Pyrimidine derivative with anticancer effect

A use and drug technology, applied in the field of pyrimidine derivatives, can solve the problems of large side effects, poor selectivity, and troubled clinical ovarian cancer treatment, etc.

Inactive Publication Date: 2020-06-09
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, clinical drugs for the treatment of ovarian cancer mainly include the following two categories: (1) Cytotoxic drugs represented by cisplatin, paclitaxel, gemcitabine and other drugs, which have poor selectivity, high toxicity, and severe side effects after use ; (2) Targeted PARP inhibitors represented by olaparib, rucapanib, and niraparib
Although PARP inhibitors have provided a revolutionary breakthrough for the treatment of ovarian cancer, the drug resistance of PARP inhibitors also plagues the clinical treatment of ovarian cancer

Method used

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  • Pyrimidine derivative with anticancer effect
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  • Pyrimidine derivative with anticancer effect

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1 Preparation of 2-(2-(2-hydroxybenzylidene)hydrazino)pyrimidine-4-ol (compound 1)

[0072]

[0073] Add 2-hydrazinopyrimidin-4-ol (53mg, 0.5mmol) and 2-hydroxybenzaldehyde (106μL, 1mmol) and 5mL methanol into a 25mL round bottom flask, and reflux overnight at 65°C. The next day, it was cooled to room temperature, filtered with suction, and the filter cake was washed successively with 10 mL of absolute ethanol and 20 mL of absolute ether, and dried to obtain 98 mg of off-white solid, with a yield of 85.2%.

[0074] 1 H NMR (400MHz, DMSO-d 6 )δ11.61(s,2H),9.01(s,1H),7.70(dd,J=7.7,1.5Hz,1H),7.43–7.37(m,2H),6.98(t,J=7.6Hz,3H ),5.81(d,J=7.6Hz,1H).

[0075] ESI-ms(m / z):231.1[M+H] +

[0076] According to the preparation method of compound 1, compound 2-compound 24 can be prepared by reacting different 2-hydrazinopyrimidine derivatives with corresponding aldehydes or ketones, and its structure and characterization data are shown in Table 1:

[0077] The struct...

Embodiment 2

[0082] Example 2 The inhibitory effect of the compound of the present invention on histone demethylase

[0083] Experiment purpose: To detect the inhibitory activity of the compound of the present invention on histone demethylase in vitro, using Succinate-Glo TM The JmjC Demethylase / Hydroxylase Assay (Promega) kit tests the in vitro inhibitory activity of compounds on arginine demethylase JMJD6.

[0084] Experimental principle: During histone demethylation, the cofactor α-ketoglutarate is reduced to succinate. If histone demethylase activity is inhibited, α-ketoglutarate will not be reduced. Therefore, the activity of histone demethylase can be reflected indirectly by measuring the concentration of succinic acid.

[0085] Experimental method: In a 384-well plate, add 2.5 μL of a certain concentration of small molecule solution and 2.5 μL of JMJD6 protein solution. The concentration of JMJD6 protein solution is 2.2 mg / mL. After incubation at room temperature for 10 minutes, a...

Embodiment 3

[0093] Example 3 Compound 11 Inhibitory Effect on Human Tumor Cell Proliferation

[0094] Experimental purpose: To detect the inhibitory activity of the compound of the present invention on human tumor cell proliferation in vitro, and to test the inhibitory activity of the tested compound on different tumor cell lines by using the Cell Counting kit-8 (CCK8) method. IC 50 (half inhibitory concentration). IC 50 The value can be obtained by calculating the inhibitory rate of the test compound on tumor cells at a series of different concentrations.

[0095] Experimental principle: WST-8(2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfobenzene)-2H-tetrazole Monosodium salt) in the presence of the electron coupling carrier 1-Methoxy PMS, can be reduced by the dehydrogenase in the mitochondria to generate a highly water-soluble orange-yellow formazan product (formazan), and the depth of the color is proportional to the proliferation of the cells. Inversely proportional...

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Abstract

The invention relates to a pyrimidine derivative with an anticancer effect, belonging to the field of chemical medicines. The invention provides an application of a compound as shown in a formula I which is described in the specification or pharmaceutically acceptable salt of the compound in preparation of drugs used for treatment and / or prevention of cancers. Biological experiment results show that the series of compounds show good inhibition effect on histone arginine demethylase, wherein the IC50 of part of the compounds is at a micromolar level and show good inhibition effect on a varietyof clinically common tumor cell strains; and the IC50 of all the compounds is smaller than 1 [mu]M. The compound provided by the invention also shows good effect in vivo, and can significantly inhibittumor growth in mice. In conclusion, the pyrimidine derivative provided by the invention provides a new effective choice for developing a new generation of targeting drugs for tumor treatment, and has good application prospect.

Description

technical field [0001] The invention relates to pyrimidine derivatives with anticancer effect, belonging to the field of chemical medicine. Background technique [0002] Epigenetics is a discipline that studies the heritable changes in gene expression without changing the nucleotide sequence of the gene. Like traditional genetics, epigenetics regulates the process of gene transcription in organisms, thereby affecting the basic physiological functions related to the growth and development of human life. Common epigenetic modification mechanisms mainly include: DNA modification, histone modification, RNA modification, chromatin remodeling, and non-coding RNA. Among them, histone modification is currently the most widely studied epigenetic modification mechanism. According to the different histone modification regulatory factors, these regulatory factors can be divided into three categories: Writer, Eraser , Identification factor (Reader). Histone demethylases are an importa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506A61P35/00C07D239/47C07D239/88C07D401/12C07D405/12C07D409/12C07D403/12C07D413/12
CPCA61K31/506A61P35/00C07D239/47C07D239/88C07D401/12C07D405/12C07D409/12C07D403/12C07D413/12
Inventor 魏霞蔚杨胜勇魏于全
Owner SICHUAN UNIV
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