CN114903926A - 珊瑚树叶中Vibsane型总二萜及其制备方法和应用 - Google Patents
珊瑚树叶中Vibsane型总二萜及其制备方法和应用 Download PDFInfo
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Abstract
一种珊瑚树叶中Vibsane型总二萜及其制备方法和应用,属于植物医药技术领域。珊瑚树叶中Vibsane型总二萜的制备方法是将珊瑚树叶用提取溶剂提取,得到提取物;将提取物用石油醚萃取除油,并用乙酸乙酯萃取,去除溶剂,干燥,得到粗浸膏;将粗浸膏用大孔吸附树脂柱色谱进行梯度洗脱,洗脱溶剂为乙醇‑水溶液,收取90%馏分,去除洗脱溶剂,即为珊瑚树叶中Vibsane型总二萜。该制备方法工艺简单,成本低,可以工业化生产,且实验证实利用方法制得的Vibsane型总二萜具有明显的抗肝癌、乳腺癌活性,可以用于制备抗肿瘤药物,具备进一步开发为新药的潜力。
Description
技术领域
本发明涉及植物医药技术领域,涉及珊瑚树叶中Vibsane型总二萜及其制备方法和应用, 尤其涉及药用及园林作物珊瑚树叶中具有显著抗癌活性的Vibsane型总二萜的制备新方法。
背景技术
珊瑚树(Viburnum odoratissimum Ker-Gawl.var.odoratissimum)为五福花科(Adoxaceae)荚 蒾属(Viburnum)植物。其枝叶可入药,具有通经活络之功效,多用来消炎、止痛、抗风湿,为 民间传统用药。目前,从珊瑚树的枝叶中分离得到多种化学成分,其中,Vibsane型二萜类化 合物是珊瑚树中的特征化合物。该类化合物结构复杂,具有显著的抗癌活性。现有技术中, 尽管已有报道表明Vibsane型二萜为珊瑚树中的主要活性成分,但精确分离活性显著的 Vibsane二萜单体流程复杂、成本高,同时得到的活性化合物含量较低,实际开发为药物的难 度较大。
发明内容
本发明的目的是提供一种珊瑚树叶中Vibsane型总二萜及其制备方法和应用,主要是提 供一种从珊瑚树叶中快速制备Vibsane型总二萜的制备方法,该制备方法工艺简单,成本低, 且实验证实利用方法制得的Vibsane型总二萜具有明显的抗肝癌、乳腺癌活性,可以用于制 备抗肿瘤药物,具备进一步开发为新药的潜力。
本发明的一种珊瑚树叶中Vibsane型总二萜的制备方法,包括以下步骤:
步骤1:
将珊瑚树叶用提取溶剂提取,得到提取物;
将提取物用石油醚萃取除油,并用乙酸乙酯萃取,去除溶剂,干燥,得到粗浸膏;
步骤2:
将粗浸膏用大孔吸附树脂柱色谱进行梯度洗脱,洗脱溶剂为乙醇-水溶液,收取90%馏分, 去除洗脱溶剂,即为珊瑚树叶中Vibsane型总二萜。
所述的步骤1中,珊瑚树叶为干燥的珊瑚树叶。
所述的步骤1中,提取采用的提取溶剂优选为甲醇或乙醇,甲醇或乙醇的体积浓度70~80%,提取次数优选为3~5次。
所述的步骤1中,去除溶剂优选为减压蒸馏。
所述的步骤1中,乙酸乙酯萃取时,按体积比,提取物:乙酸乙酯=1:(2~3)。
所述的步骤2中,大孔吸附树脂柱色谱中,大孔吸附树脂选用D-101大孔吸附树脂或 HP-20大孔吸附树脂中的一种。
所述的步骤2中,梯度洗脱采用的乙醇-水溶液中,乙醇的质量百分比梯度为30%,60%, 90%。
所述的步骤2中,去除洗脱溶剂采用减压蒸馏去除。
本发明的珊瑚树叶中Vibsane型总二萜,通过以上制备方法制得,其珊瑚树叶中Vibsane 型总二萜的Vibsane型总二萜的质量百分含量≥65%。
