CN103845314B - 一种丹参新酮在制备抗肿瘤药物中的应用 - Google Patents
一种丹参新酮在制备抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种丹参新酮在制备抗肿瘤药物中的应用,丹参新酮为式I结构。丹参新酮作为STAT3的抑制剂,其具有抑制STAT3异常激活的肿瘤细胞的生长和增殖从而引起肿瘤细胞凋亡,同时可以增强细胞毒药物的敏感性和抑制肿瘤血管形成。本发明式I结构的丹参新酮通过抑制STAT3激酶Tyr705磷酸化水平达到促进肿瘤细胞凋亡、化疗药物增敏和抑制新生血管形成的功效。丹参新酮在低毒或无毒浓度与低毒或无毒浓度的阿霉素联用以及丹参新酮和低毒或无毒浓度的顺铂联合应用能显著抑制肿瘤细胞增殖。式I结构的丹参新酮上述功效对预防肿瘤和治疗肿瘤都具有积极的意义。
Description
技术领域
本发明涉及丹参新酮的应用领域,具体涉及一种丹参新酮在制备抗肿瘤药物中的应用。
背景技术
恶性肿瘤及其并发症严重威胁人类生命健康,且其发病率呈逐年快速上升的趋势。世界卫生组织统计数据显示,2000年全世界新发恶性肿瘤患者近1000万例,其发病率仅次于心脑血管疾病。现阶段肿瘤治疗手段包括外科手术治疗、化学疗法、放射治疗等。目前首选的治疗手段为手术切除,但手术切除仅适用于少部分早期局限性肿瘤患者,且术后常伴有复发和转移。因此,化疗是现阶段最常用的肿瘤治疗方法,常规的化疗药物如阿霉素、顺铂、5-氟尿嘧啶等,存在毒副作用大、患者的耐受性差、易转移复发等问题。近年来研发的新型分子靶向药物如盐酸厄洛替尼、吉非替尼、PI3K抑制剂,存在易耐药、价格贵等问题。因此,研究新的治疗药物或新的化疗配伍以提高肿瘤患者生存期及改善患者的生存质量具有非常重要的意义。
信号传导与转录激活因子3(SignalTransducerandActivatorofTranscription3,简称STAT3)与肿瘤发生、转移侵袭、肿瘤新生血管生成、化疗抗性密切相关。大量研究表明,肺癌、胃癌、头颈部癌、乳腺癌、多发性骨髓瘤和其它血液系统恶性肿瘤中STAT3异常激活。STAT3结构域包括N-端的四聚体和亮氨酸拉链、SNA结合域和羧基端的SH2激活区。STAT3蛋白通过SH2结构域相互结合形成二聚体,迅速移位至核内,与特异的DNA启动子序列结合,启动相应的基因如抗凋亡基因Bcl-2、Bcl-Xl、Mcl-1、Xiap和survivin、细胞周期调控基因cyclinD1和c-myc、血管生成因子VEGF、基质金属酶mmp2/9的表达,促进肿瘤细胞增殖、存活、凋亡抗性、肿瘤新生血管形成及转移侵袭。因此,STAT3在肿瘤发生、化疗耐药、转移侵袭等方面发挥重要的调控作用。最新研究发现,抑制STAT3酪氨酸Tyr705水平可阻断肿瘤细胞异常活化的STAT3信号通路,进而促肿瘤细胞凋亡、抑制肿瘤新生血管形成和转移侵袭,与化疗药物联合应用可发挥增效减毒的功效。因此,研制新型STAT抑制剂有望为肿瘤治疗提供新的方法和新的途径。
丹参始载于汉代的《神农本草经》,具有活血祛淤和凉血消痈等功效。丹参新酮是从丹参中提取的二萜菲醌类化合物,现代药理学研究表明,丹参新酮具有抗氧化(JAgricFoodChem.2002Mar27;50(7):1845-51)、抗焦虑(Phytomedicine.2013Feb15;20(3-4):367-74.)、抑制肿瘤细胞增殖(MolCancerTher.2008Jan;7(1):152-61.)和减少酒精体内摄入(AlcoholClinExpRes.2006May;30(5):754-62.)的功效。但迄今尚无相关研究报道丹参新酮具有诱导肿瘤细胞凋亡、化疗药物增敏和抑制新生血管形成的功效。
发明内容
