CN115634224A - Application of Terestacin derivative in preparation of medicine for treating brain glioma - Google Patents
Application of Terestacin derivative in preparation of medicine for treating brain glioma Download PDFInfo
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- CN115634224A CN115634224A CN202211184954.3A CN202211184954A CN115634224A CN 115634224 A CN115634224 A CN 115634224A CN 202211184954 A CN202211184954 A CN 202211184954A CN 115634224 A CN115634224 A CN 115634224A
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- brain glioma
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- terestacin
- stem cells
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses application of a Terestacin derivative in preparation of a medicament for treating brain glioma. The structural formula of the Terestacin derivative is shown as follows. Terestacin derivatives have inhibitory activity against proliferation of brain glioma stem cells, IC 50 The value reaches 2.8-6.9 mu M, the compounds 1,2,3 and 4 also have stronger formation ability and invasion ability for inhibiting the stem cell tumor neurosphere, and the compounds are expected to be used for researching and preparing a candidate drug with potential anticancer activity and have great development potential.
Description
The technical field is as follows:
the invention belongs to the field of chemical medicine research and development, and particularly relates to application of a Terestacin derivative in preparation of a medicine for treating brain glioma.
The background art comprises the following steps:
cancer is a serious threat to human health, and solid tumor tissues contain various subcellular components, such as malignant proliferating tumor cells in tissue organs, and also have some small amount of tumor stem cells, which not only can form rapidly proliferating cancer cells, but also can differentiate into cancer cells of other tissue organs. Numerous literature studies have shown that such stem cells play a key role in the development, progression, invasion, metastasis, recurrence, and resistance of cancer. Brain glioma is the major lethal cancer in brain tumors, accounting for about 80% of all brain tumors, with a median survival rate of about 7 months. The prior treatment schemes such as radiotherapy, chemotherapy or combined medication and the like have no obvious effect. The discovery and research of the tumor stem cells have been over 20 years, but the research of new drugs for treating the brain glioma stem cells is slow, no new drug for treating the brain glioma stem cells is available on the market, and the development of active small molecules with novel structures is also deficient. Therefore, the development of the micromolecule with a novel structure for inhibiting the growth of the brain glioma stem cells has important significance and potential huge application value. The literature reports that small molecules are combined with ubiquinol cytochrome C reductase binding protein (UQCRB), can regulate the level of Reactive Oxygen Species (ROS), and regulate differentiation, growth and proliferation of brain glioma stem cells by regulating an HIF-1 alpha/C-met pathway to achieve the aim of inhibiting growth of brain glioma and formation of brain tumor spheroids, so that the development of the active small molecules with the function of targeted regulation of brain glioma stem cell proliferation has wide application prospects and important development and research values in the aspect of brain glioma treatment.
The invention content is as follows:
the first purpose of the invention is to provide the application of the Terestacin derivative or the medicinal salt thereof in preparing anti-tumor medicines, in particular the application in preparing medicines for treating brain glioma.
The structural formula of the Terestacin derivative or the medicinal salt thereof is shown as any one of the following formulas (I):
preferably, the anti-tumor pharmaceutical dosage form is a liquid dosage form or a solid dosage form.
Preferably, the liquid dosage form is an injection, a solution, a suspension, an emulsion or an aerosol.
Preferably, the solid dosage form is a tablet, a capsule, a pill, a powder injection, a sustained release preparation or a microparticle drug delivery system.
Preferably, the medicament for treating brain glioma is a medicament for inhibiting the proliferation of brain glioma stem cells.
Preferably, the medicament for treating the brain glioma is a medicament for inhibiting the formation of a brain glioma stem cell tumor sphere.
Preferably, the medicament for treating brain glioma is a medicament for inhibiting infiltration of brain glioma stem cells.
The second object of the present invention is to provide an antitumor agent comprising a Terestacin derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
The compounds 1,2,3 and 4 have strong capability of inhibiting the proliferation of glioma stem cells and can also inhibit the formation of tumor balls and invasion, are derivatives of natural products, have the characteristics of novel structure and good own intellectual property rights, and provide guarantee for developing novel anti-cancer drugs for the glioma stem cells
Description of the drawings:
figure 1 is a compound inhibiting the formation of glioma stem cells into globular tissue, note: NT is negative control, 4-200 is compound N- (4-hydroxyphenyl) - [1,1' -biphenyl ] -4-sulfonamide, and both positive control and Termescalin are positive control.
FIG. 2 is a graph of the inhibition of invasion of brain glioma stem cells by Compound 1,2,3, 4; note: NT is negative control, 4-200 is compound N- (4-hydroxyphenyl) - [1,1' -biphenyl ] -4-sulfonamide, and both positive control and Termescalin are positive control.
