CN112920198A - Artemisinin-chlorambucil composition and preparation method thereof - Google Patents
Artemisinin-chlorambucil composition and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of artemisinin derivatives, and particularly relates to an artemisinin-chlorambucil composition and a preparation method thereof. Aiming at the problems that the effect of artemisinin on tumors is to be improved, the toxic and side effects of chlorambucil are great and the like, the artemisinin-chlorambucil ester with a novel structure is designed and synthesized according to the pharmacophore split principle, and the structure of the artemisinin-chlorambucil ester is formed by1H NMR、13C NMR and HRMS-ESI characterization. It has good antitumor activity and reduced toxic and side effects of chlorambucil. The preparation method of the invention is simple, the obtained derivative has strong anti-tumor activity,has low toxic and side effects, provides a new medicament for resisting tumors, and has good application value.
Description
Technical Field
The invention belongs to the technical field of artemisinin derivatives, and particularly relates to an artemisinin-chlorambucil composition and a preparation method thereof.
Background
Artemisinin is a sesquiterpene lactone natural product separated from Artemisia annua L of Compositae, and has unique peroxy bridge structure. The research shows that the artemisinin has various important pharmacological activities, such as insect resistance, tumor resistance, anti-inflammation and the like. Because the pharmacokinetic property of the artemisinin is poor, people derive and transform the structure of the artemisinin greatly, and a plurality of artemisinin derivatives are applied to clinical antimalarial treatment, such as artemether, artesunate and other drugs, can effectively reduce the death rate of malaria patients and save the lives of tens of thousands of patients. Our country scientist yoyo makes an outstanding contribution in the field of artemisinin, gaining the physiological or medical prize of nobel in 2015. In addition, recent researches show that artemisinin and derivatives thereof also have remarkable antitumor activity and show potential application values at a cellular level and an animal level. Among them, artemisinin derivatives also show strong effects in anti-leukemia.
On the other hand, chlorambucil, as a nitrogen mustard antineoplastic drug, has a long application history in clinic, and can treat lymphoma, chronic lymphatic leukemia, breast cancer and the like. However, chlorambucil, as a DNA alkylating agent, has significant disadvantages, such as short half-life and strong toxicity to normal tissues. In order to improve the clinical treatment effect, people construct a large number of chlorambucil derivatives by utilizing the principles of prodrug design, molecular heterozygosis and the like, and obtain some antitumor drugs which are widely used clinically, such as uracil mustard, estramustine and the like.
Although chlorambucil has strong anti-tumor activity, chlorambucil has large toxic and side effects, and how to reduce the toxic and side effects and enhance the anti-tumor effect is an urgent problem to be solved in the industry.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the antitumor effect of the artemisinin needs to be improved, and the toxic and side effects of the chlorambucil are great.
The technical scheme for solving the technical problems comprises the following steps: an artemisinin-chlorambucil composition is provided. The artemisinin-chlorambucil ester composition has a structural formula as follows:
wherein the artemisinin-chlorambucil composition has a structure of1H NMR、13C NMR and HRMS-ESI characterization.
Wherein, the artemisinin-chlorambucil ester composition is prepared by reacting dihydroartemisinin with chlorambucil.
The equation for the reaction is:
the invention also provides a preparation method of the artemisinin-chlorambucil composition, which comprises the following steps:
dissolving dihydroartemisinin, chlorambucil and 4-dimethylaminopyridine in anhydrous N, N-dimethylformamide, stirring at 0-5 deg.C for 5-20min, adding 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, and stirring at room temperature for reaction for 6-10 h; adding 50-100mL of water to terminate the reaction, separating out a light yellow solid, filtering to obtain a crude product, washing with a small amount of water, drying in vacuum, and performing silica gel column chromatography to obtain the light yellow solid, namely the artemisinin-chlorambucil composition.
In the preparation method of the artemisinin-chlorambucil ester composition, the molar ratio of dihydroartemisinin, chlorambucil, 4-dimethylaminopyridine and 1-ethyl-3 (3-dimethylpropylamine) carbodiimide is as follows: 1-2: 2-4: 2-3.
In the preparation method of the artemisinin-chlorambucil ester composition, the chromatographic solution of silica gel column chromatography is prepared by mixing ethyl acetate and petroleum ether according to the volume ratio of 1-3: 8-10.
The invention has the beneficial effects that:
according to the invention, chlorambucil and artemisinin with anti-tumor activity and low toxicity are combined to construct a novel artemisinin-chlorambucil ester, which has good anti-tumor activity and reduces the toxic and side effects of chlorambucil. The preparation method is simple, and the obtained derivative has strong antitumor activity and low toxic and side effects, provides a new medicament for resisting tumors, and has good application value.
