CN105001188A - Eremophilane dimer and preparation method and application thereof - Google Patents
Eremophilane dimer and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000004526 eremophilane derivatives Chemical class 0.000 title 1
- 229930003839 sesquiterpene dimer Natural products 0.000 claims abstract description 14
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000284 extract Substances 0.000 claims description 13
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 6
- 241000196324 Embryophyta Species 0.000 claims description 4
- 241000208827 Ligularia Species 0.000 claims description 4
- NOTFZGFABLVTIG-UHFFFAOYSA-N Cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 claims description 3
- 229920005654 Sephadex Polymers 0.000 claims description 3
- 239000012507 Sephadex™ Substances 0.000 claims description 3
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 239000002038 ethyl acetate fraction Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 150000002611 lead compounds Chemical class 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 241000051192 Ligularia pleurocaulis Species 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 3
- 241000208838 Asteraceae Species 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 241000132092 Aster Species 0.000 description 1
- 241000244355 Ligusticum Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
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- 239000006143 cell culture medium Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
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- 238000002651 drug therapy Methods 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
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- 150000002148 esters Chemical class 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- 239000000203 mixture Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
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Abstract
本发明公开了一种新的艾里莫芬烷型倍半萜二聚体及其制备方法和应用。该化合物分离自菊科橐吾属植物侧茎橐吾(Ligularia？pleurocaulis)的全草，命名为Ligupleurolide？A，经体外抗肿瘤活性研究表明该化合物具有显著的抗肿瘤活性。该化合物可进一步作为活性成分，制备抗肿瘤药物。The invention discloses a novel erimofane-type sesquiterpene dimer, its preparation method and application. The compound is isolated from the whole herb of Ligularia pleurocaulis in the genus Asteraceae, named Ligupleurolide? A, the in vitro anti-tumor activity research shows that the compound has significant anti-tumor activity. The compound can be further used as an active ingredient to prepare antitumor drugs.
Description
技术领域：本发明涉及医药技术领域，具体涉及从植物侧茎橐吾中分离得到的一种新的艾里莫芬烷型倍半萜二聚体Ligupleurolide A及其制备方法和应用。Technical field: The present invention relates to the field of medical technology, in particular to a new erimofane-type sesquiterpene dimer Ligupleurolide A isolated from the lateral stem of the plant Ligupleurolide A and its preparation method and application.
背景技术：癌症是严重威胁人类健康的一类重大疾病。随着人口老龄化及社会工业化进程的加快、人类食物有害有毒物质污染和环境污染的加剧，癌症的发病率呈不断上升的趋势，并且逐步成为了人类死亡的首位因素。根据国际癌症研究署预测，如不采取有效措施，我国癌症发病数和死亡数到2020年将上升至400万人和300万人；2030年将上升至500万人和350万人。因此癌症的预防及治疗是我国乃至全世界疾病防治研究的重大课题，是全社会特别是医学领域急待解决的核心问题之一。药物治疗是癌症预防及治疗的主要手段之一，高效低毒的新型抗癌药物的研究开发是延长患者存活时间、提高生存质量的希望。据统计来源于天然产物的小分子药物约占到抗癌治疗药物的60％，因此以天然产物为先导化合物开发抗癌药物是抗癌新药开发研究的主要途径之一。Background technology: Cancer is a serious disease that seriously threatens human health. With the aging of the population and the acceleration of social industrialization, the pollution of harmful and toxic substances in human food and the aggravation of environmental pollution, the incidence of cancer is on the rise, and it has gradually become the number one factor in human death. According to the forecast of the International Agency for Research on Cancer, if no effective measures are taken, the number of cancer cases and deaths in my country will rise to 4 million and 3 million by 2020; and will rise to 5 million and 3.5 million by 2030. Therefore, the prevention and treatment of cancer is a major topic of disease prevention and control research in my country and even the world, and is one of the core issues to be solved urgently by the whole society, especially in the medical field. Drug therapy is one of the main means of cancer prevention and treatment. The research and development of new anticancer drugs with high efficiency and low toxicity is the hope of prolonging the survival time of patients and improving the quality of life. According to statistics, small molecule drugs derived from natural products account for about 60% of anticancer therapeutic drugs. Therefore, the development of anticancer drugs using natural products as lead compounds is one of the main approaches for the development and research of new anticancer drugs.
