Application of 2-phenylpyrazole [1,5-a] pyrimidine compounds serving as tumor drug resistance reversal agent

A drug resistance reversal and compound technology, applied in the field of medicine, can solve the problems of complex formation mechanism of MDR, and achieve the effect of reversing the degree of cell resistance, good guiding significance, and realizing reversal effect.

Active Publication Date: 2020-07-10
SHANDONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The formation mechanism of MDR is complex, in which the overexpression of ABC drug transport pump is the main reason for mediating MDR

Method used

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  • Application of 2-phenylpyrazole [1,5-a] pyrimidine compounds serving as tumor drug resistance reversal agent
  • Application of 2-phenylpyrazole [1,5-a] pyrimidine compounds serving as tumor drug resistance reversal agent
  • Application of 2-phenylpyrazole [1,5-a] pyrimidine compounds serving as tumor drug resistance reversal agent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1 computer drug screening

[0040] (1) Acquisition, analysis and processing of the three-dimensional structure of ABCG2 protein;

[0041] The three-dimensional structure (PDB code: 5NJ3) of the breast cancer resistance protein ABCG2 was obtained from the protein database (https: / / www.rcsb.org / ). The AUTODOCK tools software package was used to prepare the protein, first hydrogenate the protein, and remove the water molecules in the protein, and then perform energy optimization and minimization of the protein under the ff99sb force field conditions.

[0042](2) Construction and processing of small molecule ligand libraries for docking;

[0043] Establish a docking small molecule ligand library; the small molecule structure is obtained from the commercial compound library ChemBridge and Chemdiv databases, and the ligands are preprocessed by using Openbabel software to convert 2D to 3D, structure optimization, and format conversion.

[0044] (3) Build a virtual...

Embodiment 2

[0051] Embodiment 2 biological activity test

[0052] Cell culture: H460 / MX20 (non-small cell lung cancer drug-resistant cell line with high ABCG2 expression) was cultured in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin, and the cells were maintained at 37°C containing 5 %CO 2 in a humid incubator.

[0053] Cytotoxicity testing: The MTT colorimetric cell proliferation assay was used to determine drug sensitivity in in vitro cell models. Prepare a single cell suspension and seed it on a 96-well plate at a density of 3000–8000 per well, and add a series of concentrations of the compound to be tested. Cells were then placed at 37 °C, 5% CO 2 48 hours in the incubator. Add 20 μL of 0.5% MTT to each well and incubate for an additional 4 hours. The supernatant was then removed, and 150 μL DMSO was added to each well to dissolve MTT crystals. Use a microplate reader to detect the absorbance at 540nm, and determine the basic non-toxic dose.

[00...

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Abstract

The invention particularly relates to application of 2-phenylpyrazole [1,5-a] pyrimidine compounds serving as a tumor drug resistance reversal agent. Aiming at the problem of cancer chemotherapy resistance, the invention provides compounds having an inhibiting effect on the ATP-binding cassette sub-family G member 2 (ABCG2), and the compounds are used for improving the drug resistance of tumor cells. According to the application, a series of 2-phenylpyrazole [1,5-a] pyrimidine compounds are obtained by study, so that the ABCG2 in drug resistance-type tumor cells can be in a resting state, pumping out of a substrate is blocked, and the drug resistance of tumors is reversed, and the therapeutic dose is safe and non-toxic. Based on the result of the study, the compounds can be combined with other ABCG2 drug resistance related antitumor drugs for treatment; and the 2-phenylpyrazole [1,5-a] pyrimidine compounds have good clinical medication significance.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a 2-phenylpyrazol[1,5-a]pyrimidine compound and the application of a pharmaceutical composition containing the compound as a drug resistance reversal agent for tumors. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] Many patients who died of tumors are related to drug resistance of tumor cells, especially multidrug resistance (MDR). MDR refers to the cross-resistance of tumor cells to other anti-tumor drugs with different structures and mechanisms of action while developing resistance to one anti-tumor drug. That is to say, MDR tumor patients are not only ineffec...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61K45/06A61P35/00A61P35/02
CPCA61K31/519A61K45/06A61P35/00A61P35/02A61K2300/00
Inventor 盛卸晃卢佳澳类红旭
Owner SHANDONG NORMAL UNIV
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