CN101157714A - 一种常春藤皂苷、其制备方法及其抗肿瘤用途 - Google Patents
一种常春藤皂苷、其制备方法及其抗肿瘤用途 Download PDFInfo
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Abstract
本发明涉及天然药物领域,具体涉及从忍冬属植物黄褐毛忍冬花蕾中提取分离一种化合物(I),其骨架属于常春藤型三萜皂苷;本发明还涉及该化合物及其碱水解产物的制备方法,以及该新化合物作为前药在制备抗肿瘤药物中的应用。
Description
技术领域
本发明涉及天然药物领域,具体涉及从忍冬属植物黄褐毛忍冬花蕾中提取分离一种新化合物,其骨架属于常春藤型三萜皂苷;本发明还涉及该化合物及其碱水解产物的制备方法,以及该新化合物作为前药在制备抗肿瘤药物中的应用。
背景技术
恶性肿瘤是严重危害人类健康的重大疾病之一。肿瘤的防治已成为世界范围内广泛重视的课题,抗肿瘤药物的研制与开发也具有极其迫切的需要。植物是新的生物活性分子的宝贵来源,从植物来源中寻找新的具有抗肿瘤活性的药物越来越受到医药工作者的重视。从植物中已分离出许多抗癌药物,如长春新碱、表鬼臼毒素葡萄糖苷和紫杉醇等。相对于人工合成的化学药物,这些天然来源的有效成分以其毒性较低的优点在肿瘤治疗中得到了大量的应用。
皂苷是广泛存在于植物界的一类特殊苷类,其中皂苷元为30个碳原子组成的三萜类衍生物的皂苷称为三萜皂苷。现代研究表明,皂苷类成分具有广泛的生理活性,除了直接杀伤和抑制肿瘤细胞的作用外,皂苷在增强机体免疫功能、遏制癌症的启动、延缓癌症的演进、抑制癌细胞的转移、抑制肿瘤血管生成、提高传统临床抗癌药的治疗效果等多个方面具有良好的活性,提示从皂苷中研究开发抗肿瘤新药有着广阔的前景。
金银花为忍冬科忍冬属植物忍冬Lonicerajaponica Thunb.的干燥花蕾(2005年版《中国药典》),为我国常用中药。黄褐毛忍冬为忍冬科忍冬属植物L.fulvotomentosa Hsu et S.C.Cheng的干燥花蕾。其药材来源是20世纪70年代后期在黔西南州发现的忍冬属植物新种,为中国特有植物种类,主要分布于贵州、广西、云南三省且资源丰富。黄褐毛忍冬花蕾具有清热解毒、凉散风热等功效,在民间已有5代人以上的药用历史,主要用于治疗肝炎、胃病、感冒等,并有解酒的功效。黄褐毛忍冬系贵州省地方标准品种,也为贵州、广西等地区金银花商品药材主流品种之一,已被纳入2005年版《中国药典》增补版,被列为山银花药材基源植物之一。
黄褐毛忍冬花蕾中富含常春藤皂苷类成分,含量高达约20%。前人对黄褐毛忍冬总皂苷的药理研究发现,其具有良好的保肝、抗炎等活性,特别是对多种作用机制和不同的化学毒物引起的肝损伤均有不同程度的保护作用。然而对其皂苷类成分的药学研究还较少,目前仅报道了从中分离鉴定黄褐毛忍冬皂苷甲(fulvotomentoside A)、无患子皂苷B(sapindoside B)和α-常春藤皂苷(α-hederin)三种皂苷类成分,但这几个有效成分在植物中的含量极低。
发明内容
本发明利用现代分离技术和结构鉴定手段对黄褐毛忍冬花蕾进行化学成分研究,从中分离得到一种新的常春藤皂苷化合物I,该化合物在药材中含量极其丰富,含量高达约5%。通过体外抗肿瘤活性筛选发现,该化合物未显示活性,但其碱水解产物具有很强的体内外抗肿瘤活性。由于该新化合物资源丰富,水解产物活性明确,工艺简便易行,产物得率及纯度高,可用作制备抗肿瘤活性成分的前药,适合工业化大量生产,具有关阔的市场前景和开发价值。
