CN110804037B - Thiophene formic acid beta-caryophyllene-5-ester compound and preparation method and application thereof - Google Patents
Thiophene formic acid beta-caryophyllene-5-ester compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a thiophene formic acid beta-caryophyllene-5-ester compound and a preparation method and application thereof, belonging to the technical field of preparation of carboxylic acid beta-caryophyllene-5-ester. The preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound comprises the steps of reacting thiophene formic acid with DCC, then adding beta-caryophyllene alcohol and DMAP for reaction, and obtaining the compound after the reaction is finished. NO inhibition rate experiments, cytotoxicity experiments and anticancer activity experiments prove that the compounds have good anticancer activity on inflammation and various cancers, and can be applied to preparation of anti-inflammatory drugs and anticancer drugs.
Description
Technical Field
The invention belongs to the technical field of preparation of carboxylic acid beta-caryophyllene-5-ester, and particularly relates to a thiophene formic acid beta-caryophyllene-5-ester compound and a preparation method and application thereof.
Background
The natural product refers to extracts of animals and plants, including proteins, polypeptides, volatile oils, terpenoids, and other naturally occurring chemical components. It has been widely developed as a therapeutic and health-care drug due to its specific physiological activity. Taxol derived from bark of Taxus chinensis is widely recognized as a broad-spectrum and most active anticancer drug in the world at present, and its discovery is known as one of the three major achievements of anticancer drugs in the last 90 th century (Shu, X., et al colloids and Surfaces B: Biointerfaces, 2019.182: p.110356.doi. org/10.1016/j. colsurfb.2019.110356). The structural modification of camptothecin (Laskar, p., et al., Nanoscale, 2019.11 (42): p.20058-20071.doi.org/10.1039/C9NR 07254C) from roots, bark, stems and seeds of camptotheca acuminata resulted in two derivatives (topotecan and irinotecan) which were approved by the FDA in the united states for clinical tumor treatment. It can be seen that the search for lead compounds from natural products for structural modification is one of the important approaches for the development of new generation drugs (Chencong et al. role of natural products in the discovery and development of anticancer drugs [ J ]. Chinese herbal medicine, 1999 (02): 144-147.).
Beta-caryophyllene is a bicyclic sesquiterpenoid compound and widely exists in natural plants such as clove leaves, cinnamon oil, pepper and the like. The molecular formula is as follows: c15H24(ii) a Molecular weight is 204.36; CAS: 87-44-5. The appearance is colorless to yellowish oily liquid, is insoluble in water, is dissolved in organic solvents such as ethanol, and is obtained by rectifying beta-caryophyllene through clove oil.
It is also known to be highly active in the field of anti-inflammatory and analgesic activities (Fidyt, K., et al. cancer Medicine, 2016.5(10), 3007-3017. doi: 10.1002/cam 4.816; Basha, R.H. chemical-Biological Interactions, 2016.245, 50-58. doi: 10.1016/J.cbi.2015.12.019). However, many studies have focused on the modification of the compound itself, and the modification positions are mostly double bonds on the ring and mostly epoxidation due to the structure of the compound itself, and the bioactivity of the compound is increased by introducing active oxygen (Chavan, M.J., et al. phytomedine, (2010) 17(2), 149-151. doi: 10.1016/j. phymed.2009.05.016).
Disclosure of Invention
The invention aims to solve the technical problem of providing a thiophene formic acid beta-caryophyllene-5-ester compound which is a novel compound and has inhibitory activity on inflammation and various tumor cells. The invention aims to solve another technical problem of providing a preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound, which is simple and has high product yield. The invention also provides an application of the thiophene formic acid beta-caryophyllene-5-ester compound, the compound has good inhibitory activity on inflammation and various cancer cells, and more ways are provided for the development of preparing anti-inflammatory drugs and anti-cancer drugs.
