CN101863871B - 蔷薇红景天总苷及其医药用途和制备方法 - Google Patents
蔷薇红景天总苷及其医药用途和制备方法 Download PDFInfo
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- CN101863871B CN101863871B CN201010177549XA CN201010177549A CN101863871B CN 101863871 B CN101863871 B CN 101863871B CN 201010177549X A CN201010177549X A CN 201010177549XA CN 201010177549 A CN201010177549 A CN 201010177549A CN 101863871 B CN101863871 B CN 101863871B
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Abstract
本发明涉及蔷薇红景天总苷及其医药用途和制备方法,从蔷薇红景天制备的总苷提取物,含有黄酮苷类、苯乙醇苷类、苯丙烯醇苷类和总萜苷类化合物,其最显著特征为含有蔷薇红景天黄酮(1)。
Description
技术领域:
本发明涉及从蔷薇红景天(Rhodiola Rosea L.)中分离的具有医药用途的总苷提取物,其特征为含有黄酮苷类、苯乙醇苷类、苯丙烯醇苷类和总萜苷类化合物。
背景技术:
红景天属于景天科(Crassulaceae)红景天属(Rhodiola L)植物,世界上有90多种,中国有70多种。要分布于喜马拉雅山地区,亚洲西北部和北美洲,我国主产于东北、华北和西南。红景天属植物民间多以全草入药,有活血止血、清肺止咳的功效,用于治疗咳血、咯血、肺炎咳嗽、妇女白带等症[15],古代亦用作滋补强壮药。红景天最早作为药用见记载于公元1200年的藏医《四部医典》中,记为“神药——苏罗玛葆”,即现在的宽果红景天(R.eurycarpa S.H.FU)。现代的医药书籍根据红景天植物学特征分成多种,作为药用的见记载有《中华人民共和国药典》(1985版)和《四川省中成药标准》(1993版)记载的大花红景天(R.crenulataH.Ohba)和狭叶红景天(R.kirilowii Maxim)。《中华人民共和国药典》(1995版)中的成方制剂“九味石灰华散”中有红景天,它是作为“清热、滋补元气”的原料。红景天为多年生草本或亚灌木植物,株高10~30cm,因其含花色素,根及根茎呈红色,浸液亦呈红色,又系景天科植物,故名红景天。新疆是我国蔷薇红景天(Rhodiola rosea L.)的主要分布地区,蔷薇红景天在新疆的植物资源丰富,据《新疆药用植物志》记载[16],其主要分布于沿天山北坡的奇台、巴里坤、阜康、石河子、伊犁、昭苏及塔城、托里、阿勒泰、哈巴河等地。主产于山坡林下或草坡上的高寒地区,海拔在1800~2700米左右。
在众多种类的红景天属植物中,国内外学者的研究主要集中于蔷薇红景天(R.rosea L.),大花红景天[R.erenulata(HK.f.etThoms.)H.Ohba],库页红景天(R.saehalinensis A.Bor),狭叶红景天[R.lirilowii(Regel)Maxim]以及圣地红景天[R.Sacra(Prain ex Hamet)S.H.Fu]等十余个种类上。药理学研究发现,红景天具有抗氧化、抗衰老作用抗缺氧、对机体双向调节作用、抗病毒作用及抗肿瘤作用、抗疲劳及提高记忆力等许多作用。但对其物质基础的研究还缺乏定论。
本专利基于以上调查研究,本发明首先实地考察了新疆产蔷薇红景天(Rhodiola RoseaL.)的生长状况,收集药材,采集标本,进行药物的鉴定和生药学的研究;新疆的蔷薇红景天根茎的95%乙醇回流提取物进行了深入研究,经石油醚、氯仿、乙酸乙酯和正丁醇萃取进行极性划分,各萃取层利用反复开放硅胶柱色谱、Sephadex LH-20、ODS、重结晶和反相HPLC等多种分离方法对其进行化学分离,得到21个化合物,并根据化合物的理化性质分析现代波 谱学手段(MS,IR,UV,NMR)鉴定出、对照品比较及与文献报道对比鉴定了20个化合物的化学结构,其中化合物1为新化合物,蔷薇红景天黄酮(1)。研究发现蔷薇红景天黄酮(1)为其中抗氧化活性最强的化合物,寻找出了新结构类型的、强生物活性的化合物,该成分的存在使得,提取制备含有该成分的蔷薇红景天总苷提取物,可以有望成为抗凝血、抗氧化、抗缺氧、抗衰老、抗疲劳、治疗和预防心脑血管疾病的药物、功能食品和食品。
发明内容:
本发明的目的:提供一种结构如下的化合物或其药用盐。
本发明还包括,提供一种含有I式化合物的药物组合物。
本发明还包括提供一种含有I式化合物的蔷薇红景天提取物。
本发明的提取物,含有黄酮苷类、苯乙醇苷类、苯丙烯醇苷类和总萜苷类化合物,其最显著特征为含有具有强抗氧化和心脑血管治疗作用的蔷薇红景天黄酮(1)
本发明还包括本发明I式化合物和含有I式化合物的蔷薇红景天提取物的制备方法,其特征在于,步骤如下:它可以采用以下任意一种方法,或这些方法的任意组合进行制备:(1)溶剂萃取法;(2)大孔吸附树脂法;(3)液-液逆流分配色谱法;(4)柱色谱法。其中优选方法为大孔吸附树脂法和/或反相C18柱色谱法、溶剂萃取法和/或葡聚糖凝胶柱色谱法。
