CN112190584B - Application of ligustrazine derivative in preparation of anti-leukemia drugs - Google Patents
Application of ligustrazine derivative in preparation of anti-leukemia drugs Download PDFInfo
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- CN112190584B CN112190584B CN202011234641.5A CN202011234641A CN112190584B CN 112190584 B CN112190584 B CN 112190584B CN 202011234641 A CN202011234641 A CN 202011234641A CN 112190584 B CN112190584 B CN 112190584B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The invention discloses an application of a ligustrazine derivative in preparing anti-leukemia drugs. The research of the invention discovers that the inhibitory activity of a ligustrazine derivative 4- (3-sulfo-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-phthalic acid ester on leukemia U937 cells is obviously superior to that of ligustrazine, and the ligustrazine derivative has a prospect of being developed into an anti-leukemia medicament.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to an application of a ligustrazine derivative in preparation of an anti-leukemia medicine.
Background
Ligustrazine (Ligustrazine) is a pharmaceutical compound, has effects of resisting platelet aggregation, dilating arteriole, improving microcirculation and cerebral blood flow, and can be used for treating occlusive vascular diseases, cerebral thrombosis, angiitis, coronary heart disease, angina pectoris, etc.
The chemical structural formula of ligustrazine is as follows.
Research shows that ligustrazine also has various pharmacological activities, such as antitumor activity. Feng Quanfu researches show that ligustrazine has therapeutic effect on various cancers such as liver cancer and breast cancer (doctor academic thesis of Nanjing university of traditional Chinese medicine, 2015). Wang Xiao found that ligustrazine has effects of inhibiting proliferation and inducing apoptosis on leukemia U937 cells, and its mechanism may be that it can reduce Bcl-2 expression by influencing cell cycle distribution, and finally activate Caspase-3, start apoptosis pathway, induce apoptosis (Wang Xiao found in China J. TCM, 6 months 2015). However, ligustrazine has good inhibitory activity only on few tumors, and has a general inhibitory effect on most tumors.
The abundant chemical derivatives provide a huge compound library for drug screening and development. 4- (3-thio-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-phthalate (compound I-2) and 4- (3-thio-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-hexahydrophthalate (compound I-4) are 2 ligustrazine derivatives disclosed in the literature (Chinese patent, publication No. CN 111825664A), and no report on the antitumor activity thereof has been found at present.
The structural formulas of the compound I-2 and the compound I-4 are shown as follows.
Disclosure of Invention
The invention aims to improve the prior art and provides application of a ligustrazine derivative in preparing anti-leukemia drugs.
The technical scheme is as follows:
the application of ligustrazine derivative in preparing medicine for treating leukemia is 4- (3-sulfo-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-phthalate and has the chemical structural formula shown in the specification.
A pharmaceutical preparation for treating leukemia contains ligustrazine derivative as active ingredient.
The technical effects are as follows:
according to experimental research, the inhibition activity of the ligustrazine derivative 4- (3-sulfo-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-phthalate on leukemia U937 cells is obviously superior to that of ligustrazine, and the ligustrazine derivative has a prospect of being developed into an anti-leukemia drug.
Drawings
FIG. 1 shows the half maximal inhibitory concentration (. Mu.g/mL) of each drug against leukemia cells.
FIG. 2 shows the half inhibitory concentration (. Mu.g/mL) of each drug against breast cancer cells.
Detailed Description
The following description and drawings are included to describe the general nature of the invention, and are not intended to limit the scope of the invention.
1. Test materials
Leukemia U937 cells and breast cancer MCF-7 cells were purchased from ATCC.
Fetal bovine serum, RPMI 1640 medium was purchased from Thermo Fisher Scientific.
CCK-8 reagent was purchased from Homophorus japonicus.
The purity of ligustrazine, 4- (3-thio-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-phthalate (compound I-2) and 4- (3-thio-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-hexahydrophthalate (compound I-4) is not less than 98%.
2. Test method
1. Cell culture
Leukemia U937 cells and breast cancer MCF-7 cells were cultured in RPMI 1640 containing 10% fetal bovine serum at 37 ℃ with 5% CO 2 Culturing under saturated humidity condition. Cells in the logarithmic growth phase were taken for the experiment.
2. CCK-8 method for measuring tumor cell proliferation
Taking tumor cells in logarithmic growth phase, digesting with pancreatin, and preparing with total culture medium to obtain the final product with concentration of 5 × 10 4 Cell suspension per mL, seeded in 96-well plates at 100 μ L per well. The test is divided into a drug group, a negative control group and a positive control group, and each group (or each drug concentration) is provided with 3 multiple wells. After 24h of culture, the drug groups replaced the original culture medium with 100. Mu.L of culture medium containing compound I-2 or compound I-4 at different concentrations, the positive control group replaced the original culture medium with 100. Mu.L of culture medium containing ligustrazine at different concentrations, and the negative control group replaced the original culture medium with 100. Mu.L of fresh complete culture medium. After further culturing for 48h, adding 10 μ L of CCK-8 reagent into each well, further incubating for 3h, measuring absorbance value (OD value) of each well at 450nm wavelength with enzyme-linked immunosorbent assay, calculating inhibition rate of drugs with different concentrations on tumor cells according to formula, and calculating half Inhibition Concentration (IC) by Graphpad Prism 6.0 software 50 ). Inhibition = (1-drug group or positive control OD value/negative control OD value) × 100%.
3. Statistical method
Data are expressed in x + -s, and the comparison among groups is carried out by adopting one-way anova, and P is less than 0.05, thus having statistical significance.
3. Test results
The results are shown in Table 1 and figures 1 and 2, the inhibitory activity of the compound I-2 on leukemia U937 cells is obviously better than that of ligustrazine, but the inhibitory activity on breast cancer MCF-7 cells is weaker; the compound I-4 has obviously better inhibitory activity on breast cancer MCF-7 cells than ligustrazine, but has weaker inhibitory activity on leukemia U937 cells.
TABLE 1 half inhibitory concentration (μ g/mL) of each drug on tumor cells
Therefore, 4- (3-thio-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-phthalate (compound I-2) has a prospect of being developed into an anti-leukemia drug, and 4- (3-thio-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-hexahydrophthalate (compound I-4) has a prospect of being developed into an anti-breast cancer drug.
The above-mentioned embodiments and the accompanying drawings are used to specifically describe the material of the present invention, but should not be construed as limiting the scope of the present invention.
Claims (1)
1. The application of ligustrazine derivative in preparing anti-leukemia medicine is 4- (3-sulfo-3H-1,2-dithiol-5-yl) phenyl-3,5,6-trimethylpyrazine-2-phthalate, and the chemical structural formula is as follows:
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| CN111825664A (en) * | 2020-08-01 | 2020-10-27 | 泰州学院 | Ligustrazine derivative, preparation method and medical application |
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| CN111825664A (en) * | 2020-08-01 | 2020-10-27 | 泰州学院 | Ligustrazine derivative, preparation method and medical application |
Non-Patent Citations (1)
| Title |
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| 你知道吗？盐酸阿那格雷治疗血小板增多一周内可减少50%，有效率达80%以;一点一点儿;《https://www.sohu.com/a/258536351_393408》;20181010;第1页第4段 * |
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