Use of indole-3-carboxamides derivatives for the preparation of anti-breast tumor drugs

Abstract

The application discloses application of indole-3-glyoxylamide derivatives in preparation of anti-breast tumor drugs. 50 The application provides application of the indole-3-glyoxylamide derivatives in preparation of anti-breast tumor drugs, and the half inhibitory concentration (IC 50 ) of the application in inhibiting tumor cells is 20 muM or above. The application also provides a time period during which the indole-3-glyoxylamide derivatives play a role in tumor cells, and the inhibitory activity can be exerted after 4 hours. The application provides the use of the indole-3-glyoxylamide derivatives, which can be used as anti-breast tumor drugs.

Description

Technical Field

[0001] This invention relates to the application of an indole-3-acetaldehyde amide derivative in the preparation of anti-breast tumor drugs, and belongs to the field of pharmaceutical science. Background Technology

[0002] Improved outcomes in the treatment of malignant breast cancer are largely attributed to mammography and adjuvant therapy; however, highly effective systemic therapies for patients with advanced breast cancer are having a significant impact. Both genetic and non-genetic factors influence breast cancer incidence. Non-genetic factors include age, reproductive risk factors (such as early menarche and late menopause), exogenous female hormones, lifestyle factors (such as postmenopausal obesity and alcohol consumption), radiation exposure, high mammographic density, and the presence of histological lesions (such as dysplasia), although some of these factors may also be influenced by genetic susceptibility. Cancer comprises multiple biological entities characterized by heterogeneity in pathology, genomic alterations, gene expression, and the tumor microenvironment (TME), all of which influence clinical behavior and treatment response. However, current classic parameters used to guide treatment decisions, such as histopathology, tumor size and grade, lymph node involvement, and biomarker expression, are not perfect. Therefore, there is an urgent need to better predict patient response to treatment and to improve and optimize treatment options. Over the past decade, the inherent molecular subtypes and predictive features of breast cancer have been further refined, while the genomics revolution has enabled the sequencing of a vast number of breast tumors at unprecedented speeds and resolutions. In-depth genomic analysis has also provided substantial insights into intratumoral heterogeneity and clonal evolution during disease progression and metastasis. Summary of the Invention

[0003] To address the aforementioned problems in the prior art, this invention provides a class of indole-3-acetaldehyde amide derivatives, and screens out indole-3-acetaldehyde amide derivatives of formula (I) that have antitumor activity.

[0004] The indole-3-acetaldehyde amide derivatives of formula (I) provided by this invention, and compounds with similar structures are shown below:

[0005]

[0006] Pharmacological tests showed that the indole-3-acetaldehyde amide derivatives of formula (I) have inhibitory activity against breast cancer cells, but the indole-3-acetaldehyde amide derivatives 1a-9a with similar structures do not have inhibitory activity against breast cancer cells, indicating that the structure of the indole-3-acetaldehyde amide derivatives of formula (I) screened in this invention is related to antitumor (breast cancer) activity.

[0007] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0008] Application of indole-3-acetaldehyde amide derivatives in the preparation of anti-breast tumor drugs, wherein the structure of the compound is shown in formula (I).

[0009]

[0010] Meanwhile, pharmacological tests showed that the indole-3-acetaldehyde amide derivatives of formula (I) of the present invention exhibited significant antitumor selectivity against different tumor cells and had significant anti-breast tumor activity. However, the indole-3-acetaldehyde amide derivatives of formula (I) of the present invention did not have antitumor activity against pancreatic cancer and other cancers.

[0011] Beneficial effects

[0012] The drug provided by this invention is used to inhibit tumor cells at a half-maximal inhibitory concentration (IC50). 50 The value is 20 μM or higher.

[0013] The present invention also provides the time period during which the indole-3-acetaldehyde amide derivative exerts its effect in tumor cells, exhibiting inhibitory activity after 4 hours.

