CN113135861B - Ligustrazine derivative and preparation method and application thereof - Google Patents
Ligustrazine derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a ligustrazine derivative and a preparation method thereofPreparation method and application. The chemical formula of the ligustrazine derivative is C 16 H 22 N 4 Se 2 The structural formula is as follows:
Description
Technical Field
The invention relates to the technical field of compounds, in particular to a ligustrazine derivative and a preparation method and application thereof.
Background
Lung cancer is a malignant tumor that originates in the trachea, bronchi and lungs. According to the differentiation degree, morphological characteristics and biological characteristics of lung cancer, the lung cancer is divided into small cell lung cancer and non-small cell lung cancer, and the non-small cell lung cancer comprises adenocarcinoma, 40023squamous cell carcinoma and large cell carcinoma. Among these, non-small cell lung adenocarcinoma is characterized by a slow growth, usually first appearing in the peripheral or outer regions of the lung, developing from cells that produce mucus in the airway lining, the most common type of lung cancer in both smokers and non-smokers, accounting for approximately 85% of all types of lung cancer. Worldwide, 182.5 million new cases of lung cancer account for 11.6 percent of the total cases of various cancers every year, and 160 ten thousand dead patients account for 18.4 percent of the total cancer deaths. The global geographical distribution of lung cancer shows significant regional differences, with the highest incidence in men being central and eastern europe (53.5 per 100000) and east asia (50.4 per 100000); in women, the incidence is generally lower than in men, with slightly different geographical areas, mainly differing effects of historical smoking exposure. From lung cancer mortality rates, the highest are north america (33.8%) and northern europe (23.7%), the east asia is relatively high (19.2%), and the west africa and middle africa are the lowest (1.1% and 0.8%, respectively). Cancer data obtained from the National Centers for Health and Statistics (NCHS) of the CDC in the united states indicate approximately 89% of lung cancer deaths, with all morbidity and mortality reaching the standard population of the united states in 2000 and over 23 million new cases in 2018 alone. The incidence and mortality of lung cancer in China are rising year by year and are at the head of various cancers, thus becoming a major public health problem to be urgently solved.
In the technical field of treating lung cancer, chemotherapy is still the most important means for treating advanced lung cancer. The chemotherapy drugs comprise traditional drugs, targeting drugs, hormone drugs, gene therapy drugs and the like, and the types of the chemotherapy drugs comprise cisplatin, docetaxel, gemcitabine, vinorelbine, pemetrexed, gefitinib, nivolumab and the like. However, the curative effect of the existing chemotherapy is not ideal, the effective rate is 30%, the annual survival rate is about 35%, the five-year survival rate is less than 5%, and serious toxic and side effects exist, so that the search for a safer, more effective, more stable and controllable lung cancer treatment medicine is still urgent.
The element selenium has the functions of eliminating free radicals, enhancing the immunity in organisms, preventing aging and the like. The development of new tumor therapeutics using the unique biological activities of selenium has been the focus of research, such as the biological activities of Ghose A et al (Ghose A, fluorening J, el-Baulomy K, et al, enhanced sensitivity of human organic pathogens to inhibition of apoptosis by selective compounds: infection of endogenous-activated protein kinase and fast pathway [ J ].2001,61 (20): 7479-7487.), shaban S et al (Shaban, negm A, ashmawy A M, biological synthesis, in silico, molecular and biological compounds of biological organic microorganisms and biological synthesis [ J ] (see 5, J.: see the biological activities of selenium-containing compounds: selenium-containing microorganisms, selenium-synthesizing ethers [ 60, J.: 2016, J.: 5, J.).
Ligustrazine (TMP) has various biological activities, such as anti-tumor, anti-inflammatory, anti-apoptosis, vasodilatation, etc., and thus is widely used for clinical treatment of cardiovascular and cerebrovascular diseases. At present, the research on the ligustrazine derivative is less, and the preparation of the ligustrazine derivative with the anti-tumor effect by combining ligustrazine and selenium is not reported.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to solve the problem that the effect of chemotherapy for treating lung cancer is not ideal in the prior art, and provides a ligustrazine derivative.
