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Quinoxaline keto-amide compound, preparation method and application thereof

A kind of technology of quinoxalinone amide and compound, which is applied in the application field of preparing anti-tumor angiogenesis drugs, and can solve the problems such as reports that quinoxalinone amide derivatives are not found.

Inactive Publication Date: 2013-01-09
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, no report has been found on the use of quinoxalinone amide derivatives as VEGFR-2 tyrosine kinase inhibitors in the preparation of anti-tumor angiogenesis drugs

Method used

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  • Quinoxaline keto-amide compound, preparation method and application thereof
  • Quinoxaline keto-amide compound, preparation method and application thereof
  • Quinoxaline keto-amide compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] In vitro pharmacological activity screening of anti-angiogenesis (cell level), the specific principle and measurement procedure are as follows: Determination of the inhibitory effect of the target compound on the formation of new capillary lumen-like structures in human umbilical vein endothelial cells (HUVEC). Under the stimulation of vascular endothelial growth factor, umbilical vein endothelial cells will form capillary lumen-like structures in the gel system formed by artificial basement membrane glue. The cell body was originally pebble-like, but the cell body was elongated and accompanied by bud-like luminal structures protruding, making the cell body irregular. As a result, adjacent deformed cells are often connected with each other by tubular structures, and translucent vacuoles or fissures can often be seen along the longitudinal axis of the cell body or the outstretched tubular structures. The current research suggests that these changes of endothelial cells i...

Embodiment 2

[0045] Determination of the inhibitory effect (tissue level) of the target compound on the rat arterial ring microangiogenesis model in vitro. The principle is as follows: Rat arterial rings can generate new microvascular networks under the stimulation of artificial Matrigel. The newly formed microvessels communicate with the endothelial cell layer, and the endothelial cells formed on the inner surface of the vascular lumen are elongated and overlap each other to form Unicellular or multicellular bridges. By generating endothelial cell pathways, the extensive fibrin glue surface is remodeled and networks and microvessels are formed. Since the formation of this structure is the same as the process of blood vessel development, this model can screen and evaluate the comprehensive effects of different drugs on the angiogenesis ability of vascular endothelial cells.

[0046] One male rat was taken and died suddenly by dislocation of the neck. The aorta was dissected and cut into a...

Embodiment 3

[0047] Example 3: Compound cytotoxicity analysis (MTT method)

[0048] MTT method, also known as MTT colorimetric method, is a method for detecting cell survival and growth. The detection principle is: succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline formazan and deposit in the cells, while dead cells have no such function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and its light absorption value is measured at a wavelength of 490nm with an enzyme-linked immunosorbent detector, which can indirectly reflect the number of living cells. Within a certain cell number range, the amount of MTT crystal formation is proportional to the cell number. In this experiment, four solid tumor adherent cell lines were selected for the cytotoxicity analysis of the test compounds, namely human cervical cancer cell HeLa, human ovarian cancer cell 3AO, human breast cancer cell MCF-7 and human prostate can...

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Abstract

The invention discloses a quinoxaline keto-amide compound. The structural general formula is represented as follows, wherein R1 represents a methoxy group or hydrogen, and R represents hydrogen or halogen. The invention further discloses a preparation method of the quinoxaline keto-amide compound and an application of the quinoxaline keto-amide compound in preparing anti-tumor angiogenesis drugs. According to the quinoxaline keto-amide compound, by means of activity evaluation of in-vitro cellular levels and organization levels, angiogenesis of new vessels can be effectively inhibited, and a methyl thiazolyl tetrazolium (MTT) experiment proves that obvious cytotoxicity is absent so that the quinoxaline keto-amide compound can be used as a novel anti-tumor angiogenesis inhibitor, wherein anti-angiogenesis activity of three compounds (SLL-4, SLL-7 and SLL-16) is superior to that of pazopanib of a positive control drug, and a further in-vitro screening result can preliminarily show that the three quinoxaline keto-amide compounds can be expected to be candidate drugs. In a word, a quinoxaline ketone framework is promising to be used for designing and synthesizing the novel anti-tumor angiogenesis inhibitor.

Description

technical field [0001] The invention relates to a quinoxalinone amide compound, its preparation method and its application in the preparation of anti-tumor angiogenesis drugs. Background technique [0002] The successful application of tyrosine kinase inhibitors in the process of inhibiting tumor angiogenesis has set a model for the development of targeted anti-tumor drugs. [0003] Neovascularization is formed in the existing microvascular network, and the process is extremely complex, mainly mediated by the vascular endothelial growth factor (vascular endothelial growth factor, VEGF) signaling pathway. Usually occurs in wound healing, organogenesis, tumor proliferation and metastasis (Hoeben A, Landuyt B, Highley MS, et a / .Vascular endothelial [0004] growth factor and angiogenesis. Pharmacol Rev. 2004;56:549-80). VEGF induces tumor angiogenesis by binding to receptors (VEGF receptors, VEGFRs) on the surface of the cell membrane. The receptors mainly include three subty...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/52A61K31/498A61P35/00
Inventor 李荀施雷雷周建峰李志宇王海钠徐文方韩雪梅
Owner SHANDONG UNIV
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