本发明提供了一种丹参新酮在制备抗肿瘤药物中的应用,丹参新酮作为STAT3的抑制剂,其具有抑制STAT3异常激活的肿瘤细胞的生长和增殖从而引起肿瘤细胞凋亡,同时可以增强细胞毒药物的敏感性和抑制肿瘤血管形成。
一种丹参新酮,为式I结构:
本发明还提供了一种丹参新酮的制备方法,制备简单,可操作性强。
一种丹参新酮的制备方法,包括以下步骤:
1)丹参药材用乙醇水溶液提取,得到乙醇提取物,将乙醇提取物用石油醚、二氯甲烷、正丁醇依次萃取,分别得到石油醚层、二氯甲烷层、正丁醇层;
2)将二氯甲烷层用硅胶柱层析法分离,采用石油醚和乙酸乙酯体系进行梯度洗脱,将石油醚和乙酸乙酯体积比7~9:1的洗脱部分用反相液相色谱进行分离,得到式I结构的丹参新酮。
步骤1)中,作为优选,所述的丹参药材与乙醇水溶液的重量比为1:5~11,提取2~5次,上述用量的乙醇水溶液能够将丹参药材中的有效成分充分提取,特别是能够将丹参药材中的式I结构的丹参新酮充分提取。
作为优选,所述的乙醇水溶液中乙醇的质量百分数为92%~98%,不同乙醇质量百分数的乙醇水溶液的极性略有不同,从而会使得提取的有效成分有略微差别,其中,最优选的是,所述的乙醇水溶液中乙醇的质量百分数为95%,最适合丹参药材中的式I结构的丹参新酮充分提取。
步骤2)中,所述的硅胶柱层析法具体包括:先将二氯甲烷层溶于乙酸乙酯,再加层析硅胶拌样,得到拌样,用层析硅胶湿法装柱,向柱子中加入拌样,然后采用石油醚和乙酸乙酯体系进行梯度洗脱。进一步优选,所述的梯度洗脱为:依次采用石油醚和乙酸乙酯体积比100:1、50:1、20:1、16:1、10:1、8:1、6:1、4:1、3:1、2:1、1.5:1、1:1、1:1.5、1:2、1:3、1:5、1:10、1:50的石油醚和乙酸乙酯体系进行洗脱。更进一步优选,将石油醚和乙酸乙酯体积比8:1的洗脱部分用反相液相色谱进行分离。所述的反相液相色谱的条件为:采用乙腈和水作为洗脱体系,洗脱条件:0-60min,乙腈的质量百分数为50%-93%(即在0到60min,洗脱体系中乙腈的质量百分数从50%变为93%),洗脱46-47min即得到式I结构的丹参新酮。
式I结构的丹参新酮是从唇形科植物丹参干燥根及根茎(即丹参药材)中分离纯化获得的二萜菲醌类化合物,具有抗肿瘤功效。
所述的式I结构的丹参新酮可用于制备抗肿瘤药物。式I结构的丹参新酮可用于STAT3异常激活的抑制剂,用于制备的抗肿瘤药物对多种肿瘤细胞有效,预示该化合物可用于包括肺癌、胃癌、骨髓癌、乳腺癌、前列腺癌、肝癌、鼻咽癌、白血病等肿瘤细胞的治疗。因此,丹参新酮作为一种新型的STAT3抑制剂,具有良好的临床应用前景。式I结构的丹参新酮具有抗肿瘤功效主要通过抑制STAT3激酶705位酪氨酸(Tyr705)的磷酸化水平进而调控STAT3下游Survivin、Bcl-2及Xiap等靶基因的转录达到促肿瘤细胞凋亡的目的。
用于制备抗肿瘤药物时,所述的肿瘤包括:肺癌、胃癌、骨髓癌、乳腺癌、前列腺癌、肝癌、鼻咽癌、白血病等。
一种抗肿瘤药物的有效成分组合物,由以下摩尔比的组分组成:
式I结构的丹参新酮7.5~10;
阿霉素5.5×10-4~9.2×10-4。
另一种抗肿瘤药物的有效成分组合物,由以下摩尔比的组分组成:
式I结构的丹参新酮7.5~10;
顺铂6~8。
上述摩尔比的式I结构的丹参新酮和阿霉素(CA号:23214-92-8)联合应用或者丹参新酮和顺铂联合应用后,具有协同作用,效果要明显优于两者的简单相加,具有明显的细胞毒功效,为肿瘤患者提供了新的治疗候选药物和新的治疗配伍。
本发明式I结构的丹参新酮,具有抑制新生血管形成的功效,可用于制备抑制新生血管药物。