[0014] The indole-3-acetaldehyde amide derivative of formula (I) provided by this invention can be used as a drug for treating breast tumors. Detailed Implementation

[0015] Example 1: MTT Assay 1. MCF-7 and U87 cells in logarithmic growth phase were seeded into 96-well cell culture plates at a density of 5000 cells / well and cultured in a 5% CO2 incubator for 24 hours. 2. After complete cell attachment, the old culture medium was discarded, and culture media containing different concentrations of compounds (50 μM, 25 μM, 12.5 μM, and 6.25 μM) and corresponding solvent controls were added, with three parallel wells for each group. After drug addition, the 96-well cell culture plates were placed in a 5% CO2 incubator and incubated statically for 48 hours. 3. For assay, 20 μL of 2.5 mg / mL MTT solution was added to each well, and the cells were cultured at 37°C for another 4 hours.

[0016] 4. After MTT incubation, discard the old culture medium and add 100 μL of DMSO to each well. The solution in the well will turn purple at this point. After shaking well, use a multi-mode microplate reader to detect the absorbance of each well at a wavelength of 570 nm. Calculate the half-maximal inhibitory concentration (IC50) of the compound on cell proliferation based on the relationship between cell viability and dosage. 50 The measured results are shown in Table 1.

[0017] Table 1. Half-maximal inhibitory concentrations (IC50) of indole-3-acetaldehyde amide derivatives in MCF-7 and U87 tumor cells.

[0018]

[0019] The experimental results are shown in Table 1: the indole-3-acetaldehyde amide derivative of formula (I) exhibited better cell inhibitory activity against MCF-7 and U87 tumor cells than compounds 1a-9a at concentration gradients of 50 μM, 25 μM, 12.5 μM, and 6.25 μM. Example 1 shows that the structure of the indole-3-acetaldehyde amide derivative of formula (I) of the present invention is related to its anti-breast cancer cell activity, and not all indole-3-acetaldehyde amide derivatives with similar structures have anti-breast cancer tumor activity. Therefore, the indole-3-acetaldehyde amide derivative of formula (I) of the present invention has inhibitory activity against breast cancer cells and can be used for the preparation of anti-breast cancer drugs.

[0020] Meanwhile, the present invention also conducted pharmacological tests on human tumor cell lines A549, as well as tumor cells such as K562, MKN45 and PANC, according to the same experimental steps described above. The experimental structures are shown in Table 2.

[0021] Table 2 shows the inhibitory effects of indole-3-acetaldehyde amide derivatives of formula (I) on multiple tumor cells and normal cells.

[0022]

[0023] Among them, TC-1 and RAW264.7 are normal cell lines, while MCF-7, U87, and A549, as well as K562, MKN45, and PANC are human tumor cells.

[0024] The experimental results are shown in Table 2: The antitumor activity of the indole-3-acetaldehyde amide derivatives of formula (I) of the present invention is selective. The indole-3-acetaldehyde amide derivatives of formula (I) exhibit inhibitory activity against MCF-7, U87, and A549 tumor cells, especially showing significant inhibitory activity against MCF-7. However, the indole-3-acetaldehyde amide derivatives of formula (I) show no inhibitory activity against K562, MKN45, and PANC. The experimental results indicate that the antitumor activity of the indole-3-acetaldehyde amide derivatives of formula (I) of the present invention is selective, exhibiting significant inhibitory activity against MCF-7. The indole-3-acetaldehyde amide derivatives of formula (I) are suitable for use in the preparation of anti-breast cancer drugs, but are not applicable to the use of inhibitory drugs against all tumor cells.

[0025] In this case, the effect of indole-3-acetaldehyde amide derivatives of formula (I) on MCF-7 was also tested. The experiment showed that the protein content of p53 in MCF-7 could be significantly upregulated within 4-8 hours after administration.

[0026] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Equivalent modifications within the scope of the technical concept of the present invention are all within the protection scope of the present invention.

Claims

1. The application of indole-3-acetaldehyde amide derivatives of formula (I) in the preparation of anti-breast tumor drugs, characterized in that... The structure of the derivative is shown in formula (I), 。

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