FIG. 3 is a graph of the inhibition of the invasion rate of glioma stem cells by Compound 1,2,3, 4; note: NT is negative control, 4-200 is compound N- (4-hydroxyphenyl) - [1,1' -biphenyl ] -4-sulfonamide, and both positive control and Terestacin are positive control.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1: the preparation of the compound 1,2,3,4 (refer to patent 202210427448.6, the invention name is Terp estacin derivatives, the preparation method thereof and the preparation method of the application in the preparation of the hypoxic factor inhibitor) is specifically detailed as follows:
1. synthesis of Compound 1
Phenylalanine methyl ester hydrochloride (1 mmol) and Et at 0 deg.C 3 N (3 mmol, 303mg) was dissolved in dichloromethane (10 ml) and a mixed solution of chloroacetyl chloride (2mmol, 226mg, 0.16ml) dissolved in dichloromethane (5 ml) was added dropwise to the solution slowly, and stirring was continued for 3 hours after the addition. After dichloromethane (50 ml) and water (20 ml. Times.3) were added to wash the reaction solution, the dichloromethane layer was dried over anhydrous sodium sulfate to remove dichloromethane, and the residue was subjected to silica gel column chromatography to obtain an intermediate.
This intermediate (0.037mmol, 3 equivalents) and Terestacin (0.01244mmol, 5mg,1 equivalent) were dissolved in DMF (0.2 ml), catalytic amount of KI (0.2 mg) was added, and then Cs was added 2 CO 3 (0.037mmol, 12mg,3 equivalents), and stirred at room temperature until the reaction is complete. After completion of the reaction, 10ml of water was added and extracted three times with ethyl acetate (3X 3 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and the product was purified by HPLC to give the title compound 1 in 42% yield.
The nuclear magnetic data for compound 1 is as follows:
1 H NMR(700MHz,MeOD)δ7.28(t,J＝7.4Hz,1H),7.24–7.21(m,1H),7.21–7.18(m,1H),5.38(d,J＝5.4Hz,1H),5.30(dd,J＝10.3,5.0Hz,1H),5.18(s,1H),4.81(d,J＝15.1Hz,1H),4.77(dd,J＝7.9,5.6Hz,1H),4.56(d,J＝15.1Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.81(dd,J＝10.6,8.4Hz,1H),3.71(s,1H),3.66(dd,J＝10.7,6.4Hz,1H),3.22–3.15(m,1H),3.07(dd,J＝13.9,7.9Hz,1H),2.77(dd,J＝11.2,2.2Hz,1H),2.72(dd,J＝14.9,6.9Hz,1H),2.45(d,J＝17.2Hz,1H),2.36–2.20(m,1H),2.13(t,J＝12.9Hz,1H),2.10–1.94(m,1H),1.85–1.72(m,1H),1.64(d,J＝5.7Hz,4H),1.57(s,2H),1.17(d,J＝7.1Hz,1H),0.96(s,1H). 13 CNMR(176MHz,MeOD)δ210.05,173.00,171.31,163.43,149.91,138.86,137.81,137.52,133.80,130.33,130.07,129.59,128.00,125.37,122.90,77.07,68.84,66.10,54.69,52.81,51.11,50.85,41.33,40.33,39.26,38.34,35.91,30.87,29.71,24.80,16.83,15.65,15.49,15.02,10.46.
2. synthesis of Compound 2
The phenylalanine methyl ester hydrochloride is replaced by tryptophan methyl ester hydrochloride, the synthesis method is the same as 1, the target compound 2 is obtained, and the yield is as follows: 58 percent.
