CN116496332B - 一种半日花烷型二萜苷化合物及其制备方法 - Google Patents
一种半日花烷型二萜苷化合物及其制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C07H1/06—Separation; Purification
- C07H1/08—Separation; Purification from natural products
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
本发明公开了一种半日花烷型二萜苷化合物及其制备方法,所述化合物是从蔷薇科植物华东覆盆子叶经水煎煮提取物中分离得到,称为覆盆子苷J1,覆盆子苷J1经超导核磁共振波谱,质谱等多种手段检测,确定其分子式为C26H42O8,分子量为505.2771,化学结构式为式(Ⅰ),本发明对覆盆子苷J1进行了体外活性筛选,结果表明该化合物对人宫颈癌细胞和人卵巢癌细胞有明显的抑制作用,可作为抗肿瘤药物应用。
Description
技术领域
本发明涉及医药技术领域,特别涉及一种从华东覆盆子叶中分离纯化得到的一种新的到的半日花烷型二萜苷化合物覆盆子苷J1及其制备方法。该化合物对肿瘤细胞株具有明显的抑制作用,可作为研制新的抗肿瘤药物的先导化合物,也可以作为研制治疗各种临床常见多发癌症的药物。
背景技术
覆盆子是蔷薇科植物华东覆盆子Rubus chingii Hu的干燥未成熟果实,具有益肾固精缩尿、养肝明目之功效,临床常用于治疗遗精滑精、遗尿、尿频、阳痿早泄、目暗昏花等。目前覆盆子收载于《中国药典》2020年版一部。
现代研究表明覆盆子中主要含有萜类、黄酮类、酚酸类成分。目前,已经从覆盆子中分离出来的化合物主要有:三萜类、二萜类、黄酮类等。
二萜类是一类由4个异戊二烯单位构成,含20个碳原子的化合物。二萜的主要骨架多达20种。其中常见的多为贝壳杉烷、赤霉烷、阿替烷、乌头烷等骨架的对映体。许多二萜类的含氧衍生物具有多种生物活性。例如紫杉醇,穿心莲内酯,丹参酮,银杏内酯,甜菊苷等。二萜具有抗肿瘤作用,抗氧化作用,抗炎,免疫抑制作用等。
现有技术Three new labdane-type diterpene glycosides from fruits ofRubus chingii and their cytotoxic activities against five humor celllines.Fitoterapia,2015,102(4),23-26公开了以下三种化合物,
Ent-labdane-type diterpene glucosides from leaves of Rubus chingii[J].Phytochemistry,1984,23(3):615-621公开了以下四种化合物
陈丽楠,付辉政,王兰欣,等.覆盆子茎中1个新的半日花烷型二萜苷[J].中草
药,2022,53(10):2941-2948.公开了以下两种化合物。
覆盆子苷B 3β,18-dihydroxy-manool
上述化合物据称均具有抗肿瘤作用。
本发明人在对华东覆盆子叶的成分进行研究的过程中,意外得到一种半日花烷型二萜苷新化合物,在已有的文献中未见报道。本发明对该化合物进行了深入研究,本发明化合物具有优于现有技术的更加明显的抗肿瘤作用,同时降低了副作用,可以在制备治疗癌症或肿瘤的药物中应用。
发明内容
本发明的一个目的在于提供从华东覆盆子中提取得到一个新的半日花烷型二萜苷化合物覆盆子苷J1。
本发明的另一个目的是提供上述半日花烷型二萜苷化合物覆盆子苷J1的制备方法。
本发明的又一个目的是提供上述半日花烷型二萜苷化合物覆盆子苷J1在制备癌症和/或抗肿瘤药物中的应用。
技术方案:本发明人在现有技术的基础上又做了进一步的研究,发现江西省抚州市崇仁县的覆盆子中其抗癌的活性成分主要是本发明中的化合物,并经资料查阅目前还没有文献报道覆盆子苷J1用于癌症和/或肿瘤的治疗。
为此,本发明提供一种结构式(I)的半日花烷型二萜苷化合物覆盆子苷J1或其药学上可接受的盐。
其中所述药学上可接受的盐,选自结构式(I)的半日花烷型二萜苷化合物覆盆子苷J1与无机酸、有机酸形成的盐,或者与碱金属、碱土金属形成的盐。