侧茎橐吾(Ligularia pleurocaulis)属于菊科(Compositae)橐吾属(Ligularia)植物，多种该属植物作为中药“紫菀”的代用品，有着很长的药用历史。对该属植物的研究发现其富含多种类型的倍半萜类化合物。本发明首次从产自四川的侧茎橐吾中分离得到一个新的艾里莫芬烷型倍半萜二聚体，并发现该化合物具有较好的抗肿瘤活性。Ligularia pleurocaulis belongs to the genus Ligularia in the Compositae family. Many plants of this genus have a long history of medicinal use as substitutes for the traditional Chinese medicine "Aster". Studies of this genus have found that it is rich in various types of sesquiterpenoids. The present invention for the first time isolates a new erimofane-type sesquiterpene dimer from Ligularia lateralis produced in Sichuan, and finds that the compound has better antitumor activity.
发明内容：本发明的目的在于提供一种新的艾里莫芬烷型倍半萜二聚体及其制备方法和其在制备抗肿瘤药物中的应用。SUMMARY OF THE INVENTION: The object of the present invention is to provide a new erimofane-type sesquiterpene dimer, its preparation method and its application in the preparation of antitumor drugs.
本发明是从侧茎橐吾(产于四川康定折多山)中分离得到一个新的艾里莫芬烷型倍半萜二聚体，命名为Ligupleurolide A，其化学结构式如下：The present invention separates and obtains a new erimofane-type sesquiterpene dimer from the side stem Ligusticum spp. (produced in Zheduo Mountain, Kangding, Sichuan), named Ligupleurolide A, and its chemical structural formula is as follows:
本发明所述的一种新的艾里莫芬烷型倍半萜二聚体的制备方法如下：The preparation method of a kind of new erimofane type sesquiterpene dimer of the present invention is as follows:
(1)提取：将侧茎橐吾干燥全草粉碎，以80﹣100％的乙醇回流提取2﹣5次，每次2﹣5小时；合并提取液，提取液减压浓缩成流浸膏，加水稀释后以乙酸乙酯萃取2﹣5次，减压回收溶剂得到乙酸乙酯部位；(1) Extraction: Grind the dried whole plant of Ligularia lateral stem, and extract 2-5 times with 80-100% ethanol under reflux, each time for 2-5 hours; combine the extracts, concentrate the extracts under reduced pressure to form a liquid extract, After diluting with water, extract with ethyl acetate for 2-5 times, and recover the solvent under reduced pressure to obtain the ethyl acetate fraction;
(2)分离：将上一步得到的乙酸乙酯部位应用硅胶柱色谱，以体积比为30:1﹣1:1的石油醚﹣丙酮梯度洗脱，薄层色谱检测，收集含Ligupleurolide A的流份，再经硅胶柱色谱，以体积比为150:1﹣5:1的石油醚﹣丙酮梯度洗脱，进一步经硅胶柱色谱，以体积比为5:1的环己烷﹣乙酸乙酯洗脱，最后经葡聚糖凝胶柱色谱，以体积比为2:1的氯仿﹣甲醇洗脱，薄层色谱检测，得Ligupleurolide A。(2) Separation: apply silica gel column chromatography to the ethyl acetate part obtained in the previous step, elute with a gradient of petroleum ether-acetone with a volume ratio of 30:1-1:1, detect by thin-layer chromatography, and collect the stream containing Ligupleurolide A Parts, and then go through silica gel column chromatography, eluting with petroleum ether-acetone gradient with a volume ratio of 150:1-5:1, and further go through silica gel column chromatography, eluting with cyclohexane-ethyl acetate with a volume ratio of 5:1 Finally, through Sephadex column chromatography, eluted with chloroform-methanol with a volume ratio of 2:1, and detected by thin-layer chromatography, Ligupleurolide A was obtained.
