Compound with anti-tumor activity

Abstract

The invention discloses a compound with antitumor activity, and relates to the technical field of medicines. The invention provides an application of a compound in preparation of antitumor drugs, the compound provided by the invention has a significant inhibition effect on proliferation of human lung cancer PC-9 cells and breast cancer MCF-7 cells, the unique chemical structure of the compound endows higher tumor treatment selectivity, the problem of drug resistance of traditional drugs is effectively overcome, and the compound can be applied to preparation of antitumor drugs. Important technical support is provided for developing novel efficient anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a class of compounds with antitumor activity. Background Technology

[0002] The incidence and mortality rates of malignant tumors are rising year by year, profoundly impacting human health and socio-economic development. In recent years, with the deepening research into the pathogenesis of cancer and the advancement of science and technology, the development of anti-tumor drugs has become a research hotspot in the global pharmaceutical field. However, despite the significant progress scientists have made in this area, many problems still urgently need to be solved.

[0003] Traditional anti-tumor drugs such as paclitaxel and cisplatin, while effectively inhibiting tumor cell proliferation, have long been hampered by poor selectivity, high toxicity, and the tendency to develop drug resistance. Furthermore, many drugs struggle to cross the blood-brain barrier, rendering them ineffective in treating central nervous system diseases, further limiting their application. Meanwhile, with the emergence of precision medicine and the development of genomics technologies, personalized treatment is becoming increasingly prevalent. Therefore, the development of novel, highly effective, low-toxicity, and targeted anti-tumor drugs is particularly urgent.

[0004] Despite significant progress made by scholars both domestically and internationally in the field of anti-tumor drugs, existing technologies still have obvious shortcomings. On the one hand, traditional chemotherapy drugs, while killing tumor cells, also damage normal cells, leading to a series of adverse reactions such as bone marrow suppression and decreased immune function. On the other hand, as tumor cells develop increasing resistance to anti-tumor drugs, the therapeutic effect gradually declines. Summary of the Invention

[0005] The purpose of this invention is to provide a class of compounds with antitumor activity to solve the problems existing in the prior art.

[0006] To achieve the above objectives, the present invention provides the following solution: One of the technical solutions of this invention is to provide the application of a compound in the preparation of an antitumor drug, wherein the compound has any one of the following structures: or .

[0007] Furthermore, the tumors include lung cancer and / or breast cancer.

[0008] The second technical solution of the present invention provides an anti-tumor pharmaceutical composition, wherein the active ingredient comprises compounds with the following structures: or .

[0009] Furthermore, the mass content of the compound in the pharmaceutical composition is 0.1-99%.

[0010] Furthermore, the pharmaceutical composition also includes a pharmaceutically acceptable carrier.

[0011] Furthermore, the carrier includes one or more of the following: diluent, excipient, filler, binder, wetting agent, disintegrant, absorption promoter, surfactant, adsorbent carrier, and lubricant.

[0012] Furthermore, the dosage form of the pharmaceutical composition includes injection, tablet, powder, granule, capsule, oral liquid, ointment or cream.

[0013] The pharmaceutical composition provided by this invention can be prepared into various dosage forms such as injections, tablets, and capsules according to clinical needs, and is suitable for different routes of administration, while taking into account the convenience of medication for special groups such as children, the elderly, and patients with dysphagia.

[0014] The structural design of the compounds in this invention provides direction for the optimization of subsequent anti-tumor drugs and provides an important molecular tool for exploring new anti-tumor mechanisms of action (such as targeting specific signaling pathways and inducing tumor cell apoptosis), thus promoting the development of anti-tumor drugs towards a more precise and efficient direction.

[0015] The present invention discloses the following technical effects: This invention relates to a class of compounds with antitumor activity. The compounds of this invention have a significant inhibitory effect on the proliferation of human lung cancer PC-9 cells and breast cancer MCF-7 cells. Their unique chemical structure endows them with low toxicity and high selectivity, effectively overcoming the problems of drug resistance and high toxicity of traditional drugs, and providing important technical support for the development of new and highly effective antitumor drugs. Detailed Implementation

[0016] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0017] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0018] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0019] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0020] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0021] The present invention will be further described in detail below with reference to the embodiments.

[0022] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0023] Cisplatin, with its strong DNA binding ability (it can form cross-links with tumor cell DNA, blocking DNA replication and transcription), has become a "cornerstone drug" for the treatment of various solid tumors, including lung cancer, breast cancer, ovarian cancer, and gastric cancer. Cisplatin is often used in combination with drugs such as paclitaxel and gemcitabine, which can significantly prolong patient survival and was once considered a "milestone drug" in the field of cancer chemotherapy. However, with the widespread clinical application, cisplatin resistance has become a core bottleneck restricting its therapeutic efficacy. Clinical statistics show that… In the field of lung cancer: lung cancer patients who are initially sensitive to cisplatin are highly likely to develop secondary drug resistance after treatment, leading to tumor recurrence or progression. Moreover, the median survival of patients after drug resistance is very short, and the difficulty of treatment is significantly increased. In the field of breast cancer: patients have a high initial response rate to cisplatin, but most of these patients will quickly develop resistance. After developing resistance, there is a lack of effective alternative treatment options, resulting in a very poor prognosis.