本发明人从江西省抚州市崇仁县中首次提取分离得到一个新的半日花烷型二萜苷化合物,命名为覆盆子苷J1,3-羰基-15-O-β-D-葡萄糖-13(E)-对映劳丹烷-8(17),13(14)-二双键-3β,15,18-三醇,分子式为C26H42O8,分子量为505.2771,化学结构式为式(I)。
本发明所述的半日花烷型二萜苷化合物覆盆子苷J1制备步骤依次如下:
(1)覆盆子叶提取液:覆盆子叶水煎煮2~3次,每次2小时得覆盆子叶水煎煮提取液;
(2)浓缩覆盆子叶提取液:将覆盆子叶提取液减压浓缩得浓缩液2.4L;
(3)萃取:取覆盆子叶浓缩液(2.4L),加纯化水稀释至48L,再用48L二氯甲烷、乙酸乙酯、正丁醇萃取三次,得二氯甲烷萃取液、乙酸乙酯萃取液、正丁醇萃取液;
(4)浓缩萃取液:将二氯甲烷萃取液、乙酸乙酯萃取液、正丁醇萃取液分别减压浓缩,二氯甲烷部位(15.0g)、乙酸乙酯部分(60.0g)、正丁醇部分(352.0g);
(5)柱层析分离:将乙酸乙酯浓缩液用适量甲醇溶解后,用1:1.5的硅胶拌样,样品干法装入硅胶层析柱(内径为9cm,柱高为120cm,柱填充硅胶粒度100~200目),以二氯甲烷-甲醇(体积比6:1、4:1、3:1、1:1)为洗脱液,每个比例15L,将洗脱液以每份1L进行收集,共收集60份,分别减压浓缩至干,经薄层检测,合并第4~12份洗脱馏分(5.63g),经过反相ODS柱色谱分离,甲醇-水(5:100→100:0)梯度洗脱每个比例2L,经高效液相色谱检测后,合并相同组分,体积分数100%甲醇洗脱的流分,该馏分经Sephadex LH-20柱色谱分离,甲醇洗脱后,经TLC检测得主斑点为覆盆子苷J1粗品(900mg);
(6)单体化合物的纯化:覆盆子苷J1粗品经反相高效制备液相色谱(色谱柱:C18 5μm,250mm×20mm,检测波长:210nm),以甲醇-水(49:51,v/v,10mL/min)为洗脱液,经制备液相在57.1min处制备得本发明的覆盆子苷J1(20.1mg)。
覆盆子苷J1经高效液相色谱检测,色谱条件为,色谱柱:C18(5μm,250mm×4.6mm);流动相:甲醇-水(49:51);检测波长:210nm;柱温:30℃;进样量:10μL,经面积归一化法计算,覆盆子苷J1纯度≥99%。
本发明进一步提供半日花烷型二萜苷化合物覆盆子苷J1或其药学上可接受的盐在制备抗肿瘤药物中的应用。所述肿瘤选自:宫颈癌,卵巢癌。
本发明还包括含有本发明所述的半日花烷型二萜苷化合物覆盆子苷J1或其药学上可接受的盐的药物组合物。所述的药物组合物,其中还包括药物可接受的载体。所述药物组合物为适合药用的制剂形式,所述药用制剂选自:片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、栓剂、滴剂、滴丸剂、口服液、贴剂。
本发明所述的半日花烷型二萜苷化合物覆盆子苷J1经超导核磁共振波谱、质谱等多种手段检测,确定了覆盆子苷J1的化学结构和理化性质,覆盆子苷J1为白色无定形粉末,易溶于丙酮、丙二醇、吡啶、甲醇等有机试剂。UV(CH3OH)λmax 197nm。
试验证明覆盆子苷J1在1×10-8mol/L~1×10-5mol/L时对人宫颈癌细胞和人结卵巢癌细胞有明显的抑制作用,IC50分别为4.3μM和3.3μM。
附图说明
图1为覆盆子苷J1的制备工艺流程示意图,附图说明了覆盆子苷J1的制备步骤为:(1)水煎煮提取;(2)浓缩提取液;(3)二氯甲烷,乙酸乙酯、正丁醇依次萃取;(4)浓缩乙酸乙酯萃取液;(5)柱层析分离;(6)纯化。
图2为高分辨质谱图,说明了覆盆子苷J1的分子量;
图3为核磁共振1H NMR谱图,说明了覆盆子苷J1结构中氢(-C=C-H,-CH2OH,-CH-O-,-OCH3等)的归属;
图4为核磁共振13C NMR谱图,说明了覆盆子苷J1结构中碳(-C=C-,-C=O,-CH2-O-,-CH-O-,-OCH3等)的归属;
图5为核磁共振HSQC谱图,说明了覆盆子苷J1结构中相关的碳与氢的归属;
图6为核磁共振HMBC谱图,说明了覆盆子苷J1结构中甲氧基、芳香氢、羰基等的位置;
具体实施方式
下面结合实施例对本发明作进一步阐述。必须说明下述实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