The nuclear magnetic data for compound 2 is as follows:
1 H NMR(700MHz,MeOD)δ7.49(d,J＝7.9Hz,1H),7.33(d,J＝8.1Hz,1H),7.10(s,1H),7.09–7.06(m,1H),7.01–6.98(m,1H),5.37(d,J＝5.2Hz,1H),5.28(dd,J＝10.4,5.0Hz,1H),5.21–5.14(m,1H),4.83(d,J＝5.9Hz,1H),4.75(d,J＝15.1Hz,1H),4.61(d,J＝15.1Hz,1H),3.97(dd,J＝9.9,4.1Hz,1H),3.73(dd,J＝10.7,8.4Hz,1H),3.69(s,3H),3.58(dd,J＝10.7,6.4Hz,1H),2.75(dd,J＝11.2,2.1Hz,1H),2.69–2.58(m,1H),2.42(d,J＝16.9Hz,1H),2.37–2.24(m,3H),2.17–2.06(m,2H),2.03(dd,J＝19.0,6.6Hz,1H),2.00–1.91(m,1H),1.85–1.73(m,3H),1.64(d,J＝14.9Hz,7H),1.57(s,3H),1.04(d,J＝7.1Hz,3H),0.95(s,3H). 13 C NMR(176MHz,MeOD)δ210.04,173.45,171.22,163.53,149.82,138.84,138.04,137.50,133.79,130.08,128.80,125.38,124.61,122.89,122.47,119.93,119.12,112.37,110.06,77.06,68.95,66.08,54.34,52.84,51.08,50.87,41.33,40.30,39.23,35.91,30.87,29.68,28.33,24.80,16.83,15.64,15.49,14.88,10.48.MS-ESI(m/z):415.1(M+H) +
3. synthesis of Compound 3
The phenylalanine methyl ester hydrochloride was replaced with isoleucine methyl ester hydrochloride, and the synthesis method was the same as in example 1 to obtain the target compound 3, with a yield: 58 percent.
The nuclear magnetic data for compound 3 are as follows:
1 H NMR(700MHz,MeOD)δ5.38(d,J＝5.3Hz,1H),5.30(dd,J＝10.5,5.0Hz,1H),5.17(d,J＝8.9Hz,1H),4.92(d,J＝15.1Hz,1H),4.66(d,J＝15.1Hz,1H),4.47(d,J＝5.8Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.88(dd,J＝10.7,8.5Hz,1H),3.73(s,3H),3.69(dd,J＝10.7,6.4Hz,1H),2.83–2.70(m,2H),2.47(d,J＝17.0Hz,1H),2.36–2.22(m,3H),2.19–1.89(m,5H),1.78(ddd,J＝18.5,14.5,10.9Hz,3H),1.71–1.60(m,7H),1.57(s,3H),1.53–1.43(m,1H),1.24(d,J＝7.1Hz,3H),0.98–0.86(m,9H). 13 C NMR(176MHz,MeOD)δ210.12,173.27,171.57,162.73,149.96,138.83,137.53,133.80,130.09,125.36,122.92,77.07,68.80,66.06,57.74,52.57,51.17,50.87,41.33,40.42,39.31,38.66,35.90,30.86,29.77,26.27,24.80,16.80,15.97,15.65,15.47,14.95,11.72,10.45.
4. synthesis of Compound 4
The phenylalanine methyl ester hydrochloride is replaced by the aspartic acid methyl ester hydrochloride, the synthesis method is the same as 1, the target compound 4 is obtained, and the yield is as follows: 50 percent.
The nuclear magnetic data for compound 4 are as follows:
1 H NMR(700MHz,MeOD)δ5.38(d,J＝5.3Hz,1H),5.30(dd,J＝10.4,5.2Hz,1H),5.22–5.14(m,1H),4.81(d,J＝15.3Hz,1H),4.64(d,J＝15.3Hz,1H),3.98(dd,J＝9.9,4.1Hz,1H),3.86(dd,J＝10.7,8.3Hz,1H),3.74(s,3H),3.72–3.67(m,4H),2.93(d,J＝5.7Hz,2H),2.79(dd,J＝11.2,2.2Hz,1H),2.75(dt,J＝13.9,6.9Hz,1H),2.47(d,J＝17.1Hz,1H),2.38–2.24(m,3H),2.13(t,J＝13.1Hz,1H),2.10–1.91(m,3H),1.84–1.72(m,3H),1.69–1.60(m,7H),1.57(s,3H),1.25(d,J＝7.1Hz,3H),0.96(s,3H). 13 C NMR(176MHz,MeOD)δ209.97,172.66,172.27,171.42,163.21,149.90,138.87,137.53,133.80,130.08,125.37,122.91,77.06,68.96,66.10,53.18,52.52,51.12,50.83,49.75,49.52,49.51,41.33,40.34,39.29,36.62,35.90,30.87,29.72,24.80,16.83,15.65,15.48,14.96,10.45.
example 1: compounds 1,2,3,4 inhibit the proliferation of brain glioma (U87 MG) stem cells and the formation of tumor neurospheres.
