CN118045092A - Pharmaceutical use of 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) - Google Patents
Pharmaceutical use of 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) Download PDFInfo
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- CN118045092A CN118045092A CN202410194236.7A CN202410194236A CN118045092A CN 118045092 A CN118045092 A CN 118045092A CN 202410194236 A CN202410194236 A CN 202410194236A CN 118045092 A CN118045092 A CN 118045092A
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- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 239000000956 alloy Substances 0.000 title claims abstract description 25
- 229910045601 alloy Inorganic materials 0.000 title claims abstract description 25
- PTRUTZFCVFUTMW-UHFFFAOYSA-N 1-ethynyl-3-fluorobenzene Chemical compound FC1=CC=CC(C#C)=C1 PTRUTZFCVFUTMW-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 23
- 201000007270 liver cancer Diseases 0.000 claims abstract description 54
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 53
- 239000003814 drug Substances 0.000 claims abstract description 32
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- 230000000431 effect on proliferation Effects 0.000 abstract description 2
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- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 34
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 34
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- 102100037401 Putative uncharacterized protein encoded by MIR7-3HG Human genes 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 6
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- 229960000397 bevacizumab Drugs 0.000 description 4
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- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 4
- 229960003784 lenvatinib Drugs 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
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- 238000000134 MTT assay Methods 0.000 description 1
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- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
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- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 206010040914 Skin reaction Diseases 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
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- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
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- 230000036770 blood supply Effects 0.000 description 1
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- 201000011510 cancer Diseases 0.000 description 1
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- 239000003684 drug solvent Substances 0.000 description 1
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- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 208000006359 hepatoblastoma Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 201000007450 intrahepatic cholangiocarcinoma Diseases 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
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- 238000001543 one-way ANOVA Methods 0.000 description 1
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Classifications
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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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of biological medicine, and in particular relates to a medicine application of a 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I). The invention discovers the medicine effect of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) and can effectively resist liver cancer by inhibiting proliferation and growth of human liver cancer cells, thereby being used as a candidate medicine for preventing or treating liver cancer related diseases caused by various reasons and having good application prospect for creating medicines for treating liver cancer. According to various experimental analysis and verification, the compound has an excellent inhibition effect on proliferation and growth of human liver cancer cells, has low side effect, can be prepared into other dosage forms for intestinal or parenteral administration according to a known method in the art, and is applied to prevention and treatment of human liver cancer; provides a new drug alternative for preventing and treating liver cancer of human and relieves the problems of relatively single treatment means and drug resistance of the current treatment means.
Description
Technical Field
The invention relates to a gold complex, belongs to the field of biological medicine, and in particular relates to a medicine application of 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) as a preventive or therapeutic medicine applied to liver cancer.
Background
Liver cancer mainly includes hepatocellular carcinoma, intrahepatic cholangiocarcinoma, hepatoblastoma, etc., wherein hepatocellular carcinoma (Hepatocellular carcinoma, HCC) is a major type of primary liver cancer, accounting for about 85% -90% of patients with liver cancer. Surgical resection and liver transplantation are effective treatments for early stage liver cancer patients. However, most patients have advanced to middle and late stages when diagnosis is confirmed because early diagnosis of liver cancer is difficult and disease progress is fast, and the opportunity for operation is lost.
Currently, first line therapies approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced liver cancer encompass the treatment regimen of sorafenib (Sorafenib), lenvatinib (Lenvatinib), and the combination of Atezolizumab (a PD-L1 inhibitor) and Bevacizumab (an anti-angiogenic drug). These drugs, as a first-line treatment regimen, provide a therapeutic effect to patients with advanced liver cancer, prolonging the Overall Survival (OS) and disease-free survival (PFS) of the patient. Sorafenib and lenvatinib are used as molecular targeting drugs to inhibit tumor growth by blocking various tyrosine kinase pathways in tumor cells, and have the effect of inhibiting angiogenesis. The combined treatment of Atezolizumab and Bevacizumab utilizes the synergistic effect of immune checkpoint inhibitor and anti-angiogenesis medicine to make immune system recognize and attack cancer cell effectively, and Bevacizumab can help reduce blood supply in tumor and inhibit tumor growth.