The technical scheme is as follows: in order to solve the problems, the technical scheme adopted by the invention is as follows:
the thiophene formic acid beta-caryophyllene-5-ester compound has a structural formula shown as the following (I):
the preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound comprises the following steps:
(1) dissolving thiophenecarboxylic acid and DCC in CH2Cl2Performing reaction at 0-5 ℃ for 20-30 min; the molar ratio of DCC to thiophenecarboxylic acid is 1: 1-1: 2, and the concentration of DCC is 0.15-0.20 mol/L;
(2) dissolving DMAP in CH2Cl2Adding the DMAP solution and beta-caryophyllenol into the solution obtained in the step (1), and reacting for 4-5 hours at the temperature of 25-35 ℃; the molar ratio of the DMAP to the beta-caryophyllenol is 1: 15-1: 20, and the concentration of the DMAP is 0.02-0.08 mol/L; the molar ratio of the thiophene formic acid to the beta-caryophyllenol is 1-3: 1;
(3) and after the reaction is finished, washing the reaction solution, drying, removing the solvent, and eluting by using a silica gel column to obtain the thiophene formic acid beta-caryophyllene-5-ester compound.
The preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound comprises the following steps of:
(a) dissolving the secondary naphthol borane in tetrahydrofuran to obtain a secondary naphthol borane solution, adding beta-caryophyllene, and carrying out reflux reaction at 70-90 ℃ for 17-19 h; the molar ratio of the naphthol borane to the beta-caryophyllene is 1-2: 1, and the concentration of the naphthol borane is 1-2 mol/L;
(b) after the reaction is finished, CH is adopted2Cl2Diluting and cooling, and sequentially adding KOH solution and 30% H2O2Reacting for 20-40 min; the molar ratio of the KOH to the beta-caryophyllene is 6.5-7.0: 1, and the concentration of the KOH solution is 3-4 mol/L; the KOH solution was mixed with 30% H2O2The volume ratio of (A) to (B) is 1: 1-1: 2;
(c) and after the reaction is finished, washing the mixture for 3 times by using saturated NaCl, drying the mixture, removing the solvent to obtain dark yellow oily liquid, and obtaining the light yellow oily liquid beta-caryophyllenol by using a 100-200-mesh silica gel column as a mobile phase, wherein the ratio of petroleum ether to ethyl acetate is 1: 7.
According to the preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound, the thiophene formic acid is thiophene-2-formic acid or thiophene-3-formic acid.
The preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound comprises the following steps of (1) reacting at 0 ℃ for 30 min; and (2) reacting at 25 ℃ for 5 h.
According to the preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound, the molar ratio of thiophene formic acid to beta-caryophyllenol is 1: 1.
According to the preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound, the molar ratio of DCC to thiophene formic acid is 1: 1, and the concentration of DCC is 0.18 mol/L; the molar ratio of the DMAP to the beta-caryophyllenol is 1: 18, and the concentration of the DMAP is 0.05 mol/L. .
The thiophene formic acid beta-caryophyllene-5-ester compound is applied to preparing anti-inflammatory drugs.
The thiophene formic acid beta-caryophyllene-5-ester compound is applied to the preparation of anti-cancer drugs.
The thiophene formic acid beta-caryophyllene-5-ester compound is applied to preparation of anti-cancer drugs, and the cancer is cervical cancer, liver cancer, breast cancer or lung cancer.
Has the advantages that: compared with the prior art, the invention has the advantages that:
(1) the preparation method of the thiophene formic acid beta-caryophyllene-5-ester compound has simple reaction steps and mild reaction conditions.
(2) The thiophene formic acid beta-caryophyllene-5-ester compound has good activity on RAW264.7 cell strain generating inflammation, and can be applied to the preparation of anti-inflammatory drugs.
(3) The thiophene formic acid beta-caryophyllene-5-ester compound prepared by the invention has good inhibitory activity on cervical cancer, liver cancer, breast cancer and lung cancer cells, and has good application prospect in preparation of anti-cancer drugs.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below.
