Application of rupestonic acid ephedrine ester in tumor treatment

Abstract

The invention provides new application of rupestonic acid ephedrine ester in cancer treatment, in-vitro anti-tumor tests of rupestonic acid ephedrine ester accidentally find that rupestonic acid ephedrine ester has remarkable inhibitory activity on pancreatic cancer cells (PANC1), cervical cancer cells (Hela), ovarian cancer cells (A2780), lung cancer cells (A549) and liver cancer cells (Hep G-2), and can be used for preparing medicines for treating tumors.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical applications of compounds, specifically relating to the use of artemisinin ephedrine ester in the treatment of tumors. Background Technology

[0003] Although some small-molecule anticancer drugs are already used clinically, and some compounds are undergoing preclinical research, most cancer patients are diagnosed at an intermediate to advanced stage, resulting in generally poor clinical treatment outcomes. The increasing prevalence of multidrug resistance further complicates cancer treatment. Therefore, developing novel anticancer drugs with high activity and low side effects to meet clinical needs is urgently needed. In particular, identifying antitumor lead compounds or candidate drugs from traditional Chinese medicine and then modifying their structures is crucial for developing new antitumor drugs.

[0004] Rupestonic acid is a polyfunctional sesquiterpene compound isolated from Artemisia annua in Xinjiang, and is one of the characteristic compounds of Artemisia annua. Artemisia annua is clinically used to treat indigestion, abdominal distension and pain, hepatitis, snake bites, and colds with fever. Rupestonic acid and its derivatives have significant anti-influenza virus activity (Mini-Reviews in Medical Chemistry, 2013, 13(2):310-315), but no literature has disclosed its anti-tumor uses. Summary of the Invention

[0005] This invention provides the use of at least one of the following formula (I): artemisinin ketone acid ephedrine ester, its stereoisomer, racemate, pharmaceutically acceptable salt or solvate, in the preparation of a medicament for treating tumors.

[0006]

[0007] According to embodiments of the present invention, pharmaceutically acceptable salts of artemisinin ephedrine derivatives represented by formula (I) can be pharmaceutically acceptable salts formed by artemisinin ephedrine represented by formula (I) and pharmaceutically acceptable acids. These pharmaceutically acceptable salts include, but are not limited to, salts formed by artemisinin ephedrine and inorganic acids, such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and similar salts; they also include salts formed by artemisinin ephedrine and organic acids, such as lactic acid, oxalic acid, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, sulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, trifluoroacetic acid, amino acids, or alkylates [such as acetate, HOOC-(CH2)]. nSalts of COOH (where n is an integer from 1 to 4) and similar salts.

[0008] According to an embodiment of the present invention, the solvate includes hydrates and alcohols.

[0009] According to an embodiment of the present invention, the tumor is selected from cancers, such as at least one selected from bladder cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, liver cancer, cervical cancer, and pancreatic cancer.

[0010] In some specific embodiments of the present invention, the cancer may be pancreatic cancer, cervical cancer, ovarian cancer, lung cancer, or liver cancer.

[0011] The present invention also provides a pharmaceutical composition comprising at least one of the following: artemisinin ephedrine ester of formula (I) as described above, its stereoisomer, racemate, pharmaceutically acceptable salt or solvate thereof.

[0012] According to an embodiment of the invention, the pharmaceutical composition contains at least one pharmaceutically acceptable excipient; for example, the excipient may be selected from excipients, carriers, and / or diluents. The pharmaceutically acceptable excipient refers to an inert, non-toxic pharmaceutical excipient.

[0013] According to an embodiment of the present invention, the pharmaceutical excipient may also be selected from one or more of the following excipients: fillers, disintegrants, lubricants, flow aids, effervescent agents, flavoring agents, preservatives, and pharmaceutically acceptable excipients for coating materials.

[0014] The present invention also provides a pharmaceutical formulation comprising at least one of the following: an artemisinin ephedrine derivative of formula (I) as described above, a stereoisomer, a racemic mixture, a pharmaceutically acceptable salt or a solvate thereof.

[0015] According to an embodiment of the present invention, the pharmaceutical preparation contains the above-described pharmaceutical composition.

[0016] According to an embodiment of the present invention, the pharmaceutical preparation is a solid oral preparation, a liquid oral preparation, or an injection.

[0017] Preferably, the formulation may be selected from tablets, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, granules, oral solutions, water for injection, lyophilized powder for injection, large-volume infusions, or small-volume infusions.

[0018] The present invention also provides a method for treating tumors, comprising administering an effective amount of at least one of the following: artemisinin ketone acetate of formula (I), its stereoisomer, racemate, pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition, or the pharmaceutical preparation thereof, to a patient in need, such as a human.

[0019] The term "effective dose" refers to the amount of ephedrine monoclonalate of formula (I) and / or at least one pharmaceutically acceptable salt of ephedrine monoclonalate of formula (I) that is effective in "treating" an individual's disease or discomfort. When the disease being treated is a tumor (e.g., cancer), the effective dose reduces the number of tumor (or cancer) cells; shrinks the size of the tumor; inhibits or prevents the invasion of tumor cells into surrounding organs, such as soft tissue or bone; inhibits or prevents tumor metastasis; inhibits or prevents tumor growth; alleviates one or more symptoms associated with the tumor (or cancer); reduces morbidity and mortality; improves quality of life; or a combination of the above effects. For the treatment of tumors (or cancer), the efficacy in in vivo experiments can be measured by assessing factors such as survival, time to disease progress (TTP), response rates (RR), duration of response, and / or quality of life. Those skilled in the art will understand that the effective dose can vary depending on the route of administration and the dosage of the excipient.