一种药物组合物,包含珊瑚树叶中Vibsane型总二萜和药学上可接受的载体或赋形剂。
本发明的珊瑚树叶中Vibsane型总二萜或药物组合物作为预防或治疗抗肿瘤药物的应用。
所述的抗肿瘤药物为抗肝癌药物或抗乳腺癌药物。
特别适用于,抑制体外肿瘤细胞生长的活性,更具体的肿瘤细胞为HepG2细胞株,Hep3B 细胞株,MCF-7细胞株。
其中,抗肿瘤药物中珊瑚树叶中Vibsane型总二萜作用于HepG2细胞株的IC50值为11.11~11.21μg/mL,抗肿瘤药物中珊瑚树叶中Vibsane型总二萜作用于Hep3B细胞株的IC50值为9.64~9.82μg/mL,抗肿瘤药物中珊瑚树叶中Vibsane型总二萜作用于MCF-7细胞株的IC50值为14.62~15.74μg/mL。
珊瑚树叶中Vibsane型总二萜或药物组合物,适用于体内抗癌活性。在两周的给药时间 内,低剂量组珊瑚树叶中Vibsane型总二萜(100mg/kg)使裸鼠移植Hep3B肿瘤的体积缩小55% 以上,高剂量组珊瑚树叶中Vibsane型总二萜(200mg/kg)使裸鼠移植Hep3B肿瘤的体积缩小 75%以上,优于阳性药索拉菲尼的40%,能够显著抑制裸鼠移植Hep3B肿瘤的生长,且未表 现出明显毒性。
本发明的一种珊瑚树叶中Vibsane型总二萜及其制备方法和应用,其有益效果在于:
珊瑚树叶的Vibsane型总二萜具有比珊瑚树叶总提物更强的肝癌、乳腺癌细胞的抑制活 性,并且可以抑制裸鼠移植HepG2、Hep3B、MCF-7肿瘤的生长。
本发明采用移植肝癌Hep3B细胞株的裸鼠模型对珊瑚树叶的Vibsane型总二萜的体内抗 肝癌活性进行测试。结果表明,珊瑚树叶的Vibsane型总二萜能够抑制肝癌、乳腺癌的增殖 并抑制人肝癌Hep3B裸鼠移植瘤的生长。毒性评估表明本发明所描述的珊瑚树叶Vibsane型 总二萜对小鼠各脏器未表现出明显毒性。因此,本发明所述的珊瑚树叶的Vibsane型总二萜 的抗癌作用安全有效,具有进一步开发为临床抗肝癌、乳腺癌预防和治疗药物的前景。
本发明的制备方法设计合理,具有过程工艺简单,可工业化生产的特点。
附图说明
图1为人肝癌Hep3B裸鼠肿瘤体积随给药量的变化情况;(a)在体裸鼠肿瘤;(b)为离体 裸鼠肿瘤。
图2为不同给药量下,小鼠肿瘤体积随时间的变化曲线。
图3为不同给药量下,小鼠肿瘤大小的变化情况图。
图4为不同给药量下,小鼠体重随时间变化曲线。
图5为小鼠心、肝、脾、肺、肾随给药量的变化情况图。
图6为赫斯特(H&E)染色结果。
图7为免疫组织化学分析结果图。
具体实施方式
下面结合实施例对本发明作进一步的详细说明。
实施例1
一种珊瑚树叶中Vibsane型总二萜的制备方法,包括以下步骤:
取干燥珊瑚树叶1kg,用75%甲醇或乙醇提取3~5次,减压浓缩得到珊瑚树叶总提物; 将所得珊瑚树叶粗提物经石油醚萃取除油,除去脂肪酸等小极性成分;随后经乙酸乙酯以珊 瑚树叶提取物:乙酸乙酯萃取液1:2的体积比例萃取3次,合并经减压浓缩得乙酸乙酯层总 浸膏。以HP-20经乙醇-水系统以30%、60%、90%的乙醇质量浓度比例进行洗脱,每个比例 洗脱4~6个保留体积,回收溶剂,对90%流分减压浓缩得到珊瑚树叶中Vibsane型总二萜浸 膏4.92g。利用紫外-可见光分光光度法,以15-O-methylvibsanin H为对照品,在230.5nm的 波长处,配置标准曲线并测定吸光度,检测结果显示所得珊瑚树叶Vibsane型总二萜得含量 为70.521%。