在使用这些方法进行制备时,包括以下几个步骤:
(1)提取:所用溶剂可以是水或任意一种醇类、酮类及酯类溶剂,或由这些溶剂按一定比例配成的混合溶剂,或由这些溶剂与酸、碱配成的酸性或碱性溶剂,其中优选结果为40%~95%乙醇。提取方法可以是加热回流、浸渍渗漉、超声提取、微波提取或高压提取等,其中优选方法为加热回流;
(2)过滤:包括离心、抽滤、压滤、超滤几个步骤,使用以下任一种澄清剂或其组合物:醇沉剂、明胶、活性炭、硅藻土、高岭土、各种树脂、聚乙二醇、聚乙三醇、壳聚糖以及天然澄清剂成品;
(3)浓缩:包括常压或减压条件下的薄膜蒸发、旋转蒸发及煎煮浓缩等;
(4)干燥:包括真空干燥、喷雾干燥、冷冻干燥等方法。
优选的本发明化合物和提取物的制备方法如下:
式I化合物的制备:
蔷薇红景天根茎以95%乙醇提取,减压回收溶剂。将浓缩后提取物用适量水稀释,依次用等体积的石油醚、氯仿、乙酸乙酯、正丁醇萃取,分别得各层萃取物,取乙酸乙酯萃取层,用常压硅胶柱色谱法,以氯仿-甲醇系统梯度洗脱,得到Fr.1~999,Fr.471~505经氯仿-甲醇梯度洗脱得化合物(1)(式I化合物)
蔷薇红景天总苷的制备:
蔷薇红景天根茎以95%乙醇提取,减压回收乙醇,得糖浆状浸膏。用适量水混悬、溶解,经大孔树脂PD101柱色谱依次以水、10%乙醇、60%乙醇、95%乙醇洗脱,分别得到水洗脱部分、10%乙醇洗脱部分、60%乙醇洗脱部分、95%乙醇洗脱部分。其中,60%乙醇洗脱部分富含蔷薇红景天总苷类成分,蔷薇红景天总苷含量达到80%以上。10%乙醇洗脱部分、95%乙醇洗脱部分也含有蔷薇红景天总苷类成分,其含量稍低,但其组成和比例与60%乙醇洗脱部分不同,因此,以上提取物方法均可用于蔷薇红景天总苷类的制备。
最优选的蔷薇红景天总苷的制备方法为:蔷薇红景天根茎以95%乙醇提取,减压回收乙醇,得糖浆状浸膏用适量水混悬、溶解,经大孔树脂PD101柱色谱依次以水、60%乙醇、95%乙醇洗脱,60%乙醇洗脱物即为蔷薇红景天总苷。
另外,本发明还提供利用含有本发明化合物的蔷薇红景天总苷经酸水解反应,制备本发明蔷薇红景天总苷中分布的次级苷化合物和提取物的方法,其中酸水解反应所用酸选自有机酸如:硫酸、盐酸、甲酸、乙酸、三氟乙酸等。
本发明还包括本发明的化合物和含有I式化合物的蔷薇红景天提取物在制备抗高原低氧性缺氧、抗脑缺氧、抗心肌缺氧、改善血液粘稠度和微循环、扩张心脑血管、清除自由基、增强人体免疫力、抗疲劳、抗凝血、保护肝损伤、延缓衰老、调节中枢神经系统、提高机体免疫力、改善心脑血管供血不足、抑制肿瘤细胞生长、以及活血脉、降血脂、降胆固醇、降甘油三脂、抗肿瘤、抗癌等食品、功能食品和药物中的应用。其作用的发挥为黄酮苷类、苯乙醇苷类、苯丙烯醇苷类和总萜苷类化合物的协同作用,其最显著特征为蔷薇红景天黄酮(1)具有强抗氧化和心脑血管治疗作用。
本发明还包括上述含有I式化合物的蔷薇红景天提取物的检测方法:如:HPLC分析,以质谱(MS)检测、紫外(UV)检测、圆二色谱(CD)检测、蒸发光散射检测器等为检测器。
本发明还包括含有本发明的化合物和含有I式化合物的蔷薇红景天提取物的药物组合物。
所述组合物可以是本发明蔷薇红景天黄酮、蔷薇红景天、蔷薇红景天提取物或者蔷薇红景天总苷和药物可接受的载体混合制备成的药物制剂。
这些制剂包括通用的药物剂型如:片剂,胶囊,颗粒,口服液,注射剂等。
本发明的药物组合物在使用时根据病人的情况确定用法用量,可每日服三次,每次1-20剂,如:1-20袋或粒或片,每剂1mg-1000mg。
以下为本发明化合物和含有I式化合物的蔷薇红景天提取物的功效测定实验:
试验表明,其具有抗高原低氧性缺氧、抗脑缺氧、抗心肌缺氧、改善血液粘稠度和微循环、扩张心脑血管、清除自由基、增强人体免疫力、抗疲劳、抗凝血、保护肝损伤、延缓衰老、调节中枢神经系统、提高机体免疫力、改善心脑血管供血不足、抑制肿瘤细胞生长、以及活血脉、降血脂、降胆固醇、降甘油三脂、抗肿瘤、抗癌等活性,提示其可用于食品、功能食品和药物。其作用的发挥为黄酮苷类、苯乙醇苷类、苯丙烯醇苷类和总萜苷类化合物的协同作用,其最显著特征为式1化合物具有强抗氧化和心脑血管治疗作用。
以下实验用于说明本发明提取物比现有类似物更加优越。
毒性试验:
药品:本发明实施例2方法制备的提取物(60%乙醇洗脱部位),式1化合物
本发明的小鼠口服一次给与最大给药浓度10g/Kg体重,均未见毒副反应,血液生化指标均正常,
对照组:本发明60%乙醇洗脱部位,式1化合物的小鼠口服一次给与最大给药浓度10g/Kg体重,解剖尸体见肝脏红肿,肝功能异常。
因此说明本发明药物毒性小于对照组。
药效试验:
药品:本发明实施例2方法制备的提取物(60%乙醇洗脱部位,RRMB,正丁醇萃取部位,RRB),式1化合物
抗疲劳试验:
对照品:人参总皂苷
延长小鼠负重(体重5%)游泳时间试验结果表明:本发明实施例2方法制备的新疆蔷薇红景天总苷和式1化合物在10mg/Kg体重即可与人参总皂苷的抗疲劳活性相当,说明其活性非常强。
与模型组比较*p<0.05,**p<0.01
抗肝损伤试验:
蔷薇红景天总苷对CCl4肝损伤小鼠血清AST、ALT的影响的测定