Ligupleurolide A：无色针晶，mp 208-210℃；HR-ESI-MS：m/z 705.2770[M+Na]+(计算值C40H42O10Na，705.2676)，分子式C40H42O10，分子量682；红外光谱υmax：3413，1778，1674，1458，1390，1204，1081，743，637cm-1；1H NMR(CDCl3，400MHz)δppm：6.20(2H,dd,J＝10.0,2.8Hz,H-2和H-2’)，6.62(2H,dd,J＝10.0,1.8Hz,H-3和H-3’)，3.10(2H,m,H-4和H-4’)，5.71(2H,d,J＝0.9Hz,H-6和H-6’)，6.79(2H,s,H-9和H-9’)，1.89(6H,d,J＝0.9Hz,H-13和H-13’)，1.10(6H,dd,s,H-14和H-14’)，1.22(6H,d,J＝7.6Hz,H-15和H-15’)，6.24(2H,q,J＝7.2Hz,H-3”和H-3”’)，1.97(6H,d,J＝7.3Hz,H-4”和H-4”’)，1.96(6H,s,H-5”和H-5”’)；和13C NMR(CDCl3，100MHz)δppm：186.2(s,C-1和C-1’)，128.1(d,C-2和C-2’)，155.2(d,C-3和C-3’)，41.7(d,C-4和C-4’)，50.1(s,C-5和C-5’)，75.8(d,C-6和C-6’)，153.3(s,C-7和C-7’)，86.0(s,C-8和C-8’)，126.6(d,C-9和C-9’)，146.7(s,C-10和C-10’)，126.3(s,C-11和C-11’)，171.3(s,C-12和C-12’)，8.7(q,C-13和C-13’)，14.0(q,C-14和C-14’)，16.4(q,C-15和C-15’)，165.0(s,C-1”和C-1”’)，125.8(s,C-2”和C-2”’)，142.4(d,C-3”和C-3”’)，15.8(q,C-4”和C-4”’)，20.2(q,C-5”和C-5”’)。Ligupleurolide A: colorless needle crystal, mp 208-210℃; HR-ESI-MS: m/z 705.2770[M+Na] + (calculated value C 40 H 42 O 10 Na, 705.2676), molecular formula C 40 H 42 O 10 , molecular weight 682; infrared spectrum υ max : 3413, 1778, 1674, 1458, 1390, 1204, 1081, 743, 637 cm -1 ; 1 H NMR (CDCl 3 , 400 MHz) δppm: 6.20 (2H, dd, J = 10.0, 2.8 Hz, H-2 and H-2'), 6.62 (2H, dd, J = 10.0, 1.8Hz, H-3 and H-3'), 3.10 (2H, m, H-4 and H-4'), 5.71 (2H, d, J = 0.9Hz, H-6 and H-6'), 6.79 (2H, s, H-9 and H-9'), 1.89 (6H, d, J=0.9Hz, H-13 and H-13'), 1.10 (6H , dd, s, H-14 and H-14'), 1.22 (6H, d, J=7.6Hz, H-15 and H-15'), 6.24 (2H, q, J=7.2Hz, H-3 " and H-3"'), 1.97 (6H, d, J=7.3Hz, H-4" and H-4"'), 1.96 (6H, s, H-5" and H-5"'); and 13 C NMR (CDCl 3 , 100MHz) δppm: 186.2 (s, C-1 and C-1'), 128.1 (d, C-2 and C-2'), 155.2 (d, C-3 and C- 3'), 41.7 (d, C-4 and C-4'), 50.1 (s, C-5 and C-5'), 75.8 (d, C-6 and C-6'), 153.3 (s, C-7 and C-7'), 86.0 (s, C-8 and C-8'), 126.6 (d, C-9 and C-9'), 146.7 (s, C-10 and C-10' ), 126.3 (s, C-11 and C-11'), 171.3 (s, C-12 and C-12'), 8.7 (q, C-13 and C-13'), 14.0 (q, C- 14 and C-14'), 16.4 (q, C-15 and C-15'), 165.0 (s, C-1" and C-1"'), 125.8 (s, C-2" and C-2 "'), 142.4 (d, C-3" and C-3"'), 15.8 (q, C-4" and C-4"'), 20.2 (q, C-5" and C-5"' ).
上述艾里莫芬烷型倍半萜二聚体(Ligupleurolide A)经体外抗肿瘤活性筛选试验，结果证实该化合物对人肝癌细胞(HepG2)、人肺癌细胞(A549)和人乳腺癌细胞(MCF-7)三种肿瘤细胞株具有显著细胞毒活性(如表1所示)。The above-mentioned erimofane-type sesquiterpene dimer (Ligupleurolide A) was screened for anti-tumor activity in vitro, and the results confirmed that the compound was effective against human liver cancer cells (HepG2), human lung cancer cells (A549) and human breast cancer cells (MCF -7) The three tumor cell lines have significant cytotoxic activity (as shown in Table 1).
本发明所述的艾里莫芬烷型倍半萜二聚体(Ligupleurolide A)可作为活性成分，进一步制备成抗肿瘤药物。The erimofane-type sesquiterpene dimer (Ligupleurolide A) described in the present invention can be used as an active ingredient to be further prepared into an antitumor drug.