While the above drugs offer therapeutic promise, there are a number of challenges in clinical treatment. First, some patients may have natural resistance to these drugs, or develop resistance gradually during the course of treatment, resulting in reduced drug efficacy. Second, even if the condition is controlled temporarily, the tumor may metastasize and recur again shortly after treatment. Metastasis and multiple metastasis of advanced liver cancer, especially common metastasis to lung and peritoneum, greatly limit the therapeutic effect and prognosis of patients. Furthermore, even if the drug is effective in inhibiting tumors, prolonged use may lead to serious side effects in the patient, such as hypertension, bleeding, enlargement of the spleen, skin reactions of hands and feet, etc., which may require further medical intervention, even leading to the patient having to interrupt the treatment.
In general, although the combination therapy of sorafenib, lenvatinib and Atezolizumab and Bevacizumab brings new treatment options for patients with advanced liver cancer, problems such as drug resistance generation, disease metastasis and recurrence, and long-term side effects of the drug are still of concern. Meanwhile, in clinical practice, it is also highly demanded to customize more personalized treatment schemes for patients with different conditions, and continue to explore and develop new treatment drugs and methods in order to improve the treatment effect and the quality of life of patients with advanced liver cancer. In view of this, the search and development of new effective liver cancer drugs remains a very critical and increasingly important research direction.
Disclosure of Invention
Aiming at the problems or the defects, the invention provides the application of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) as a preventive or therapeutic drug for liver cancer, aiming at solving the problems of relatively single effective drugs, drug resistance and long-term side effects of the existing prevention or treatment of liver cancer.
The structural formula of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) is as follows:
Further, the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) is used as a medicinal carrier or an excipient or an additive pharmaceutical composition, and the pharmaceutical composition has the effect of preventing and treating liver cancer.
Furthermore, the corresponding medicaments and medicament combinations of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) can be prepared into other formulations for intestinal or parenteral administration, such as tablets, capsules, granules, injection and the like according to a method known in the art.
Further, a preventive and therapeutic agent for liver cancer comprising the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) as an active ingredient.
In summary, the invention discovers the novel application of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) as a medicament, and the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) can effectively resist liver cancer by inhibiting proliferation and growth of human liver cancer cells, so that the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) is taken as a candidate medicament for preventing or treating liver cancer related diseases caused by various reasons, and has good application prospect for creating medicaments for treating liver cancer. According to various experimental analysis and verification, the compound has an excellent inhibition effect on proliferation and growth of human liver cancer cells, has low side effect, can be prepared into other dosage forms for intestinal or parenteral administration according to a known method in the art, and is applied to prevention and treatment of human liver cancer; provides a new drug alternative for preventing and treating liver cancer of human and relieves the problems of relatively single treatment means and drug resistance of the current treatment means.
Drawings
FIG. 1 is a graph showing the survival of Huh7 hepatoma cell lines treated with various concentrations of the compounds of example 1 for 72 hours.
FIG. 2 is a graph showing the growth of liver cancer transplants in Huh7 transplants mice of example 2.
FIG. 3 is a diagram showing tumor-bearing mice after the mice transplanted with Huh7 in example 2 were sacrificed.
FIG. 4 is a graph showing the average tumor weight of liver cancer transplants obtained by dissecting Huh7 transplants in example 2.
Fig. 5 is a graph of average body weight versus the average body weight of Huh7 engrafted tumor mice in example 2 prior to sacrifice.
Detailed Description
The invention will now be described in further detail by way of examples with reference to the accompanying drawings.
Example 1
The effect on the proliferation and growth of hepatoma cells was analyzed by MTT assay using 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) (labeled as GC002 in the present invention), and sorafenib (Sorafenib) was used as a positive control.
