 2020-01-03 | 2020-05-05 | 中南大学 | 一种3,4-裂环达玛烷型四环三萜化合物及其提取方法和应用 |
-
2021
- 2021-04-20 CN CN202110424558.2A patent/CN113004354B/zh active Active
- 2021-04-20 CN CN202210609872.2A patent/CN115154476B/zh active Active
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- 2021-04-20 CN CN202110424563.3A patent/CN113150048B/zh active Active
- 2021-04-20 CN CN202110424564.8A patent/CN113150049B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102212093A (zh) * | 2010-04-01 | 2011-10-12 | 中国人民解放军第二军医大学 | 黄酮苷类化合物及其制备方法和用途 |
CN102302555A (zh) * | 2011-09-21 | 2012-01-04 | 中国人民解放军第二军医大学 | 一种治疗痛风性关节炎的中药提取物及其制备方法和应用 |
CN105232623A (zh) * | 2015-11-16 | 2016-01-13 | 吴申龙 | 一种青钱柳提取物在制备胃癌药物中的应用 |
CN105560262A (zh) * | 2016-01-04 | 2016-05-11 | 中国科学院昆明植物研究所 | Graveobioside A在制备抗高尿酸血症和抗痛风的药物或保健食品中的应用 |
CN107087697A (zh) * | 2017-03-29 | 2017-08-25 | 广西凌云县盘古生态产业发展有限公司 | 一种可降尿酸的助眠型青钱柳茶及其制备方法 |
CN113150049A (zh) * | 2020-04-20 | 2021-07-23 | 中南大学 | 青钱柳的提取物及其抗痛风和降尿酸应用 |
Non-Patent Citations (2)
Title |
---|
YE Z J,等: ""Four new prenylflavonol glycosides from the leaves ofCyclocarya paliurus"", 《NATURAL PRODUCT RESEARCH》, vol. 36, no. 3, pages 772 - 779 * |
李利生,等: ""淫羊藿苷抗尿酸钠诱导的大鼠急性痛风性关节炎作用"", 《中国实验方剂学杂志》, vol. 23, no. 11, pages 134 * |
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