与正常组相比,模型组小鼠血清AST、ALT活力明显升高,存在显著性差异(P<0.05),表明实验造模成功;与阳性药益肝灵相比,蔷薇红景天总苷部分(RBB)高剂量和式1化合物可使升高的血清AST、ALT活力值下降。结果见表2,图7。
注:与模型组比较,*P<0.05;与正常组比较,##P<0.01
抗氧化损伤试验:
蔷薇红景天总苷对CCl4肝损伤小鼠抗氧化损伤的影响测定
与正常组相比,模型组肝组织GSH活性明显降低、MDA含量明显升高(P<0.01)表明本实验造模成功;与模型组相比,新疆蔷薇红景天总苷和式1化合物高可显著降低肝组织中MDA含量(P<0.05),并能使降低的肝组织GSH活性升高。结果见表3,图8,图9。
注:与模型组比较,*P<0.05;与正常组比较,#P<0.05
血液学试验:蔷薇红景天总苷抗凝血药理活性测试
蔷薇红景天大孔树脂处理物(RRMB)和式1化合物连续给大鼠灌胃7d后,低、中、高剂量组与溶剂对照组比较均显著延长了APPT和TT(P<0.01),中、高剂量组能显著延长PT和RT(P<0.01),表明蔷薇红景天总苷部分(RRMB)和式1化合物对内源性凝血系统及外源性凝血系统均有抑制作用。结果见表4。
表4 新疆红景天大孔树脂处理物的抗凝血活性
注:与溶剂对照组比较*P<0.05,**P<0.01
因此说明本发明提取物和化合物比其他类似物具有更大的优势。
附图说明:
图1蔷薇红景天提取流程图
图2蔷薇红景天乙酸乙酯萃取部分分离流程图
图3苯乙醇苷类化合物
图4苯丙烯醇苷类化合物
图5黄酮类化合物
图6萜苷类化合物
图8红景天95%醇提物的正丁醇萃取部分对四氯化碳致肝损伤小鼠肝组织中GSH的影响
图9红景天95%醇提物的正丁醇萃取部分对四氯化碳致肝损伤小鼠肝组织中MDA的影响
图10蔷薇红景天95%醇提物的正丁醇萃取部分对CCL4所致的小鼠急性肝损伤的肝组织病理变化(A)正常组;(B)模型组;(C)益肝灵组;(D)(E)and(F)分别为蔷薇红景天95%醇提物的正丁醇萃取物低、中、高剂量组。肝组织切片采用HE染色(200×)
图11混合对照品、化合物(1)、化合物(2)、化合物(3)、化合物(4)、化合物(5)、化合物(6)、化合物(7)液相色谱图(从下至上)。
图12混合对照品、新疆蔷薇红景天(1)、(2)、(3)、(4)、青海狭叶红景天的色谱图(从下至上)。
具体实施方式:
1、从蔷薇红景天中提取分离制备以上蔷薇红景天黄酮(1)、蔷薇红景天提取物或者蔷薇红景天总苷的方法。其关键技术为它可以采用以下任意一种方法,或这些方法的任意组合进行制备:(1)溶剂萃取法;(2)大孔吸附树脂法;(3)液-液逆流分配色谱法;(4)柱色谱法。其中优选方法为大孔吸附树脂法和/或反相C18柱色谱法、溶剂萃取法和/或葡聚糖凝胶柱色谱法。
在使用这些方法进行制备时,包括以下几个步骤:
(1)提取:所用溶剂可以是水或任意一种醇类、酮类及酯类溶剂,或由这些溶剂按一定比例配成的混合溶剂,或由这些溶剂与酸、碱配成的酸性或碱性溶剂,其中优选结果为40%~95%乙醇。提取方法可以是加热回流、浸渍渗漉、超声提取、微波提取或高压提取等,其中优选方法为加热回流;
(2)过滤:包括离心、抽滤、压滤、超滤几个步骤,使用以下任一种澄清剂或其组合物:醇沉剂、明胶、活性炭、硅藻土、高岭土、各种树脂、聚乙二醇、聚乙三醇、壳聚糖以及天然澄清剂成品;
(3)浓缩:包括常压或减压条件下的薄膜蒸发、旋转蒸发及煎煮浓缩等;
(4)干燥:包括真空干燥、喷雾干燥、冷冻干燥等方法。
当采用溶剂萃取法时,是先将提取物混悬于水中,接着用乙酸乙酯、氯仿、正丁醇,或这些溶剂的组合物,萃取获得中药活性成分组合物蔷薇红景天总苷,其中优选的是乙酸乙酯或者正丁醇。其中包括应用石油醚、正己烷、环己烷、汽油等低极性溶剂和/或以上低极性溶剂与氯仿、乙酸乙酯、正丁醇、异丙醇、甲醇等的不同比例混合物先萃取除去部分低极性杂质。
当采用大孔吸附树脂法时,其处理的对象可以是上述提取步骤所获得的产物,也可以是经过乙醇沉淀或上述溶剂萃取法初步纯化后的产物,所用大孔吸附树脂可以是非极性、弱极性、中等极性,弱酸性和弱碱性任何一种类型,所用树脂型号由于生产厂家不同而不同,其中优选的是非极性苯乙烯型大孔吸附树脂,所用的洗脱剂是水及含水的乙醇、甲醇、丙酮,其中优选的是0~100%的乙醇。
当采用液-液逆流分配色谱法时,其处理的对象可以是上述提取步骤所获得的产物,也可以是经过上述溶剂萃取法、大孔吸附树脂法初步纯化后的产物,是先将提取物混悬于水中,接着用石油醚、正己烷、环己烷、乙酸乙酯、正丁醇、异丙醇、氯仿,或这些溶剂 的组合物,萃取获得中药活性成分组合物蔷薇红景天总苷,其中优选的是乙酸乙酯或正己烷-乙酸乙酯组成的混合溶剂。
当采用柱色谱法时,其处理的对象可以是上述提取步骤所获得的产物,也可以是经过上述溶剂萃取法、大孔吸附树脂法、液-液逆流分配色谱法初步纯化后的产物,所用固定相可以是硅胶、氧化铝、聚酰胺、葡聚糖凝胶G-10、葡聚糖凝胶G-25、葡聚糖凝胶LH-20、C8、ODS、活性炭、纤维素,及非极性、弱极性、中等极性,弱酸性和弱碱性大孔吸附树脂等;所用的洗脱溶媒因固定相不同而不同,一般是水、甲醇、乙醇、丙酮、氯仿、乙酸乙酯或正己烷-乙酸乙酯组成的混合溶剂,或这些溶剂按一定比例配成的混合溶剂。其中固定相优选的是非极性大孔吸附树脂、硅胶、ODS和葡聚糖凝胶LH-20。