Brain glioma U87MG stem cells were cultured in serum-free medium DMEM/F12 (Dulbecco's modified Eagle's medium/Nutrient Mixture F-12 (Gibco) stabilizing 1X B-27serum-free supplement containing 1 XB-27, 5 μ g/mL heparin,2mM L-glutamine,20 ng/EGF mL, 20ng/mL bFGF, and 1 penicillin/streptomycin) using 96-well plates at approximately 5X 10 per well 3 Individual cells, stem cells containing 5% CO at 37 ℃ 2 Cultured in an incubator (Thermo Scientific, vantaa, finland). After the stem cells grow normally, the stem cells are treated for 7 days by adding DMSO as a negative control, terestacin and 4-200 as positive controls, and treating the stem cells at 7 concentrations of 30,15,10,5,2.5,1.25,0.625 mu M and the like in different concentrations of different compounds. Each set of experiments was repeated in 3 parallel groups, and the number of tumor neurospheres formed with a diameter of more than 70 μm was counted using a light microscope (Olympus, tokyo, japan). By using
2.0 method for counting and calculating cell proliferation. The fluorescence intensity of the samples was measured using a multimode microscopic reading platform (BioTek, inc., winooski, VT, USA). IC of the compounds was calculated using GraphPad Prism 5 (GraphPad Software, la Jolla, calif., USA) Software 50 The value is obtained. The results are shown in tables 1 and 2:
TABLE 1 Compounds inhibit proliferation of glioma stem cells
Note: a 4-200 is compound N- (4-hydroxyphenyl) - [1,1' -biphenyl ]]-4-sulfonamide, positive control with Termescalin
EXAMPLE 2 inhibition of invasion of brain glioma (U87 MG) stem cells by Compounds
Invasion assay of Stem cells in a Transwell cell with a pore size of 8.0 μmIn the chamber (Corning Costar, acton, MA, USA). The lower layer of the cell was coated with 10. Mu.L of gelatin (1 mg/mL) and the upper layer was coated with 10. Mu.L of Matrigel (3 mg/mL) primer. U87MG stem cell (5X 10) 4 cells/well) was cultured in the serum-free medium DMEM/F12 in the upper chamber, the test compound (2.5. Mu.M) was mixed in the serum-free medium DMEM/F12 in the lower layer, and the Transwell cell was adjusted to contain 5% CO 2 The culture was carried out in an incubator at 37 ℃ for 18h. The cells were then fixed with 70% methanol and stained with hematoxin/eosin. The invading cells in the lower chamber were counted using an optical microscope (Olympus, tokyo, japan), and then the invasion rate of stem cells was calculated. As can be seen from fig. 2 and 3, compounds 1,2,3,4 inhibited glioma stem cell invasion.
Claims (10)
- The application of the Terpenstacin derivative or the medicinal salt thereof in preparing the antitumor drugs is disclosed, wherein the structural formula of the Terpenstacin derivative is shown as any one of the following formulas:
- 2. the use according to claim 1, wherein the anti-neoplastic drug is a drug for the treatment of brain glioma.
- 3. The use of claim 1, wherein the anti-neoplastic drug further comprises a pharmaceutically acceptable excipient.
- 4. The use according to claim 1, wherein the anti-tumor pharmaceutical dosage form is a liquid dosage form or a solid dosage form.
- 5. The use according to claim 4, wherein the liquid dosage form is an injection, a solution, a suspension, an emulsion or an aerosol.
- 6. The use of claim 4, wherein the solid dosage form is a tablet, capsule, pill, powder injection, sustained release formulation or microparticle delivery system.
- 7. The use according to claim 2, wherein the medicament for the treatment of brain glioma is a medicament for inhibiting the proliferation of brain glioma stem cells.
- 8. The use according to claim 2, wherein the medicament for the treatment of brain glioma is a medicament for inhibiting the formation of brain glioma stem cell tumor spheres.
- 9. The use according to claim 2, wherein the medicament for the treatment of brain glioma is a medicament for inhibiting the infiltration of brain glioma stem cells.
- 10. An antitumor drug, which is characterized by comprising a Terestacin derivative or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the Terestacin derivative has a structural formula shown in any one of the following formulas:
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| KR20090083619A (en) * | 2008-01-30 | 2009-08-04 | 연세대학교 산학협력단 | Methods for screening anti-angiogenic agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20090083619A (en) * | 2008-01-30 | 2009-08-04 | 연세대학교 산학협력단 | Methods for screening anti-angiogenic agents |
| WO2017149502A1 (en) * | 2016-03-03 | 2017-09-08 | Bioup Sagl | Method for reducing the resistance to anticancer drugs, radioresistance and cancer stem cells formation and metastatic phenotype |
| CN114751863A (en) * | 2022-04-21 | 2022-07-15 | 中国科学院南海海洋研究所 | Terestacin derivative, preparation method thereof and application of Terestacin derivative in preparation of low-oxygen factor inhibitor |
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