In order to solve the technical problems, the invention adopts the following technical scheme:
a ligustrazine derivative has a chemical formula of C16H22N4Se2, and a structural formula of the ligustrazine derivative is as follows:
wherein the ligustrazine derivative is amorphous or crystalline.
The invention also provides a preparation method of the ligustrazine derivative, which comprises the steps of putting disodium diselenide and 2-bromo-3, 5, 6-trimethyl pyrazine into a reaction bottle, adding a proper amount of water to enable the disodium diselenide and the 2-bromo-3, 5, 6-trimethyl pyrazine to be milky, stirring at room temperature for reacting for 3h to 3.5h, standing for layering, shaking a lower organic phase to obtain a yellow solid, filtering, drying, preparing, separating and drying again to obtain the ligustrazine derivative of claim 1.
Preferably, the molar ratio of the disodium diselenide to the 2-bromo-3, 5, 6-trimethylpyrazine is 1-4.
The invention also provides application of the ligustrazine derivative, and the ligustrazine derivative is used for preventing and/or treating lung cancer.
Further, the unit dosage form of the ligustrazine derivative is tablets, capsules, granules, injection, powder for injection, transdermal patches, ointments, gels, suppositories, oral solutions, oral suspensions, emulsions for injection, oral emulsions, etc., sustained-release tablets or controlled-release tablets.
Preferably, in the dosage form of the ligustrazine derivative, the ligustrazine derivative accounts for 10-1000 mg in unit dosage form.
Furthermore, the dosage form of the ligustrazine derivative comprises the ligustrazine derivative and auxiliary materials.
Further, the auxiliary materials are one or more of preservatives, wetting agents, emulsifying agents, dispersing agents and suspending agents.
Compared with the prior art, the invention has the following beneficial effects:
1. the ligustrazine derivative (ligustrazine diselenide or Se2, the same below) provided by the invention shows excellent in-vitro anti-tumor activity and has an obvious inhibition effect on human lung adenocarcinoma cisplatin-resistant A549/DDP tumor cells, so that the ligustrazine derivative has a high-efficiency anti-lung cancer effect. Compared with other anti-lung cancer drugs, the same dose of the ligustrazine derivative has better anti-lung cancer effect than the existing first-line clinical drugs, and the ligustrazine derivative has very low toxic and side effects. Provides possibility for developing a new medicine for treating lung cancer and has good application prospect.
2. The preparation method of the ligustrazine derivative provided by the invention is simple, the preparation process is environment-friendly, and the preparation cost is low.
Drawings
FIG. 1 shows the effect of Se2 on transwell migration of A549 cells (. Times.200).
FIG. 2 is a graph showing the effect of Se2 on the ability of A549 cells to migrate directionally.
FIG. 3 is the effect of Se2 on A549 cell invasion (. Times.200).
FIG. 4 is a graph showing the effect of Se2 on the invasive targeting ability of A549 cells.
Fig. 5 is a graph of the effect of Se2 on a549 cell cycle distribution.
FIG. 6 is a graph showing that Annexin V-FITC/PI double staining detects the effect of Se2 on apoptosis of A549 cells.
Fig. 7 is the effect of Se2 on apoptosis of a549 cells.
FIG. 8 is a graph showing the effect of Se2 on Caspase3 activity.
Detailed Description
The invention will be further explained with reference to the drawings and the embodiments.
1. Preparation of ligustrazine derivatives
Example 1
10.2g of disodium diselenide, 10.8g of 2-bromo-3, 5, 6-trimethyl pyrazine are taken and placed in a reaction bottle, 200mL of water is added, the mixture is stirred and reacted for 3 hours at room temperature, the mixture is kept stand and layered, a large amount of yellow solid is obtained by shaking the lower organic phase, and the yellow solid is filtered, dried, separated and dried again, so that the yield is 81.5%.
