Natural-like diaryl propane dimer compound and application thereof in preparation of medicine for treating cancer

Abstract

The invention relates to the technical field of medicines, and discloses a natural diaryl propane-like dimer compound and an application thereof in preparation of medicines for treating cancers. The tumor inhibition activity of the various natural diaryl propane dimer compounds is remarkably improved, particularly, the inhibition activity of the various natural diaryl propane dimer compounds on breast cancer cells is improved more remarkably, and the various natural diaryl propane dimer compounds are candidate drugs for treating cancers.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a natural-like diarylpropane dimer compound and its application in the preparation of anti-cancer drugs. Background Art

[0002] The statements in this section merely provide background information related to the disclosure of this application and may not constitute prior art.

[0003] The incidence and mortality of cancer worldwide are increasing year by year, posing a major threat to people's quality of life and life expectancy. In 2024, the International Agency for Research on Cancer released the latest global cancer statistics GLOBOCAN 2022. There were 18.74 million new cancer cases and 9.67 million cancer deaths globally, and 4.78 million new cancer cases and 2.56 million cancer deaths in China. According to the statistics of the World Health Organization (WHO), cancer is the second leading cause of death globally, and its incidence and mortality are increasing year by year. Cancer not only brings great physical pain to patients but also imposes a heavy burden on their mental and economic conditions. With the influence of factors such as environmental pollution, lifestyle changes, and population aging, the prevention and control situation of cancer is becoming increasingly severe. Data shows that the incidence and mortality of lung cancer, breast cancer, and colon cancer are among the top 5 cancers.

[0004] At present, effective cancer treatment remains a major challenge. The common treatment methods for cancer mainly include surgical resection, radiotherapy, and chemotherapy. Surgical resection is suitable for early-stage local tumors, but it has limited effectiveness for advanced cancers with metastasis. Radiotherapy kills cancer cells through high-energy rays but is prone to damage normal tissues. Chemotherapy inhibits cancer cell proliferation by using chemotherapeutic drugs, but it has poor selectivity and is often accompanied by severe side effects such as bone marrow suppression and gastrointestinal reactions. Existing cancer treatment drugs mainly include cytotoxic drugs, targeted drugs, and immunotherapy drugs. Cytotoxic drugs such as cisplatin and paclitaxel are effective against various cancers, but they have large toxic side effects and are prone to drug resistance. Targeted drugs such as gefitinib and trastuzumab have high selectivity, but they are expensive and prone to drug-resistant mutations. Immunotherapy drugs such as PD-1 / PD-L1 inhibitors show significant efficacy in some cancers, but their scope of application is limited and they may cause immune-related adverse reactions. The drawbacks of these drugs limit their wide application in clinical practice.

[0005] In contrast, natural drugs have shown unique advantages in cancer treatment. Natural drugs are usually derived from plants, animals, or microorganisms, and have the characteristics of multi-target and multi-pathway actions, and can inhibit tumor growth through multiple mechanisms. In addition, natural drugs have relatively small toxic side effects and are not prone to drug resistance. Therefore, natural drugs have broad application prospects in cancer treatment.

[0006] Horsfiequinone B is a compound extracted from natural plants. Preliminary studies have shown that it has certain anti-tumor activity. However, the existing research data indicate that the anti-tumor activity of Horsfiequinone B is poor and it is difficult to meet the needs of clinical treatment. Its mechanism of action is not clear, and its bioavailability is low, which limits its further development and application.

[0007] The prior art "Dimeric Diarylpropanoids from Horsfieldia tetratepala (Horsfiequinones B-F)" states that the cytotoxicity evaluation of horsfiequinones B against five human tumor lines shows that the compound Horsfiequinones B has a selective inhibitory effect on HL-60.

[0008] In order to improve the anti-tumor activity of Horsfiequinone B, it is urgent to modify and optimize its structure. However, the anti-tumor mechanism of action of Horsfiequinone B is unclear, and how to improve its anti-tumor effect through structural modification or dosage form improvement remains an urgent problem to be solved. Therefore, it is particularly important to study its analogs to increase the possibility of these compounds becoming drugs. Summary of the Invention

[0009] The object of the present invention is to provide a natural-like diarylpropane dimer compound and its application in the preparation of anti-cancer drugs in view of the limited anti-tumor activity of natural products at present. By optimizing the structure of horsfiequinones B, the anti-tumor activity of its analogs is improved. Its analogs have lower IC 50 values against cancer cells MDA-MB-468 and JIMT-1 compared to the original compound horsfiequinones B itself, and at the same time, the IC 50 values against cancer cells A549 and HEPG2 are also reduced to below 12 μm.