建立了分析方法:HPLC分析,以质谱(MS)检测、紫外(UV)检测、圆二色谱(CD)检测、蒸发光散射检测器等为检测器。
对照品溶液的配置:取表5中蔷薇红景天中分离得到的化合物作为化学对照品,精密称取适量,用甲醇配制成适量的对照品溶液。
表5 从蔷薇红景天中分离得到的化合物的名称、编号和结构
*:新化合物
样品溶液的配置:精密称取蔷薇红景天黄酮、蔷薇红景天、蔷薇红景天提取物或者蔷薇红景天总苷样品各适量,用100ml氯仿(或甲醇、乙酸乙酯、丙酮、乙腈、石油醚、环己烷等有机溶剂及其不同浓度的水溶液)提取,回收提取液,甲醇(或氯仿、乙酸乙酯、丙酮、乙腈、石油醚、环己烷等有机溶剂及其不同浓度的水溶液)溶解,经装填ODS的SPE小色谱柱预处理,95%乙腈(或甲醇、乙酸乙酯、丙酮、氯仿、石油醚、环己烷等有机溶剂及其不同浓度的水溶液)洗涤,合并洗脱液,甲醇定容,过滤,即得。
测试方法:进行HPLC分析,以质谱(MS)检测、紫外(UV)检测、圆二色谱(CD)检测、蒸发光散射检测器等为检测器。以样品中各化合物的色谱峰面积,与标准对照样品相应色谱峰面积,按照标准曲线法(或外标1点法、外标2点法等),进行定量分析,计算,即得。
实施例1:式I化合物的制备:
蔷薇红景天根茎2.0kg,粉碎,以95%乙醇(10、8、8倍量)回流提取三次,每次3h,合并提取液,减压回收溶剂。将浓缩后提取物用适量水稀释,依次用等体积的石油醚、氯仿、乙酸乙酯、正丁醇萃取,分别得各层萃取物20g、33g、62g、204g。见图1
取乙酸乙酯萃取层浸膏56g,用常压硅胶柱色谱法,以氯仿-甲醇系统梯度洗脱,得到Fr.1~999,合并Fr.122~170经氯仿-甲醇梯度洗脱得化合物(3,20);合并Fr.311~326经反复使用Sephadex LH-20柱色谱法,甲醇为流动相,纯化得化合物(2);合并Fr.331~337经经氯仿-甲醇梯度洗脱,再反复使用Sephadex LH-20柱色谱法,甲醇为流动相,纯化得化合物(13);合并Fr.338~393经氯仿-甲醇梯度洗脱,再反复使用Sephadex LH-20柱色谱法,甲醇为流动相,纯化得化合物(14);Fr.430~452经氯仿-甲醇重结晶,得化合物(15),经SephadexLH-20柱色谱法,甲醇为流动相,纯化得化合物(17);Fr.471~505经氯仿-甲醇梯度洗脱得化合物(1)(式I化合物);Fr.706~712经氯仿-甲醇梯度洗脱得化合物(21),详细的分离流程图如图2。
实施例2:蔷薇红景天总苷的提取制备
蔷薇红景天根茎2.0kg,粉碎,以95%乙醇(10、8、8倍量)回流提取三次,每次3h,合并提取液。减压回收乙醇,得糖浆状浸膏。用适量水混悬、溶解,经大孔树脂PD101柱色谱依次以水、10%乙醇、60%乙醇、95%乙醇洗脱,分别得到水洗脱部分、10%乙醇洗脱部分、60%乙醇洗脱部分、95%乙醇洗脱部分。其中,60%乙醇洗脱部分富含蔷薇红景天总苷类成分,蔷薇红景天总苷含量达到80%以上。10%乙醇洗脱部分、95%乙醇洗脱部分也含有蔷薇红景天总苷类成分,其含量稍低,但其组成和比例与60%乙醇洗脱部分不同,因此,以上提取物方法均可用于蔷薇红景天总苷类的制备。最佳制备方法为用适量水混悬、溶解,经大孔树脂 PD101柱色谱依次以水、60%乙醇、95%乙醇洗脱,60%乙醇洗脱物即为蔷薇红景天总苷。
实施例3:蔷薇红景天总苷的HPLC-TOF-MS分析
对照品溶液的配置:表1所列对照品精密称取适量,用甲醇配制成适量的对照品溶液。
样品溶液的配置:精密称取蔷薇红景天黄酮、蔷薇红景天、蔷薇红景天提取物或者蔷薇红景天总苷样品各适量,用100ml甲醇(或氯仿、乙酸乙酯、丙酮、乙腈、石油醚、环己烷等有机溶剂及其不同浓度的水溶液)提取,回收提取液,甲醇(或氯仿、乙酸乙酯、丙酮、乙腈、石油醚、环己烷等有机溶剂及其不同浓度的水溶液)溶解,经装填ODS的SPE小色谱柱预处理,95%甲醇(或乙腈、乙酸乙酯、丙酮、氯仿、石油醚、环己烷等有机溶剂及其不同浓度的水溶液)洗涤,合并洗脱液,甲醇定容,过滤,即得。
测试方法:进行HPLC分析,以质谱(MS)检测、紫外(UV)检测、圆二色谱(CD)检测、蒸发光散射检测器等为检测器。以样品中各化合物的色谱峰面积,与标准对照样品相应色谱峰面积,按照标准曲线法(或外标1点法、外标2点法等),进行定量分析,计算,即得。
利用表1所列对照品的精确分子量,进行HPLC-TOF-MS等分析,定性、定量地确定蔷薇红景天总苷中的化学成分及其含量。结果见表6-表9和图3--图6。
表6 苯乙醇苷类化合物
化合物英文名称 | 分子式 | 检测离子 [M+Na]+ | 英文俗名 | 文献对照 |
2-(4-hydroxyphenyl)ethyl, β-D-Glucopyranoside 2-(4-羟基苯基)乙醇,β-D-葡萄 糖苷 | C14H20O7 | 323.1107 | Salidroside Rhodosin Rhodioloside | Rhodiola rosea[8] |
2-[4-[(3,4,5-trihydroxybenzoyl)o xy]phenyl]ethyl, β-D-Glucopyranoside 2-[4-[(3,4,5-三羟基苯甲酰基)氧 基]苯基]乙醇,β-D-葡萄糖苷 | C21H24O1 1 | 475.1216 | Pharienside | Rhodiola phariensis[9] |