[0024] Cisplatin, a widely used platinum-based chemotherapy drug, plays a crucial role in the treatment of various solid tumors. However, drug resistance developed by tumor cells has become a major bottleneck limiting its efficacy. This resistance involves the synergistic effects of multiple mechanisms, including enhanced DNA repair, reduced drug accumulation, upregulation of the antioxidant system, and inhibition of apoptosis pathways, leading to treatment failure and disease progression.

[0025] Based on the aforementioned technological status, this invention designs compounds with unique chemical structures that can not only effectively inhibit cisplatin-sensitive lung and breast cancer cells, but also overcome the bottleneck of cisplatin resistance, providing a safe and effective treatment option for drug-resistant patients. At the same time, it provides key molecular entities and technical directions for the development of novel anti-tumor drugs, which is of great significance for improving the prognosis of cancer patients and promoting the development of the field of anti-tumor treatment.

[0026] The first aspect of this invention is to provide the use of a compound in the preparation of an antitumor drug, said compound having any of the following structures: or .

[0027] As a further preferred embodiment of the invention, the tumor includes lung cancer and / or breast cancer.

[0028] A second aspect of the present invention is to provide an antitumor pharmaceutical composition, wherein the active ingredient comprises a compound with the following structure: or .

[0029] As a further preferred embodiment of the present invention, the mass content of the compound in the pharmaceutical composition is 0.1-99%.

[0030] As a further preferred embodiment of the invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier.

[0031] As a further preferred embodiment of the present invention, the carrier includes one or more of the following: diluent, excipient, filler, binder, wetting agent, disintegrant, absorption promoter, surfactant, adsorbent carrier, and lubricant.

[0032] As a further preferred embodiment of the present invention, the dosage form of the pharmaceutical composition includes injection, tablet, powder, granule, capsule, oral liquid, ointment or cream.

[0033] The pharmaceutical composition provided by this invention can be prepared into various dosage forms such as injections, tablets, and capsules according to clinical needs, and is suitable for different routes of administration, while taking into account the convenience of medication for special groups such as children, the elderly, and patients with dysphagia.

[0034] The structural design of the compounds in this invention provides direction for the optimization of subsequent anti-tumor drugs and provides an important molecular tool for exploring new anti-tumor mechanisms of action (such as targeting specific signaling pathways and inducing tumor cell apoptosis), thus promoting the development of anti-tumor drugs towards a more precise and efficient direction.

[0035] As a further preferred embodiment of the invention, the tumor includes lung cancer and / or breast cancer.

[0036] In the specific embodiment of the present invention, the room temperature is 23±2℃.

[0037] Example 1: Preparation of Compound 1 (1) Dissolve 9-methoxy-1H-phenanthrene-1-one (2.0 g, 9.43 mmol) in DCM (50 ml), add trimethyloxonium tetrafluoroborate (3.52 g, 23.7 mmol), stir at room temperature for 24 hours, filter and collect the filter cake, no purification is required and proceed directly to the next step.

[0038] (2) The methyl[(1E)-9-(methyloxonyl)-3a,3a'-dihydro-1H-phenanthren-1-ylidene]oxonium di(tetrafluoroborate) (500 mg, crude, 1.24 mmol) prepared in step (1) was dissolved in ethanol (10 ml), and a methanol solution of ammonia (0.44 ml, 3.10 mmol) was added. The mixture was stirred at room temperature for 24 hours, and the filter cake was collected by filtration. The filter cake was then slurried again with ethanol and filtered to obtain 80 mg of the target compound in a wine-red solid state, with a yield of 32.9%.

[0039] Example 2 Preparation of Compound 2 (1) Dissolve 9-[(pyridin-2-ylmethyl)amino]phenanthrene-1-one (2.0 g, 6.99 mmol) in DCM (30 ml), add trimethyloxonium tetrafluoroborate (2.58 g, 17.4 mmol), stir at room temperature for 24 hours, filter and collect the filter cake, no purification is required and proceed directly to the next step.

