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4-amide substituted pyrimidine targeted DDR1 inhibitor as well as preparation and anti-tumor activity application thereof

A technology of anti-tumor drugs and small molecule inhibitors, which is applied in the field of medicinal chemistry and can solve problems such as not particularly effective effects

Active Publication Date: 2020-12-22
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, we found that the YFQ07 compound still has shortcomings. For example, although YFQ07 can reduce the level of DDR1 phosphorylation sites in PC-9GR (DDR1 high-expressing cells), the effect of reducing the effect is not particularly significant, and we need to further develop the activity higher inhibitor

Method used

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  • 4-amide substituted pyrimidine targeted DDR1 inhibitor as well as preparation and anti-tumor activity application thereof
  • 4-amide substituted pyrimidine targeted DDR1 inhibitor as well as preparation and anti-tumor activity application thereof
  • 4-amide substituted pyrimidine targeted DDR1 inhibitor as well as preparation and anti-tumor activity application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The synthesis of embodiment 1 compound

[0047] 1.1 The specific synthetic route of compound (alkali listed in route, solvent and acid-binding agent are only exemplary, not limitation of the present invention) as follows:

[0048]

[0049] 1.2 Examples of synthetic steps

[0050] Synthesis of 4-((6-amino-5-chloropyrimidin-4-yl)oxy)phenol: add substituted phenol 1.2mmol (150mg) and CsCO 3 3.0mmol (576mg) was dissolved in DMSO 25mL, and magnetite was added at the same time. Stir and heat at 80°C for half an hour to fully dissolve, then add 1.0 mmol of 4-amino-5,6-chloropyrimidine (163 mg) dissolved in 5 mL of absolute ethanol to react. Note that if it is added in a dropwise manner, in order to achieve the effect of long-term excessive reaction, the dropping time is controlled at about 1h. After reacting for 15 hours, extract with EA, remove water with anhydrous sulfuric acid, make sand, and separate by column chromatography to obtain N4-(substituted phenyl)-5,6-dich...

Embodiment 2

[0143] Embodiment 2 compound antitumor cell activity (kinase experiment)

[0144] 2.1 Experimental operation steps

[0145] (1) Prepare 1×Kinase buffer.

[0146] (2) Preparation of compound concentration gradients: the test compound concentration was 10 μM, repeated wells were detected, and a solution with a final concentration of 100 times was prepared in a 384-well plate. Then use Echo550 to transfer 250nl to the 384 reaction plate for later use. Add 250 nl of 100% DMSO to negative control wells and positive control wells, respectively.

[0147] (3) Prepare a kinase solution with a final concentration of 2.5 times with 1×Kinase buffer.

[0148] (4) Add 10 μL of 2.5-fold final concentration of kinase solution to compound wells and positive control wells; add 10 μL of 1×Kinase buffer to negative control wells.

[0149] (5) Centrifuge at 1000 rpm for 30 seconds, shake and mix well, and incubate at room temperature for 10 minutes.

[0150] (6) Use 1×Kinase buffer to prepare...

Embodiment 3

[0161] Embodiment 3 MTT method measures the inhibitory effect of target compound on tumor cell line

[0162] All target compounds were dissolved in DMSO and prepared as 1 mM initial solution, which was stored in a cool drug storage cabinet for future use. The initial screening concentration is 10μM, IC 50 The concentrations selected for the test were 10 μM, 5 μM, 1 μM, 0.5 μM, 0.1 μM, and 0.01 μM. First, the effect of the target compound on the proliferation of normal lung cell BEAS-2B at a concentration of 10 μM was determined by MTT method, that is, the toxic effect. Further, all compounds were screened for antitumor activity at a concentration of 10 μM, and the selected cell types included: BEAS-2B, A431, and PC-9GR. Finally, select the compound with better antiproliferative activity on these cell lines, and do IC at six concentrations of 10 μM, 5 μM, 1 μM, 0.5 μM, 0.1 μM, and 0.01 μM 50 experiment.

[0163] These cells are all adherent cells and were cultured in comple...

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Abstract

The invention discloses an N-substituted (5-chloro-6-(substituted phenoxy)pyrimidin-4-yl)benzamide targeted DDR1 small molecule inhibitor as well as preparation and application thereof. Provided is the N-substituted (5-chloro-6-(substituted phenoxy)pyrimidin-4-yl)benzamide target DDR1 inhibitor. The synthesized 45 compounds have low toxicity to normal lung cells, the best compound is C1 in 10 [mu]M DDR1 kinase preliminary screening, and the inhibition rate of the compound on DDR1 under 10 [mu] M is significantly superior to that of a lead compound YFQ07. In the aspect of cell experiments, theIC50 value of C1 to PC-9GR is significantly superior to that of YFQ07. In addition, it is found that the inhibition rate of the designed and synthesized compound on PC-9 cells (EGFR L858R mutation) mostly exceeds 50%, and the C1 can inhibit formation of lung cancer cell colonies and migration of tumor cells.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an N-substituted (5-chloro-6-(substituted phenoxy)pyrimidin-4-yl)benzamide knot-targeting DDR1 small molecule inhibitor and its preparation and Application of antitumor activity. Background technique [0002] In the past ten years, targeted therapy has become one of the research hotspots in cancer therapy. In targeted therapy, the tyrosine kinase family is closely related to the pathogenesis of tumors, and protein kinases participate in the regulation of cell growth, proliferation and survival. Important signaling network. Among the tyrosine kinase family, epidermal growth factor receptor (EGFR) has attracted much attention. After a period of treatment of NSCLC patients with first-generation EGFR inhibitors such as Gefitinib and Erlotinib, many patients develop resistance to EGFR-TKIs. [0003] In non-small cell lung cancer, abnormal expression of DDR1 ...

Claims

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Application Information

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IPC IPC(8): C07D239/47C07D401/12C07D409/12C07D405/12A61P35/00A61K31/506A61K31/5377A61K31/505
CPCC07D239/47C07D401/12C07D409/12C07D405/12A61P35/00
Inventor 叶发青陈波杜宗轩杨小娇钱锦恒屠思军谢自新张园王学宝
Owner WENZHOU MEDICAL UNIV
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