实施例2
一种珊瑚树叶中Vibsane型总二萜的制备方法,包括以下步骤:
取干燥珊瑚树叶1kg,用75%甲醇或乙醇提取3~5次,减压浓缩得到珊瑚树叶总提物; 将所得珊瑚树叶粗提物经石油醚萃取除油;随后经乙酸乙酯以珊瑚树叶提取物:乙酸乙酯萃 取液1:2的体积比例萃取3次,合并经减压浓缩得乙酸乙酯层总浸膏。以HP-20经乙醇-水 系统以30%、60%、90%的乙醇质量浓度比例进行洗脱,每个比例洗脱4~6个保留体积,回 收溶剂,对90%流分减压浓缩得到珊瑚树叶中Vibsane型总二萜浸膏4.46g。利用紫外-可见光 分光光度法,以15-O-methylvibsanin H为对照品,在230.5nm的波长处,配置标准曲线并测 定吸光度,检测结果显示所得珊瑚树叶Vibsane型总二萜得含量为72.436%。
实施例3
取干燥珊瑚树叶1kg,用75%甲醇或乙醇提取3~5次,减压浓缩得到珊瑚树叶总提物; 将所得珊瑚树叶粗提物经石油醚萃取除油;随后经乙酸乙酯以珊瑚树叶提取物:乙酸乙酯萃 取液1:2的体积比例萃取3次,合并经减压浓缩得乙酸乙酯层总浸膏。以HP-20经乙醇-水 系统以30%、60%、90%的乙醇质量浓度比例进行洗脱,每个比例洗脱4~6个保留体积,回 收溶剂,对90%流分减压浓缩得到珊瑚树叶中Vibsane型总二萜浸膏4.66g。利用紫外-可见光 分光光度法,以15-O-methylvibsanin H为对照品,按照此方法制备的珊瑚树叶Vibsane型总 二萜含量以标准曲线法,在230.5nm的波长处,配置标准曲线并测定吸光度,检测结果显示 所得珊瑚树叶Vibsane型总二萜得含量为69.268%。
实施例4
一种珊瑚树叶中Vibsane型总二萜的制备方法,包括如下步骤:
将珊瑚树叶日光下晒干,用体积浓度为80%甲醇提取,减压浓缩得到珊瑚树叶提取物; 提取次数为:4次;
将所得的珊瑚树叶提取物用石油醚萃取,除去脂肪酸等小极性成分;
将粗提物进一步用乙酸乙酯以珊瑚树叶提取物:乙酸乙酯萃取液1:2的体积比例进行萃 取,重复三次并合并,减压回收溶剂;
将乙酸乙酯萃取所得粗提物利用D-101大孔吸附树脂柱色谱以乙醇-水中,乙醇的质量浓 度为30%、60%、90%进行梯度洗脱得到三个流分A1、A2、A3;
对流分A3减压回收溶剂,即得到Vibsane二萜含量较高得粗流分。
实施例5
一种珊瑚树叶中Vibsane型总二萜的制备方法,包括如下步骤:
将珊瑚树叶日光下晒干,用体积浓度为75%甲醇提取,减压浓缩得到珊瑚树叶提取物; 提取次数为:3次;
将所得的珊瑚树叶提取物用石油醚萃取,除去脂肪酸等小极性成分;
将粗提物进一步用乙酸乙酯以珊瑚树叶提取物:乙酸乙酯萃取液1:3的体积比例进行萃 取,重复三次并合并,减压回收溶剂;
将乙酸乙酯萃取所得粗提物利用HP-20大孔吸附树脂柱色谱以乙醇-水中,乙醇的质量浓 度为30%、60%、90%进行梯度洗脱得到三个流分A1、A2、A3;
对流分A3减压回收溶剂,即得到Vibsane二萜含量较高得粗流分。
实施例6
一种珊瑚树叶中Vibsane型总二萜的制备方法,包括如下步骤:
将珊瑚树叶日光下晒干,用体积浓度为80%乙醇提取,减压浓缩得到珊瑚树叶提取物; 提取次数为:4次;
将所得的珊瑚树叶提取物用石油醚萃取,除去脂肪酸等小极性成分;
将粗提物进一步用乙酸乙酯以珊瑚树叶提取物:乙酸乙酯萃取液1:2的体积比例进行萃 取,重复三次并合并,减压回收溶剂;
