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Phosphatidylinositol-3-kinase inhibitor and application thereof

A technology of kinase inhibitor and phosphatidylinositol, which is applied in the field of tumor treatment drugs, can solve the problems of unseen function and application reports, and achieve the effect of low toxicity

Inactive Publication Date: 2010-10-06
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The compound 2-(4-fluorophenyl)-3-nitro-8-oxo-ethyl-2-hydro-benzopyran is an existing compound, which was prepared by Maybridge Chemicals Ltd. (Maybridge Chemicals, UK). Co.Ltd.), but there is no report on its function and application

Method used

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  • Phosphatidylinositol-3-kinase inhibitor and application thereof
  • Phosphatidylinositol-3-kinase inhibitor and application thereof
  • Phosphatidylinositol-3-kinase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Synthesis of PI3K inhibitors

[0033] First synthesize p-fluoro-β-nitrostyrene with fluorobenzaldehyde and nitromethane, then synthesize 2-p-fluorophenyl- 3-nitro-8-ethoxy-2H-benzopyran. The specific method is as follows:

[0034] Preparation of p-fluoro-β-nitrostyrene:

[0035] Dissolve p-fluorobenzaldehyde (50.0 g, 0.4 mol) in 3 liters of nitromethane, add ammonium acetate (34.0 g, 0.44 mol), and react under reflux for 24 h. After concentration under reduced pressure, a 1:1 mixture of dichloromethane and water was added, and the aqueous layer was extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. Filter and concentrate. Recrystallized from ethyl acetate-petroleum ether to obtain 37.3 g (92%) of p-fluoro-β-nitrostyrene as a yellow solid, melting point: 98-100°C;

[0036] Synthesis of 2-p-fluorophenyl-3-nitro-8-ethoxy-2H-benzopyran

[0037] Add 3-ethoxy ...

Embodiment 2

[0038] Example 2: Inhibiting the proliferation of malignant hematological tumor cells

[0039] Culture myeloma cell lines, leukemia cell lines, primary acute myeloid leukemia cells, and peripheral blood stem cells in RPMI-1640 or IMDM cell culture medium, add 10% fetal bovine serum, 100 μg / ml ampicillin, 100 units / ml streptomycin. The cell culture environment was 37 degrees Celsius, 5% carbon dioxide; different concentrations of XM002S were given to incubate for 72 hours, and the cell viability was analyzed by MTS / PMS staining method according to conventional techniques (the wavelength for reading optical density was 490nm), and the attached Figure 2a (myeloma cell line), with Figure 2b (leukemia cell line), with Figure 2c (acute myeloid leukemia primary cells), with Figure 2d (peripheral blood stem cells).

[0040] from Figure 2a-2d It can be seen that the toxicity of XM002S to malignant hematological tumor cells is dose-dependent, but it has no obvious effect on t...

Embodiment 3

[0041] Example 3: Inhibition of tumor growth in tumor-bearing mice

[0042] 5-6 weeks old female NOD / SCID mice were subcutaneously injected with K562 cells (5×10 5 ) or U937 cells (1×10 6 ), when the tumor grew to be palpable, XM002S (100mg / kg / d) was injected intraperitoneally for intervention, and the control group was injected with the same amount of XM002S solvent (10% DMSO) for 10 consecutive days. The change in tumor volume was measured every other day, and the body weight of the mice was monitored at the same time to obtain image 3 a (cell tumor-bearing mice, cell tumor-bearing mice), image 3 b (U937 cell tumor-bearing mice), where the left graph is the curve of tumor size change, and the right graph is the curve of body weight change.

[0043] according to image 3 a, 3b: XM002S significantly inhibited the growth of tumors in the two tumor-bearing mice. From the 6th day to the end of the experiment, the tumor volume of the XM002S intervention group was significantly...

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Abstract

The invention discloses new application of a 2-(4-fluorophenyl)-3-nitro-8-O-ethyl-2-hydro-benzopyran compound, in particular application of the compound serving as phosphatidylinositol-3-kinase (PI3K) inhibitor. The PI3K inhibitor can inhibit PI3K and disturb a PI3K / AKT signal channel, has good treatment effect on multiple tumors, particularly malignant hematological diseases, can effectively control the propagation of tumor cells and induce the apoptosis thereof, and has the effect of inhibiting and treating the tumors; and meanwhile, the PI3K has low toxicity.

Description

technical field [0001] The invention belongs to the field of drugs for treating tumors, and in particular relates to a phosphatidylinositol-3-kinase inhibitor and its application as an anti-tumor drug. Background technique [0002] Due to various reasons, the incidence of tumors has been increasing year by year. Statistics show that cancer has become the number one cause of death. In terms of tumor drugs, in 2005, the global sales of anti-cancer drugs totaled 28.2 billion US dollars, while the sales of anti-cancer drugs in my country are also increasing at an annual rate of 15% to 17%. , with an annual growth rate of more than 30%. Unfortunately, most of the antineoplastic drugs currently on the market are controlled by developed countries such as the United Kingdom and the United States, so actively developing new drugs with independent intellectual property rights has a very broad prospect. [0003] The phosphatidylinositol 3-kinase (PI3K) signaling pathway is the main s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/352A61P35/00A61P35/02
Inventor 毛新良艾伦·什莫
Owner SUZHOU UNIV
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