Application of trienone compounds in antitumor drugs

Abstract

The invention discloses application of a trienone compound in anti-tumor drugs, and belongs to the technical field of application of anti-tumor drugs. Through MTT cell viability experiments, cancer cells are treated by the trienone compounds with different concentrations, a good cell viability inhibition effect is found, and the inhibition effect of the four trienone compounds is superior to that of a positive drug cis-platinum. The trienone compound provided by the invention can be used for preparing or developing an anti-tumor drug, can contain a carrier and an auxiliary agent, can be prepared into a tablet, a particle, a capsule, an oral liquid or an injection form, and has a good practical application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical applications, and particularly to the application of trienone compounds in anti-tumor drugs. Background Art

[0002] Cancer is one of the important diseases that have attracted worldwide attention. Worldwide, the number of newly diagnosed cancer cases can reach tens of millions every year. At present, the treatment of cancer is developing in the direction of multidisciplinary and multi-faceted combined treatment. The drug treatment of cancer is also undergoing various changes and developments. Emerging drug therapies, such as ADC drug (antibody-drug conjugate) therapy, CAR-T cell therapy, and radioligand therapy, etc., show great therapeutic potential. This also provides more options for the treatment of patients with cancer. Colorectal cancer is one of the common cancers worldwide, with high incidence and mortality rates. At present, the main treatments for colorectal cancer are still common methods such as surgical resection and chemotherapy, and its treatment effect is difficult to meet the treatment needs of patients. Breast cancer is a malignant tumor that occurs in the human breast epithelial tissue and has become one of the diseases affecting the lives and health of women globally due to its high incidence and mortality rates. At present, it is difficult to cure breast cancer, with high recurrence and metastasis rates, and cases of tumor drug resistance are often reported, and the drug resistance mechanism has not been clarified. Therefore, the development of new anti-tumor drugs is of great significance for the treatment of cancer currently.

[0003] Due to its advantages such as high purity, relatively low production cost, rapid development, and continuous innovation, chemically synthesized drugs have great competitiveness in terms of the efficiency and cost of treating diseases, and also have huge prospects in terms of innovation and market potential. The research and development of anti-tumor compounds is an important field in the directions of medicine and medicinal chemistry, and significant progress has been made in recent years, with the continuous emergence of some anti-tumor drugs targeting specific molecular targets. The research prospect of anti-tumor compounds is broad, and the development of new discoveries and innovative drugs is expected to provide more strategies for the treatment of tumors.

[0004] Trienones, its chemical name: spiro[5.5]undecane-1,4,7-triene-3,9-dione, it has three carbon-carbon double bonds and two ketone groups. It is an unstable compound that easily reacts with itself and is often used as an intermediate in organic synthesis and is an important structural unit of various natural products and active pharmaceutical ingredients. At present, there are only a small number of studies on the activity of trienone derivatives in inhibiting cancer cell proliferation. Trienone compounds or their derivatives have great anti-tumor research value, and designing new drugs with such compounds as the structural unit will provide new solutions for the treatment of tumors in the future. Summary of the Invention

[0005] The object of the present invention is to overcome the disadvantages and deficiencies of the prior art and provide the use of trienone compounds in the preparation of anti-tumor drugs.

[0006] The object of the present invention is achieved by the following technical solutions:

[0007] The use of trienone compounds and their pharmaceutically acceptable salts in the preparation of anti-tumor drugs, wherein the tumor is any one or more of colon cancer and breast cancer;

[0008] The trienone compounds are any one or more of compound 3c, compound 3f, compound 3g, compound 3m, compound 3q, compound 3r, compound 3s, compound 3u, compound 3v, compound 3w, compound 3z, compound 4a, compound 4c, compound 4d, compound 4e, compound 4f, compound 4g, compound 4h, compound 4i, compound 4k and compound 4o; the structural formulas of compounds 1 to are shown as follows:

[0009]

[0010] Furthermore, the anions of the pharmaceutically acceptable salts are inorganic anions or organic anions; the inorganic anions are chloride ions, bromide ions, iodide ions, sulfate ions, nitrate ions, nitrite ions, phosphate ions or hydrogen phosphate ions, etc.; the organic anions are acetate ions, propionate ions, cinnamate ions, benzenesulfonate ions, citrate ions, lactate ions or gluconate ions, etc.

[0011] Furthermore, the anti-tumor drug is a drug having the activity of inhibiting cancer cell proliferation.