将乙酸乙酯萃取所得粗提物利用D-101大孔吸附树脂柱色谱以乙醇-水中,乙醇的质量浓 度为30%、60%、90%进行梯度洗脱得到三个流分A1、A2、A3;
对流分A3减压回收溶剂,即得到Vibsane二萜含量较高得粗流分,即为。
应用例1
用实施例1~3制备得到的珊瑚树叶Vibsane型总二萜,对人肝癌HepG2,Hep3B及人乳腺 癌MCF-7细胞增殖有明显的抑制作用。
采用改良MTT法:将融合为单层的HepG2、Hep3B和MCF-7肿瘤细胞消化为单细胞 悬浮液,加入96孔培养板中,90μL/孔。在37℃、5%CO2培养箱中孵育24h后,加入一 定浓度的受试样品,10μL/孔。受试样品组设置3个复孔。阴性对照为等体积的PBS,阳性 对照为顺铂(DDP),继续孵育48小时后,每孔加入10μl的MTT溶液5mg/ml,10μL/孔, 避光37℃孵育2-4h;每孔加入100μl的MTT溶解buffer(20%SDS,1M HCl),37℃孵育 至结晶完全溶解;利用全自动酶标仪读取570nm及490nm处的吸光度,计算OD(570) -OD(490)的数值作为每孔的OD值;根据以下公式计算计算相对抑制率:细胞相对抑制 率(%)=100%-(实验组OD值/对照组平均OD值)×100%。用SPSS12.0软件计算各样 品的IC50值,结果见表1。
表1本发明Vinsane型总二萜对三种肿瘤细胞的抑制作用
应用例2
用实施例4~6制备得到的珊瑚树叶Vibsane型总二萜,对人肝癌HepG2,Hep3B及人乳腺 癌MCF-7细胞增殖有明显的抑制作用。
所述的珊瑚树叶的Vibsane型总二萜具有比珊瑚树叶总提物更强的肝癌、乳腺癌细胞的 抑制活性,并且可以抑制裸鼠移植HepG2、Hep3B、MCF-7肿瘤的生长。
采用改良MTT法,测试珊瑚树叶的Vibsane型总二萜对人肝癌HepG2细胞株,Hep3B细胞株及乳腺癌MCF-7细胞株的体外抗肿瘤作用进行评估。实验结果表明珊瑚树叶的Vibsane 型总二萜在体外对上述三种细胞株具有显著的细胞增殖抑制活性,IC50值分别为11.11μg/ml, 9.64μg/ml,14.62μg/ml(见表2)。
表2珊瑚树总提物与Vibsane型总二萜对多种肿瘤细胞抑制作用的考察。
通过表2说明Vibsane型总二萜对肿瘤细胞的抑制作用具有选择性,并非对所有肿瘤细 胞都均有抑制作用。
实施例5
用实施案列1~3制备得到的Vibsane型总二萜,对人肝癌Hep3B裸鼠移植瘤的生长具有 明显的抑制作用。
取对数生长期Hep3B细胞,经胰酶消化后离心收集细胞,用PBS清洗一次后同转速再次 离心,对得到的细胞采用无血清DMEM配成细胞悬液并控制细胞密度为1×107/mL。所用动 物为SPF级BALB/c无胸腺裸鼠,雄性,6-8周龄,体重18-22g。实验育种严格遵守SPF级标准的要求。在无菌条件下,用1mL胰岛素针向每只裸鼠背后右侧前肢皮下旁进行注射Hep3B细胞悬液0.2mL。注射后每日观测裸鼠状况和皮下的肿瘤生长情况,当裸鼠皮下出现粟粒大小的结节时表示裸鼠模型构建成功。当肿瘤体积大约到100mm3时,将5只小鼠随机分配为一组,共4组。低剂量组为100mg/kg的Vibsane型总二萜,高剂量为200mg/kg的Vibsane型总二萜,阳性药组为30mg/kg的索拉非尼,对照组注射相同体积的生理盐水,均采用灌胃给药的方式,每2天一次,连续给药2周。结果表明经低剂量组及高剂量组Vibsane二萜给药后,小鼠肿瘤体积随时间显著减小,说明Vibsane型总二萜对人肝癌Hep3B裸鼠移植瘤的生长具有明显的抑制作用(图1、图2和图3)。
