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Application of 5-methyl-dihydrobenzofuran-imidazole salts in pharmacy

A salt compound, dihydrobenzene technology, applied in the field of medicine, can solve the problems of large toxic and side effects, poor pharmacokinetic properties, anti-tumor and anti-tumor stem cell activity has not been reported, and achieves inhibition of proliferation, induction of apoptosis, The effect of inducing apoptosis

Inactive Publication Date: 2019-08-16
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds still have the disadvantages of large toxic and side effects and poor pharmacokinetic properties. Therefore, it is necessary to discover new PI3K / Akt / mTOR pathway inhibitors to develop new anti-tumor drugs
[0005] So far, novel 5-methyl-dihydrobenzofuran-imidazolium salt compounds have not been reported as PI3K kinase inhibitors and mTOR signaling pathway inhibitors, and their anti-tumor and anti-tumor stem cell activities

Method used

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  • Application of 5-methyl-dihydrobenzofuran-imidazole salts in pharmacy
  • Application of 5-methyl-dihydrobenzofuran-imidazole salts in pharmacy
  • Application of 5-methyl-dihydrobenzofuran-imidazole salts in pharmacy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Preparation of 5-methyl-dihydrobenzofuran-imidazolium salt compounds shown in general structural formula I and II:

[0063] Using 2,3-dihydrobenzofuran as raw material, carry out Vilsmeier reaction to synthesize 5-formyl-dihydrobenzofuran, which is reduced to 5-methanolyl-dihydrobenzofuran with sodium borohydride in alcohol solution Furan, then converted to mesylate, and then reflux reaction with imidazole or substituted benzimidazole in a solvent to synthesize 5-methyl-dihydrobenzofuran-imidazole, and on this basis, react with halides to synthesize 5-methyl Base-dihydrobenzofuran-imidazolium salt compounds.

Embodiment 2

[0065] B591 is a PI3K kinase inhibitor.

[0066] 1. Experimental method: PI3K activity detection kit (purchased from Echelon) was used to detect the effect of B591 (see Figure 1A for the structural formula) on PI3K kinase activity according to the operating instructions. PIP 2 Mass ELISA and PIP 3 Mass ELISA kit (purchased from Echelon) was used to detect the effect of B591 on the production of PIP2 and PIP3 in HCT116 cells.

[0067] 2. Experimental results: B591 can inhibit the activity of PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, IC50 are: PI3Kα=1.30±0.27μmol / L; PI3Kβ=0.36±0.13μmol / L; PI3Kγ=0.11±0.07μmol / L; PI3Kδ = 1.58±0.16μmol / L( Figure 1B ). B591 also significantly inhibited PIP 3 / PIP 2 The ratio of PIP 2 to PIP 3 The conversion of B591 was significantly reduced, further proving that B591 directly targets PI3K ( Figure 1C ). In addition, with the increase of ATP concentration, the kinase inhibitory activity of B591 decreased, indicating that B591 is an ATP-competitive...

Embodiment 3

[0069] B591 significantly inhibits mTORC1 and mTORC2 signaling pathways in different tumor cells.

[0070] 1. Cell lines: Human lung cancer A549 cells, human colon cancer HCT116 cells, human rhabdomyosarcoma RD cells and human breast cancer MDA-MB-468 cells were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. Cells were placed at 37°C, 5% CO 2 A549, HCT116 and RD cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum; MDA-MB-468 cells were cultured in DMEM medium containing 10% fetal bovine serum.

[0071] 2. Experimental method: A549, HCT116, RD and MDA-MB-468 cell suspensions in the logarithmic growth phase were inoculated in 6-well plates. After the cells adhered to the wall, the original culture medium was removed, and different concentrations of B591 were added to each well of the experimental group, and the same amount of culture medium without B591 was added to each well of the control group, and the cells were processed and...

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Abstract

The invention relates to an application of 5-methyl-dihydrobenzofuran-imidazole salts in preparation of PI3K kinase inhibitors, mTOR signaling pathway inhibitors and tumor prevention and treatment drugs. Compounds with 3-(2-bromobenzyl)-1-((2,3-dihydrobenzofuran-5-yl)methyl)-5,6-dimethyl-1H-benzo[d]imidazol-3-ium bromide(B591) as a representative can target to PI3K kinase to inhibit an mTOR signaling pathway and inhibit tumor growth. More importantly, compared with normal tumor cells, B591 more significantly inhibits tumor stem cells and effectively prevents breast cancer cell metastasis and recurrence of breast cancer after treatment with a chemotherapeutic drug paclitaxel. The compounds have the advantages of strong pharmacological activity, clear action mechanism, safety, low toxicity and good stability, can be used as novel drugs, health care products and / or dietary additives, are used for preparing anti-tumor drugs, provide a new choice for the field of tumor treatment and have great application value, and can also be used as chemical tool molecules for research on the PI3K / Akt / mTOR signaling pathways.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to the application of 5-methyl-dihydrobenzofuran-imidazolium salt compounds in the preparation of PI3K inhibitors, mTOR signaling pathway inhibitors, and drugs for preventing and treating tumors. Background technique [0002] Tumor is a major disease that threatens human health. Cancer stem cells are the key root cause of tumor occurrence, metastasis, drug resistance and recurrence, and the root cause of tumor treatment failure. Therefore, a new strategy for tumor treatment is to kill tumor cells and tumor stem cells at the same time. [0003] The PI3K / Akt / mTOR pathway is a very important signal transduction pathway in cells. As a key kinase in this signaling pathway, the activation of PI3K is mainly caused by the direct combination of Ras and p110, leading to the activation of PI3K. After PI3K is activated, the plasma membrane Generate second messenger PIP 3 , then pip 3 Combin...

Claims

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Application Information

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IPC IPC(8): A61K31/4178A61P35/00A61P35/02C07D405/06
CPCA61K31/4178A61P35/00A61P35/02C07D405/06
Inventor 李艳孔令梅张洪彬羊晓东闫居明周宏宇于春雷徐晓亮
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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