本发明的化合物I结构如下:
其中R1、R2、R3中一个为木糖基(Xyl’),另两个为H。即葡萄糖基(Glc)与木糖(Xyl’)可以是1-2位,1-4位或1-6位连接。
优选的化合物是:
化合物III:分子式为C57H92O25,其分子量为1176,mp 214~215℃,[α]D 20-37.35°(c 0.5,MeOH)。化学名:3-O-β-D-吡喃木糖基(1→3)-α-L-吡喃鼠李糖基(1→2)-α-L-吡喃阿拉伯糖基常春藤皂苷元-28-O-β-D-吡喃木糖基(1→6)-β-D-吡喃葡萄糖酯苷,命名为黄褐毛忍冬皂苷乙(fulvotomentoside B)。
本发明的化合物I为药物前药,其本身没有活性,但在机体内通过水解、代谢、衍生等途径而产生可以发挥预期药效的活性成分的药物。
本发明的通式I化合物可用下列方法制备:
以黄褐毛忍冬干燥花蕾为原料,以30-90%乙醇回流提取,提取液减压浓缩至无醇味,过滤或高速离心,滤液或离心上清液上大孔树脂柱,充分吸附后,以乙醇-水系统梯度洗脱,合并50-70%乙醇液洗脱液,减压蒸干,得到黄褐毛忍冬总皂苷。总皂苷再经硅胶柱层析、反相C18柱和葡聚糖凝胶柱层析进一步分离纯化,即得。
较优选的制备方法是:取黄褐毛忍冬干燥花蕾为原料,以50-90%乙醇回流提取,提取液减压浓缩至无醇味,过滤或高速离心,滤液或离心上清液上大孔树脂充分吸附后,依次用水、30%乙醇、70%乙醇液洗脱至洗脱液近无色,收集70%乙醇液洗脱液,减压蒸干,得到黄褐毛忍冬总皂苷,总皂苷再经硅胶(200-300目)、反相C18柱和葡聚糖凝胶柱层析进一步分离纯化,即可得化合物I。其中大孔树脂优选D101、AB-8、HPD100、HPD300或D1型大孔树脂。最优选的是D101型大孔树脂。
化合物I可以加入乙酰化试剂形成乙酰化产物,或者根据需要,加入其它试剂形成新的衍生物,还可以利用生物活性酶的作用,改变连接位置,如由1-6连接改变成1-4或1-2连接。
本发明的化合物I,体外抗肿瘤试验未显示活性。但本发明的化合物I通过碱水解28位糖酯键,可转化成具有抗肿瘤活性的次级皂苷化合物II。
化合物II:分子式为C46H74O16,其分子量为882,mp 224~226℃。化学名:常春藤皂苷元-3-O-β-D-吡喃木糖基-(1→3)-α-L-吡喃鼠李糖基-(1→2)-α-L-吡喃阿拉伯糖苷,即无患子皂苷B。
化合物I可通过本领域技术人员常用的水解方法制备得到化合物II,也可用下列方法制备:
化合物I加入1~8%氢氧化钾或氢氧化钠水溶液,于40~80℃水浴中温热或回流提取2~6h,冷后加酸调pH值至4~6。再用正丁醇萃取,萃取液回收溶剂后,进行硅胶柱层析,用乙酸乙酯∶甲醇∶水系统洗脱,浓缩,得白色粉末状化合物II。其中乙酸乙酯∶甲醇∶水优选体积比5∶1∶0.1。经药理试验证明,化合物II具有良好的抗肿瘤效果。
由于黄褐毛忍冬植物资源极为丰富,并且该新化合物在黄褐毛忍冬花蕾中的含量高达约5%,来源充足;由该化合物制备活性次级皂苷II的步骤简便,仅水解28位糖酯键而不破坏3位糖链,克服了酸水解产物复杂、分离纯化困难的缺点,目的性强、转化率高,因此可作为前药在制备抗肿瘤药物中应用。
下面是本发明部分药理学试验及结果:
一、本发明新化合物I及其水解产物化合物II体外对肿瘤细胞的抑制作用:
1)细胞系与试剂:人肺癌细胞A549,人宫颈癌细胞Hela,黑色素瘤细胞B16,乳腺癌细胞MDA-MB-231。DMEM高糖培养基购自美国Gibco公司。小牛血清、非必需氨基酸购自Hyclone公司。胰蛋白酶、MTT试剂购自Sigma公司。