通过实验,本发明证实丹参新酮抑制STAT3Tyr705磷酸化水平,下调STAT3下游抗凋亡蛋白survivin、Bcl-2和XIAP的蛋白表达水平。本发明的丹参新酮通过抑制STAT3激酶Tyr705磷酸化水平达到促进肿瘤细胞凋亡、化疗药物增敏和抑制新生血管形成的功效。丹参新酮和阿霉素联合应用,或者,丹参新酮和顺铂联合应用,均能够显著抑制肿瘤细胞增殖。
与现有技术相比,本发明具有如下优点:
本发明式I结构的丹参新酮通过抑制STAT3激酶Tyr705磷酸化水平达到促进肿瘤细胞凋亡、化疗药物增敏和抑制新生血管形成的功效。丹参新酮在低毒或无毒浓度与低毒或无毒浓度的阿霉素联用以及丹参新酮和低毒或无毒浓度的顺铂联合应用能显著抑制肿瘤细胞增殖。就当前治疗肿瘤药物及其而言,为临床医生在药物选择上提供了一种新的手段和新的配伍,为肿瘤患者带来新的希望。式I结构的丹参新酮上述功效对预防肿瘤和治疗肿瘤都具有积极的意义。
附图说明
图1为丹参新酮对肿瘤细胞NCI-H1975STAT3酪氨酸705位点和丝氨酸727位点磷酸化水平的影响对比图;
图2为丹参新酮对肿瘤细胞NCI-H1975STAT3上游调控激酶P-src/jak2磷酸化水平的影响对比图;
图3为丹参新酮抑制肿瘤细胞NCI-H1975STAT3下游基因Bcl-2、survivin和Xiap的蛋白表达水平的对比图;
图4为免疫荧光检测丹参新酮对NCI-H1975STAT3转录活性检测的效果对比图;
图5为荧光素酶检测丹参新酮抑制NCI-H1975STAT3的转录活性图;
图6为丹参新酮诱导肺癌细胞NCI-H1975凋亡相关caspase活化和PARP剪切的对比图;
图7为丹参新酮和阿霉素联合应用的协同抗肺癌NCI-H1975的作用效果对比图;
图8为丹参新酮和顺铂联合应用的协同抗肺癌NCI-H1975的作用效果对比图;
图9为丹参新酮对EAhy926细胞新生血管环形成的抑制作用图。
具体实施方式
下面结合具体实例进一步解释
实施例1:为了进一步理解本发明,下面就式I结构的丹参新酮制备进行详细说明,在此,本发明提供一种制备方法或合成技术。
丹参药材(3kg)用8倍重量的乙醇质量百分数为95%乙醇水溶液提取,每次24Kg丹参药材,共3次,合并得到乙醇提取物,乙醇提取物用石油醚、二氯甲烷、正丁醇依次萃取,分别得到石油醚层、二氯甲烷层、正丁醇层。
将二氯甲烷层(70g)溶于100mL乙酸乙酯,加70g200-300目层析硅胶拌样,得到拌样。以300g200-300目层析硅胶湿法装柱,将拌样加入,固定柱子。用石油醚冲洗柱子,直到柱子内充满液体后换上石油醚和乙酸乙酯体系,先以石油醚:乙酸乙酯体积比(100:1)流动相进行洗脱,具体分别以石油醚:乙酸乙酯体积比100:1,50:1,20:1,16:1,10:1,8:1,6:1,4:1,3:1,2:1,1.5:1,1:1,1:1.5,1:2,1:3,1:5,1:10,1:50进行洗脱,每个梯度洗脱容积为1.6L,分成4瓶,每瓶400mL。将所得溶液浓缩,浓缩液转移至10mL青霉素瓶,点板分析后将相同样品进行合并。对石油醚:乙酸乙酯体积比8:1洗脱的部分进行分离,主要分离方法为反相液相色谱。反相液相色谱的条件为:采用乙腈和水作为洗脱体系,以梯度乙腈/水0-60min从洗脱体系中乙腈的质量百分数50%-93%进行洗脱,洗脱46.5min即得到式I结构的丹参新酮。式I结构的丹参新酮的NMR数据如表1所示:
表1
实施例2:丹参新酮抑制肺癌细胞NCI-H1975p-stat3-tyr(705)的激活,对p-stat3-ser没有抑制
肺癌细胞NCI-H19754H(0,5μM,10μM,20μM)处理后,免疫印迹技术检测p-STAT3-tyr(705)、p-STAT3-ser(727)、STAT3[(抗体均购自CST公司(CellSignalingTechnology,Inc)],实验结果表明,随着浓度的增加,p-STAT3-tyr(705)呈现明显下降趋势,而p-STAT3-ser(727)则没有变化,具体结果见图1。
