Use of a benzothiazepine compound in the preparation of a medicament for treating cancer

Abstract

The application belongs to the field of medicine, and particularly relates to application of a benzothiazepine compound in preparation of a cancer treatment drug, wherein the benzothiazepine compound has a structural formula as shown in formula I, and the cancer is at least one selected from liver cancer, intestinal cancer, bone cancer and lung cancer. According to a cell activity experiment of the application, it is found that the compound shown in formula I shows clear and different activities on human liver cancer cells, human lung cancer cells, human osteosarcoma cells and human colorectal cancer cells in vitro. The inventors of the application find, for the first time, through activity screening on a small molecule skeleton, that the benzothiazepine compound shown in formula I has excellent activity on various different types of human tumors, and the benzothiazepine compound provides an optional scheme for a broad-spectrum anticancer drug.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to the application of a benzothiocyanate compound in the preparation of cancer treatment drugs. Background Technology

[0002] Cancer is currently one of the leading causes of death worldwide, posing a serious threat to human health. Over the past three decades, significant progress has been made in the development of anti-tumor drugs, with treatment strategies gradually shifting from traditional chemotherapy to molecularly targeted therapy and immunotherapy, forming a new treatment landscape with multiple mechanisms. Statistics show that small molecule drugs account for approximately 78% of the 174 widely used anti-tumor drugs globally.

[0003] Benzothiazides are a class of seven-membered bridged heterocyclic systems containing a benzene ring, sulfur atom, and nitrogen atom. In recent years, these compounds have become a hot topic in antitumor drug development due to their unique three-dimensional structure and broad bioactivity spectrum. Although studies have reported the wide application of benzothiazides in the pharmaceutical field, their comprehensive chemical composition and antitumor mechanisms remain relatively scarce. Summary of the Invention

[0004] The purpose of this invention is to address the shortcomings of existing technologies by providing an application of benzothiocyanate compounds in the preparation of drugs for treating cancer.

[0005] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows:

[0006] This invention provides the application of benzothiocyanate compounds in the preparation of cancer treatment drugs, wherein the structural formula of the benzothiocyanate compound is shown in Formula I:

[0007] , Formula I.

[0008] Furthermore, the cancer is selected from at least one of liver cancer, colorectal cancer, bone cancer, and lung cancer. According to the cell activity experiments of the present invention, the compound represented by Formula I exhibited clear and differential activity against human liver cancer cells, human lung cancer cells, human osteosarcoma cells, and human colorectal cancer cells in vitro.

[0009] Furthermore, the drug uses a compound of Formula I or a pharmaceutically acceptable salt thereof as its active pharmaceutical ingredient.

[0010] Furthermore, based on the total mass of the drug, the mass fraction of the active pharmaceutical ingredient is 0.1%-99%.

[0011] Furthermore, the medicament comprises a therapeutically effective amount of the compound shown in Formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0012] Furthermore, the carrier is selected from at least one of fillers, binders, disintegrants, lubricants, pH adjusters, stabilizers, solubilizers, and sustained-release materials. The drug can be formulated as an oral dosage form (e.g., tablets, capsules, granules), injection, transdermal formulation, inhaler, or other suitable dosage form, and the formulation maintains the expected physical stability, chemical stability, and biological activity during preparation, storage, and use.

[0013] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0014] The present invention has the following technical effects:

[0015] This invention is the first to discover the application of a benzothiazepine compound in the preparation of a cancer treatment drug. The structural formula of the benzothiazepine compound is shown in Formula I. The benzothiazepine compound is 7-{5-[2-(1H-indol-3-yl)ethyl]-1,2,4-oxadiazol-3-yl}-10-propyldibenzo[b,f][1,4]thiazepin-11(10H)-one, with the English name: 7-[5-[2-(1H-Indol-3-yl)ethyl]-1,2,4-oxadiazol-3-yl]-10-propyldibenzo[b,f][1,4]thiazepin-11(10H)-one. The inventors discovered that 7-{5-[2-(1H-indol-3-yl)ethyl]-1,2,4-oxadiazol-3-yl}-10-propyldibenzo[b,f][1,4]thiazide-11(10H)-one exhibits strong inhibitory activity against tumor cells. Based on the cell activity experiments according to the present invention, the compound shown in Formula I exhibited clear and differential activity against human liver cancer cells, human lung cancer cells, human osteosarcoma cells, and human colorectal cancer cells in vitro.