2)受试药物:黄褐毛忍冬皂苷乙(I)由黄褐毛忍冬L.fulvotomentosa Hsu et S.C.Cheng的花蕾中分离得到。无患子皂苷B(II)由黄褐毛忍冬皂苷乙水解制备。阳性对照药物为阿霉素(Doxorubicin)。
3)细胞培养:4种肿瘤细胞均用含10%小牛血清的DMEM培养液于37℃,5%CO2及饱和湿度条件下培养。取对数生长期状态良好的细胞,用0.25%胰蛋白酶消化,制成细胞悬液,计数约5×104个/mL,按每孔5000个细胞取细胞悬液接种入96孔板,100μL/孔,置于细胞培养箱内培养24小时;给药组用不同浓度的化合物I或II处理,药物终浓度为2,4,8,16,32μM/mL。同时以含0.02%二甲亚砜的培养液为阴性对照组,以阿霉素为阳性对照组,每组6个复孔。培养48小时后,观察细胞形态,每孔加MTT溶液(5mg/mL)10μL,37℃下孵育4小时后,小心吸弃孔内培养上清,每孔加入100μL DMSO,振荡3min,使结晶充分溶解。选择570nm波长,在酶标仪上测定各孔光吸收值(OD值),取3个复孔OD值平均数,按下式计算细胞抑制率:
细胞抑制率(%)=(阴性对照组OD值-受试物组OD值)/阴性对照组OD值×100%
结果见表1,表1显示本发明新化合物I不显示抗肿瘤活性,但不同浓度的碱水解产物对4种癌细胞均具备较强的生长抑制作用。
表1 本发明新化合物I及其碱水解产物化合物II对不同肿瘤细胞系的ED50(μM)
A549 | Hela | B16 | MDA-MB-231 | |
化合物I化合物II阿霉素 | >10011.91.4 | >1009.1未测 | >10010.00.2 | >10012.8未测 |
二、本发明化合物II的体内抗肿瘤药效学研究
1)肿瘤动物模型的建立:雌性C57BL/6J小鼠,6-8周龄,一级,体重18±2g。本实验建立的实体瘤模型为Lewis肺癌模型。取指数生长期的肿瘤细胞,经胰酶消化后,用PBS洗两遍,将细胞皮下注射到C57BL/6J小鼠右侧背部皮下,LLC肿瘤模型每只小鼠接种1×106个肿瘤细胞(50μl),约5天后可见原位肿瘤,待肿瘤直径达5mm左右时将动物随机分为5组,即无患子皂苷B组(均为6μM/kg)、阿霉素(Doxorubicin)组和对照组(Control),使每组小鼠达到8只以上。每日腹腔注射给药1次,持续7天,对照组于腹腔内注射等体积PBS。同时检测小鼠体重和存活情况。
2)药品 无患子皂苷B(II)由黄褐毛忍冬皂苷乙碱水解制备。阳性对照药物为阿霉素(Doxorubicin)。
3)肿瘤测量和体积计算:用游标卡尺测量小鼠皮下肿瘤,每3天测量一次,分别量取肿瘤的长径(L)和短径(W),根据公式V=L×W2×0.52计算肿瘤体积。按下式计算抑瘤率:
抑瘤率=[(对照组平均瘤体积-实验组平均瘤体积)/对照组平均瘤体积]×100%
实验结果见图1。本发明化合物的碱水解产物化合物II具有明显的抗肿瘤活性,对Lewis荷瘤小鼠的肿瘤生长抑制率为52.7%,高于阳性对照药物阿霉素(30.7%),并且对荷瘤小鼠的体重没有明显影响,对正常小鼠的器官也没有明显损伤。
图1 本发明化合物I的碱水解产物化合物II对小鼠肿瘤生长抑制作用
具体实施方式
实施例1