具体实施方法如下:
取对数生长期的肺癌细胞NCI-H1975,配制成单细胞悬液,计数1×106/瓶加入5mL培养瓶中,隔天待细胞贴壁后,加入不同浓度(0,5μM,10μM,20μM)的药物,4h后收集细胞样本至15ml离心管,800rpm/5min,弃上清后转移细胞至1.5mLEP管(离心管)中,在5000rpm离心3min,弃上清后再次在5000rpm离心3min,吸干上清液后将细胞样本储存在-80℃或直接进行裂解。细胞裂解时,向细胞团中加入含1%(wt)磷酸化酶抑制剂的RIPA裂解液,立即吹打均匀。置于冰上,每隔10min吹打若干次并用涡旋振荡器涡旋。30min后,在13000rpm、4℃下离心15min,取上清,即为蛋白溶液。采用双缩脲法检测蛋白浓度,蛋白溶液中加等体积2*上样缓冲液,100度水浴变性5min后置于冰上冷却,蛋白溶液置于-20℃保存或直接Westernblot(蛋白质印迹法)上样。根据检测蛋白的分子量大小配置(8%-12%)聚丙烯酰胺凝胶,加样后电泳,根据分子量分离后的蛋白质转移至PVDF膜上,转膜装置购于Bio-Rad公司。转膜后用5%(wt)的脱脂奶粉封闭PVDF膜1h,4℃过夜孵育相应的抗体(Antirabbitp-stat3-tyr(705),Antirabbitp-stat3-ser,Antimousestat3,AntiRabbitβ-actin)第二天用洗膜缓冲液TBST每10min洗膜1次,共3次,TBST稀释相对应的二抗(IgG-Rabbit),室温25℃孵育2h,TBST每10min洗膜1次,共3次。ECL试剂盒,孵育PVDF膜1min,暗室检测曝光。
实验例3:丹参新酮对肺癌细胞NCI-H1975的Stat3上游调控激酶P-Src和P-jak2磷酸化水平的影响。
肺癌细胞NCI-H1975(0,5μM,10μM,20μM)4H处理后,免疫印迹技术检测P-jak2、P-Src、β-actin[(抗体均购自CST公司(CellSignalingTechnology,Inc)],实验结果表明,STAT3上游激酶均没有明显变化,具体结果见图2。
具体实施方法与实施例2中基本一致。
实验例4:WestronBlot检测丹参新酮抑制肺癌细胞NCI-H1975stat3下游基因Bcl-2、survivin和Xiap的蛋白表达水平
肺癌细胞NCI-H1975药物24h处理后,免疫印迹技术检测Bcl-2、survivin、XIAP和内参β-actin[(抗体均购自CST公司(CellSignalingTechnology,Inc)],实验结果表明,stat3下游抗凋亡基因Bcl-2、survivin和XIAP的蛋白表达水平明显下降,具体结果见图3。
具体实施方法如下:
取对数生长期的肺癌细胞NCI-H1975,配制成单细胞悬液,计数1×106/瓶加入5mL培养瓶中,隔天待细胞贴壁后,加入不同浓度(0,5μM,10μM,20μM)的药物,24h后收集细胞样本至15ml离心管,在800rpm离心5min,弃上清后转移细胞至1.5mLEP管(离心管)中在5000rpm离心3min,弃上清后再次在5000rpm离心3min,吸干上清液后将细胞样本储存在-80℃或直接进行裂解。细胞裂解时,向细胞团中加入RIPA裂解液,立即吹打均匀。置于冰上,每隔10min吹打若干次并用涡旋振荡器涡旋。30min后,在13000rpm、4℃下离心15min,取上清,即为蛋白溶液。采用双缩脲法检测蛋白浓度,蛋白溶液中加等体积2*上样缓冲液,100度水浴变性5min后置于冰上冷却,蛋白溶液置于-20℃保存或直接Westernblot上样。根据检测蛋白的分子量大小配置(8%-12%)聚丙烯酰胺凝胶,加样后电泳,根据分子量分离后的蛋白质转移至PVDF膜上,转膜装置购于Bio-Rad公司。