2-(4-methoxyphenyl)ethyl,β-D- Glucopyranoside 2-(4-甲氧基苯基)乙醇,β-D-葡 萄糖苷 | C15H22O7 | 337.1263 | Viridoside | Rhodiola viridula[10] |
表7 苯丙烯醇苷类化合物
表8 黄酮类化合物
化合物英文名称 | 分子式 | 检测离子 [M+Na]+ | 英文俗名 | 文献对照 |
3,4,5-trihydroxy-,1,1′-[(2R,2′R,3 R,3′R,4R)-3,3′,4,4′-tetrahydro-5, 5′,7,7′-tetrahydroxy-2,2′-bis(3,4, 5-trihydroxyphenyl)[4,8′-bi-2H- 1-benzopyran]-3,3′-diyl]ester, Benzoic acid 3,4,5-三羟基 -,1,1′-[(2R,2′R,3R,3′R,4R)-3,3′,4 ,4′-四氢-5,5′,7,7′-四羟基 -2,2′-bis(3,4,5-三羟基苯 基)[4,8′-bi-2H-1-苯并呋 喃]-3,3′-二醇],苯甲酸酯 | C44H34O2 2 | 913.1464 | Rhodisin | Rhodiola semenovii[14] |
3,3′,4′,5,7,8-Hexahydroxyflavon e 3,3′,4′,5,7,8-六羟基黄酮 | C15H10O8 | 317.0298 | Articulatidin Equisporol | Rhodiola rosea[15] |
3,3′,4′,5,7,8-Hexahydroxyflavon e,7-O-α-L-Rhamnopyranoside 3,3′,4′,5,7,8-六羟基黄酮, 7-O-α-L-鼠李糖苷 | C21H20O1 2 | 463.0876 | Rhodiolgin | Rhodiola rosea[16] |
3,4′,5,7,8-Pentahydroxyflavone, 4′-O-β-D-Glucopyranoside 3,4′,5,7,8-五羟基黄酮, 4′-O-β-D-葡萄糖苷 | C21H20O1 2 | 463.0876 | Gelidolin | Rhodiola gelida[17] |
3,3′,4′,5,7,8-Hexahydroxyflavon e,7-O-[β-D-Glucopyranosyl-(1 →3)-α-L-rhamnopyranoside] | C27H30O1 7 | 625.1405 | Rhodioflavono side | Rhodiola quadrifida[18] |
3,3′,4′,5,7,8-Hexahydroxyflavon e,7-O-α-L-Rhamnopyranoside, 8-O-β-D-glucopyranoside 3,3′,4′,5,7,8-六羟基黄酮, 7-O-α-L-鼠李糖基,8-O-β-D-葡 萄糖苷 | C27H30O1 7 | 625.1405 | Rhodiolgidin | Rhodiola rosea[16] |
3,4′,5,7,8-Pentahydroxyflavone 3,4′,5,7,8-五羟基黄酮 | C15H10O7 | 301.0348 | Herbacetin | Rhodiola algida[19] |
3,4′,5,7,8-Pentahydroxyflavone, 3-O-β-D-Glucopyranoside, 8-β-D-xylopyranoside 3,4′,5,7,8-五羟基黄酮, 3-O-β-D-葡萄糖苷,8-β-D-木糖 苷 | C26H28O1 6 | 595.1299 | Rhodalidin | Rhodiola rosea[16] |
3,4′,5,7,8-Pentahydroxyflavone, 4′,8-Di-O-β-D-xylopyranoside 3,4′,5,7,8-五羟基黄酮,4′,8-双 O-β-D-木糖基 | C25H26O1 5 | 565.1193 | Herbacetin 4′,8-dixyloside | Rhodiola krylovii[20] |
3,4′,5,7,8-Pentahydroxyflavone, 4′-O-β-D-Xylopyranoside, 8-O-α-L-arabinopyranoside 3,4′,5,7,8-五羟基黄酮, 4′-O-β-D-木糖基,8-O-α-L-吡 喃阿拉伯糖苷 | C25H26O1 5 | 565.1193 | Rhodalide | Rhodiola algida[21] |
3,4′,5,7,8-Pentahydroxyflavone, 4′-O-α-L-Rhamnopyranoside 3,4′,5,7,8-五羟基黄酮, 4′-O-α-L-鼠李糖苷 | C21H20O1 1 | 447.0927 | Rhodiolatuntos ide | Constit.of Rhodiola atuntsuensis[22] |