Example 1
Synthesis method of beta-caryophyllenol C1(6, 10, 10-trimethyl-2-methylidenebic [7.2.0] uncacan-5-ol):
adding 4.4mmol of beta-caryophyllene into 6.6mL of 1M tetrahydrofuran solution of naphthol borane, carrying out reflux reaction at 80 ℃ for 18h, and reacting with 40mL of CH2Cl2Diluting and cooling, adding 20mL of 3M KOH and 20mL of 30% H in sequence2O2Reacting for 30min, washing with saturated NaCl for 3 times, drying, removing the solvent to obtain dark yellow oily liquid, and obtaining light yellow oily liquid C1 by using 100-mesh 200-mesh silica gel column mobile phase petroleum ether and ethyl acetate as 1: 7. The reaction process is as follows:
C1 1HNMR(600M,DMSO-d6)δ:4.83(d,2H,=CH2,J=6Hz),4.22(d,1H,-OH,J=6Hz),3.32(s,1H,-CH),2.46-2.42(m,1H,-CH),2.22-2.12(m,2H,-CH2),1.92-1.86(m,1H,-CH),1.74-1.71(m,2H,-CH2),1.70(t,1H,-CH,J=6Hz),1.58-1.53(m,1H,-CH),1.51-1.48(m,2H,-CH2),1.44-1.39(m,2H,-CH2),0.38(s,3H,-CH3),0.97(s,3H,-CH3),0.96-0.95(m,1H,-CH),0.83(d,3H,-CH3,J=6Hz);13CNMR(DMSO-d6,150MHz)δppm:153.05,108.59,56.83,55.20,42.02,36.75,35.64,33.87,32.6,30.78,30.25,26.84,21.87;IR,υ(cm-1):3372(-OH),3076(C=CH2)997(C-O);Elemental Anal.Calcd for C15H26O:C 81.02;H 11.79;O 7.19;Found:C 81.14;H 11.82;O 7.21.HRMS(ESI+):m/z[C15H26O+H]+223.2056 test value 223.2064.
The method for synthesizing thiophene-2-formic acid beta-caryophyllene-5-ester C2(6, 10, 10-trimethyl-2-methylinebicyclo [7.2.0] undecan-5-ylthiophene-2-carboxylate) comprises the following steps:
thiophene-2-carboxylic acid 0.9mmol and DCC (dicyclohexylcarbodiimide, 0.9mmol) were dissolved in 5mL of CH2Cl2And reacting at 0 ℃ for 30 min. AddingInto C10.9mmol and dissolved in 1mL CH2Cl2Reacting 4-dimethylaminopyridine (DMAP, 0.05mmol) at normal temperature for 5 hours, washing, drying and removing the solvent. 150mg of yellow oily liquid was obtained by passing through a silica gel column. The reaction process is as follows:
C2 1HNMR(600M,CDCl3)δ:7.79-7.78(m,1H,CH),7.54-7.53(m,1H,CH),7.11-7.09(m,1H,CH),4.98-4.91(m,2H,=CH2),2.49-2.44(m,1H,CH),2.35-2.32(m,1H,CH),2.19-2.14(m,1H,CH),2.07-2.02(m,1H,CH),1.92-1.88(m,1H,CH),1.82-1.77(m,2H,CH2),1.68-1.64(m,2H,CH2),1.58-1.55(m,2H,CH2),1.28-1.22(m,1H,CH),1.01(d,6H,CH3,J=21Hz),0.95(d,3H,CH3,J=6.6;13C(CDCl3,150MHz):161.95,152.22,134.69,133.01,131.98,109.24,56.54,42.54,36.85,35.07,33.95,31.40,30.01,28.64,26.88,21.47;13CNMR(CDCl3,150MHz)δppm:161.95,152.22,134.69,133.01,131.98,127.67,109.24,56.54,42.25,36.85,35.07,33.95,31.40,20.01,28.64,26.88,2147.IR,υ(cm-1):3076(C=CH2),1705(C=O),1458(C-C),1095(C-O-C);Elemental Anal.Calcd for C20H28O2S:C 72.25;H 8.49;O 9.62,S 9.64;Found:C 72.31;H 8.51;O 9.63;S 9.66.HRMS(ESI+):m/z[C20H28O2S+Na+]+355.1702 test value 355.1713.