[0020] The beneficial effects of this invention are:

[0021] In the in vitro antitumor testing of artemisinin ephedrine ester, this invention unexpectedly discovered that artemisinin ephedrine ester exhibits significant inhibitory activity against pancreatic cancer cells (PANC1), cervical cancer cells (HeLa), ovarian cancer cells (A2780), lung cancer cells (A549), and liver cancer cells (Hep G-2), with an IC50 value of [missing information]. 50 The values ​​were 198.8 mg / L, 197.8 mg / L, 113.4 mg / L, 231.7 mg / L, and 198.2 mg / L, respectively. Therefore, it can be used to prepare drugs for treating tumors. Detailed Implementation

[0022] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the contents of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by this invention.

[0023] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0024] Instruments and reagents:

[0025] Ephedrine ketone ester (prepared according to the method described in patent CN 202210135516.1); CCK8 (Shanghai Beibo Biotechnology Co., Ltd.); DMEM high glucose medium (Thermo Fisher Scientific (Suzhou) Instruments Co., Ltd.); EDTA (trypsin) (gibco); Foetal Bovine Serum (Biological Industries); phosphate buffer solution; 96-well cell culture plate; multi-functional microplate reader.

[0026] Example 1: In vitro antitumor activity test

[0027] The in vitro antitumor activity of artemisinin ketone ester was tested using the CCK-8 assay. The main inhibitory activities against pancreatic cancer cells (PANC1), cervical cancer cells (HeLa), ovarian cancer cells (A2780), lung cancer cells (A549), and liver cancer cells (Hep G-2) were tested. All cell lines were obtained from cell lines preserved at Ningxia Medical University.

[0028] The specific testing process will be illustrated using pancreatic cancer cells (PANC1) as an example. The testing process for other tumor cells is the same as that for pancreatic cancer cells (PANC1). The specific process is as follows:

[0029] Pancreatic cancer cell line (PANC1) was cultured for 24 hours at 37°C, saturated humidity, and 5% CO2. When the cells were in the logarithmic growth phase, the supernatant was aspirated, and the cells were digested with 0.25% trypsin-EDTA solution, followed by termination of digestion with high-glucose medium. Cells were seeded into 96-well plates at a density of 5000 cells / well. The plates were incubated for 24 hours. The cell culture medium was then aspirated, and 100 μL of high-glucose medium was added to each well. Then, 1 μL of different concentrations of test sample (five replicates per concentration) was added to each well. The plates were then incubated at 37°C, saturated humidity, and 5% CO2 for another 48 hours. Finally, 10 μL of CCK8 was added to each well, and the plates were incubated at 37°C for 1-4 hours. The absorbance of each well was measured at 450 nm using a multi-mode microplate reader. Inhibition rate % = [(OD200%)... 对照细胞 -OD 加药细胞 ) / (OD 对照细胞 -OD 空白 )]×100. The negative control is V 高糖培养基 / V DMSO A mixed solution with a ratio of 10:1.

[0030] The inhibitory activity of ephedrine monosodium ketone on pancreatic cancer cells (PANC1), cervical cancer cells (HeLa), ovarian cancer cells (A2780), lung cancer cells (A549), and liver cancer cells (Hep G-2) is shown in Table 1 below.

[0031] Table 1. Inhibitory effect of ephedrine ketone ester on five types of tumor cells.

[0032]

[0033]

[0034] The test results above show that ephedrine monosodium glutamate has significant inhibitory activity against pancreatic cancer cells (PANC1), cervical cancer cells (HeLa), ovarian cancer cells (A2780), lung cancer cells (A549), and liver cancer cells (Hep G-2), with an IC50 value of [missing information]. 50 The values ​​were 198.8 mg / L, 197.8 mg / L, 113.4 mg / L, 231.7 mg / L, and 198.2 mg / L, respectively. Therefore, it can be used to prepare drugs for treating tumors.

[0035] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Use of at least one of the following: artemisinin ketone acetate of formula (I), its stereoisomer, racemate, pharmaceutically acceptable salt or solvate, in the preparation of a medicament for treating tumors.

2. The use according to claim 1, wherein, The pharmaceutically acceptable salt of the artemisinin ephedrine derivative shown in formula (I) is a pharmaceutically acceptable salt formed by the artemisinin ephedrine derivative shown in formula (I) and a pharmaceutically acceptable acid.

3. The use according to claim 1, wherein, The pharmaceutically acceptable salt is a salt formed by ephedrine monosodium acetoate and an inorganic acid.

4. The use according to claim 3, wherein, The pharmaceutically acceptable salt is selected from hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, or nitrate.

5. The use according to claim 2, wherein, The pharmaceutically acceptable salt is a salt formed by ephedrine monosodium acetoate and an organic acid.

6. The use according to claim 5, wherein, The pharmaceutically acceptable salt is selected from lactic acid, oxalic acid, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, sulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, trifluoroacetic acid, amino acids, or alkylates.

7. The use according to claim 6, wherein, The alkylate is HOOC-(CH2). n Salts of -COOH, where n is an integer from 1 to 4.

8. The use according to claim 1, wherein, The solvates include hydrates and alcohols.

9. The use according to any one of claims 1-8, wherein, The tumor mentioned is selected from cancer.

10. The use according to claim 9, wherein, The cancer is selected from at least one of bladder cancer, ovarian cancer, breast cancer, stomach cancer, esophageal cancer, lung cancer, head and neck cancer, colon cancer, pharyngeal cancer, liver cancer, cervical cancer, and pancreatic cancer.

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