[0040] (2) The methyl{9-[(pyridin-2-ylmethyl)amino]phenanthreneide}oxonium tetrafluoro-λ obtained in step (1) 5 - Borate (500 mg, crude, 1.28 mmol) was dissolved in ethanol (5 ml), and dodecyl primary amine (596 mg, 3.22 mmol) was added. The mixture was stirred at room temperature for 24 hours, filtered, and the filter cake was collected. The filter cake was then slurried again with ethanol and filtered to obtain 200 mg of the target compound as a wine-red solid, with a yield of 37.0%.

[0041] The structures of the above compounds were identified using nuclear magnetic resonance (NMR). The molecular weight, yield, and NMR characterization data of the compounds are shown in Table 1.

[0042] Table 1 Example of effect verification: (1) Experimental tumor cells: Two common tumor cell lines were selected as experimental subjects: human lung cancer cells PC-9 and human breast cancer cells MCF-7. Both cell lines were purchased from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.

[0043] (2) Test methods: a. Cell culture medium preparation: Add 10% fetal bovine serum and 1% penicillin antibiotics to 45 mL of RPMI-1640 medium.

[0044] b. Cell preparation: Human lung cancer cells PC-9 and human breast cancer cells MCF-7 in logarithmic growth phase were selected for the experiment. Frozen cells were removed from the -80°C freezer and thawed in a preheated water bath until they reached the appropriate cell density.

[0045] c. Preparation of compound solutions: The compound was added to serum-containing cell culture medium to prepare concentrations of 10, 50, 100, and 150 μg / mL. -1 The solution.

[0046] d. Cell seeding: Add 1 mL of 0.25% trypsin to the cells and incubate at 37°C with 5% CO2 for 5 min to digest and detach the adherent cells. Centrifuge (1000 rpm, 5 min) and count the cells to ensure an appropriate cell concentration.

[0047] e. Cell seeding: Add 100 µL of cell suspension to each well of a 96-well plate, with a cell count of 6000 cells / well. Set up 3 replicates. Also set up a blank control group with only culture medium and no test solution and a cell control group with only cells and culture medium.

[0048] f. Cultivation and Treatment Culture conditions: Place the 96-well plate in an incubator at 37°C and 5% CO2 for 24 h to allow the cells to adhere.

[0049] Drug treatment: After the cells adhered, 100 μL of the prepared concentration gradient drug solution was added to each well of the tumor cells, and the cells were cultured for another 72 h.

[0050] Positive control drug: Cisplatin exists in powder form with a molar mass of 300.05 g / mol. When its solubility in water reaches 1 mg / mL, the concentration is 3.33 mmol / L. Weigh 1 mg of cisplatin and dissolve it in 1 mL of pure water, simultaneously using sonication to promote dissolution and prepare a stock solution. Then, prepare drug solutions with concentrations of 3.0005 μg / mL, 6.001 μg / mL, 12.002 μg / mL, 24.004 μg / mL, and 48.008 μg / mL using culture medium. g. MTS reagent addition and incubation Add MTS reagent: Prepare the reagent at a ratio of MTS:RPMI-1640 medium = 1:9, and add 100 μL of MTS reagent to each well of tumor cells (including the control group) and blank group (protect from light).

[0051] Incubation: Place the 96-well plate back into an incubator at 37°C and 5% CO2 and incubate for 1 h.

[0052] h. Absorbance measurement: After incubation, the absorbance of each well was measured at a wavelength of 490 nm using a microplate reader.

[0053] i. Data Analysis: Cell viability was calculated based on absorbance values. Using the absorbance of the control group as a baseline, the percentage of cell viability in each treatment group was calculated, and then the IC50 was calculated. 50 .

[0054] Cell viability (%) = (OD value of drug-treated group - OD value of blank group) / (OD value of control group - OD value of blank group) × 100%.

[0055] This compound can effectively inhibit the proliferation of human lung cancer cells PC-9 and human breast cancer cells MCF-7. The results of the antitumor activity test are shown in Table 2.

[0056] Table 2 Results of antitumor activity test The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. Use of a compound for the manufacture of an antitumor medicament, characterized in that, The compound is any one of the following structures: or .

2. Use according to claim 1, characterized in that, The tumor includes lung cancer and / or breast cancer.

3. An antitumor pharmaceutical composition, characterized by, The active ingredient includes a compound having the structure shown below: or .

4. The pharmaceutical composition of claim 3, wherein, The mass content of the compound in the pharmaceutical composition is 0.1-99%.

5. The pharmaceutical composition of claim 3, wherein, The pharmaceutical composition further includes a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 5, wherein, The carrier includes one or more of a diluent, an excipient, a filler, a binder, a humectant, a disintegrant, an absorption enhancer, a surfactant, an adsorption carrier, and a lubricant.

7. The pharmaceutical composition of claim 3, wherein, The dosage form of the pharmaceutical composition includes an injection, a tablet, a powder, a granule, a capsule, an oral liquid, a paste, or a cream.

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