岛津LC-20AR型液相色谱仪(日本岛津公司);岛津20-AD型制备高效液相色谱仪(日本岛津公司);Buchi中压液相制备色谱仪(瑞士步琪公司);Sartorius BP211D型电子天平(德国赛托利斯集团);Autopol IV-T/V旋光仪(美国DKSH公司);Varian UNITY INOVA600超导核磁共振仪(美国Varian公司);Waters ACQUITY UPLC/Xevo G2 Q TOF高分辨质谱仪(美国Waters公司);电热恒温水浴锅(上海跃进医疗器械厂);EYELA SB-1000旋转蒸发仪,EYELA A-1000S型循环水真空泵(日本EYELA公司)。Sephadex LH-20(瑞典AmershamBiosciences公司);C18反相填料为日本YMC产品;制备色谱柱为YMC(10μm,250×20mm);柱色谱硅胶、薄层色谱硅胶为青岛海洋化工厂生产;水为Milli-Q一级水;色谱所用试剂为色谱级试剂;其他所用试剂均为分析纯。
实施例1:覆盆子叶中半日花烷型二萜苷化合物覆盆子苷J1的提取分离方法
覆盆子叶采自江西省抚州市崇仁县,经江西省药品检测研究院付辉政研究员鉴定为蔷薇科植物华东覆盆子Rubus chingii Hu的叶,标本保留在江西省药品检测研究院标本室。
覆盆子苷J1的制备步骤依次如下:
(1)覆盆子叶提取液:覆盆子叶水煎煮2~3次每次2小时得覆盆子叶水煎煮提取液;
(2)浓缩覆盆子叶提取液:将覆盆子叶提取液减压浓缩得浓缩液2.4L;
(3)萃取:取覆盆子叶浓缩液(2.4L),加纯化水稀释至48L,再用48L二氯甲烷、乙酸乙酯、正丁醇萃取三次,得二氯甲烷萃取液、乙酸乙酯萃取液、正丁醇萃取液;
(4)浓缩萃取液:将二氯甲烷萃取液、乙酸乙酯萃取液、正丁醇萃取液分别减压浓缩,二氯甲烷部位(15.0g)、乙酸乙酯部分(60.0g)、正丁醇部分(352.0g);
(5)柱层析分离:将乙酸乙酯浓缩液用适量甲醇溶解后,用1:1.5的硅胶拌样,样品干法装入硅胶层析柱(内径为9cm,柱高为120cm,柱填充硅胶粒度100~200目),以二氯甲烷-甲醇(体积比6:1、4:1、3:1、1:1)为洗脱液,每个比例15L,将洗脱液以每份1L进行收集,共收集60份,分别减压浓缩至干,经薄层检测,合并第4~12份洗脱馏分(5.63g),经过反相ODS柱色谱分离,甲醇-水(5:100→100:0)梯度洗脱每个比例2L,经高效液相色谱检测后,合并相同组分,体积分数100%甲醇洗脱的流分,该馏分经Sephadex LH-20柱色谱分离,甲醇洗脱后,经TLC检测得主斑点为覆盆子苷J1粗品(900mg);
(6)单体化合物的纯化:单体化合物的纯化:覆盆子苷J1粗品经反相高效制备液相色谱(色谱柱:C18 5μm,250mm×20mm,检测波长:210nm),以乙腈-水(49:51,v/v,10mL/min)为洗脱液,经制备液相在57.1min处制备得本发明的覆盆子苷J1(20.1mg)。
覆盆子苷J1经高效液相色谱检测,色谱条件为,色谱柱:C18(250mm×4.6mm,5μm);流动相:甲醇-水(49:51);检测波长:210nm;柱温:30℃;进样量:10μL,经面积归一化法计算,覆盆子苷J1纯度≥99%。
实施例2:半日花烷型二萜苷化合物覆盆子苷J1结构鉴定
覆盆子苷J1的理化性质如下:白色无定形粉末,易溶于丙酮、吡啶、甲醇等有机试剂,UV(CH3OH)λmax 197nm。超高效液相色谱-四极杆-飞行时间质谱给出准分子离子峰m/z505.2771[M+Na]+,(calcd.for C26H42O8Na,505.2777),结合1H-NMR和13C-NMR谱确定其分子式为C26H42O8。1H与13C NMR数据见表1,同时,通过测定二维H-C相关谱(HSQC)、H-C远程相关谱(HMBC)等,确定了所有碳原子和氢原子的信号归属及该化合物的化学结构。化学结构式如下:
表1覆盆子苷J1的氢谱和碳谱数据表(δin ppm,J in Hz)
注:INOVA 600MHz;δ化学位移单位ppm,1H-NMR测试溶剂为C5D5N,13C-NMR测试溶剂为CD3OD;核磁共振信号的归属是在HSQC、HMBC二维谱基础上完成的。
经查,和本发明化合物结构最接近的化合物是goshonoside F1,结构对比如下:
实施例3:goshonoside F1的制备方法
(1)覆盆子叶提取液:覆盆子叶水煎煮2~3次每次2小时得覆盆子叶水煎煮提取液;
(2)浓缩覆盆子叶提取液:将覆盆子叶提取液减压浓缩得浓缩液2.4L;