[0016] The inventors of this invention, through activity screening of small molecule skeletons, have for the first time discovered that benzothiazide compounds as shown in Formula I exhibit excellent activity against a variety of different types of human tumors, providing an option for broad-spectrum anticancer drugs. Attached Figure Description

[0017] Figure 1 The graph shows the inhibition curves of benzothiocyanate compounds on the activity of four types of human tumor cells. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments.

[0019] The benzothiazazonium compound 7-{5-[2-(1H-indol-3-yl)ethyl]-1,2,4-oxadiazol-3-yl}-10-propyldibenzo[b,f][1,4]thiazazonium-11(10H)-one (hereinafter referred to as benzothiazazonium compound I) of this invention has the structural formula shown in Formula I. It is derived from a drug-like compound library containing 5000 compounds developed by Shanghai Taoshu Biotechnology Co., Ltd., with Library ID G946-0405, Plate layout PHD198947, CAS Number 1190017-17-4, and molecular formula C. 28 H 24 N4O2S has a relative molecular mass of 480.59. The benzothiocyanate compounds of formula I used in Examples 1-4 were purchased from Shanghai Taoshu Biotechnology Co., Ltd.

[0020] , Formula I.

[0021] The human liver cancer cells described in the following examples are human liver cancer cells LM3, the human lung cancer cells are human lung cancer cells A549, the human colorectal cancer cells are human ileocecal colorectal adenocarcinoma cells HCT-8, and the human osteosarcoma cells are human osteosarcoma cells MG63. All the conventional cancer cells used above were obtained from Kunming Medical University.

[0022] Unless otherwise specified, all reagents used in the embodiments of this invention are commercially available. RPMI 1640 medium, DMEM medium, and fetal bovine serum were purchased from Biological Industries; phosphate-buffered saline (PBS) and 0.25% trypsin (containing EDTA) were purchased from Gibco.

[0023] Cell lines were cultured in DMEM or RPMI 1640 medium containing 10% fetal bovine serum at 37°C, 5% CO2 and 90% humidity.

[0024] Example 1

[0025] The CCK-8 assay was used to detect cell growth inhibition. The CCK-8 assay, short for Cell Counting Kit-8, is a commonly used method for detecting cell proliferation and cytotoxicity. The principle of the CCK-8 assay is based on the compound WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid phenyl)-2H-tetrazole monosodium salt). In the presence of the electron carrier 1-Methoxy PMS (menaquinone phosphate), WST-8 can be reduced by intracellular mitochondrial dehydrogenases to produce a highly water-soluble orange-yellow formazan product. The amount of formazan produced is directly proportional to the number of viable cells, and the color intensity reflects cellular metabolic activity. The number of viable cells can be indirectly reflected by measuring the absorbance at 450 nm using a microplate reader. Therefore, CCK-8 can be used to assess cell proliferation, cytotoxicity, or the cellular effects of drugs.

[0026] 7-{5-[2-(1H-indol-3-yl)ethyl]-1,2,4-oxadiazol-3-yl}-10-propyldibenzo[b,f][1,4]thiazazide-11(10H)-one (hereinafter referred to as benzothiazazide compound I) was dissolved in DMSO (dimethyl sulfoxide), and then solutions with compound concentrations of 10 μM, 5 μM, 1 μM, 0.5 μM and 0.1 μM were prepared using DMSO. The above concentration solutions were used as test solutions.