每次裸鼠给药前均观察并记录各组裸鼠体重、摄食、饮水、活动能力、大便形态、精神 状态、反应及接种部位移植瘤的生长情况。给药期间,每天需用游标卡尺测量裸鼠肿瘤长径 (L)和短径(W),肿瘤体积计算公式:V=0.5236×L×W2,并分别计算四组肿瘤的平均体 积,数据表示为mean±SD,并绘制为肿瘤生长随时间变化曲线。待药物干预2周后停止实验并按公式抑瘤率(%)=[(V(control group)-V(drug groups))/V(control group)]×100%计算肿 瘤体积与肿瘤生长抑制率。实验结果表明,与索拉菲尼对照组相比,Vibsane型总二萜干预期 间裸鼠体重无显著改变(图4)。
化合物作用结束后,每只裸鼠腹腔注射1mL 10%水合氯醛进行深度麻醉处死并拍照。用 消毒后的手术器械将移植瘤完整剥离,取出每只裸鼠的重要器官(心、肝、脾、肺、肾),用 电子分析天平称重、记录。取出的肿瘤及器官组织用0.85%生理盐水漂洗以洗去血液及物质, 然后用手术刀切成适当的组织块。将每组每只裸鼠的肿瘤及器官组织分成两份,一份浸泡于 10%中性福尔马林溶液固定(组织块体积与10%中性福尔马林溶液体积的比例约为1:20),另 一份包装好后置于-80℃长期保存,并做好标记(图5)。将裸鼠脏器组织浸没于4%中性福尔马 林中固定,将固定好的脏器组织放置于包埋盒中,放入组织自动脱水机上,经梯度酒精(70%、 80%、90%、95%和100%)脱水。经透明及充分浸蜡后,对组织进行包埋并切片,石蜡切片 厚度为5μm。65℃烤箱烘烤3h,常温保存,备用。依次将切片放入二甲苯Ⅰ10min,二甲 苯Ⅱ10min,无水乙醇Ⅰ5min,无水乙醇Ⅱ5min,95%乙醇5min,90%乙醇5min,80% 乙醇5min,70%乙醇5min,蒸馏水洗。切片入Harris苏木素染3-8min,自来水洗,1%的 盐酸酒精分化数秒,自来水冲洗,0.6%氨水返蓝,流水冲洗。切片入伊红染液中染色1-3min。 紧接着将切片依次放入95%乙醇I 5min,95%乙醇II 5min,无水乙醇Ⅰ5min,无水乙醇Ⅱ5 min,二甲苯Ⅰ5min,二甲苯Ⅱ5min中脱水透明,将切片从二甲苯拿出来稍晾干,中性树 胶封片,在显微镜下观察(图6)。结果表明Vibsane型总二萜流分对裸鼠的心肝脾肺肾无明显 的影响。
将裸鼠脏器组织浸没于4%中性福尔马林中固定,将固定好的脏器组织放置于包埋盒中, 放入组织自动脱水机上,经梯度酒精(70%、80%、90%、95%和100%)脱水。经透明及充 分浸蜡后,对组织进行包埋并切片,石蜡切片厚度为5μm。65℃烤箱烘烤3h,常温保存, 备用。首先进行将石蜡切片置于摊片机上,50-60℃,摊片40-50min,用于固定切片上的病 理组织。按如下步骤进行脱蜡:二甲苯Ⅰ(20min),二甲苯Ⅱ(20min),100%乙醇Ⅰ(10min)100%乙醇Ⅱ(10min),95%的乙醇(5min),85%乙醇(5min),75%乙醇(5min),蒸馏水 洗3次(3min),PBS缓冲液清洗3次(3min)。每张组织切片加一滴过氧化酶阻断溶液(3% H2O2)37℃孵育20min,PBS缓冲液洗片3次,每次5min;组织切片在柠檬酸盐缓冲液中 加热以进行抗原修复。