Example 2
The method for synthesizing thiophene-3-carboxylic acid beta-caryophyllene-5-ester C3(6, 10, 10-trimethyl-2-methylinebicyclo [7.2.0] undecan-5-ylthiophene-3-carboxylate):
dissolving thiophene-3-carboxylic acid 0.9mmol and DCC 0.9mmol in 5mL CH2Cl2And reacting at 0 ℃ for 30 min. C10.9m prepared in example 1 was addedmol and dissolved in 1mL CH2Cl20.05mmol of DMAP, reacting for 5 hours at normal temperature, washing, drying and removing the solvent. The mixture was eluted through a silica gel column to give 150mg of a yellow oily liquid. The reaction process is as follows:
C3 1HNMR(600M,CDCl3)δ:8.11(s,1H,-CH),7.56(d,1H,-CH,J=6Hz),7.33(d,1H,-CH,J=6Hz),5.01-4.94(m,2H,=CH2),2.57-2.46(m,1H,CH),2.39-2.35(m,1H,CH),2.20-2.07(m,2H,CH2),1.93-1.89(m,1H,CH),1.84-1.82(m,1H,CH),1.81-1.79(m,1H,CH),1.72(s,1H,CH),1.70-1.68(m,1H,CH),1.66-1.65(m,1H,CH),1.59-1.56(m,1H,CH),1.45(s,1H,CH),1.36(s,1H,CH),1.30(d,1H,CH,J=18Hz),1.06,(s,3H,CH3),1.00(d,3H,J=24Hz),0.94(d,3H,CH3,J=6Hz);13CNMR(DMSO-D6,150MHz)δppm:153.05,108.59,56.83,55.20,42.02,36.75,35.64,33.87,32.6,30.78,30.25,26.84,21.87;IR,υ(cm-1):3076(C=CH2),1705(C=O),1458(C-C),1095(C-O-C);Elemental Anal.Calcd for C15H26O:C 81.02;H 11.79;O 7.19;Found:C 81.14;H 11.82;O 7.21.HRMS(ESI+):m/z[C20H28O2S+Na+]+355.1702 test value 355.1718.
Example 3
First, NO inhibition experiments of compounds C2, C3:
(1) taking a mouse macrophage RAW264.7 with logarithmic growth cycle, inoculating 3-4 ten thousand of the macrophage RAW in each hole in a 96-hole plate, and inoculating 5% CO at 37 DEG C2Incubating for 24 hours in an incubator; taking out the culture plate, removing the culture medium, and washing with PBS for 3-4 times;
(2) setting a control group, an LPS + Dexamethasone (DIM) positive drug group and compound C2 and compound C3 sample groups; experimental groups are shown below:
control group: 1. adding 50 μ L of 2 μ g/mL LPS and 50 μ L of caryophyllene C0 with concentration of 40, 20, 10, 5, 2.5 μ M respectively into each well; 2. adding 50 μ L of 2 μ g/mL LPS and 50 μ L of beta-caryophyllenol C1 with concentration of 40, 20, 10, 5, 2.5 μ M respectively into each well;
LPS + DIM positive drug group: add 50. mu.L of LPS 2. mu.g/mL and 50. mu.L DIM at concentrations of 40, 20, 10, 5, 2.5. mu.M, respectively, to each well;
compound C2 sample set: add 50. mu.L of 2. mu.g/mL LPS and 50. mu.L of C2 at 40, 20, 10, 5, 2.5. mu.M concentration to each well;
compound C3 sample set: add 50. mu.L of 2. mu.g/mL LPS and 50. mu.L of 40, 20, 10, 5, 2.5. mu.M C3 per well;
adding the liquid of the experimental groups in sequence, and incubating for 24h in an incubator;
(3) centrifuging to take cell culture supernatant to a 96-hole mildew standard plate, and sequentially adding A and B of the ELISA kit according to the volume ratio of 1: 1; reacting for 3min in dark place, and testing absorbance at 540nm with a mold standard instrument; the formula for calculating the NO inhibition rate is shown in the following formula (1):
the results of the NO inhibition test of compounds C2 and C3 are shown in table 1. As can be seen from table 1, the inhibition experiments of NO in RAW264.7 cells producing inflammation by C2 and C3 found that, although the inhibition effect of NO after the heterocyclic thiophene is introduced is not as good as that of β -caryophyllene (C0), the inhibition effect is still 1.1 to 1.4 times higher than that of positive control DIM, and the thiophene at the 3-position has a certain advantage over the thiophene at the 2-position. This provides a concept for better improvement of NO inhibition by selecting the position of the carboxylic acid at a later stage.