转膜后用5%的脱脂奶粉封闭PVDF膜1h,4℃过夜孵育相应的抗体(Antirabbitp-stat3-tyr(705),Antirabbitp-stat3-ser(727),Antimousestat3,AntiRabbitβ-actin)第二天用洗膜缓冲液TBST每10min洗膜1次,共3次,TBST稀释相对应的二抗(IgG-Rabbit),室温25℃孵育2h,TBST每10min洗膜1次,共3次。ECL试剂盒,孵育PVDF膜1min,暗室检测曝光。
实验例5:免疫荧光技术检测丹参新酮对NCI-H1975STAT3转录活性检测
肺癌细胞NCI-H1975(0,20μM)4h处理后,激光共聚焦检测STAT3入核情况,用药组(20μM)与空白组(control)相比,用药组细胞核内亮点明显减少,表明用药组STAT3入核情况明显受到抑制,具体结果见图4,merge是指STAT3和DAPI染色后的照片合并之后的情形。
具体实施方法如下:
取对数生长的肺癌细胞NCI-H1975,配制成单细胞悬液,计数为1×105/ml,将预先消毒好的盖波片置于12孔板中,接种1ml细胞悬液于12孔板中,第二天待细胞贴壁后加药组用丹参新酮20μM处理肺癌细胞NCI-H19754h,弃上清,PBS洗涤三次,4%(wt)多聚甲醛室温25℃固定30min,PBS洗涤三次,后0.5%(wt)TritonX-100透化5min,再用1:100的STAT3(购自美国CST公司)4度孵育过夜,隔天用PBS洗涤三次,遂后2hAnti-RabbitIgG二抗(购自美国CST公司),DAPI染色30min,将盖波片从24孔板中取出,凉干,用含抗猝灭的封片剂封片,后可用激光共聚焦拍照。
实验例6:荧光毒酶检测丹参新酮对肺癌细胞NCI-H1975STAT3转录活性检测
肺癌细胞NCI-H1975用pSTAT3-TA-luc(报告基因质粒)和海肾以7:1转染后加药(0,5μM,10μM,20μM)8h处理后,用双荧光素酶报告基因试剂盒检测STAT3活性。实验结果表明,丹参新酮作用肺癌细胞NCI-H1975后STAT3的活性受到明显抑制,结果见图5,其中control为空白,即加药为0,其中,横坐标为加药浓度,单位为μΜ,纵坐标为STAT3活性。
具体实施方法如下:
取对数生长的肺癌细胞NCI-H1975,配制成单细胞悬液,计数为1×105/ml,接种1ml细胞悬液于12孔板中,待细胞贴壁后用pSTAT3-TA-luc和海肾以7:1的比例转染24h,弃上清,加药组用丹参新酮(0,5μM,10μM,20μM)处理NCI-H1975肺癌细胞8H,遂后按照双荧光素酶报告基因试剂盒操作步骤即可。
实验例7:丹参新酮诱导肿瘤细胞的凋亡
肺癌细胞NCI-H1975(0,5μM,10μM,20μM)24H处理后,免疫印迹技术检测Cle-caspase3/9、Cle-PARP、β-actin(抗体均购自CST公司),实验结果表明,丹参新酮能诱导细胞凋亡,随着浓度的增加,凋亡标记蛋白Cle-caspase3/9、Cle-PARP明显升高,具体结果见图6。
具体实施方法与实施例2中基本一致。
丹参新酮对肺癌细胞NCI-H1975的抑制作用
肺癌细胞NCI-H1975加药后24h、48h、72h,MTT法检测细胞抑制率。实验结果表明,用药组与空白(control)组相比,用药组可明显降低各种细胞的OD值,表明丹参新酮可显著抑制肿瘤细胞的增殖,抑制率与浓度具有较好的剂量与效应依赖关系,结果见表2。
表2
具体实施方法如下:
取对数生长期肺癌NCI-H1975细胞,配制成单细胞悬液,计数5×104/ml,加入96孔板中,每孔200ul,加入不同浓度的药物((0,5μM,10μM,20μM)24h、48h、72h后加入CCK8(购自达文科技有限公司,为日本同仁公司生产)孵育2-4小时后用全波长酶标仪(Thermo)波长450μm检测OD值,细胞相对存活率=(OD加药组-OD背景颜色)/(OD空白-OD背景颜色)。
实验例8:丹参新酮增强凋亡诱导剂敏感性
丹参新酮在低毒或无毒浓度(7.5~10μM)与低毒或无毒浓度(0.25~0.5μg,即4.6×10-4~9.2×10-4μM)阿霉素和丹参新酮在低毒或无毒浓度(7.5~10μM)与低毒或无毒浓度(6~8μM)顺铂联合作用于肺癌细胞NCI-H1975,随着浓度的增加和时间的延长,发现细胞凋亡率明显增加,细胞毒性增强,表明联合抑制肺癌细胞NCI-H1975增殖效果佳,结果见图7和图8,其中图7为丹参新酮(miltrone)在低毒或无毒浓度(7.5~10μM)与低毒或无毒浓度(0.25~0.5μg,即4.6×10-4~9.2×10-4μM)阿霉素(DOX)联用和单独使用的对比图,图8为丹参新酮(miltrone)在低毒或无毒浓度(7.5~10μM)与低毒或无毒浓度(6~8μM)顺铂(DDP)联用和单独使用的对比图,图7和图8中右栏中的从上到下依次对应横坐标中的从左到右。
具体实施方法如下:
取对数生长期细胞—肺癌细胞NCI-H1975,配制成单细胞悬液,计数5×104/mL加入200μl于96孔板中,隔天待细胞贴壁后,加入不同浓度的药物,丹参新酮选取7.5~10μM、阿霉素选取0.25~0.5μg、顺铂选取6~8μM,分别设空白对照组、单药组及丹参新酮与阿霉素联合用药组和丹参新酮与顺铂联合用药组,24H后加入CKK(购自日本同仁公司)孵育2-4小时后用全波长酶标仪(Thermo)波长450um检测OD值,细胞相对存活率=(OD加药 组-OD背景颜色)/(OD空白-OD背景颜色)。
实验例9:丹参新酮抑制肿瘤血管形成实验
式I结构的丹参新酮作用于细胞后,随着化合物浓度的增加,能显著抑制管腔的形成,说明具有潜在的肿瘤血管生成抑制作用,结果见图9。
Claims (5)
1.一种丹参新酮在制备抗肿瘤药物中的应用,其特征在于,所述的丹参新酮为式I结构:
所述的肿瘤为肺癌、胃癌、骨髓癌、乳腺癌、前列腺癌、肝癌、鼻咽癌或者白血病;
所述的抗肿瘤药物的有效成分组合物,由以下摩尔比的组分组成:
式I结构的丹参新酮7.5~10;
阿霉素4.5×10-4~9.2×10-4;
或者,所述的抗肿瘤药物的有效成分组合物,由以下摩尔比的组分组成:
式I结构的丹参新酮7.5~10;
顺铂6~8。
2.根据权利要求1所述的应用,其特征在于,所述的丹参新酮的制备包括:
1)丹参药材用乙醇水溶液提取,得到乙醇提取物,将乙醇提取物用石油醚、二氯甲烷、正丁醇依次萃取,分别得到石油醚层、二氯甲烷层、正丁醇层;
2)将二氯甲烷层用硅胶柱层析法分离,采用石油醚和乙酸乙酯体系进行梯度洗脱,将石油醚和乙酸乙酯体积比7~9:1的洗脱部分用反相液相色谱进行分离,得到式I结构的丹参新酮。
3.根据权利要求2所述的应用,其特征在于,步骤1)中,所述的丹参药材与乙醇水溶液的重量比为1:5~11,所述的乙醇水溶液中乙醇的质量百分数为92%~98%。
4.根据权利要求2所述的应用,其特征在于,步骤2)中,所述的硅胶柱层析法具体包括:先将二氯甲烷层溶于乙酸乙酯,再加层析硅胶拌样,得到拌样,用层析硅胶湿法装柱,向柱子中加入拌样,然后采用石油醚和乙酸乙酯体系进行梯度洗脱。
5.根据权利要求2所述的应用,其特征在于,步骤2)中,所述的反相液相色谱的条件为:采用乙腈和水作为洗脱体系,洗脱条件:0-60min,乙腈的质量百分数为50%-93%,洗脱46-47min得到式I结构的丹参新酮。
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