然后,在室温下用正常山羊血清处理切片20min。并在4℃下用一级 抗体孵育过夜。组织切片室温复温45min,回收一抗,PBS缓冲液洗片3次(5min);每张 组织切片滴加一滴生物素标记的山羊抗鼠IgG二抗,37℃孵育30min,甩去二抗,PBS缓冲 液洗片3次(5min);甩去PBS缓冲液,每张组织切片滴加一滴链霉素抗生物素-过氧化物酶 溶液,37℃孵育30min,PBS缓冲液洗片3次,每次5min;最后,用DAB染色,用中性树 脂密封,自然风干,在显微镜下观察。抗体包括Ki67、Bax、p-AKT(图7)。结果表明Bax阳 性比例明显增加,Ki67以及p-AKT的阳性比例下降,表明Vibsane型总二萜可以明显抑制 Hep3B细胞异种移植模型的生长。
综合以上分析结果表明,Vibsane型总二萜可以明显的抑制Hep3B裸鼠移植瘤的体积和 大小,且对小鼠体重及主要脏器物明显影响,在体内安全有效。
Claims (10)
1.一种珊瑚树叶中Vibsane型总二萜的制备方法,其特征在于,包括以下步骤:
步骤1:
将珊瑚树叶用提取溶剂提取,得到提取物;
将提取物用石油醚萃取除油,并用乙酸乙酯萃取,去除溶剂,干燥,得到粗浸膏;
步骤2:
将粗浸膏用大孔吸附树脂柱色谱进行梯度洗脱,洗脱溶剂为乙醇-水溶液,收取90%馏分,去除洗脱溶剂,即为珊瑚树叶中Vibsane型总二萜。
2.根据权利要求1所述的珊瑚树叶中Vibsane型总二萜的制备方法,其特征在于,所述的步骤1中,提取采用的提取溶剂为甲醇或乙醇,甲醇或乙醇的体积浓度70~80%,提取次数为3~5次;
和/或,乙酸乙酯萃取时,按体积比,提取物:乙酸乙酯=1:(2~3)。
3.根据权利要求1所述的珊瑚树叶中Vibsane型总二萜的制备方法,其特征在于,所述的步骤2中,大孔吸附树脂柱色谱中,大孔吸附树脂选用D-101大孔吸附树脂或HP-20大孔吸附树脂中的一种;
和/或,梯度洗脱采用的乙醇-水溶液中,乙醇的质量百分比梯度为30%,60%,90%。
4.一种珊瑚树叶中Vibsane型总二萜,其特征在于,通过权利要求1-3任意一项所述的制备方法制得,其珊瑚树叶中Vibsane型总二萜的Vibsane型总二萜的质量百分含量≥65%。
5.一种药物组合物,其特征在于,包含权利要求4所述的珊瑚树叶中Vibsane型总二萜和药学上可接受的载体或赋形剂。
6.权利要求4所述的珊瑚树叶中Vibsane型总二萜或权利要求5所述的药物组合物作为预防或治疗抗肿瘤药物的应用。
7.权利要求6所述的应用,其特征在于,抗肿瘤药物为抗肝癌药物或抗乳腺癌药物。
8.权利要求6所述的应用,其特征在于,抑制体外肿瘤细胞生长的活性,更具体的肿瘤细胞为HepG2细胞株,Hep3B细胞株,MCF-7细胞株。
9.权利要求8所述的应用,其特征在于,抗肿瘤药物中珊瑚树叶中Vibsane型总二萜作用于HepG2细胞株的IC50值为11.11~11.21μg/mL,抗肿瘤药物中珊瑚树叶中Vibsane型总二萜作用于Hep3B细胞株的IC50值为9.64~9.82μg/mL,抗肿瘤药物中珊瑚树叶中Vibsane型总二萜作用于MCF-7细胞株的IC50值为14.62~15.74μg/mL。
10.权利要求6所述的应用,其特征在于,所述的珊瑚树叶中Vibsane型总二萜或所述的药物组合物,适用于体内抗癌活性,且未表现出明显毒性。
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