And (3) detection results: amorphous powder, crystallization in methanol to give lamellar crystals, ESI-MSm/z [ M + H ]] + ＝431； 1 H NMR(600MHz,MeOD)：δ4.17(s,4H),2.49(d,J＝6.9 Hz,18H)； 13 C NMR(151 MHz,MeOD):δ149.64,148.99,148.83,148.14,30.66,19.83,19.76,19.65。
The compound of the present invention synthesized as described above was finally confirmed to be 1, 2-bis ((3, 5, 6-trimethylpyrazin-2-yl) methyl) diselenide having the chemical formula C 16 H 22 N 4 Se 2 The molecular weight is 430.02, and is popularly named as ligustrazine diselenide. The chemical structure is as follows:
2. preparation of ligustrazine derivative composition
Example 2
The preparation method of the ligustrazine diselenide hydrochloride comprises the following steps:
taking 43g of the synthetic ligustrazine diether prepared in the example 1, putting the synthetic ligustrazine diether into a reaction bottle, adding 50mL of absolute ethyl alcohol to dissolve the synthetic ligustrazine diether, 43g of the synthetic ligustrazine diether, slowly adding 45mL of hydrochloric acid, uniformly stirring, placing the mixture in a refrigerator, standing overnight, collecting precipitates, and drying in vacuum to obtain the ligustrazine diether.
Example 3
The preparation method of the ligustrazine diselenide injection comprises the following steps:
the ligustrazine diselenide hydrochloride prepared in the embodiment 2 is used as a raw material to prepare the ligustrazine diselenide hydrochloride for injection, and the formula of 1000 bottles is as follows:
| ligustrazine diselenide hydrochloride (with C) 16 H 22 N 4 Se 2 Meter) | Mannitol, glycine and other auxiliary materials |
| 5g | 25g |
Mixing the raw materials and adjuvants, dissolving with water for injection, packaging, lyophilizing, tamponading, and packaging.
Example 4
The preparation method of the ligustrazine diselenide tablet specifically comprises the following steps:
the ligustrazine diselenide compound prepared in the example 1 is used as a raw material to prepare ligustrazine diselenide tablets, and the formula of 1000 tablets is as follows:
| ligustrazine diselenide (with C) 16 H 22 N 4 Se 2 Meter) | Starch and other auxiliary materials |
| 30g | 220g |
Mixing the raw materials and adjuvants, grinding into fine powder, sieving with 100 mesh sieve, weighing according to formula, tabletting, molding, and packaging.
Example 5
The preparation method of the ligustrazine diselenide capsule specifically comprises the following steps:
the ligustrazine diselenide compound prepared in the embodiment 1 is used as a raw material to prepare the ligustrazine diselenide capsule, and the formula of 1000 capsules is as follows:
| ligustrazine diselenide (with C) 16 H 22 N 4 Se 2 Meter) | Starch and other auxiliary materials |
| 30g | 220g |
Mixing the raw materials and adjuvants, grinding into fine powder, sieving with 100 mesh sieve, weighing according to formula, granulating, and packaging.
3. Research on anti-lung cancer effect of ligustrazine derivative
(1) Effect of ligustrazine diselenide (Se 2) on proliferation of human lung adenocarcinoma cells (A549)
The method comprises the following steps: the CCK8 method is used for detecting the activity of A549 cells and observing the effect of ligustrazine diselenide (Se 2) on human lung adenocarcinoma cells (A549) used in experiments. Single cell suspensions were prepared at 5X 10 per well 4 One cell/mL was inoculated into a 96-well plate and cultured in 1640 medium containing 5% fetal bovine serum. After 24h, ligustrazine diselenide (Se 2) solutions with different concentrations are added. After further culturing for 24 hours, 100. Mu.L of a medium containing 10% of CCK8 solution was added to each well, and mixed by gentle shaking. After 2h, the OD value is measured at 450nm on a full-automatic enzyme calibration instrument, the cell proliferation inhibition rate (%) is calculated, and the proliferation inhibition effect on A549 cells is shown in Table 1.