3,4′,5,7,8-Pentahydroxyflavone, 7-O-α-L-Rhamnopyranoside 3,4′,5,7,8-五羟基黄酮, 7-O-α-L-鼠李糖苷 | C21H20O1 1 | 447.0927 | Rhodionin | Rhodiola rosea[16] |
3,4′,5,7,8-Pentahydroxyflavone, 8-O-α-L-Rhamnopyranoside 3,4′,5,7,8-五羟基黄酮, 8-O-α-L-鼠李糖苷 | C21H20O1 1 | 447.0927 | Litvinolin | Rhodiola krylovii[20] |
3,4′,5,7-tetrahydroxyflavone, 3-O-β-D-glucopyranoside 3,4′,5,7-四羟基黄酮,3-O-β-D- 葡萄糖苷 | C21H20O1 1 | 447.0927 | Isoastragalin | Gossypium hirsutum flowers[29] |
3,4′,5,7,8-Pentahydroxyflavone, 4′-O-β-D-Glucuronopyranoside 3,4′,5,7,8-五羟基黄酮, 4′-O-β-D-葡萄糖苷 | C21H18O1 3 | 477.0669 | Alginin | Rhodiola algida[23] |
3,4′,5,7,8-Pentahydroxyflavone, | C27H30O1 | 609.1456 | Rhodiosin | Rhodiola rosea[24] |
7-O-[β-D-Glucopyranosyl-(1→ 3)-α-L-rhamnopyranoside] 3,4′,5,7,8-五羟基黄酮, 7-O-[β-D-葡萄糖基-(1→3)- α-L-鼠李糖苷] | 6 | |||
3,4′,5,7,8-Pentahydroxyflavone, 7-O-α-L-Rhamnopyranoside, 8-O-β-D-glucopyranoside 3,4′,5,7,8-五羟基黄酮, 7-O-α-L-鼠李糖基,8-O-β-D-葡 萄糖苷 | C27H30O1 6 | 609.1456 | Rhodionidin | Rhodiola rosea[16] |
3,4′,5,7,8-Pentahydroxyflavone, 8-O-α-D-xylopyranoside 3,4′,5,7,8-五羟基黄酮, 8-O-α-D-木糖苷 | C20H18O1 1 | 433.0771 | Herbacetin 8-xylopyranosi de | Rhodiola fastigiata[25] |
3,4′,5,7,8-Pentahydroxyflavone, 8-O-α-L-Arabinopyranoside 3,4′,5,7,8-五羟基黄酮 8-O-α-L-吡喃阿拉伯糖苷 | C20H18O1 1 | 433.0771 | Rhodalgin | Rhodiola algida[23] |
3,4′,5,7,8-Pentahydroxyflavone, 8-O-β-D-Arabinofuranoside 3,4′,5,7,8-五羟基黄酮, 8-O-β-D-呋喃阿拉伯糖苷 | C20H18O1 1 | 433.0771 | Rhodiola fastigiata[26] | |
3,4′,5,7,8-Pentahydroxyflavone, 8-O-β-D-Xylopyranoside 3,4′,5,7,8-五羟基黄酮, 8-O-β-D-吡喃木糖苷 | C20H18O1 1 | 433.0771 | Rhodalin | Rhodiola algida[27] and Rhodiola rosea[24] |
3,4′,5,7,8-Pentahydroxyflavone, 7-O-β-L-Arabinopyranoside 3,4′,5,7,8-五羟基黄酮, 7-O-β-L-吡喃阿拉伯糖苷 | C20H18O1 1 | 433.0771 | Gelolin | Rhodiola gelida[21] |
3,4′,5,7-tetrahydroxyflavone, 7-O-α-L-Rhamnopyranoside 3,4′,5,7-四羟基黄酮,7-O-α-L- 鼠李糖苷 | C15H10O6 | 285.0399 | Kaempferol | Rhodiola coccinea and Rhodiola quadrifida[28] |
3,4,5-trihydroxy-Benzoic acid 3,4,5-三羟基-苯甲酸 | C7H6O5 | 169.0137 | Gallica acid | Rhodiola coccinea and Rhodiola quadrifida[28] |
表9 萜苷类化合物
化合物英文名称 | 分子式 | 检测离子 [M+Na]+ | 俗名 | 文献对照 |
3,7-Dimethyl-2,6-octadiene-1,4 -diol,(2E,4R)-型, 1-O-β-D-Glucopyranoside 3,7-二甲基-2,6-辛二烯-1,4-二 醇,(2E,4R)-型,1-O-β-D-葡萄 | C16H28O7 | 355.1733 | Rosiridin | Rhodiola rosea[24] |
