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Polysubstituted 2-aminopyridine compound and application thereof in preparation of anti-tumor drugs

An anti-tumor drug, aminopyridine technology, applied in the field of pharmacy, can solve the problems that specific WSB-1 inhibitors have not yet been reported, and achieve significant anti-tumor metastasis effect, high specificity, and novel mechanism of action

Active Publication Date: 2019-02-22
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, at present, the inhibition of WSB-1 activity can only be achieved by gene mutation (SOCS domain deletion) and gene silencing (SiRNA) technology, and no specific WSB-1 inhibitor has been reported yet.

Method used

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  • Polysubstituted 2-aminopyridine compound and application thereof in preparation of anti-tumor drugs
  • Polysubstituted 2-aminopyridine compound and application thereof in preparation of anti-tumor drugs
  • Polysubstituted 2-aminopyridine compound and application thereof in preparation of anti-tumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Preparation method and structural characterization of polysubstituted 2-aminopyridine compounds

[0032] The preparation of polysubstituted 2-aminopyridine compounds refers to patents (WO2005100353, WO2016135048) and literature (Lingam VS, Dahale DH, Rathi VE et al. Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H) -one Derivativesas Phosphodiesterase 10A(PDE10A) Antagonists.J Med Chem.2015,58(20):8292-8308.) The synthesis method, through simple Miyaura boronation reaction, Suzuki coupling reaction, reductive amination, condensation reaction And so on. The structure characterization data of the prepared polysubstituted 2-aminopyridine compounds are as follows:

[0033] 5,6-Bis(3-methyl4-methoxyphenyl)-2-aminopyridine (I-1)

[0034] 1 H NMR(500MHz, CDCl 3 )δ7.44(d,J=8.3Hz,1H), 7.25(d,J=1.5Hz,1H), 7.00(dd,J=8.4,2.1Hz,1H), 6.94(d,J=1.6Hz, 1H), 6.85 (dd, J = 8.4, 2.1 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 6.49 ...

Embodiment 2

[0043] Example 2: Evaluation of the inhibitory activity of polysubstituted 2-aminopyridine compounds on tumor cell migration in vitro

[0044] The present invention uses models based on phenotypic screening, namely the scratch experiment and the Transwell chamber experiment, to determine the ability of polysubstituted 2-aminopyridine compounds to inhibit tumor cells from repairing scratches and to inhibit tumor cells from migrating through the Transwell membrane, thereby To evaluate the ability of the test compound to inhibit tumor cell migration in vitro. The cell strain used in the present invention is human osteosarcoma cell KHOS, and the experimental results are based on cell coverage and cell migration as parameters.

[0045] Scratch test method: In a hypoxic environment, inoculate osteosarcoma cells KHOS in a 24-well culture plate, and when they are fully confluent (dense monolayer cells), use a 10μl tip to scratch each well of the monolayer cells Create a wound model of cul...

Embodiment 3

[0056] Example 3: Compound I-1 for WSB-1-RhoGDI 2 Pathway inhibitory activity measurement

[0057] In the present invention, the inhibitory activity of compound I-1 on WSB-1-RhoGDI2 signal pathway was investigated by Western Blot method.

[0058] Experimental method: Inoculate H1299 cells stably transformed with WSB-1 in a 24-well culture plate, incubate with test compound I-1 (5μM) for 48 hours under hypoxia, collect the cells, and use DMSO as a blank control group , The Western Blot method was used to analyze the degree of inhibition of WSB-1 and RhoGDI2 protein ubiquitination degradation in the administration group.

[0059] The experimental results are as figure 2 Shown. Compound I-1 can significantly inhibit the expression of WSB-1 at a concentration of 5 μM (the inhibition rate is about 72%), thus increasing the expression level of the downstream protein RhoGDI2, while no obvious cytotoxicity (normal cell morphology) is observed. The experimental results show that compound I...

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Abstract

The invention discloses a polysubstituted 2-aminopyridine compound and application thereof in preparation of anti-tumor drugs. The polysubstituted 2-aminopyridine compound is characterized by having the general formula as shown in the figure (I) in the specification, wherein R1 and R2 are each independently selected from substituted phenyl, substituent of the R1 and the R2 is selected from C1-C3 alkyl, C1-C3 alkoxy and halogen, R3 is selected from hydrogen, C1-C3 alkoxy, benzyl or substituted benzyl, substituent of the R3 is selected from C1-C3 alkyl, C1-C3 alkoxy and halogen, and R4 and R5 are each independently selected from hydrogen, C1-C3 alkyl and C1-C3 alkoxy. The polysubstituted 2-aminopyridine compound has a remarkable anti-tumor metastasis effect and acts on brand-new tumor metastasis kinesin WSB-1 (WD-40 repeat-containing SOCS Box protein) under the hypoxia condition, so that the tumor metastasis process is directly inhibited, and the compound has great significance in the anti-tumor metastasis drugs with a novel development action mechanism and high specificity.

Description

Technical field [0001] The invention belongs to the field of pharmacy, and specifically relates to a polysubstituted 2-aminopyridine compound and its application in the preparation of antitumor drugs. Background technique [0002] Malignant tumors are major diseases threatening human life and health. Epidemiological investigations show that tumor invasion and metastasis are key factors affecting prognosis and leading to recurrence, and are an important cause of death for most tumor patients. At present, the drugs used in clinical anti-tumor metastasis are all based on the inhibition of primary tumors and metastatic tumors as evaluation indicators, but the research on the inhibition of metastasis has not yet made breakthrough progress. [0003] WSB-1 (WD-40 repeat-containing SOCS Box protein) is a hypoxic tumor metastasis driver protein. WSB1 induces ubiquitination of RhoGDI2 (inhibitor of cell movement) and promotes its degradation by the proteasome, thereby activating RhoGTPases ...

Claims

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Application Information

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IPC IPC(8): A61K31/4418C07D213/74C07D213/75A61P35/00A61P35/04
CPCA61K31/4418A61P35/00A61P35/04C07D213/74C07D213/75
Inventor 陈斌辉董晓武何俏军杨波谢江峰朱虹曹戟严芳洁
Owner ZHEJIANG UNIV
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