黄褐毛忍冬忍冬药材(干燥花蕾)5kg,分别用10倍量90%、80%和70%乙醇各回流提取一次,每次3h,合并三次提取液,减压浓缩至无醇;过滤或高速离心,滤液或离心上清液上大孔树脂充分吸附后,依次用水、30%乙醇、70%乙醇液洗脱至洗脱液近无色,收集70%乙醇液洗脱液,减压蒸干,得到黄褐毛忍冬总皂苷部位约1.5kg。该部位浸膏用甲醇溶解,加入约1.5kg硅胶(200-300目)拌匀、研碎,上硅胶柱层析,以氯仿-甲醇系统(20∶1、15∶1、10∶1、9∶2、8∶2.5、7∶3.5、1∶1),每500ml为一流分,共得72个流分。减压浓缩,浓缩产物经薄层色谱检测,合并相似流分,获1-10、11-18、19-25、26-34、35-72共五个部份(Fractionl-Fraction 5)。取70g Fraction 4用50%甲醇-水溶解,上RP-C18 ODS反相硅胶柱,55%甲醇-水洗脱,收集到64个流分,减压浓缩,浓缩产物经薄层色谱检测,合并相同流分,共获四个部分(Fraction A1-D1)。FractionB1经Sephadex LH-20柱70%甲醇-水洗脱,得到化合物III(2.5g)。
结构解析:
化合物III,白色无定形粉末,mp 214~215℃,[α]D 20-37.35°(c0.5,MeOH),TLC香草醛-浓硫酸试液加热显紫红色,数分钟后变为蓝色,Molish反应和Liebermann-Burchard反应均为阳性,提示可能为三萜皂苷类化合物。薄层酸水解:取少量皂苷,溶于甲醇,点于高效薄层板上,置于浓盐酸蒸气中12 h,挥干浓盐酸,再点上各单糖对照品,以氯仿-甲醇-水(16∶9∶2)为展开剂展开,再用氯仿-甲醇-水(30∶12∶4,下层,每9mL加1mL醋酸)二次展开,苯胺-邻苯二甲酸溶液显色,可检出葡萄糖、阿拉伯糖、木糖和鼠李糖。高分辨质谱:1199.5887[M+Na]+,结合1H NMR、13C NMR及2D NMR可知其分子式为C57H92O25。
1H NMR(C5D5N,500MHz)δ:6.30(1H,brs),6.25(1H,d,J=8.1Hz),5.31(1H,d,J=7.6Hz),5.05(1H,d,J=6.6Hz),4.90(1H,d,J=7.1Hz)依次为鼠李糖、葡萄糖、木糖、阿拉伯糖和木糖的端基质子信号,该结果得到HSQC谱验证,5.38(1H,brs)为12位烯氢质子信号,1.20,1.12,1.10,0.98,0.86,0.84(each 3H,s)为6个甲基质子信号,1.54(3H,d,J=6.2Hz)为鼠李糖6位甲基质子信号。
表2 新皂苷(III)和已知化合物decaisoside E(IV)13C NMR谱(C5D5N,125MHz,δ,ppm)
C | III | IV | C | III | IV | C3-Sugar | III | IV | C28-Sugar | III | IV |
123456789101112131415 | 39.126.381.143.647.618.133.139.948.236.923.4123.3144.142.228.3 | 39.126.481.143.647.718.233.140.048.236.923.4123.1144.142.128.3 | 161718192021222324252627282930 | 23.747.041.746.230.734.032.664.014.116.217.526.1176.532.823.8 | 23.747.141.746.230.734.032.664.014.216.217.626.1176.532.823.9 | Ara-12345Rha-123456Xyl-12345 | 104.675.675.169.666.2101.372.083.073.069.718.4107.675.178.471.167.4 | 104.775.775.169.666.2101.372.083.073.069.718.4107.675.278.571.167.4 | Glc-123456Glc′-123456Xyl′-12345 | 95.273.978.871.078.069.2105.674.777.871.167.0 | 95.773.978.571.078.069.5105.375.278.871.678.462.7 |
13C NMR中共显示57个碳信号,包括30个苷元碳信号及27个糖上碳信号。其中苷元碳信号常春藤苷元基本一致,且C-3位羟基和C-28羧基均被苷化,形成双糖链皂苷。比较化合物III和已知化合物decaisodie E糖上的碳信号(表2),发现化合两者C-3位糖链中的碳信号一致,故推测化合物I可能含有3-O-β-D-吡喃木糖基(1→3)-α-L-吡喃鼠李糖基(1→2)-α-L-吡喃阿拉伯糖基结构片断;C-28位糖链中则有一组糖的化学位移存在较大差异,而与文献[Kim J.S.,Shim S.H.,Chae S.,et al..Chem.Pharm.Bull.[J],2005,53(6):696-700]中化合物6的C-28位糖链中化学位移一致,故推测I化合物可能含有28-O-β-D-吡喃木糖基-(1→6)-β-D-吡喃葡萄糖酯苷结构片断。
综合以上分析,化合物III的结构确定为3-O-β-D-吡喃木糖基-(1→3)-α-L-吡喃鼠李糖基-(1→2)-α-L-吡喃阿拉伯糖基-常春藤皂苷元-28-O-β-D-吡喃木糖基-(1→6)-β-D-吡喃葡萄糖酯苷,经文献检索,为一新化合物,命名为黄褐毛忍冬皂苷乙(Fulvotomentoside B)。
其化学结构如下式:
实施例2
取2g黄褐毛忍冬皂苷乙,加入5%NaOH溶液20mL,于60℃水浴回流提取2h,放冷,加入浓HCL调节pH值至4~5。加入水饱和正丁醇溶液(1∶1,v/v)萃取3次,合并正丁醇萃取液,减压回收溶剂至干,得正丁醇萃取物。正丁醇萃取物上样于硅胶柱,以乙酸乙酯∶甲醇∶水(5∶1∶0.1)洗脱,共得45个流分,用旋转蒸发以减压浓缩,合并其中10~40流分,得白色粉末,即为无患子皂苷B(1.1g)。
Claims (8)
1.下列通式(I)的皂苷化合物:
R1、R2或R3其中一个为木糖基,另两个为H。
3.权利要求1或2的皂苷化合物的制备方法,包括以下步骤:
以黄褐毛忍冬干燥花蕾为原料,用30-90%乙醇回流提取,提取液减压浓缩至无醇味,过滤或高速离心,滤液或离心上清液上大孔树脂柱,充分吸附后,以乙醇-水系统梯度洗脱,合并50-70%乙醇液洗脱液,减压蒸干,得到黄褐毛忍冬总皂苷,总皂苷再经硅胶柱层析、反相C18柱和葡聚糖凝胶柱层析进一步分离纯化,即得。
4.权利要求3的制备方法,其中大孔树脂是D101、AB-8、HPD100、HPD300或D1型大孔树脂。
5.权利要求1或2的的皂苷化合物用于制备抗肿瘤药物的前药的用途。
7.权利要求5的用途,其中皂苷化合物由以下方法制备得到抗肿瘤药物:化合物I加入1~8%氢氧化钾或氢氧化钠水溶液,于40~80℃水浴中温热或回流提取2~6h,冷后加酸调pH值至4~6,再用正丁醇萃取,萃取液回收溶剂后,进行硅胶柱层析,用乙酸乙酯∶甲醇∶水系统洗脱,浓缩,即得化合物II。
8.权利要求7的用途,其中乙酸乙酯∶甲醇∶水体积比是5∶1∶0.1。
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