The experimental method is as follows:
1. Inoculating cells: taking liver cancer cells Huh7 in logarithmic growth phase, digesting and blowing into single cells by pancreatin, suspending the cells in a complete culture solution containing 10% fetal bovine serum to prepare a cell suspension, and inoculating 6000 cells per well into a 96-well plate, wherein the volume of each well is 200 mu l.
2. Culturing the cells: after the cells were attached, liver cancer cells Huh7 were treated with GC002 (experimental group) and Sorafenib at different concentrations, respectively. The cells were incubated at 37℃for 72 hours with 5% CO 2.
3. Color development: after 72 hours of incubation, 20. Mu.l MTT solution (5 mg/ml in PBS) was added to each well. Incubation was continued for 4 hours. The culture supernatant in the wells was carefully aspirated. 150 μl DMSO was added to each well and the mixture was shaken for 10 minutes to allow the crystals to fully thaw.
4. Colorimetric: the light absorption value of each hole is measured on an ELISA monitor by selecting 490nm wavelength, and the result is recorded. The respective cell viability was calculated for the treatments with the different concentrations of the compound, plotted on the abscissa with the concentration of the compound and on the ordinate with the cell viability (Cell Viability,%) and then the concentration of the compound at 50% inhibition, i.e. IC 50, was obtained.
The experimental results are as follows:
As shown in fig. 1, fig. 1 is a graph showing the survival of Huh7 cell lines treated with GC002 and Sorafenib at different concentrations for 72 hours in this example. The cell line used in the experiment is a human liver cancer cell line Huh7, the abscissa represents the compound concentration, and the ordinate represents the cell survival rate (Cell Viability,%).
Experimental results show that after Huh7 cell lines are treated with GC002 (experimental group) or Sorafenib (sorafenib, positive control) at different concentrations for 72 hours, the two affect proliferation and growth of Huh7 cells to different extents, the GC002 treated group IC 50 is 0.49 μm, and the Sorafenib treated group IC 50 is 10.46 μm; compared with the first-line targeting drug Sorafenib, the GC002 can remarkably inhibit the proliferation and growth of human liver cancer cell Huh 7.
Example 2
The inhibition of the growth of liver cancer transplants by 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) (marked as GC002 in the invention) was examined by nude mice transplantable tumor experiments, and compared with a blank Control group (Control) and a sorafenib-treated group (Sorafenib).
The experimental method is as follows:
First, human liver cancer cell Huh7 was subcutaneously injected into the right back of nude mice. After the neoplasia to be transplanted is between 130mm 3 and 170mm 3 to ensure successful modeling, the mice are randomly divided into three groups, namely (1) blank control group (DMSO); (2) GC002 treated group at a dose of 10mg/kg; (3) Sorafenib treatment group (Sorafenib) at a dose of 10mg/kg.
GC002 treatment group was injected intratumorally GC002 once every four days, sorafenib treatment group was injected intratumorally with sorafenib once every four days, and blank control group was injected intratumorally without drug solvent once every four days, all for 2 weeks. The size of the transplanted tumor was recorded every two days, the mice were weighed after 14 days and sacrificed by cervical scission, photographed, the transplanted tumor was peeled off and weighed.
The test results are as follows:
as shown in fig. 2, fig. 2 is a graph showing the growth of liver cancer transplants in mice in the blank control group, GC 002-treated group and sorafenib-treated group of the present example; the growth of liver cancer transplants of the GC002 treatment group and the sorafenib treatment group is obviously slower than that of the blank control group, and the growth of liver cancer transplants of the GC002 treatment group is obviously slower than that of the sorafenib treatment group.
As shown in fig. 3, fig. 3 is a physical diagram of a liver cancer-bearing transplanted tumor of a mouse after the mice in the blank control group, the GC 002-treated group and the sorafenib-treated group are sacrificed in this example; the mice of the GC002 treatment group and the sorafenib treatment group have the transplanted tumor which is obviously smaller than that of the blank control group, and the mice of the GC002 treatment group have the transplanted tumor which is obviously smaller than that of the sorafenib treatment group.