(3)萃取:取覆盆子叶浓缩液(2.4L),加纯化水稀释至48L,再用48L二氯甲烷,乙酸乙酯,正丁醇萃取三次,得二氯甲烷萃取液,乙酸乙酯萃取液,正丁醇萃取液;
(4)浓缩萃取液:将二氯甲烷萃取液,乙酸乙酯萃取液,正丁醇萃取液分别减压浓缩,二氯甲烷部位(15.0g),乙酸乙酯部分(60.0g)、正丁醇部分(352.0g);
(5)柱层析分离:将乙酸乙酯浸膏用适量甲醇溶解后,用1:1.5的硅胶拌样,样品干法装入硅胶层析柱(内径为9cm,柱高为120cm,柱填充硅胶粒度100~200目),以二氯甲烷-甲醇(体积比6:1,4:1,3:1,1:1)为洗脱液,每个比例15L,将洗脱液以每份1L进行收集,共收集60份,分别减压浓缩至干,经薄层检测,合并第4~12份洗脱馏分(5.63g),经过反相ODS柱色谱分离,甲醇-水(5:100→100:0)梯度洗脱每个比例2L,经高效液相色谱检测后,合并相同组分,体积分数82%甲醇洗脱的流分,该馏分经Sephadex LH-20柱色谱分离,甲醇洗脱后,经TLC检测得主斑点为覆盆子苷F1粗品(500mg);
(6)单体化合物的纯化:覆盆子苷F1粗品经反相高效制备液相色谱(色谱柱:C18(5μm,250mm×20mm,检测波长:210nm),以乙腈-水(26.5:73.5,v/v,10mL/min)为洗脱液,经制备液相在75min处制备得覆盆子苷F1(20mg),覆盆子苷F1经高效液相色谱检测,色谱条件为,色谱柱:C18(250mm×4.6mm,5μm);流动相:乙腈-水(26.5:73.5);检测波长:210nm;柱温:30℃;进样量:10μL,经面积归一化法计算,覆盆子苷F1纯度≥99%。
实施例4:半日花烷型二萜苷化合物覆盆子苷J1的体外抗肿瘤活性测试
实验用药物:阴性对照:生理盐水,阳性对照:goshonoside F1,待测药物:本发明覆盆子苷J1。
测试原理:CCK-8法:活细胞的线粒体中存在着与NAAP(烟酰胺腺嘌呤二核苷酸磷酸,辅酶Ⅱ)相关的脱氢酶,可将黄色的WST-8(2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐)还原为高度水溶性的橙黄色甲臜(Formanzan)产物,死细胞中此酶消失,CCK-8不被还原。用DMSO(二甲亚砜)溶解甲臜后可用酶标仪在450nm处检测光密度(OA),光密度值与活细胞数成正比。
所用细胞株为:Caski(人宫颈癌细胞)和A2780(人卵巢癌细胞)。
试验方法:CCK-8法:取对数生长期细胞,消化后充分吹打成单细胞悬液,计数后稀释成1×104cell/mL,接种于96孔培养板中,100μL每孔。每一个样品5~7个细胞浓度梯度,每组4~6个复孔,培养2~4小时使细胞贴壁,然后实验组加入不同浓度的药物,对照组加等量培养基,100μL/孔。将96孔板置于37℃、5%CO2饱和湿度培养箱中培养48小时后,每孔加入10μL的CCK-8指示剂培养4小时后,在Multiskan go酶标仪上测定450nm处的吸光度。按照下列公式计算肿瘤细胞生长抑制率,再以药物浓度对肿瘤细胞生长抑制率为作图得到计量曲线,从曲线上读出药物的半数抑制浓度(IC50)值。
肿瘤细胞生长抑制率(%)=(1-实验孔测定值/对照组测定值)×100%
实验结果见下表。
表2覆盆子苷J1对Caski(人宫颈癌细胞)的抑制作用
表3覆盆子苷J1对A2780(人卵巢癌细胞)的抑制作用
样品 | 浓度(mol/L) | 抑制率(%) | IC50(μM) |
生理盐水(阴性) | 0 | 0 | 0 |
goshonoside F1(阳性) | 1×10-5 | 28.9 | 25.5 |
本发明覆盆子苷J1 | 1×10-5 | 58.2 | 3.8 |
本发明覆盆子苷J1 | 1×10-6 | 39.7 | |
本发明覆盆子苷J1 | 1×10-7 | 15.4 | |
本发明覆盆子苷J1 | 1×10-8 | 6.4 |
总结:覆盆子苷J1对人宫颈癌细胞和人卵巢癌细胞均有抑制作用,可用于研制治疗癌症或肿瘤的药物。
Claims (7)
1.结构式(I)的半日花烷型二萜苷化合物覆盆子苷J1或其药学上可接受的盐
2.权利要求1所述的半日花烷型二萜苷化合物覆盆子苷J1或其药学上可接受的盐的制备方法,其特征是,所述方法,制备步骤依次如下:
(1)覆盆子叶提取液:覆盆子叶水煎煮2~3次每次2小时得覆盆子叶水煎煮提取液;