Table 1 results of NO inhibition (%) of Compounds C2 and C3
Secondly, cytotoxicity test of compound C2 and compound C3:
(1) RAW26 in logarithmic growth cycle4.7, 3-4 million inoculations per well in 96-well plates, 5% CO at 37 ℃2After incubation in the incubator for 24h, the medium was removed and washed 3-4 times with PBS;
(2) setting a control group, an LPS + DIM positive drug group and compound C2 and compound C3 sample groups; experimental groups are shown below:
control group: 1. adding 50 μ L of 2 μ g/mL LPS and 50 μ L of caryophyllene C0 with concentration of 40, 20, 10, 5, 2.5 μ M respectively into each well; 2. adding 50 μ L of 2 μ g/mL LPS and 50 μ L of beta-caryophyllenol C1 with concentration of 40, 20, 10, 5, 2.5 μ M respectively into each well;
LPS + DIM positive drug group: add 50. mu.L of LPS 2. mu.g/mL and 50. mu.L DIM at concentrations of 40, 20, 10, 5, 2.5. mu.M, respectively, to each well;
compound C2 sample set: add 50. mu.L of 2. mu.g/mL LPS and 50. mu.L of 40, 20, 10, 5, 2.5. mu.M C2 per well;
compound C3 sample set: add 50. mu.L of 2. mu.g/mL LPS and 50. mu.L of C3 at 40, 20, 10, 5, 2.5. mu.M:
incubating in an incubator for 24h, removing the supernatant, adding 1mg/mL MTT dye, and incubating for 4 h;
(3) after the incubation is finished, removing the culture solution, adding 200 mu L DMSO, shaking the plate at 37 ℃ for 10min, detecting the absorbance at 595 position by a mildew standard instrument, and calculating the cell survival rate according to the formula (2):
the results of the cell viability assay for compounds C2 and C3 are shown in table 2.
The cytotoxicity test of the RAW264.7 cell line shows that although the NO inhibition effect of the compound is not improved after thiophene is introduced, the cytotoxicity of the compound is obviously reduced on the cytotoxicity of the RAW264.7 cell, and the reduction of the C2 is most obvious. This indicates that the toxicity of the compound on the RAW264.7 cell line can be effectively reduced by introducing the thiophene ring.
TABLE 2 Experimental results of cell viability of Compounds C2 and C3
Third, MTT method for testing the anticancer activity of compounds C2 and C3
(1) Taking Hela (cervical cancer cell), HepG2 (liver cancer cell), MCF-7 (breast cancer cell), A549 (lung cancer cell) and HUVEC (human umbilical vein endothelial cell) with logarithmic growth cycle, inoculating the cells in a 96-well plate in 1-2 ten thousand per well, and inoculating 5% CO at 37 ℃ in 5%2The incubator is incubated for 24 hours;
(2) removing the culture medium, adding diluted samples of a control group and an experimental group, incubating for 48 hours, removing the culture medium, adding 1mg/mL MTT, and incubating for 4 hours; wherein, the control group adopts DOX (doxycycline), and the concentration of the samples of the control group and the experimental group is 100, 10, 1, 0.1 and 0.01 mu M;
(3) after the incubation is finished, removing the culture medium, adding 200 mu L DMSO, shaking the plate at 37 ℃ for 10min, detecting the absorbance at 595 position by a mildew standard instrument, and calculating the cell inhibition rate according to the formula (3):
the results of antitumor activity of compounds C2, C3 are shown in table 3: the research on the antitumor activity of C2 and C3 shows that C2 and C3 both have the antitumor activity and have the characteristic inhibiting effect on MCF-7 cells. Wherein C2 has better anticancer activity and better safety factor than C0 positive control DOX.