[0027] Human liver cancer cells LM3 (4×10) 3 Cells were seeded in 96-well plates with 99 μL of culture medium per well and incubated at 37°C with 5% CO2 for 24 h. Then, 1 μL of the test solution was added to each well. For the control group, only 1 μL of DMSO was added to the cell culture, and the plates were incubated for 72 h. Then, 10 μL of CCK8 solution was added to each well, and the mixture was gently mixed to avoid air bubbles. The plates were incubated for another 1 h, and the absorbance of each well was measured at 450 nm using a microplate reader. The average OD value of each well was calculated, and the results were compared with the control group (untreated cells) to analyze changes in cell proliferation or toxicity. The percentage of absorbance in the experimental group relative to the absorbance in the control group represents the cell viability or proliferation level; the control group is assumed to be 100%.

[0028] The results are shown in Table 1 and Figure 1 As shown:

[0029] .

[0030] According to Table 1 and Figure 1The results showed that benzothioza compounds (CAS No. 1190017-17-4) exhibited cytotoxicity against the human liver cancer cell line LM3.

[0031] Example 2

[0032] In Example 1, human liver cancer cells LM3 were replaced with human lung cancer cells A549. Other procedures were the same as in Example 1. Results are shown in Table 2 and... Figure 1 As shown.

[0033] .

[0034] According to Table 2 and Figure 1 The results showed that benzothioza compounds (CAS No. 1190017-17-4) exhibited cancer cell toxicity against the human lung cancer cell line A549.

[0035] Example 3

[0036] In Example 1, human liver cancer cells LM3 were replaced with human osteosarcoma cells MG63. Other procedures were the same as in Example 1. Results are shown in Table 3. Figure 1 As shown. The calculated half-maximal inhibitory concentration (IC50) of compound I for MG63 was obtained. 50 =7.33 μM. In comparison, the IC50 of cisplatin for MG63 is 7.33 μM. 50 =27.49μM.

[0037] .

[0038] According to Table 3 and Figure 1 The results showed that the benzothiozaza compound (CAS No. 1190017-17-4) had strong cytotoxicity against human osteosarcoma cell line MG63.

[0039] Example 4

[0040] In Example 1, the human liver cancer cells LM3 were replaced with human ileocecal colorectal adenocarcinoma cells HCT-8. Other procedures were the same as in Example 1. Results are shown in Table 4. Figure 1 As shown.

[0041] .

[0042] According to Table 4 and Figure 1 The results showed that benzothioza compounds (CAS No. 1190017-17-4) had strong cytotoxicity against human ileocecal colorectal adenocarcinoma cell line HCT-8.

[0043] In summary: as shown in Tables 1-4 and Figure 1As shown, the benzothiazazonium compound 7-{5-[2-(1H-indol-3-yl)ethyl]-1,2,4-oxadiazol-3-yl}-10-propyldibenzo[b,f][1,4]thiazazon-11(10H)-one (CAS No. 1190017-17-4) exhibited significant dose-dependent inhibitory activity against human liver cancer cells, human lung cancer cells, human osteosarcoma cells, and human colorectal cancer cells. Cell activity decreased with increasing concentration, indicating that this compound has a clear anti-proliferative effect.

[0044] The above are merely embodiments of the present invention and do not limit the scope of the patent. Any equivalent modifications made based on the content of this specification, or direct or indirect applications in other related technical fields, are similarly included within the scope of patent protection of the present invention.

Claims

1. The application of a benzothiocyanate compound in the preparation of cancer treatment drugs, characterized in that, The structural formula of the benzothiocyanate compounds is shown in Formula I: Equation I; The cancer is selected from at least one of liver cancer, colorectal adenocarcinoma, bone cancer, and lung cancer.

2. The application according to claim 1, characterized in that, The drug uses the compound of Formula I or a pharmaceutically acceptable salt thereof as its active pharmaceutical ingredient.

3. The application according to claim 2, characterized in that, The mass fraction of the active pharmaceutical ingredient is 0.1%-99% based on the total mass of the drug.

4. The application according to claim 2, characterized in that, The drug comprises a therapeutically effective amount of the compound shown in Formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

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