[0010] The technical solution of the present invention is as follows:

[0011] The present invention provides a natural-like diarylpropane dimer compound on the one hand, and its structural formula is shown as the following formula (Ⅰ):

[0012]

[0013] In the formula,

[0014] Wherein R1 Selected from OMe, OH;

[0015] R 2 Selected from OH, H;

[0016] R 3 Selected from OBz, OH, H;

[0017] R 4 Selected from H, F.

[0018] Preferably, the aforementioned natural-like diarylpropane dimer compound is specifically the following compound:

[0019]

[0020] The preparation method of the aforementioned natural-like diarylpropane dimer compound refers to the prior art: (Lumin Li; Ruiling Liu; Rui Yang; Hanwei Li; Ya Liu; Rui Zhan; Wenjing Wang; Lidong Shao; Dashan Li, Biomimetic Total Synthesis of Horsfiequinone B Enabled by a Friedel-Crafts Alkylation-Type Non-homodimerization, Organic Chemistry Frontiers, 2024, 11(19), 5358-5362).

[0021] On the other hand, the present invention provides the application of the aforementioned natural-like diarylpropane dimer compound in the preparation of a drug for treating or adjuvant treating cancer.

[0022] Preferably, the cancer is breast cancer, lung cancer or liver cancer.

[0023] A pharmaceutical composition for treating cancer, comprising the aforementioned natural-like diarylpropane dimer compound, and one or more pharmaceutically acceptable carriers or excipients.

[0024] Preferably, in the pharmaceutical composition, the mass ratio of the natural-like diarylpropane dimer compound to the pharmaceutically acceptable carrier and / or excipient is 1:1 - 1:10.

[0025] Preferably, the pharmaceutical composition can be prepared into tablets, capsules or injections.

[0026] The present invention has no special limitation on the pharmaceutical carrier or the excipient, and the well-known pharmaceutical carrier or excipient in the art can be used, specifically one or more of solid, semi-solid or liquid diluents, fillers or pharmaceutical product adjuvants. In the present invention, the preparation types of the natural-like diarylpropane dimer compound pharmaceutical composition preferably include liquid preparations, solid preparations, sprays or aerosols; the liquid preparations preferably include injections, suspensions, emulsions, solutions or syrups; the solid preparations preferably include tablets, capsules, granules or infusion preparations. There is no special limitation on the preparation method of the natural-like diarylpropane dimer compound pharmaceutical composition in the present invention, and the well-known preparation method in the art can be used.

[0027] In the present invention, the administration methods of the natural-like diarylpropane dimer compound pharmaceutical composition are preferably injection, oral administration or sublingual administration; the injection preferably includes intravenous injection, intravenous drip, intramuscular injection, intraperitoneal injection or subcutaneous injection.

[0028] In the present invention, the natural-like diarylpropane dimer compound pharmaceutical composition is preferably used in the form of the dosage per unit body weight. In the present invention, the natural-like diarylpropane dimer compound pharmaceutical composition is preferably used in the form of the dosage per unit body weight. In the present invention, the dosage per unit body weight is preferably 0.5 - 20 mg / kg.

[0029] Another aspect of the present invention provides the use of Compound 1 in the preparation of a drug for treating or adjuvantly treating triple-negative breast cancer.

[0030] Another aspect of the present invention provides the use of Compound 2 in the preparation of a drug for treating or adjuvantly treating triple-negative breast cancer.

[0031] Another aspect of the present invention provides the use of Compound 3 in the preparation of a drug for treating or adjuvantly treating triple-negative breast cancer or lung cancer.

[0032] Another aspect of the present invention provides the use of Compound 4 in the preparation of a drug for treating or adjuvantly treating liver cancer or lung cancer.

[0033] Compared with the existing technology, the beneficial effects of the present invention are as follows:

[0034] 1. The structure of the natural compound horsfiequinones B is improved. The prepared natural-like diarylpropane dimer compound not only has inhibitory effects on breast cancer, lung cancer and liver cancer, but also its inhibitory effects are better than those of the natural compound horsfiequinones B;

[0035] 2. The use of the improved natural-like diarylpropane dimer compound or its pharmaceutical composition in the preparation of anti-cancer drugs is provided. Description of the Drawings

[0036] Figure 1 is the general structural formula of the natural product-like diarylpropane dimer compound;

[0037] Figure 2 are the structural formulas of Compound 1-8 of the natural product-like diarylpropane dimer compound;

[0038] Figure 3 is the structural formula of the natural compound horsfiequinones B;

[0039] Figure 4 is the IC 50 after treating different cells with horsfiequinone B, respectively compared with the IC 50 after treating different cells with Compounds 1, 2, and 3 (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001). Detailed implementation manners

[0040] The specific examples listed in the present invention are only used as examples of the present invention, and the present invention is not limited to the specific examples described below. For those skilled in the art, any equivalent modifications and substitutions to the examples described below are also within the scope of the present invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention. Those not specified in the examples are carried out under conventional conditions or conditions recommended by the manufacturer. All reagents or instruments not specified by the manufacturer can be obtained through commercial purchase as conventional products. To better illustrate the present invention, numerous specific details are given in the following detailed implementation manners. Those skilled in the art should understand that the present invention can still be implemented without some specific details. In other examples, methods, means, equipment, and steps well known to those skilled in the art are not described in detail to highlight the gist of the present invention.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. Without special instructions, the units used in this specification are all international standard units, and the numerical values and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0042] The features and properties of the present invention will be further described in detail below in conjunction with the examples.