TABLE 3 half inhibitory concentration IC of Compounds C2, C3 on cancer cells50μM
Hela | HepG2 | MCF-7 | A549 | HUVEC | |
C0 | 12.35 | 11.10 | 1.21 | 5.29 | 0.68 |
C1 | 7.58 | 1.82 | 0.48 | 7.10 | 5.32 |
C2 | 42.86 | >100 | 0.48 | >100 | 4.00 |
C3 | 3.63 | 7.60 | 1.66 | 17.98 | 0.01 |
DOX | 3.55±0.17 | 1.20±0.04 | 14±0.3 | 3.35±0.69 | 4.40±0.55 |
Claims (10)
2. the method for preparing the thiophene formic acid beta-caryophyllene-5-ester compound as claimed in claim 1, characterized by comprising the following steps:
(1) dissolving thiophenecarboxylic acid and DCC in CH2Cl2Performing reaction at 0-5 ℃ for 20-30 min; the molar ratio of DCC to thiophenecarboxylic acid is 1: 1-1: 2, and the concentration of DCC is 0.15-0.20 mol/L;
(2) DMAP was dissolved in CH2Cl2A DMAP solution is formed, the DMAP solution and beta-caryophyllenol are added into the solution obtained in the step (1), and the reaction is carried out for 4-5 hours at the temperature of 25-35 ℃; the molar ratio of the DMAP to the beta-caryophyllenol is 1: 15-1: 20, and the concentration of the DMAP solution is 0.02-0.08 mol/L; the molar ratio of the thiophene formic acid to the beta-caryophyllenol is 1-3: 1;
(3) and after the reaction is finished, washing the reaction solution, drying, removing the solvent, and eluting by using a silica gel column to obtain the thiophene formic acid beta-caryophyllene-5-ester compound.
3. The method for preparing the thiophene formic acid beta-caryophyllene-5-ester compound according to claim 2, wherein the preparation of the beta-caryophyllene alcohol comprises the following steps:
(a) dissolving the secondary naphthol borane in tetrahydrofuran to obtain a secondary naphthol borane solution, adding beta-caryophyllene, and carrying out reflux reaction at 70-90 ℃ for 17-19 h; the molar ratio of the naphthol borane to the beta-caryophyllene is 1-2: 1, and the concentration of the naphthol borane solution is 1-2 mol/L;
(b) after the reaction is finished, CH is adopted2Cl2Diluting and cooling, and sequentially adding KOH solution and 30% H2O2Reacting for 20-40 min; the molar ratio of the KOH to the beta-caryophyllene is 6.5-7.0: 1, and the concentration of the KOH solution is 3-4 mol/L; the KOH solution was mixed with 30% H2O2The volume ratio of (A) to (B) is 1: 1-1: 2;
(c) and after the reaction is finished, washing the product for 3 times by using saturated NaC1, drying the product, removing the solvent to obtain dark yellow oily liquid, eluting the dark yellow oily liquid by using a 100-200-mesh silica gel column, and obtaining light yellow oily liquid beta-caryophyllenol by using a mobile phase petroleum ether and ethyl acetate which are 1: 7.
4. The method for preparing the thiophenecarboxylic acid beta-caryophyllene-5-ester compound according to claim 2 or 3, wherein the thiophenecarboxylic acid is thiophene-2-carboxylic acid or thiophene-3-carboxylic acid.
5. The method for preparing thiophene formic acid beta-caryophyllene-5-ester compounds according to claim 2 or 3, wherein in the step (1), the reaction is carried out at 0 ℃ for 30 min; and (2) reacting at 25 ℃ for 5 h.
6. The method for preparing the thiophene carboxylic acid beta-caryophyllene-5-ester compound according to claim 2 or 3, wherein the molar ratio of the thiophene carboxylic acid to the beta-caryophyllene alcohol is 1: 1.
7. The method for preparing thiophene formate beta-caryophyllene-5-ester compounds according to claim 2 or 3, wherein the molar ratio of DCC to thiophene formate is 1: 1, and the concentration of DCC is 0.18 mol/L; the molar ratio of the DMAP to the beta-caryophyllenol is 1: 18, and the concentration of the DMAP is 0.05 mol/L.
8. The thiophene formate beta-caryophyllene-5-ester compound of claim 1 for use in the preparation of anti-inflammatory drugs.
9. The thiophene formic acid beta-caryophyllene-5-ester compound of claim 1 for use in preparing an anti-cancer medicament.
10. The use of the thiophene carboxylic acid β -caryophyllene-5-ester compound of claim 9 in the preparation of an anti-cancer medicament, wherein the cancer is cervical cancer, liver cancer, breast cancer, or lung cancer.
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