As can be seen from Table 1, the results of the reaction of A549 cells with ligustrazine diselenide (Se 2) show that Se2 inhibits the proliferation of A549 cells in a concentration-dependent manner.
TABLE 1 inhibition (%) of proliferation of A549 cells (n = 3)
P < 0.05, P < 0.01, P < 0.001
(2) Effect of ligustrazine diselenide (Se 2) on migration and invasion of human lung adenocarcinoma cells (A549)
1) Transwell migration test
Using a 24-well plate with polycarbonate membrane chamber, the lower chamber was filled with 100. Mu.L of 1640 medium containing 20% FBS, the positive drug Gefitinib (50. Mu.M) and Se2 cell suspensions (5X 10) of various concentrations 4 one/mL) 500. Mu.L was added to the upper chamber and only the cell suspension was added to the Control group. After the cells migrated in the incubator for 24 hours, the cells on the upper and lower surfaces of the chamber were fixed with 4% paraformaldehyde and stained with 0.1% crystal violet staining solution for 20min. Multiple fields were randomly selected under a 200-fold fluorescence microscope and the number of cells crossing the membrane was counted for each field, see figure 1. The experiment was repeated 3 times and the mobility inhibition was calculated and the results are shown in fig. 2. In fig. 2, P < 0.05, P < 0.01, n =3, compared to Control group.
2) Transwell invasion test
The upper chamber of the chamber was coated with Matrigel gel (1 mg/mL) and after air drying, the remaining test steps were performed as in the Transwell migration test, with the results shown in FIGS. 3 and 4, where P < 0.05, P < 0.01 and n =3 in FIG. 4 compared to Control.
As can be seen from table 1 and fig. 1 to 3, the results of Transwell migration and invasion test show that Se2 dose-dependently inhibits migration and invasion of a549 cells.
(3) Flow cytometry analysis of apoptosis and cycle
1) Flow cytometry for detecting influence of ligustrazine diselenide (Se 2) on A549 cell cycle
Logarithmic growth phase of 5X 10 cells 4 one/mL was seeded in 6-well plates, 2mL per well. After 24h of culture, the experimental group and the positive drug group are added with 2mL of drug-containing culture medium, and the control group is added with the same amount of culture medium. After 24h incubation, cells were harvested and washed 1 time with 4 ℃ pre-chilled PBS. The cell suspension was added dropwise to 700. Mu.L of pre-cooled absolute ethanol and cells were fixed overnight at-20 ℃. After centrifugation, 150. Mu.L of propidium iodide staining solution was added to each group, mixed well, and incubated at 37 ℃ for 30min in the dark. Detecting on the computer and utilizing Flowjo software to carry out detection resultThe results of the analysis are shown in FIG. 5 and Table 2.
Table 2 effect of Se2 on a549 cell cycle distribution (%,
)(n＝3)
2) Flow cytometry for detecting influence of ligustrazine diselenide (Se 2) on A549 cell apoptosis
Annexin V-FITC-PI double staining for 5X 10 cells in logarithmic growth phase 4 one/mL was seeded in 6-well plates, 2mL per well. After 24h of culture, the experimental group and the positive drug group are added with 2mL of drug-containing culture medium, and the control group is added with the same amount of culture medium. After 24h of culture, cells were collected and washed 2 times with 4 ℃ pre-chilled PBS. 200uL of binding buffer resuspended cells. 5uL Annexin V-FITC and 10 uL propidium iodide staining solution are added into each group respectively, mixed evenly and incubated for 10min in the dark. And (4) detecting on the computer and analyzing the detection result by using Flowjo software, wherein the result is shown in a figure 6 and a figure 7. In fig. 6, P < 0.05, P < 0.01 compared to Control group.