[0043] In this example, 8 compounds with similar structures were screened for anti-tumor activity. The general formulas of the 8 natural product-like diarylpropane dimer compounds to be tested are as Figure 1As shown, the structural formula corresponding to the specific compound is as Figure 2 shown. The structural formula of the natural compound horsfiequinones B is as Figure 3 shown.

[0044] Example 1

[0045] The compounds of the present invention have significant anti-proliferative activity against tumor cell lines including human triple-negative breast cancer cell line MDA-MB-468, HER2-positive breast cancer cell line JIMT-1, human lung cancer cell A549, and human liver cancer cell HEPG2. The experimental methods and results are as follows:

[0046] I. Experimental methods

[0047] 1. The samples of natural diarylpropane dimer compounds to be tested were separately dissolved in DMSO to prepare working solutions with a concentration of 20 μM and stored for later use.

[0048] 2. The working solution concentration started from 20 μM and was diluted two-fold into 5 concentration gradients. The triple-negative breast cancer cell line MDA-MB-468 (3650 cells / well), HER2-positive breast cancer cell line JIMT-1 (4300 cells / well), human leukemia tumor cell line HL-60 (8000 cells / well), human lung cancer cell A549 (4000 cells / well), and human liver cancer cell HEPG2 (4000 cells / well) in the logarithmic growth phase were inoculated in 96-well plates and cultured overnight for 24 h, and then treated with the gradient-diluted compound working solutions. Each concentration was set with three replicates, and a control group and a blank group were also set. The morphological changes of the cells were observed after 24 h, 48 h, and 72 h; the cell viability of HL-60 cells was detected by CCK-8 at 72 h, and the cell viability of MDA-MB-468, JIMT-1, and HL-60 cells was detected by MTT.

[0049] Cell viability = (OD of the drug treatment group - OD of the blank) / (OD of the DMSO group - OD of the blank).

[0050] 3. IC 50 Determination

[0051] HL-60 (20 μM, 72 h) was selected for primary screening, and compounds with an inhibition rate greater than 50% were obtained. Compounds 1, 2, 3, and 4 were screened out. MDA-MB-468 (3650 cells / well), JIMT-1 (4300 cells / well), human leukemia tumor cell line HL-60 (8000 cells / well), human lung cancer cell A549 (4000 cells / well), and HEPG2 (4000 cells / well) in the logarithmic growth phase were cultured in 96-well plates. After 24 h, 10 μL of the compound passed in the primary screening was added to each well for a new round of rescreening (starting from a concentration of 20 μM, diluted in a two-fold gradient for 5 concentration gradients) and treated for 72 h. Three replicates were set for each concentration, and a positive control group (vincristine, starting from a concentration of 20 μM, diluted in a two-fold gradient for 5 concentration gradients) and a blank group (treated with PBS solution) were also set. For HL-60, CCK-8 was used for staining at 37 °C for 1 h, and the absorbance was detected at 450 nm. For the remaining cells, 5 mg / mL MTT was used for staining at 37 °C for 2.5 h. The culture medium was removed, 100 μL of DMSO was added, and the absorbance was detected at 490 nm. Nonlinear regression analysis was performed using GraphPad Prism 10 software to determine the IC 50 value.

[0052] II. Experimental Results

[0053] See Table 1. The present invention evaluated the in vitro anti-proliferative activity of 8 natural-like diarylpropane dimmer compounds against glioma. The results showed that compounds 1-3 of this class had obvious inhibitory effects on the growth of human triple-negative breast cancer cell line MDA-MB-468, HER2-positive breast cancer cell line JIMT-1, human lung cancer cell A549, and human liver cancer cell HEPG2. Their anti-tumor activity was superior to that of the natural diarylpropane dimmer compound horsfiequinone B, indicating that the test compounds have anti-tumor uses. In addition, compounds 5, 6, 7, and 8 with similar compound skeleton structures did not show clear anti-tumor activity.

[0054] Table 1 Anti-proliferative activity of natural-like diarylpropane dimers against various tumor cells a

[0055]

[0056] a The experimental results are the average values of three independent experiments. b Positive control.