[0012] Furthermore, the use is any one or more of the following uses: (1) the use of any one or more of compound 3c, compound 3f, compound 3g, compound 3m, compound 3q, compound 3r, compound 3s, compound 3u, compound 3v, compound 3w, compound 4a, compound 4c, compound 4d, compound 4e, compound 4g, compound 4h, compound 4i and compound 4k in the preparation of anti-colon cancer drugs;

[0013] (2) the use of any one or more of compound 3c, compound 3f, compound 3g, compound 3m, compound 3q, compound 3r, compound 3s, compound 3u, compound 3v, compound 3z, compound 4a, compound 4d, compound 4e, compound 4g, compound 4h, compound 4i and compound 4k in the preparation of anti-breast cancer drugs.

[0014] Further, the application is the application of any one or more of compound 3s, compound 4h, compound 4i, and compound 4k in the preparation of anti-colorectal cancer and / or breast cancer drugs.

[0015] Further, the drug further comprises any one or more of a carrier and an adjuvant.

[0016] Further still, the carrier is selected from one or more of lactose, starch, gelatin, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, and water.

[0017] Further still, the adjuvant is selected from one or more of a disintegrant, a lubricant, and a solubilizer.

[0018] The disintegrant is preferably microcrystalline cellulose; the lubricant is preferably one or more of talc powder, colloidal silica gel, glyceryl stearate, calcium stearate, and magnesium powder; the solubilizer is preferably one or more of methanesulfonic acid, fumaric acid, mannitol, sorbitan monolaurate, monostearate, and monooleate.

[0019] Further, the drug can be prepared into tablets, granules, capsules, oral liquids, or injections.

[0020] The present invention has the following advantages and effects compared with the prior art:

[0021] Through MTT cell viability experiments, the present invention treated cancer cells with different concentrations of compounds and the clinical positive drug cisplatin, and found that there was a good effect of inhibiting cell viability, and the inhibitory effects of 4 drugs were better than those of the positive drug cisplatin. Therefore, the trienone compounds described in this application can be used to prepare or develop into anti-tumor drugs, which can include carriers and adjuvants, and can be prepared into tablets, granules, capsules, oral liquids, or injection forms, and have good practical application prospects.

[0022] The present invention for the first time discovered that a series of trienone compounds have good inhibitory effects on tumor cells, and the inhibitory cell concentrations of 4 of these compounds are much lower than those of the positive chemotherapy drug cisplatin, indicating that this series of compounds can be used to prepare or develop into new anti-tumor drugs, and the medicinal prospects are very broad. Description of the Drawings

[0023] Figure 1 is a structural formula diagram of the trienone compounds of the present invention. Detailed Embodiments

[0024] The following listed embodiments are helpful for those skilled in the art to better understand the purpose, technical methods, and advantages of the present invention, and will be elaborated in detail below. The present invention is achieved through the following technical methods:

[0025] The trienone compounds used in the following examples have been disclosed in the literature "Zhang Y, Ma C, Struwe J, et al. Electrooxidative Dearomatization of Biaryls: Synthesis of Tri- and Difluoromethylated Spiro[5.5]trienones[J]. Chemical Science, 2021. DOI: 10.1039 / D1SC02682H.", and their structural formulas are as follows (also as Figure 1 shown):

[0026]

[0027] Example 1

[0028] Colon cancer cells S1 and breast cancer cells MDAMB-453 were cultured in high-glucose medium DMEM containing 10% fetal bovine serum, penicillin (50 kU / L) and streptomycin (50 mg / L). The culture temperature was 37 °C in an environment containing 5% CO 2 environment.

[0029] In vitro activity experiments of the above 21 compounds against colon cancer cells S1 and breast cancer cells MDAMB-453 were carried out by the MTT method, and the clinically common chemotherapeutic drug cisplatin was used as a positive control. The specific implementation method was as follows: Different cancer cells were placed in a 96-well plate (3000 cells / well) and cultured at 37 °C for 12 h. After they adhered to the wall, different doses of the compounds and the positive drug were added respectively, and the culture was continued for 72 h. Then, 10 μL (5 mg / mL) of MTT was added to each well, and the incubation was continued in the incubator for 4 h. After the incubation was completed, the liquid in the well plate was aspirated, 50 μL of DMSO was added to each well, and the incubation was carried out on a low-speed shaker for 10 minutes. Finally, the absorbance value at 490 nm was measured with an enzyme-linked immunosorbent assay (ELISA) reader, and the IC50 values of different compounds against cancer cells were calculated.

[0030] The IC50 values of the 21 compounds against the two types of cells for 72 h are shown in Table 1. The results showed that these compounds had good inhibitory effects on colon cancer cells S1 and breast cancer cells MDAMB-453, and the IC50 values of the vast majority of the compounds were below 100 μM. Compared with the positive drug cisplatin, the IC50 values of the trienone compounds 3s, 4h, 4i, and 4k against intestinal cancer cells S1 were lower than those of cisplatin (18.1 μM), and the anticancer activity was 2 to 3 times that of cisplatin. Compound 3s showed good inhibitory activity, and its inhibitory activity against the two types of cancer cells was higher than that of the positive drug cisplatin, and its IC50 (μM) values were 7.36 (S1) and 1.01 (MDAMB-453) respectively.