(4) Influence of ligustrazine diselenide (Se 2) on A549 cell caspase3 expression
Logarithmic growth phase cell 5X 10 4 one/mL was seeded in 6-well plates, 2mL per well. After 24h of culture, the test group and the positive drug group are added with 2mL of drug-containing culture medium, and the control group is added with the same amount of culture medium. After 24 incubation, cells were harvested and washed 1 time with 4 ℃ pre-chilled PBS. Add 150. Mu.L of lysate to each group, resuspend and mix well, and lyse for 15min in ice bath. And adding the groups into a reaction system according to a Caspase3 activity detection kit, and uniformly mixing to avoid generating bubbles. After incubation for 2h at 37 ℃ in the dark, the OD was measured at 405nm when the color change was evident, and the unit of caspase3 activity contained in each group was calculated, and the results are shown in FIG. 8, P < 0.05, P < 0.01, P < 0.001, and n =3, as compared to the Control group.
Flow cytometry and caspase3 activity detection results show that the amount of early apoptosis, late apoptosis and caspase3 is gradually increased along with the increase of the drug concentration, and the primary action mechanism of the method can up-regulate the amount of caspase3 in A549 cells to induce the apoptosis of the A549 cells by blocking the cell cycle at the G2/M stage. The suggestion that Se2 has the effects of inhibiting the proliferation, migration and invasion of the non-small cell lung adenocarcinoma A549 and inducing the apoptosis of the non-small cell lung adenocarcinoma A549 is superior to the positive medicament Gefitinib. In conclusion, the ligustrazine diselenide (Se 2) shows excellent in vitro anti-tumor activity.
(5) In vitro anti-drug-resistant lung cancer effect of ligustrazine diselenide
The CCK8 method is adopted to measure and respectively investigate the influence of ligustrazine diselenide, positive medicaments of cis-platinum (DDP), 5-fluorouracil (5-FU) and Gefitinib (Gefitinib) on the proliferation of a drug-resistant cell strain A549/DDP, the CCK8 method is operated in the same way, and graph pad software is adopted to calculate IC 50 And the reversal fold of drug Resistance (RF) was calculated, and the results are shown in table 3.
TABLE 3 IC of various classes of compounds on A549/DDP cells 50 Value of
As can be seen from Table 3, ligustrazine diselenide has obvious inhibition effect on human lung adenocarcinoma cis-platinum drug-resistant A549/DDP tumor cells, and IC thereof 50 Is nearly 200 times of metal-based anticancer drug cisplatin, nearly 800 times of 5-fluorouracil and 5 times of gefitinib.
In conclusion, the ligustrazine derivative (ligustrazine diselenide) provided by the invention has a high-efficiency anti-lung cancer effect, and development of the ligustrazine derivative compound brings good news to lung cancer patients.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the technical solutions, and those skilled in the art should understand that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all that should be covered by the claims of the present invention.
Claims (4)
1. A ligustrazine derivative is characterized in that the ligustrazine isThe chemical formula of the derivative is C 16 H 22 N 4 Se 2 The structural formula is as follows:
；
the ligustrazine derivative is amorphous or crystalline.
2. A preparation method of the ligustrazine derivative as claimed in claim 1, which is characterized in that disodium diselenide and 2-bromo-3, 5, 6-trimethylpyrazine are placed in a reaction bottle, a proper amount of water is added to enable the disodium diselenide and the 2-bromo-3, 5, 6-trimethylpyrazine to be in a milk state, the mixture is stirred at room temperature for reaction for 3h to 3.5h, the mixture is kept stand for layering, a lower organic phase is shaken to obtain a yellow solid, and the yellow solid is filtered, dried, prepared, separated and dried again to obtain the ligustrazine derivative as claimed in claim 1.
3. The method for preparing ligustrazine derivatives according to claim 2, wherein the molar ratio of disodium diselenide to 2-bromo-3, 5, 6-trimethylpyrazine is 1 to 4.
4. The use of a ligustrazine derivative according to claim 1 for the preparation of a medicament for the prevention and/or treatment of lung cancer.
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