CN116370466B - Imidazole ligand complex compound pharmaceutical composition and application thereof - Google Patents

Imidazole ligand complex compound pharmaceutical composition and application thereof Download PDF

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CN116370466B
CN116370466B CN202310304140.7A CN202310304140A CN116370466B CN 116370466 B CN116370466 B CN 116370466B CN 202310304140 A CN202310304140 A CN 202310304140A CN 116370466 B CN116370466 B CN 116370466B
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王武
赫娜
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Hainan Medical College
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Abstract

The invention provides an imidazole ligand complex compound pharmaceutical composition and application thereof. The imidazole ligand complex compound pharmaceutical composition consists of the following raw materials: h 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O，H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 20-30: 70-80. The invention has found that H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The O combination has stronger breast cancer resisting effect. H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 After the O and the O are matched in a certain proportion, the compound has a synergistic effect and can be applied to the preparation of breast cancer resisting medicaments.

Description

Imidazole ligand complex compound pharmaceutical composition and application thereof
Technical Field
The invention relates to the field of medicines, in particular to an imidazole ligand complex compound medicine composition and application thereof.
Background
Imidazolyl is an important component of histidine, histamine, carnosine ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) purines in organisms, and can constitute a series of physiologically active imidazole derivatives. Wherein purines, adenosines and the like have antiviral and antitumor activities. For example, a 4H-pyrrolo 1,2-a ] benzimidazole (PBIS) derivative is an antitumor agent, which is a nitrogen-containing tri-heterocyclic compound having a strong biological activity and capable of effectively inhibiting the diffusion of tumor cells. However, single components tend to have less than ideal antitumor activity.
Disclosure of Invention
In view of the above, the present invention provides imidazole ligand complex compound pharmaceutical compositions and uses thereof, providing H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The O compound composition has stronger breast cancer resisting activity.
The technical scheme of the invention is realized as follows: the invention provides an imidazole ligand complex compound pharmaceutical composition, which is prepared from H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O composition.
Wherein H is 2 the structural formula of tbtpa is as follows:
wherein, bmib has the structural formula:
further, the H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 20-30: 70-80.
Further, the H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 20-25: 75-80.
Further, the H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 23:77.
further, according to the invention H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The preparation method of O comprises the following steps:
1.1H 2 tbtpa/bmib/H 2 o preparation: adding 2,3,5, 6-tetrabromoterephthalic acid, 1, 4-di (2-methylimidazole-1-yl) butane, triethylamine and water into a reaction vessel, addingHeating to 120deg.C, reacting at 120deg.C for 48H, cooling to room temperature, collecting colorless crystals to obtain H 2 tbtpa/bmib/H 2 O. Wherein, the mol ratio of 2,3,5, 6-tetrabromoterephthalic acid to 1, 4-di (2-methylimidazole-1-yl) butane is 1:1, and the mol ratio of the 2,3,5, 6-tetrabromoterephthalic acid to triethylamine to water-liquid is 1mol:0.1mL:40mL.
1.2Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O preparation: cd (NO) 3 ) 2 ·4H 2 O, bmib and H 2 tbtpa, KOH (0.05 mol/L) and DMF-H 2 O (v: v=2:1) was added to a reaction vessel, heated to 140 ℃, reacted at 140 ℃ for 72 hours, then cooled to room temperature, yellow crystals were collected, washed with absolute ethanol, and dried to obtain Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O. Wherein Cd (NO) 3 ) 2 ·4H 2 O, bmib and H 2 tbtpa、0.05M KOH、DMF-H 2 The feed liquid ratio of O is 1mol:0.28mol:0.15mol:1L:30L.
The invention provides application of an imidazole ligand complex compound pharmaceutical composition, and application of the pharmaceutical composition in preparation of a medicine for resisting breast cancer.
Compared with the prior art, the invention has the beneficial effects that:
the invention has found that H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The O combination, preferably the proportion, has stronger anti-breast cancer effect and can be applied to the preparation of anti-breast cancer drugs.