[0057] Example 2 A pharmaceutical composition for treating cancer

[0058] A pharmaceutical composition for treating cancer, comprising one or more of the natural-like diarylpropane dimer compounds 1-4 of the present invention, wherein the natural-like diarylpropane dimer compound and an excipient are added in a weight ratio of 1:1, and granulated and tabletted. The excipient is specifically a common excipient such as hydroxypropyl cellulose or gelatin.

[0059] Example 3 A pharmaceutical composition for treating cancer

[0060] A pharmaceutical composition for treating cancer, comprising one or more of the natural-like diarylpropane dimer compounds 1-4 of the present invention, wherein the natural-like diarylpropane dimer compound is made into a capsule preparation.

[0061] Example 4 A pharmaceutical composition for treating cancer

[0062] A pharmaceutical composition for treating cancer, comprising one or more of the natural-like diarylpropane dimer compounds 1-4 of the present invention, as well as starch, corn steep liquor and magnesium stearate, and made into tablets by combination.

[0063] The content of the natural-like diarylpropane dimer compound in each tablet is 10 mg.

[0064] The preparation method is to mix the natural-like diarylpropane dimer compound or its pharmaceutical composition with an auxiliary agent, granulate and tablettize to obtain tablets.

[0065] Example 5 A pharmaceutical composition for treating cancer

[0066] A pharmaceutical composition for treating cancer, comprising one or more of the natural-like diarylpropane dimer compounds 1-4 of the present invention, and also comprising auxiliary agents starch and magnesium stearate. It is prepared into a capsule.

[0067] The preparation method is as follows: Mix the natural-like diarylpropane dimer compound with auxiliary agents starch and magnesium stearate, sieve, uniformly mix in a suitable container, and fill the obtained mixture into hard gelatin capsules.

[0068] In each capsule, the content of the natural-like diarylpropane dimer compound is 10 mg.

[0069] Example 6 A pharmaceutical composition for treating cancer

[0070] A pharmaceutical composition for treating cancer, comprising a total of 2 mg of one or more of the natural-like diarylpropane dimer compounds 1-4 of the present invention and 10 mg of sodium chloride. It is prepared into an ampoule.

[0071] Preparation method: Dissolve the natural-like diarylpropane dimer compound and sodium chloride in an appropriate amount of water for injection, filter the obtained solution, and fill it into ampoules under aseptic conditions to prepare an ampoule.

[0072] The above-described embodiments merely represent specific implementation manners of the present application. The description thereof is relatively specific and detailed, but it should not be construed as a limitation on the protection scope of the present application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the technical solution of the present application, several variations and improvements can still be made, and these all fall within the protection scope of the present application.

Claims

1. A natural-like diarylpropane dimer compound, characterized in that: The structural formula is shown in the following formula (I): In the formula, Where R 1 Selected from OMe, OH; R 2 Selected from OH, H; R 3 Selected from OBz, OH, H; R 4 Selected from H, F.

2. The natural-like diarylpropane dimer compound according to claim 1, characterized in that: The natural-like diarylpropane dimer compound can be any of the following compounds:

3. Use of a natural diarylpropane dimer compound in the preparation of a drug for treating cancer, characterized in that: The natural-like diarylpropane dimer compound is one or more natural-like diarylpropane dimer compounds as described in any one of claims 1-2.

4. Use of a natural diarylpropane dimer compound according to claim 3 in the preparation of a drug for treating or assisting in treating cancer, characterized in that: The cancer is breast cancer, lung cancer or liver cancer.

5. The use of a natural diarylpropane dimer compound according to claim 4 in the preparation of a drug for treating cancer, characterized in that: The cancer is lung cancer or liver cancer.

6. A pharmaceutical composition for treating cancer, characterized in that: The method comprises the natural-like diarylpropane dimer compound according to any one of claims 1 to 2 and one or more pharmaceutically acceptable carriers or excipients, wherein the mass ratio of the natural-like diarylpropane dimer compound to the pharmaceutically acceptable carriers and / or excipients is 1:1-1:

10.

7. A pharmaceutical composition for treating cancer according to claim 6, characterized in that: The dosage of the pharmaceutical composition is 0.5 to 20 mg / kg based on the content of the natural diarylpropane dimer compound as an effective component.

8. Use of a natural diarylpropane dimer compound in the preparation of a drug for treating or adjuvant treating triple-negative breast cancer, characterized in that: The natural-like diarylpropane dimer compound is compound 1 as claimed in claim 2.

9. Use of a natural diarylpropane dimer compound in the preparation of a drug for treating or adjuvant treating triple-negative breast cancer, characterized in that: The natural-like diarylpropane dimer compound is compound 2 as claimed in claim 2.

10. Use of a natural diarylpropane dimer compound in the preparation of a drug for treating or assisting the treatment of triple-negative breast cancer or lung cancer, characterized in that: The natural-like diarylpropane dimer compound is compound 3 as claimed in claim 2.

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