As shown in fig. 4, fig. 4 is a graph showing the average tumor weight (g) of the exfoliated liver cancer transplants of the mice of the blank control group, GC 002-treated group and sorafenib-treated group in the present example; the average tumor weight of the liver cancer transplanted tumors of the GC002 treatment group and the sorafenib treatment group is obviously smaller than that of the blank control group; and the GC002 treated group had a lower average tumor weight than the sorafenib treated group of liver cancer transplants. The average tumor weight of the blank group was 0.6024g, the average tumor weight of the GC002 treated group was 0.1791g, and the average tumor weight of the sorafenib treated group was 0.3082g.
As shown in fig. 5, fig. 5 is a graph showing average body weight (g) comparison of mice in the blank group, GC 002-treated group and sorafenib-treated group before the sacrifice of Huh 7-transplanted tumor mice in the present example; there was no significant difference between the average mouse weights of GC 002-treated and sorafenib-treated groups and the average mouse weight of the blank group. The average mouse weight of the placebo group was 20.45g, the average mouse weight of the gc002 treated group was 20.22g, and the average mouse weight of the sorafenib treated group was 19.70g.
Test results show that compared with the clinic first-line medicine sorafenib, the GC002 has more remarkable inhibiting effect on liver cancer transplantation tumor, and the GC002 does not cause strong side effect of mice.
Carrying out statistical analysis on experimental data by using SPSS13.0 statistical software, wherein the obtained experimental data is expressed by mean ± variance; the difference analysis between the control group and the experimental group adopts One-way ANOVA and Two-way ANOVA analysis and a fisher test. * P <0.05, with differential significance; * P <0.01, with high difference significance; * P <0.001, with very significant differences.
The experimental results of the two examples show that compared with the clinic first-line medicine sorafenib, the GC002 provided by the invention has more remarkable inhibiting effect on liver cancer transplantation tumor: the average tumor weight of the blank control group is about 0.6024g, the average tumor weight of the GC002 treatment group is reduced to 0.1791g, and the average tumor weight of the sorafenib treatment group is 0.3082g; and there was no significant difference in body weight between the GC 002-treated group and the blank group, indicating that GC002 did not cause strong side effects in mice.
In summary, the invention finds the application of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) in medicines, and the alloy can be prepared into other dosage forms for intestinal or parenteral administration according to the known method in the art, and the alloy can effectively resist liver cancer by inhibiting the proliferation and growth of human liver cancer cells, has low side effects, and is used as a candidate medicine for preventing or treating liver cancer related diseases caused by various reasons; the invention provides a new drug alternative for preventing and treating liver cancer, relieves the problems of relatively single current treatment means, drug resistance and long-term side effect, and has good application prospect for creating drugs for treating liver cancer.
Claims (4)
- The pharmaceutical use of 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) characterized in that:the structural formula of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) used as a preventive or therapeutic drug applied to liver cancer is as follows:
- 2. The pharmaceutical use of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) according to claim 1, wherein: the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) is used as a medicinal carrier, an excipient or an additive.
- 3. The pharmaceutical use of the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) according to claim 1, wherein: the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridine phosphine alloy (I) is a tablet, a capsule, a granule or an injection.
- 4. A medicament for preventing and treating liver cancer is characterized in that: an active ingredient comprising the 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) as defined in claim 1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410194236.7A CN118045092A (en) | 2024-02-21 | 2024-02-21 | Pharmaceutical use of 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410194236.7A CN118045092A (en) | 2024-02-21 | 2024-02-21 | Pharmaceutical use of 1-ethynyl-3-fluorobenzene diphenyl-2-pyridinium phosphine alloy (I) |
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| CN118045092A true CN118045092A (en) | 2024-05-17 |
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