H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 After the O and the O are matched in a certain proportion, the compound has a synergistic effect and can be well applied to the preparation of the breast cancer resistant medicaments.
In addition, H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The preparation method of O is simple, is easy for large-scale production, and has good application prospect.
Detailed Description
In order to better understand the technical content of the present invention, the following provides specific examples to further illustrate the present invention.
The experimental methods used in the embodiment of the invention are conventional methods unless otherwise specified.
Materials, reagents, and the like used in the examples of the present invention are commercially available unless otherwise specified.
Inventive example H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O is prepared by the following method. The specific reaction steps are as follows:
1.1H 2 tbtpa/bmib/H 2 o preparation
Adding 2,3,5, 6-tetrabromoterephthalic acid, 1, 4-di (2-methylimidazole-1-yl) butane, triethylamine and pure water into a reaction vessel, mixing, heating to 120deg.C, reacting at 120deg.C for 48H, slowly cooling to room temperature, collecting colorless crystals, and making into H 2 tbtpa/bmib/H 2 O。
Wherein, the mol ratio of 2,3,5, 6-tetrabromoterephthalic acid to 1, 4-di (2-methylimidazole-1-yl) butane is 1:1, and the mol ratio of the 2,3,5, 6-tetrabromoterephthalic acid to triethylamine to water-liquid is 1mol:0.1mL:40mL.
1.2Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O preparation
Cd (NO) 3 ) 2 ·4H 2 O、bmib、H 2 tbtpa, KOH (0.05 mol/L) and DMF-H 2 O (v: v=2:1) was added to a reaction vessel, mixed, heated to 140 ℃, reacted at 140 ℃ for 72 hours, then slowly cooled to room temperature, yellow crystals were collected, washed with absolute ethanol, and dried to obtain Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O。
Wherein Cd (NO) 3 ) 2 ·4H 2 O、bmib、H 2 tbtpa、0.05M KOH、DMF-H 2 The feed liquid ratio of O is 1mol:0.28mol:0.15mol:1L:30L.
Example 1
An imidazole ligand complex compound pharmaceutical composition,
from H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The composition of O is that,
H 2 tbtpa/bmib/H 2 o and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 20:80.
example 2
An imidazole ligand complex compound pharmaceutical composition,
from H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The composition of O is that,
H 2 tbtpa/bmib/H 2 o and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 23:77.
example 3
An imidazole ligand complex compound pharmaceutical composition,
from H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The composition of O is that,
H 2 tbtpa/bmib/H 2 o and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 25:75.
example 4
An imidazole ligand complex compound pharmaceutical composition,
from H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The composition of O is that,
H 2 tbtpa/bmib/H 2 o and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 30:70.
comparative example 1
An imidazole ligand complex compound pharmaceutical composition,
from H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The composition of O is that,
H 2 tbtpa/bmib/H 2 o and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 50:50. 1. in vitro anti-human breast cancer cell (MCF-7) assay
1.1 test drug
The formulations were prepared with reference to examples 1-4 and comparative example 1, while testing H 2 tbtpa/bmib/H 2 O、Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O single component effect.