[0031] Table 1 IC of trienone compounds and cisplatin against S1 and MDA-MB-453 cells 50 value

[0032]

[0033]

[0034] The above results indicate that the trienone compounds described in the present invention have good inhibitory effects on colon cancer and breast cancer. The inhibitory effects of some compounds are better than those of the clinical drug cisplatin. It can be inferred from this that the above compounds have good inhibitory effects on tumor cells. Therefore, the trienone compounds described in the present invention have the potential for further development and preparation into anti-cancer drugs, and have very good application value and prospects.

[0035] The above embodiments are the best implementation methods of the present invention, but the implementation manners of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement manners and are all included in the protection scope of the present invention.

Claims

1. Use of trienone compounds and pharmaceutically acceptable salts thereof in the preparation of anti-tumor drugs, characterized in that: The tumor is any one or more of colon cancer and breast cancer; The trienone compound is any one or more of compound 3c, compound 3f, compound 3g, compound 3m, compound 3q, compound 3r, compound 3s, compound 3u, compound 3v, compound 3w, compound 3z, compound 4a, compound 4c, compound 4d, compound 4e, compound 4f, compound 4g, compound 4h, compound 4i, compound 4k and compound 4o; the structural formulas of the above compounds are shown below:

2. The use of the trienone compound and the pharmaceutically acceptable salt thereof according to claim 1 in the preparation of anti-tumor drugs, characterized in that: The anions of the pharmaceutically acceptable salts are inorganic anions or organic anions; the inorganic anions are chloride, bromide, iodide, sulfate, nitrate, nitrite, phosphate or hydrogen phosphate, etc.; the organic anions are acetate, propionate, cinnamate, toluenesulfonate, citrate, lactate or gluconate, etc.

3. The use of the trienone compound and the pharmaceutically acceptable salt thereof according to claim 1 in the preparation of anti-tumor drugs, characterized in that: The anti-tumor drug is a drug with the activity of inhibiting the proliferation of cancer cells.

4. The use of the trienone compound and the pharmaceutically acceptable salt thereof according to claim 1 in the preparation of anti-tumor drugs, characterized in that: The application is any one or more of the following applications: (1) Use of any one or more of Compound 3c, Compound 3f, Compound 3g, Compound 3m, Compound 3q, Compound 3r, Compound 3s, Compound 3u, Compound 3v, Compound 3w, Compound 4a, Compound 4c, Compound 4d, Compound 4e, Compound 4g, Compound 4h, Compound 4i and Compound 4k in the preparation of anti-colon cancer drugs; (2) Use of any one or more of Compound 3c, Compound 3f, Compound 3g, Compound 3m, Compound 3q, Compound 3r, Compound 3s, Compound 3u, Compound 3v, Compound 3z, Compound 4a, Compound 4d, Compound 4e, Compound 4g, Compound 4h, Compound 4i and Compound 4k in the preparation of anti-breast cancer drugs.

5. Use of the trienone compound and its pharmaceutically acceptable salt according to claim 1 in the preparation of anti-tumor drugs, characterized in that: The application is the application of any one or more of compound 3s, compound 4h, compound 4i and compound 4k in the preparation of anti-colon cancer and / or breast cancer drugs.

6. Use of the trienone compound and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of an anti-tumor drug, characterized in that: The medicine also includes any one or more of a carrier and an adjuvant.

7. Use of the trienone compound and its pharmaceutically acceptable salt according to claim 6 in the preparation of anti-tumor drugs, characterized in that: The carrier is selected from one or more of lactose, starch, gelatin, sodium carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone and water.

8. Use of the trienone compound and its pharmaceutically acceptable salt according to claim 6 in the preparation of anti-tumor drugs, characterized in that: The auxiliary agent is selected from one or more of a disintegrant, a lubricant and a cosolvent.

9. Use of the trienone compound and its pharmaceutically acceptable salt according to claim 8 in the preparation of anti-tumor drugs, characterized in that: The disintegrant is microcrystalline cellulose; the lubricant is one or more of talc, colloidal silica, glyceryl stearate, calcium stearate and magnesium powder; the cosolvent is one or more of methanesulfonic acid, fumaric acid, mannitol, sorbitan monolaurate, monostearate and monooleate.

10. Use of the trienone compound and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of an anti-tumor drug, characterized in that: The medicine is prepared into tablets, granules, capsules, oral liquid or injection.

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