Drawings
FIG. 1 shows the effect of artemisinin-chlorambucil 3 on the K562 and K562/ADR cell cycles;
FIG. 2 shows the effect of artemisinin-chlorambucil 3 on apoptosis in K562 and K562/ADR cells.
Detailed Description
The following examples are intended to illustrate specific embodiments of the present invention without limiting the scope of the invention to the examples.
EXAMPLE 1 preparation of artemisinin-chlorambucil compositions
1.1 Main instruments and reagents
Agilent-400M nuclear magnetic resonance apparatus (CDCl)3As solvent, TMS as internal standard, Agilent, usa); an Agilent Agilent Accurate-Mass-Q-TOF-MS model 6520 Mass spectrometer (HRMS-ESI, Agilent Inc., USA); BD FACSCalibur flow cytometer (Becton-Dickinson, USA).
K562 human leukemia cells (tokyo bai biotechnology limited, south kyoto); K562/ADR human leukemia doxorubicin-resistant cells (Kyowa Kaiyi Biotechnology Co., Ltd.); dihydroartemisinin, chlorambucil, EDCI, DMAP (Sahn chemical technology (Shanghai) Co., Ltd.); column chromatography and thin-layer silica gel plates (Qingdao maritime works); other reagents used were analytically pure and purchased from Shanghai Tantake technologies, Inc.
1.2 Synthesis method
Dihydroartemisinin (0.35mmol,1eq), chlorambucil (1.3eq) and DMAP (3eq) were dissolved in 3mL anhydrous DMF in 10mL eggplant-shaped bottles and stirred at 2 ℃ for 15 min. EDCI (2.5eq) was added and the reaction was stirred at room temperature for 9 h. Adding 70mL of water to stop the reaction, precipitating a light yellow solid, filtering, washing the crude product with a small amount of water, vacuum drying, performing silica gel column chromatography on the obtained crude product, and performing chromatography on the crude productEthyl acetate-petroleum ether (2: 9) to give a pale yellow solid in 85% yield,1H NMR(CDCl3,400MHz),δ:7.07(2H,d,J＝8.4Hz),6.62(2H,d,J＝8.8Hz),5.80(1H,d,J＝10.0Hz),5.44(1H,s),3.70(4H,t,J＝6.0Hz),3.62(4H,t,J＝6.0Hz),2.56(3H,t,J＝6.8Hz),2.40(3H,t,J＝7.2Hz),2.06-2.00(1H,m),1.96-1.87(3H,m),1.80-1.70(2H,m),1.65-1.59(1H,m),1.54-1.46(1H,m),1.43(3H,s),1.38-1.24(3H,m),1.06-0.99(1H,m),0.97(3H,d,J＝6.0Hz),0.85(3H,d,J＝6.8Hz)；13C NMR(CDCl3,100MHz),δ:72.31,144.27,130.50,129.69,112.13,104.42,91.70,91.44,80.11,53.58,51.53,45.22,40.49,37.24,36.19,34.06,33.87,33.58,31.76,26.50,25.95,24.55,21.97,20.20,12.15；HRMS-ESI(m/z):calcd for C29H42Cl2NO6[M+H]+570.2384,found 570.2384。
structural characterization of the prepared artemisinin-chlorambucil composition:
the configuration of the 10 th site of the artemisinin derivative structure is related to a coupling constant J of H-9 and H-10, the J value of the alpha configuration is more than 9Hz, and the J value of the beta configuration is 3-4 Hz. Compound 3 synthesized in this example had a structure in which the coupling constant J between H-9 and H-10(δ 5.81ppm) was 10.0Hz, and thus compound 3 had the α configuration at position 10.
Example 2 Effect of artemisinin-chlorambucil composition
2.1 in vitro antitumor Activity test
The target compound is tested for the cytotoxic activity on K562 and K562/ADR by using the CCK-8 method by taking adriamycin as a positive drug. Cells were seeded in 96-well plates at 5% CO2And incubated at 37 ℃ for 24 h. Culture media containing different concentrations of compounds were added separately, and negative control groups were established. After incubation for 72h, 10. mu.L of CCK-8 was added to each well and incubation continued in the incubator for 3 h. Lambda is 450nm, and the absorbance (OD) of each well is read by a microplate reader to calculate the inhibition. Statistical software SPSS17.0 calculation of median Inhibitory Concentration (IC)50) The value is obtained. The experiment was repeated 3 times.
The in vitro antiproliferative activity of the novel artemisinin-chlorambucil 3 on K562 and K562/ADR cell strains was tested by the CCK-8 method with doxorubicin as the positive drug, and the results are shown in Table 1. TestingThe results show that the compound 3 has stronger cytotoxic activity on K562 and K562/ADR cell strains, and has stronger effect on sensitive cell strains than drug-resistant cell strains and IC50The values are 3.065 + -0.568 and 15.173 + -1.297 mu mol/L respectively, which are stronger than the parent dihydroartemisinin and chlorambucil and weaker than the positive drug adriamycin.