TABLE 1 dosage ratio (mass percent)
1.2 test methods
Human breast cancer cells were cultured in RPMI-1640 medium containing 10wt% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin at 37℃in an incubator (containing 5% CO) 2 ) Medium culture, passage 1 time every 2 days; cell count after digestion with trypsin; 100. Mu.L of human breast cancer cells were inoculated into 96-well plates and placed in a 37℃incubator (containing 5% CO) 2 ) After the cells are completely adhered to the wall after medium culture for 24 hours, 20 mu l of sample solutions to be tested with different concentrations (test groups 1-7 correspond to medicaments A-G respectively) are respectively added into each hole, meanwhile, a negative group without drug intervention, a blank group with complete culture medium and no cells are added, and six compound holes are arranged in parallel in each group; after 48 hours of culture, 20 μl (5 mg/mL) of MTT solution was added to each well, the culture was continued for 4 hours, the culture solution was discarded, 150 μLDMSO was added to each well, and after the crystallization was completely dissolved, the absorbance OD value was measured at 490nm with an ELISA reader, and the proliferation inhibition rate and IC50 value of human breast cancer cells were calculated, IC50 value: the drug concentration required for the proliferation inhibition rate of human breast cancer cells to reach 50% was repeated 3 times for each group of experiments, and the results were averaged. Wherein, the inhibition rate of cell proliferation= { (average value of negative group OD value-blank group OD value)Average of test group OD value-average of blank group OD value)](average value of negative group OD values-average value of blank group OD values) } ×100%; and calculating the Q value of the synergy coefficient of the combined drug, and recording the Q value when the drug concentration is 4.0 mug/mL, wherein the Q=I of the synergy coefficient of the combined drug a+b /(I a +I b -I a *I b ) Wherein I a+b Inhibition rate of combined drug, E a And E is b The inhibition rates of the independent administration of the A medicine and the B medicine are respectively.
Q <0.85 is antagonism; q is more than or equal to 0.85 and less than or equal to 1.15 and is added; q is more than or equal to 1.15 and is synergistic.
1.2 test results
Dissolving the test drug with DMSO, preparing a stock solution with 200 mug/mL by using a serum-free culture solution, and storing at 4 ℃; immediately before use, the culture broth was diluted to the corresponding concentration (1.0. Mu.g/mL, 2.0. Mu.g/mL, 4.0. Mu.g/mL, 8.0. Mu.g/mL, 12.0. Mu.g/mL) using RPMI-1640; the operation process is completed in the ultra-clean workbench in a sterile mode; the test results are as follows:
table 2 test drug inhibitory Effect (cell proliferation inhibition ratio) on MCF-7 cell lines
Table 2 test drug IC50 values for inhibition of MCF-7 cell lines
Table 3 inhibition synergy coefficient Q of test drugs on MCF-7 cell lines
Results of the tableThe test drugs C-F have lower IC50 values on human breast cancer cells, and show that the drugs C-F have stronger breast cancer resisting effects. Compared with the medicines A-B, the test medicines C-F have the synergy coefficient Q value of 1.55-2.45, which indicates H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O has a synergistic effect after being matched according to a certain proportion.
2. In vivo anti-tumor test
2.1 animals: healthy Kunming mice were selected and all were male in body weight (20+ -2) g.
2.2 tumor strains: selecting tumor-bearing mice with vigorous growth and no burst of breast cancer tumor and good health condition, killing and sterilizing. Taking out solid tumor blocks under aseptic condition, weighing, cutting into small pieces with scissors, grinding into homogenate with an aseptic glass homogenizer, diluting with aseptic physiological saline (tumor weight to physiological saline volume ratio of 1:3) to obtain tumor cell suspension, subcutaneously injecting into armpit of each mouse for transplanting 0.2mL, and weighing.
2.3 grouping: the mice were randomized into 4 groups of 30 mice each, a blank control group, a positive control group (tegafur 30 mg/kg), a low dose group (2 mg/kg) of the pharmaceutical composition of example 2, and a high dose group (10 mg/kg).
2.5 method: the doses were administered by gavage 24 hours after tumor implantation, 1 time a day for 10 consecutive days. Animals were sacrificed 24 hours after the last dose, tumor mass was removed, weighed, and differences between groups were compared. The test was repeated 3 times.
Tumor inhibition = (average tumor weight of control group-average tumor weight of dosing group)/average tumor weight of control group × 100%.