糖苷 | ||||
3,7-Dimethyl-2,6-octadiene-1,4 -diol,(2E,4R)-型, 4-O-(3,4,5-Trihydroxybenzoyl), 8-O-β-D-glucopyranoside 3,7-二甲基-2,6-辛二烯-1,4-二 醇,(2E,4R)-型,4-O-(3,4,5-三 羟基苯基),8-O-β-D-葡萄糖苷 | C23H32O11 | 507.1842 | Sachalinoside A | Rhodiola sachalinensis[31] |
(2Z)-3,7-dimethyl-2,6-octadien -1-yl, 6-O-α-L-arabinopyranosyl-β-D- Glucopyranoside (2Z)-3,7-二甲基-2,6-辛二烯-1- 醇,6-O-α-L-吡喃阿拉伯糖基 -β-D-葡萄糖苷 | C21H36O10 | 471.2206 | Sacranoside B | Rhodiola sacra and Rhodiolae radix[32] |
3,7-Dimethyl-2-octene-1,4,7-tri ol,(2E,4R)-型 3,7-二甲基-2-辛烯-1,4,7-三 醇,(2E,4R)-型 | C10H20O3 | 211.1310 | Sachalinol A | Rhodiola sachalinensis[31] |
3-(4-Hydroxy-5,5-dimethyl-2-f uranyl)-2-buten-1-ol, (2E,4R,6R)-型 3-(4-羟基-5,5-二甲基-2-呋喃 基)-2-丁烯-1-醇, (2E,4R,6R)-型 | C10H18O3 | 209.1154 395.2410 | Sachalinol C | Rhodiola sachalinensis[31] |
3-(4-Hydroxy-5,5-dimethyl-2-f uranyl)-2-buten-1-ol, (2E,4R,6S)-型 3-(4-羟基-5,5-二甲基-2-呋喃 基)-2-丁烯-1-醇,(2E,4R,6S)- 型 | C10H18O3 | 209.1154 395.2410 | Sachalinol B | Rhodiola sachalinensis[31] |
2-Methyl-3-buten-2-ol, O-β-D-Glucopyranoside 2-甲级-3-丁烯-2-醇,O-β-D-葡 萄糖苷 | C11H20O6 | 271.1158 | Crenulatin | Rhodiola crenulata[34] |
2-Hydroxymethyl-2-butenoic acid,(Z)-型,Nitrile, O-β-D-glucopyranoside 2-羟基甲基-2-丁烯氰,(Z)- 型,O-β-D-葡萄糖苷 | C11H17NO6 | 282.0954 | Rhodiocyanos ide D | Rhodiola sacra[32] |
4-Hydroxy-2-methyl-2-butenoi c acid,(Z)-型,Nitrile, 4-O-β-D-glucopyranoside 4-羟基-2-甲基-2-丁烯氰,(Z)- 型,4-O-β-D-葡萄糖苷 | C11H17NO6 | 282.0954 | Multifidin Rhodiocyanos ide A | Rhodiola quadrifida[33] |
3,7-Dimethyl-2,6-octadiene-1,4 ,7-triol,(2E,4R)-型, | C16H28O8 | 371.1682 | Rhodioloside A | Rhodiola rosea[35] |
1-O-β-D-Glucopyranoside 3,7-二甲基-2,6-辛二烯-1,4,7- 三醇,(2E,4R)-型,1-O-β-D-葡 萄糖苷 | ||||
3,7-Dimethyl-2,6-octadiene-1,4 -diol,(2E,4R)-型, 1-[α-D-Glucopyranosyl-(1-6)-O -β-D-Glucopyranoside 3,7-二甲基-2,6-辛二烯-1,4-二 醇,(2E,4R)-型,1-[α-D-葡萄糖 基-(1-6)-O-β-D-葡萄糖苷 | C22H38O12 | 517.2261 | Rhodioloside B | Rhodiola rosea[35] |
3,7-Dimethyl-2,6-octadiene-1,4 -diol,(2E,4R)-型, 1-O-[β-D-Glucopyranosyl-(1-3) -O-β-D-Glucopyranoside 3,7-二甲基-2,6-辛二烯-1,4-二 醇,(2E,4R)-型,1-O-[β-D-葡萄 糖基-(1-3)-O-β-D-葡萄糖苷 | C22H38O12 | 517.2261 | Rhodioloside C | Rhodiola rosea[35] |
