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Application of beta-lactam compounds

A technology of lactams and compounds, applied in the field of new applications of known drugs, to prevent and inhibit postoperative metastasis of malignant tumors, with good clinical application prospects

Inactive Publication Date: 2020-05-22
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there is no research report that β-lactam compounds can inhibit the metastasis of malignant tumor cells by inhibiting the activity of HDAC6

Method used

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  • Application of beta-lactam compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1. The inhibitory activity of cefoperazone sodium on HDAC6 was studied by substrate-enzyme binding experiment.

[0032] Using substrate-enzyme binding assay, different concentrations of cefoperazone sodium were incubated with HDAC6 substrate and enzyme, and the inhibitory effect of cefoperazone sodium on HDAC6 activity was detected by the fluorescence intensity generated.

[0033] Dilute the Ac-Lys(Ac)-AMC fluorescent substrate to 80 μM with buffer, and dilute the HDAC6 enzyme to 1 μg / mL for use. Then take a black microplate, add 10 μL of HDAC6 enzyme, 20 μL of fluorescent substrate and 20 μL of gradiently diluted cefoperazone sodium into the wells, mix evenly, and incubate in a 37°C incubator for 2 hours. Then add 50 μL of stop solution to each well, and incubate again at 37° C. for 15 minutes to terminate the reaction. Subsequently, the fluorescence intensity was detected using a multifunctional microplate reader (excitation wavelength 380 nm, emission wavele...

Embodiment 2

[0037] Example 2. The effect of cefoperazone sodium on the expression of HDAC6-related substrate proteins in human pancreatic cancer PANC-1 cells.

[0038] Broad-spectrum HDAC inhibitors can induce hyperacetylation of histone and non-histone substrates, such as histone H3 and α-tubulin, whereas the sirtuin activity of HDAC6 is mainly concentrated On non-histone substrates, selective HDAC6 inhibitors significantly catalyze the hyperacetylation of α-tubulin but not histone H3. PANC-1 cells were pretreated with cefoperazone sodium (150, 300, 600 μM), Tubacin (5 μM) and SAHA (1 μM) for 48 hours, and the total protein was extracted to detect the expression level of related proteins. Such as figure 1 It was shown that the HDAC6-specific inhibitor Tubacin, the broad-spectrum HDAC inhibitor SAHA and cefoperazone sodium could all induce an increase in the expression of Ac-α-tubulin, but only the broad-spectrum HDAC inhibitor SAHA could induce hyperacetylation of histone H3. Furthermo...

Embodiment 3

[0039] Example 3. Effect of cefoperazone sodium on HDAC6 activity in PANC-1 cells.

[0040] PANC-1 cells were treated with cefoperazone sodium (150, 300, 600 μM), Tubacin (5 μM) or vehicle (Control) for 48 hours, then added cell lysate, collected lysed cells, centrifuged at 4°C to get supernatant, and used BCA protein quantification kit Quantitative. After the protein was diluted to a uniform concentration, the black microplate was taken out, and the protein was co-incubated with the HDAC6 fluorescent substrate at 37°C for 30 min. Then add 10 μL of developer to each well, incubate at 37°C for 10 min to generate fluorescence, and use a multi-functional microplate reader to detect the fluorescence intensity (excitation wavelength 380 nm, emission wavelength 490 nm). The experimental results show( figure 2 ), cefoperazone sodium inhibited the activity of HDAC6 in PANC-1 cells in a dose-dependent manner.

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Abstract

The invention belongs to the technical field of medicines, and relates to application of beta-lactam compounds, in particular to application of beta-lactam compounds in production of histone deacetylase inhibitors and application of the beta-lactam compounds in production of anti-tumor-metastasis medicines. According to application of the beta-lactam compounds in production of the histone deacetylase inhibitors and application of the beta-lactam compounds in production of the anti-tumor-metastasis medicines, it is found by research through a substrate-enzyme binding test, immunoblotting, cellenzyme activity detection, a scratch test and a Transwell test that cefoperazone has a significant inhibiting effect on malignant tumor metastasis by inhibiting the activity of HDAC6. Therefore, the beta-lactam compounds represented by the cefoperazone can be used for production of the anti-tumor-metastasis medicines, and have excellent application prospects in prevention and inhibition of postoperative metastasis of malignant tumors.

Description

technical field [0001] The present invention belongs to the field of new application of known medicines, and relates to the application of β-lactam compounds, in particular to the application of β-lactam compounds in the preparation of histone deacetylase inhibitors, and also to β-lactams Application of the compound in the preparation of anti-tumor metastasis medicine. Background technique [0002] As the morbidity and mortality of tumors continue to rise, malignant tumors have become the number one killer that seriously threatens people's health. Tumor metastasis is an important biological feature of malignant tumors. Most cancer patients die not from primary cancer but from metastatic cancer. The ability to invade and metastasize is the most basic feature that distinguishes cancer cells from normal cells, and is also the pathological basis that leads to postoperative tumor recurrence, disease progression, and eventual death in patients. [0003] Tumor metastasis can be r...

Claims

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Application Information

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IPC IPC(8): A61K31/546A61P35/04
CPCA61K31/546A61P35/04
Inventor 马恩龙邓勇宋昊轩张金李艳春
Owner SHENYANG PHARMA UNIVERSITY
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