2.6 test results:
TABLE 3 influence of test drugs on the S180 tumor weight of mice
The results in the table above show that the pharmaceutical composition of example 2 (high dose group) has a strong in vivo anti-breast cancer effect on mice.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (6)

1. The application of the imidazole ligand complex compound pharmaceutical composition is characterized in that the pharmaceutical composition consists of the following raw materials: h 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O, the pharmaceutical composition is applied to preparation of medicines for resisting breast cancer, and the H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 20-30: 70-80 parts;
wherein H is 2 the structural formula of tbtpa is shown as formula (1):
（1）；
the structural formula of bmib is shown as formula (2):
（2）；
the H is 2 tbtpa/bmib/H 2 The preparation method of O comprises the following steps: adding 2,3,5, 6-tetrabromoterephthalic acid, 1, 4-di (2-methylimidazole-1-yl) butane, triethylamine and water into a reaction vessel, heating to 120 ℃, reacting at 120 ℃ for 48 hours, and then cooling to room temperature to obtain a target compound; the molar ratio of 2,3,5, 6-tetrabromoterephthalic acid to 1, 4-di (2-methylimidazole-1-yl) butane is 1:1, and the ratio of the 2,3,5, 6-tetrabromoterephthalic acid to triethylamine to water-liquid is 1mol:0.1mL:40 mL;
the Cd is 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The preparation method of O comprises the following steps: cd (NO) 3 ) 2 ·4H 2 O、bmib、H 2 tbtpa, 0.05M KOH and DMF-H 2 O is added into a reaction vessel, the DMF-H 2 DMF and H in O 2 The volume ratio of O is 2:1, heating to 140 ℃, reacting for 72 hours at 140 ℃, and then cooling to room temperature to obtain a target compound; cd (NO) 3 ) 2 ·4H 2 O、bmib、H 2 tbtpa、0.05M KOH、DMF-H 2 The feed liquid ratio of O is 1mol:0.28mol:0.15mol:1L:30L.
2. Use of an imidazole ligand complex in combination with a pharmaceutical composition according to claim 1, characterized in that H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 20-25: 75-80.
3. Use of an imidazole ligand complex in combination with a pharmaceutical composition according to claim 1, characterized in that H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 23:77.
4. the imidazole ligand complex compound pharmaceutical composition is characterized by comprising the following raw materials: h 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 O, said H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 20-30: 70-80 parts;
wherein H is 2 the structural formula of tbtpa is shown as formula (1):
（1）；
the structural formula of Bmib is shown as formula (2):
（2）；
the H is 2 tbtpa/bmib/H 2 The preparation method of O comprises the following steps: adding 2,3,5, 6-tetrabromoterephthalic acid, 1, 4-di (2-methylimidazole-1-yl) butane, triethylamine and water into a reaction vessel, heating to 120 ℃, reacting at 120 ℃ for 48 hours, and then cooling to room temperature to obtain a target compound; the molar ratio of 2,3,5, 6-tetrabromoterephthalic acid to 1, 4-di (2-methylimidazole-1-yl) butane is 1:1, and the ratio of the 2,3,5, 6-tetrabromoterephthalic acid to triethylamine to water-liquid is 1mol:0.1mL:40 mL;
the Cd is 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The preparation method of O comprises the following steps: cd (NO) 3 ) 2 ·4H 2 O、bmib、H 2 tbtpa, 0.05M KOH and DMF-H 2 O is added into a reaction vessel, the DMF-H 2 DMF and H in O 2 The volume ratio of O is 2:1, heating to 140 ℃, reacting for 72 hours at 140 ℃, and then cooling to room temperature to obtain a target compound; cd (NO) 3 ) 2 ·4H 2 O、bmib、H 2 tbtpa、0.05M KOH、DMF-H 2 The feed liquid ratio of O is 1mol:0.28mol:0.15mol:1L:30L.
5. The imidazole ligand complex pharmaceutical composition of claim 4, wherein H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 20-25: 75-80.
6. The imidazole ligand complex pharmaceutical composition of claim 4, wherein H 2 tbtpa/bmib/H 2 O and Cd 2 (bmib)(H 2 O) 2 (tbtpa) 2 ·H 2 The mass ratio of O is 23:77.
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