3,7-Dimethyl-2-octene-1,4,7-tri ol,(2E,4R)-型, 1-O-β-D-Glucopyranoside 3,7-二甲基-2-辛烯-1,4,7-三 醇,(2E,4R)-型,1-O-β-D-葡萄 糖苷 | C16H30O8 | 373.1838 | Rhodioloside D | Rhodiola rosea[35] |
3,7-Dimethyl-2-octene-1,4,7-tri ol,(2E,4R)-型, 1-O-[α-L-Arabinopyranosyl-(1- 6)-β-D-Glucopyranoside 3,7-二甲基-2-辛烯-1,4,7-三醇, (2E,4R)-型,1-O-[α-L-吡喃阿 拉伯糖基-(1-6)-β-D-葡萄糖苷 | C21H38O11 | 489.2312 | Rhodioloside E | Rhodiola rosea[35] |
实施例4:蔷薇红景天总苷对CCl4肝损伤小鼠血清AST、ALT的影响的测定
与正常组相比,模型组小鼠血清AST、ALT活力明显升高,存在显著性差异(P<0.05),表明实验造模成功;与阳性药益肝灵相比,蔷薇红景天总苷部分(RBB)高剂量可使升高的血清AST、ALT活力值下降。结果见表2,图7。
注:与模型组比较,*P<0.05;与正常组比较,##P<0.01
实施例5:蔷薇红景天总苷对CCl4肝损伤小鼠肝组织中GSH、MDA的影响测定
与正常组相比,模型组肝组织GSH活性明显降低、MDA含量明显升高(P<0.01)表明本实验造模成功;与模型组相比,新疆蔷薇红景天高可显著降低肝组织中MDA含量(P<0.05),并能使降低的肝组织GSH活性升高。结果见表3,图8,图9。
注:与模型组比较,*P<0.05;与正常组比较,#P<0.05
实施例6:蔷薇红景天总苷对肝损伤小鼠肝组织病理变化的影响
HE染色,在光镜下发现,正常对照组肝细胞以中央静脉为中心呈放射状排列,结构正常、清晰。CCl4模型组小鼠肝窦及中央静脉明显扩张,肝细胞广泛坏死,细胞膜不清楚,胞浆液连成一片,病灶区周围肝细胞发生不同程度的气球样变及嗜酸性变,有大量炎性细胞浸润,新疆蔷薇红景天高剂量组肝细胞变性、坏死、炎症反应明显减轻。新疆蔷薇红景天中剂量组和低剂量组肝细胞的肿胀变性、坏死和炎症反应较四氯化碳组有所改善。结果见图10。
实施例7:蔷薇红景天总苷抗凝血药理活性测试
蔷薇红景天正丁醇萃取物连续给大鼠灌胃7d后,中、高剂量组与溶剂对照组比较均显著延长了APTT、PT、TT和RT时间。表明蔷薇红景天对内源性凝血系统及外源性凝血系统均有抑制作用,结果见表8。
对于TT的测定,低、中、高三个剂量组都能明显的延长TT的时间(P<0.01),结果表明蔷薇红景天具有显著的抗凝血活性。
对于APTT的测定,中、高剂量组都能明显的延长APTT的时间(P<0.01),结果表蔷薇红景天对内源性凝血途径有显著的影响。
对于PT的测定,低、中、高三个剂量组都能明显的延长PT的时间(P<0.01),结果表明蔷薇红景天对外源性凝血途径有影响。
对于TT、APTT、PT三个指标的测定结果表明,蔷薇红景天具有显著的抗凝血活性,对内源性凝血途径和外源性凝血途径均有影响。
注:与溶剂对照组比较*P<0.05,**P<0.01
实施例8:蔷薇红景天总苷抗凝血药理活性测试
蔷薇红景天大孔树脂处理物连续给大鼠灌胃7d后,低、中、高剂量组与溶剂对照组比较均显著延长了APPT和TT(P<0.01),中、高剂量组能显著延长PT和RT(P<0.01),表明蔷薇红景天对内源性凝血系统及外源性凝血系统均有抑制作用。结果见表4。
注:与溶剂对照组比较*P<0.05,**P<0.01
实施例9:酸水解反应
分别取100mg的样品,用100ml 2N三氟乙酸(TFA)溶解于安瓿瓶中,封瓶,110℃反应2h。CHCl3萃取三次,水层用N2吹干,加甲醇,再用N2吹干,反复此过程直至产物中不存在TFA,即得。
实施例10:式1化合物的鉴定
片状结晶(甲醇),m.p.192~193℃;FeCl3-Fe[K3(CN)6]反应阳性,示含酚羟基。
表11 化合物1的1H-NMR(600MHz in(D6)DMSO)and 13C-NMR(150MHz in(d6)DMSO)数据
实施例11:HPLC测定蔷薇红景天中7个黄酮类化合物的含量
建立了HPLC法同时测定红景天中7种主要黄酮类成分含量的方法(化合物结构见表12)。结果表明本方法快速、灵敏、准确、可靠,重复性好。
表12 标准对照品的化合物结构
分析方法:365nm为HPLC测定波长,分别精密移取1、2、3、4、5、6、7对照品储备溶液50.5μl、188μl、320μl、56μl、117μl、10μl、66.4μl,至2ml的容量瓶中,用甲醇定溶至刻度,即得对照品溶液。精密称取样品约1.0g,加入20ml甲醇,称重,超声提取30min,放至室温,补足失重,过滤,弃去初滤液,取续滤液用0.22um微孔滤膜过滤,即为供试品溶液。
色谱柱:Scienhome Kromasil C18 150mm×4.6mm,5μm);流动相:甲醇-乙腈-0.1%磷酸水梯度洗脱(见表13);流速1ml/min;柱温30℃;检测波长365nm。在该色谱条件下,样品中被测成分能够达到基线分离,保留时间在65min内。(图11和图12)
表13 梯度洗脱条件
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