具体实施方式：Detailed ways:
实施例1：Ligupleurolide A的制备Embodiment 1: the preparation of Ligupleurolide A
侧茎橐吾(Ligularia pleurocaulis)干燥全草8.5kg，粉碎，以95％乙醇回流提取3次，每次3小时，合并所有的提取液，减压浓缩成流浸膏，加水稀释后以乙酸乙酯萃取3次，合并萃取液，减压浓缩得乙酸乙酯部位270g。将上述乙酸乙酯部位与280g硅胶混合拌样，应用硅胶柱色谱，以体积比为30:1﹣1:1的石油醚﹣丙酮梯度洗脱，薄层色谱检测，收集含有Ligupleurolide A的流分，再经硅胶柱色谱，以体积比为150:1﹣5:1的石油醚﹣丙酮梯度洗脱，进一步经硅胶柱色谱，以体积比为5:1的环己烷﹣乙酸乙酯洗脱，最后经葡聚糖凝胶柱色谱，以体积比为2:1的氯仿﹣甲醇洗脱，薄层色谱检测，得Ligupleurolide A纯品11mg。Ligularia pleurocaulis (Ligularia pleurocaulis) dried whole herb 8.5kg, pulverized, extracted 3 times with 95% ethanol under reflux, each time for 3 hours, combined all the extracts, concentrated under reduced pressure to form a liquid extract, diluted with water, dilute with ethyl acetate The ester was extracted three times, and the extracts were combined and concentrated under reduced pressure to obtain 270 g of ethyl acetate. Mix the above-mentioned ethyl acetate part with 280g of silica gel, apply silica gel column chromatography, elute with petroleum ether-acetone gradient with a volume ratio of 30:1-1:1, detect by thin-layer chromatography, and collect the fraction containing Ligupleurolide A , and then go through silica gel column chromatography, eluting with petroleum ether-acetone gradient with a volume ratio of 150:1-5:1, and further go through silica gel column chromatography, eluting with cyclohexane-ethyl acetate with a volume ratio of 5:1 , and finally through Sephadex column chromatography, eluted with chloroform-methanol with a volume ratio of 2:1, and detected by thin-layer chromatography, 11 mg of pure Ligupleurolide A was obtained.
实施例2：体外抗肿瘤实验(MTT法)Embodiment 2: In vitro anti-tumor experiment (MTT method)
分别利用含10％胎牛血清的高糖DMEM培养基培养人肝癌细胞(HepG2)和人肺癌细胞(A549)，含10％胎牛血清的低糖DMEM培养基培养人乳腺癌细胞(MCF-7)。然后将处于对数生长期的三种细胞接种到96孔培养板中，5000细胞/孔。24小时后，往三种肿瘤细胞中分别加入不同浓度的待测化合物，继续培养72小时。倒去细胞培养基，各孔加入100μl的MTT溶液(PBS配制，0.5mg/ml)，继续孵育4小时。倒去MTT溶液，各孔中加入150μl的DMSO，振荡10分钟，测定570nm波长下的吸光度，计算不同浓度待测化合物对肿瘤细胞的生长抑制率并计算待测化合物对肿瘤细胞半数生长抑制时的药物浓度(IC50)，每个实验重复三次。Human liver cancer cells (HepG2) and human lung cancer cells (A549) were cultured in high-glucose DMEM medium containing 10% fetal bovine serum, and human breast cancer cells (MCF-7) were cultured in low-sugar DMEM medium containing 10% fetal bovine serum . Then the three kinds of cells in the logarithmic growth phase were seeded into 96-well culture plates, 5000 cells/well. After 24 hours, different concentrations of the compound to be tested were added to the three kinds of tumor cells, and the culture was continued for 72 hours. Pour off the cell culture medium, add 100 μl of MTT solution (prepared in PBS, 0.5 mg/ml) to each well, and continue to incubate for 4 hours. Pour off the MTT solution, add 150 μl of DMSO to each well, shake for 10 minutes, measure the absorbance at a wavelength of 570 nm, calculate the growth inhibition rate of the test compound at different concentrations on tumor cells, and calculate the half-inhibition rate of the test compound on tumor cell growth. Drug concentration (IC 50 ), each experiment was repeated three times.
上述艾里莫芬烷型倍半萜二聚体(Ligupleurolide A)经体外抗肿瘤活性筛选试验结果证实，Ligupleurolide A对人肝癌细胞(HepG2)、人肺癌细胞(A549)和人乳腺癌细胞(MCF-7)三种肿瘤细胞株均显示出明显的抑制作用(如表1所示)。The results of in vitro anti-tumor activity screening tests for the above-mentioned erimofane-type sesquiterpene dimer (Ligupleurolide A) confirmed that Ligupleurolide A has an effect on human liver cancer cells (HepG2), human lung cancer cells (A549) and human breast cancer cells (MCF -7) All three tumor cell lines showed obvious inhibitory effects (as shown in Table 1).
本发明所述的一种新的艾里莫芬烷型倍半萜二聚体(Ligupleurolide A)可作为活性成分，进一步制备成抗肿瘤药物。A novel erimofane-type sesquiterpene dimer (Ligupleurolide A) described in the present invention can be used as an active ingredient to be further prepared into an antitumor drug.
表1 Ligupleurolide A对三种肿瘤细胞株的抑制作用(IC50，μM)Table 1 Inhibitory effect of Ligupleurolide A on three tumor cell lines (IC 50 , μM)
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