(2)浓缩覆盆子叶提取液:将覆盆子叶提取液减压浓缩得浓缩液2.4L;
(3)萃取:取覆盆子叶浓缩液2.4L,加纯化水稀释至48L,再用48L二氯甲烷、乙酸乙酯、正丁醇萃取三次,得二氯甲烷萃取液、乙酸乙酯萃取液、正丁醇萃取液;
(4)浓缩萃取液:将二氯甲烷萃取液、乙酸乙酯萃取液、正丁醇萃取液分别减压浓缩,二氯甲烷部位15.0g、乙酸乙酯部分60.0g、正丁醇部分352.0g;
(5)柱层析分离:将乙酸乙酯浓缩液用适量甲醇溶解后,用1:1.5的硅胶拌样,样品干法装入内径为9cm,柱高为120cm,柱填充硅胶粒度100~200目硅胶层析柱,以每个比例15L的二氯甲烷:甲醇体积比为6:1、4:1、3:1、1:1的洗脱液洗脱,将洗脱液以每份1L进行收集,共收集60份,分别减压浓缩至干,经薄层检测,合并第4~12份洗脱馏分5.63g,经过反相ODS柱色谱分离,每个比例2L的甲醇-水5:100→100:0梯度洗脱,经高效液相色谱检测后,合并相同组分,体积分数100%甲醇洗脱的流分,该馏分经Sephadex LH-20柱色谱分离,甲醇洗脱后,经TLC检测得主斑点为覆盆子苷J1粗品900mg;
(6)单体化合物的纯化:覆盆子苷J1粗品经反相高效制备液相色谱洗脱,色谱柱:C18 5μm,250mm×20mm,检测波长:210nm,以体积比甲醇-水49:51为洗脱液,流速10mL/min,收集制备液相在57.1min处的产物覆盆子苷J120.1mg,覆盆子苷J1经高效液相色谱检测,色谱条件为,5μm,250mm×4.6mm的C18色谱柱;流动相:甲醇-水49:51;检测波长:210nm;柱温:30℃;进样量:10μL,经面积归一化法计算,覆盆子苷J1纯度≥99%。
3.权利要求1所述的半日花烷型二萜苷化合物覆盆子苷J1或其药学上可接受的盐在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的应用,所述肿瘤选自:宫颈癌,卵巢癌。
5.一种药用组合物,含有权利要求1所述的所述的半日花烷型二萜苷化合物覆盆子苷J1或其药学上可接受的盐。
6.根据权利要求5所述的药物组合物,其中还包括药物可接受的载体。
7.根据权利要求6所述的药物组合物,所述药物组合物为适合药用的制剂形式,所述药用制剂选自:片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、栓剂、滴剂、口服液、贴剂。
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JPH07118136A (ja) * | 1993-10-21 | 1995-05-09 | Pola Chem Ind Inc | メラニン産生抑制剤及び皮膚外用剤 |
WO2009126950A2 (en) * | 2008-04-11 | 2009-10-15 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Diterpene glycosides as natural solubilizers |
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JPH07118136A (ja) * | 1993-10-21 | 1995-05-09 | Pola Chem Ind Inc | メラニン産生抑制剤及び皮膚外用剤 |
WO2009126950A2 (en) * | 2008-04-11 | 2009-10-15 | Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College | Diterpene glycosides as natural solubilizers |
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Takashi Tanaka等.Ent-labdane-type diterpene glucosides from leaves of Rubus chingii.Phytochemistry.1984,第23卷(第3期),615-621. * |
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