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Application of compound in tumor resistance

A technology of compounds and uses, applied in the field of medicine, can solve problems such as side effects, and achieve the effect of promoting apoptosis and blocking the cell cycle of tumor cells

Inactive Publication Date: 2015-05-13
WUHU YANGYAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional antineoplastic drugs kill normal tissue cells while killing tumor cells, often causing serious side effects

Method used

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  • Application of compound in tumor resistance
  • Application of compound in tumor resistance
  • Application of compound in tumor resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of N-(3-(6-(2-7H-pyrrolo[2,3-d]pyrimidinyl)oxy)pyridyl)benzamide (I-1)

[0034] (1) Preparation of 2-((2-5-nitropyridyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine

[0035] Add 15.3g (100mmol) of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine, 15.4g (110mmol) of 2-hydroxy-5-nitropyridine, 65.2g (200mmol) of cesium carbonate into a 500ml three-necked flask ), cuprous iodide 0.2g and anhydrous DMF200ml. The temperature was raised to 75°C and stirred for 3 hours, then cooled to room temperature, the reaction solution was slowly poured into 1000ml of water, and a large amount of gray solid was precipitated. Stand still, filter with suction, wash the filter cake with 50ml of water, and dry under vacuum at 60°C to obtain 22g of 2-((2-5-nitropyridyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine. The rate is 86%. MS [M+H] + 258.1.

[0036] (2) Preparation of 2-((2-5-aminopyridyl)oxy)-7H-pyrrolo[2,3-d]pyrimidine

[0037] Add 2-((2-5-nitropyridyl) oxygen group)-7H-pyrrolo[2,3-d]pyrimidine 22g, 10...

Embodiment 2

[0043] Test of the inhibitory activity of compound (I-1)~compound (I-9) on CDK2

[0044] The inhibitory activity of the compound of the present invention on CDK2 / cyclin A kinase was tested by fluorescence resonance energy transfer (FRET), and the positive control drug was AZD5438.

[0045] Specific test method: CDK2 / cyclin A is used after diluting to an appropriate concentration with kinase diluent. The kinase reaction mixture contains CDK2 / cyclin A, peptide substrate, HEPES (pH7.5), BRIJ-35, MgCl 2 and EDTA. CDK2phospho-peptide substrate was used as a 100% phosphorylation control, and no ATP was used as a 0% phosphorylation control. After reacting at room temperature for 1 h, moderately diluted Development Reagent A was added to the reaction system. The reaction was continued for 1 h at room temperature, and Stop Reagent was added to terminate the reaction. The excitation wavelength is 400nm, and the fluorescence intensity at the wavelengths of 445nm (coumarin) and 520nm ...

Embodiment 3

[0049] In vitro tumor cell inhibitory activity test of compound (I-1)~compound (I-9)

[0050] Adopt methyl thiazolyl tetrazolium (methyl thiazolyl tetrazolium, MTT) colorimetric method to test the inhibitory activity of the compound of the present invention to tumor cell proliferation in vitro, the selected cell lines are human colon cancer cell HCT-116, human breast cancer cell MCF-7 , human lung cancer cell A549 and human liver cancer cell SMMC-7721, and the positive control drug is AZD5438.

[0051] During the test, take a bottle of cells in the exponential growth phase and in good condition, digest and count them, adjust to the required density and inoculate them in a 96-well cell culture plate. After culturing for 24 hours, add different concentrations of the compound to be tested, and set a positive control drug at the same time. Group and solvent control group, each drug concentration set 3 parallel wells. After 72 hours of drug action on the cells, discard the culture...

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Abstract

The invention relates to the technical field of medicines, in particular to application of a compound with a structure shown in a formula (I) (shown in the description) in preparation of a medicine for preventing or treating malignant tumor associated with cyclin-dependent kinase 2 (CDK2). Based on researches, the compound and pharmaceutically acceptable salt thereof have excellent inhibitory activity to the CDK2, remarkably inhibit the growth activity of a human colonic cancer cell HCT-116, a human breast cancer cell MCF-7, a human lung cancer cell A549 and a human liver cancer cell SMMC-7721, can block the cell cycle of cancer cells and facilitate apoptosis of the cancer cells; the compound and the pharmaceutically acceptable salt thereof can be applied to treatment of various malignant tumors.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the use of a compound in the preparation of medicines for preventing or treating malignant tumors related to CDK2. Background technique [0002] Malignant tumors are one of the chronic diseases that seriously threaten human life and health. How to prevent and treat tumors has become one of the major research topics in the field of biological sciences. Traditional antitumor drugs kill normal tissue cells while killing tumor cells, often causing serious side effects. In recent years, with the development of molecular biology, molecular oncology and molecular pharmacology, the research on antineoplastic drugs has developed from traditional cytotoxic drugs to molecular targeted antineoplastic drugs. [0003] Studies have found that the occurrence and development of most malignant tumors are related to the disorder of cell cycle regulation, and the overactivation of cyclin-dependent...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61P35/00
Inventor 程智
Owner WUHU YANGYAN PHARMA
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