TABLE 1 in vitro antiproliferative Activity of Compound 3 on K562 and K562/ADR cells
2.2 cell cycle testing
To further investigate the mechanism of antitumor action of compound 3, we examined the effect of compound 3 on the K562 and K562/ADR cell cycles using flow cytometry. Cells in logarithmic growth phase were seeded in 6-well plates at 5% CO2And incubated at 37 ℃ for 24 h. Culture media containing different concentrations of compounds were added separately, and negative control groups were established. After incubation for 48h, cells were washed 2 times with PBS and collected at 5X 105Adding 100 mu L of RNase A into cells, and then carrying out water bath at 37 ℃ for 0.5 h; then adding 400 mu L of PI for dyeing, and keeping out of the sun for 0.5h at 4 ℃; the fluorescence at the excitation wavelength of 488nm was recorded. The experiment was repeated 3 times.
The results of the experiment are shown in FIG. 1. Compound 3 was able to block K562 and K562/ADR cell cycle arrest at G1 compared to control and the effect on cycle correlated with drug concentration.
2.3 apoptosis assay
To investigate the effect of Compound 3 on apoptosis, we used Annexin V-FITC/7-AAD double staining to investigate the effect of Compound 3 on apoptosis in K562 and K562/ADR cells. Cells in logarithmic growth phase were seeded in 6-well plates at 5% CO2And incubated at 37 ℃ for 24 h. Culture media containing different concentrations of compounds were added separately, and negative control groups were established. After incubation for 48h, the cells were washed 2 times with PBS, and 500. mu.L of Binding Buffer was added, followed by 5. mu.L of Annexin V-APC, followed by 5. mu.L of 7-AAD. The reaction was carried out at room temperature in the dark for 15 min. And finally detecting the apoptosis by using a flow cytometer. The experiment was repeated 3 times。
The results of the experiment are shown in FIG. 2. Compound 3 was able to induce apoptosis in K562 and K562/ADR cells in a concentration-dependent manner, respectively, compared to the control group. In addition, IC with Compound 3 on K562 and K562/ADR cell lines50Consistent with the values, compound 3 at the same concentration induced less apoptosis in resistant cells than in sensitive cells.
Based on the pharmacophore split principle, the invention carries out heterozygosis on the artemisinin skeleton with the antitumor activity and the chlorambucil, and designs and synthesizes the artemisinin-chlorambucil ester 3 with a novel structure. Meanwhile, the cytotoxic activity of the compound 3 on K562 and K562/ADR was measured by the CCK-8 method. The results show that the compound 3 has stronger antiproliferative activity on two tumor cell strains. Flow cytometry detection showed that compound 3 was able to block the K562 and K562/ADR cell cycle and induce apoptosis.
Claims (6)
1. An artemisinin-chlorambucil ester composition, which is characterized in that: the structural formula is as follows:
2. the artemisinin-chlorambucil composition of claim 1, wherein: is structurally composed of1H NMR、13C NMR and HRMS-ESI characterization.
3. The artemisinin-chlorambucil composition of claim 1, wherein: is prepared by the reaction of dihydroartemisinin and chlorambucil.
4. A process for the preparation of an artemisinin-chlorambucil composition according to any one of claims 1 to 3, comprising the steps of:
dissolving dihydroartemisinin, chlorambucil and 4-dimethylaminopyridine in anhydrous N, N-dimethylformamide, stirring at 0-5 deg.C for 5-20min, adding 1-ethyl-3 (3-dimethylpropylamine) carbodiimide, and stirring at room temperature for reaction for 6-10 h; adding 50-100mL of water to terminate the reaction, separating out a light yellow solid, filtering to obtain a crude product, washing with a small amount of water, drying in vacuum, and performing silica gel column chromatography to obtain the light yellow solid, namely the artemisinin-chlorambucil composition.
5. The method of preparing an artemisinin-chlorambucil composition of claim 4, wherein: the mol ratio of the dihydroartemisinin, the chlorambucil, the 4-dimethylaminopyridine and the 1-ethyl-3 (3-dimethylpropylamine) carbodiimide is as follows: 1-2: 2-4: 2-3.
6. The method of preparing an artemisinin-chlorambucil composition of claim 4, wherein: the chromatographic solution of silica gel column chromatography is prepared by mixing ethyl acetate and petroleum ether according to the volume ratio of 1-3: 8-10.
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| CN113480559A (en) * | 2021-07-13 | 2021-10-08 | 北京大学深圳医院 | Artemether derivative with high anti-cancer biological activity and preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113480559A (en) * | 2021-07-13 | 2021-10-08 | 北京大学深圳医院 | Artemether derivative with high anti-cancer biological activity and preparation method and application thereof |
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