Preparation method of 2,3-indolediketone-3-oxime and application in prevention and control of cancer

A technology of indoledione and cancer, which is applied in the field of preparing cancer prevention or treatment drugs, and can solve the problems of cumbersome purification steps, unstable product quality, and low yield

Inactive Publication Date: 2010-09-01
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the carbonyl of isatin is antiaromatic and very active. In fact, both the 2- and 3-position carbonyls of isatin may form oximes and several isomers; 1. Under the condition that the reaction temperature is too high, a variety of side reactions will occur, resulting in unstable product quality, low yield, cumbersome subsequent purification steps, excessive energy consumption and cost
For example, the method reported in the literature is usually that hydroxylamine hydrochloride, sodium carbonate and isatin are dissolved in a reaction system containing ethanol and water and heated to reflux, but when the pH value is 7.6, it can cause the generation of by-product isatin-2-oxime[ 6]
As another example, another recent document reported the method of isatin-3-oxime cyclization from Isonitrosoacetanilide under the action of ionic liquid, but the cost of ionic liquid is very high, and the reaction requires a high temperature of 135°C[7]

Method used

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  • Preparation method of 2,3-indolediketone-3-oxime and application in prevention and control of cancer
  • Preparation method of 2,3-indolediketone-3-oxime and application in prevention and control of cancer
  • Preparation method of 2,3-indolediketone-3-oxime and application in prevention and control of cancer

Examples

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Effect test

Embodiment 1

[0028] Example 1: Preparation of 2,3-indoledione-3-oxime according to the optimized conditions of the present invention.

[0029] The molar ratio of hydroxylamine hydrochloride, isatin and lithium hydroxide monohydrate in the reaction system is set at 1.2:1:1. Take hydroxylamine hydrochloride 8.33g, be dissolved in 50ml DMF, be made into the solution that concentration is 2.4mol / L, and be placed in the container of a magnetic stirring device; In container, add lithium hydroxide monohydrate 4.2g, and carry out Magnetic stirring; add isatin 14.7g, react at room temperature and magnetic stirring. Within minutes, the solution turned from an initial orange-red color to a light orange-yellow color. After the reaction was carried out for 30 minutes, the color of the solution was no longer lighter, and the end point of the reaction was detected by the method of the present invention, and it was confirmed that all isatin had been consumed. Add 150ml of distilled water pre-cooled at 4...

Embodiment 2

[0031] Example 2: Growth inhibitory and chemosensitizing effects of 2,3-indoledione-3-oxime on cancer cells, malignant tumor cells and transformed cells.

[0032] Dissolve 2,3-indoledione-3-oxime in DMSO to make a solution with a concentration of 100 mg / ml, and store it in a -20°C refrigerator until use. Culture cells in RPMI-1640 medium containing 10% newborn bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin at 37°C, 5% CO 2 1. Cultivate a variety of cancer cells, malignant glioma cells and human fetal liver L02 transformed cells under saturated humidity conditions, and routinely digest and passage. Take cells in logarithmic growth phase, digest and make cell suspension, press 5×10 per well 3The density of cells seeded in 96-well plates. After culturing for 24 hours, the experimental group was added with the above-mentioned 2,3-indoledione-3-oxime dissolved in dimethyl sulfoxide (DMSO) and then diluted with RPMI-1640 culture solution to a final concentration of ...

Embodiment 3

[0035] Example 3: Effect of 2,3-indoledione-3-oxime on cell cycle G1 phase arrest and proliferation inhibition of cancer cells.

[0036] Human nasopharyngeal carcinoma CNE cells were treated with 2,3-indoledione-3-oxime DMSO solution at a concentration of 4.2 μg / ml. After 24 hours of treatment, the cells were collected and a cell suspension was prepared, washed twice with PBS, and washed with 200 mesh Cells were filtered through a stainless steel mesh to obtain a single cell suspension. Cells were fixed with -20°C pre-cooled 70% ethanol. After fixing at 4°C for more than 30 minutes, the cells were centrifuged, ethanol was discarded, and washed twice by PBS centrifugation. Adjust cell concentration to 1 x 10 6 / ml, add RNase (final concentration is 20μg / ml), and stand at room temperature for 30 minutes. Centrifuge, discard the supernatant, and resuspend the cells in PBS. After adding 20 μg / ml propidium iodide (PI) to the sample, the ratio of each phase of the cell cycle was...

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Abstract

The invention discloses a preparation method of 2,3-indolediketone-3-oxime or isatin-3-oxime and discloses application of the 2,3-indolediketone-3-oxime in preparing cancer prevention or control drugs. The application of the 2,3-indolediketone-3-oxime in prevention and control of cancer or other malignant tumours is characterized in that the substance has obvious growth inhibition action on various tumour cells, has specific G1-phase blocking action on cell generation cycle, i.e. the substance can stop the tumour cells carrying out DNA (deoxyribonucleic acid) replication, and has obvious down regulation action on the expression of cycle proteins cyclin E, cyclin B and cyclin A, obvious up regulation action on the expression of a cell cycle inhibiting factor p21, induction action on cancer cells or precancerosis cells and sensitization action on gene toxic chemotherapeutic agents.

Description

Technical field: [0001] The invention discloses a preparation method of 2,3-indoledione-3-oxime, or isatin-3-oxime, and the 2,3-indoledione-3-oxime obtained by the method is in Use in preparing medicines for preventing or treating cancer. Background technique: [0002] Genome instability is the most essential feature of malignant tumor cells[1], manifested in two aspects: high gene mutation rate and chromosome abnormality. The total number of mutations in a tumor cell genome is as high as 10,000 to 100,000 times. The inherently high mutation rate of the tumor cell population contributes to the emergence of new mutations with higher malignancy, which can be passed on to more offspring cell clones through clonal selection, making their genomes more abnormal, forming a vicious circle of continuous evolution . Thus, genomic instability is both a prerequisite for carcinogenesis and a driving force for malignancy recurrence and metastasis. The root cause of genome instability ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/404A61P35/00C07D209/40
Inventor 张页林维佳张丽君赵翔张瑶薛非凡
Owner PEKING UNIV
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