Platinum-based compound based on nucleolar stress

A technology of nucleolus stress and compounds, applied in platinum anti-tumor compounds to overcome clinical platinum drug resistance and achieve excellent anti-tumor activity

Inactive Publication Date: 2019-08-16
TIANJIN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, severe adverse reactions (such as myelosuppression, leukopenia, ototoxicity, neurotoxicity, liver and kidney toxicity, etc.) and tumor drug resistance (including primary drug resistance...

Method used

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  • Platinum-based compound based on nucleolar stress

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis and characterization of a monofunctional platinum-based antitumor compound P1B1 based on nucleolus stress

[0044]

[0045] As shown in the above chemical formula, weigh 1.68g (10.68mmol) 2-chloronicotinic acid (substance 1 in the chemical formula) and 2g (10.68mmol) 3-amino-2-naphthoic acid (substance 2 in the chemical formula) in a round bottom flask, Add 70mL ethanol to dissolve, add 0.9mL (29.13mmol) hydrochloric acid (aqueous hydrogen chloride solution, the concentration is 2mol / L), reflux at room temperature 20-25 degrees Celsius for 72h, monitor the reaction progress by thin-layer chromatography, after the reaction is almost complete, let it stand for cooling . The cooled reaction solution was filtered, and the solid was taken, washed with absolute ethanol, and dried to obtain an orange solid. The obtained orange-yellow solid was uniformly dispersed in ethanol for purification, refluxed at 80°C for 2 hours, suction-filtered, and dried to obtain subs...

Embodiment 2

[0053] Example 2—P1-B1 and cisplatin antitumor activity evaluation

[0054] MTT colorimetry is one of the methods used to detect cell growth and survival in experimental research. In the mitochondria of living cells, exogenous MTT can be reduced by intracellular succinate dehydrogenase to formazan, a purple-blue crystal formazan that is insoluble in water. Formazan is deposited in the cytoplasm of cells, but dead cells do not This phenomenon occurs. When formazan encounters DMSO, the formazan deposited in the cells will be dissolved by DMSO. Use a microplate reader to detect the formazan optical density value (OD value) at a wavelength of 570nm to indirectly reflect the number of living cells. The amount of MTT crystals formed is positively correlated with the number of living cells. Use Graphpad Prism 5 software to process data and calculate IC 50 Value and plot, IC 50 The value refers to the half-inhibitory concentration of the measured drug on cell growth.

[0055] The ...

Embodiment 3

[0060] Based on the copper-catalyzed azido-alkynyl addition reaction (CuAAC reaction), the thymidine analogue 5-ethynyl-2'-deoxyuridine was introduced into the system in order to solve the investigation of DNA replication level, and then The intracellular mechanism of action of the monofunctional platinum compound of the present invention was investigated. 5-Ethynyl-2'-deoxyuridine (EdU) can replace deoxythymine in the newly synthesized DNA duplex during cell proliferation, because it has an alkynyl group that can be labeled with CuAAC reaction, Therefore, fluorescent molecules containing azide modification can be used to selectively label EdU, and effectively detect the level of DNA synthesis in cells and the proportion of cells in S phase. Transcriptional inhibition is an important mechanism of the antitumor effect of platinum-based drugs. Similar to EdU, we introduced 5-ethynyl-2'-uridine nucleoside (EU), based on CuAAC reaction, and used AlexaFluor 647- Azide dye labeling...

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Abstract

The invention discloses a platinum-based compound based on nucleolar stress, wherein the platinum-based compound is a platinum-based antitumor compound formed by carrying out a nitrile-secondary amineClick reaction on cis-monochloro mononitrile diamino platinum and a primary amine-containing RNA polymerase I inhibitor. According to the present invention, the platinum-based antitumor compound hasgood RNA polymerase I inhibitory activity and good tumor selectivity, such that the platinum-based compound has antitumor activity suprior to classical platinum-based drugs, and can reduce toxic-sideeffects and overcome the drug resistance of clinical platinum-based drugs.

Description

technical field [0001] The invention belongs to the technical field of platinum compounds, and more specifically relates to a class of platinum anti-tumor compounds based on nucleolus stress and the research on anti-tumor effect, reduction of toxic and side effects and overcoming clinical platinum drug resistance. Background technique [0002] Cancer is a major killer that threatens human beings all the time in today's world, and the research on cancer treatment has very far-reaching practical significance. Platinum antineoplastic drugs are an important class of metal chemotherapeutic drugs, which are used in more than half of chemotherapy methods. The representative drug, cisplatin, has a broad anti-tumor spectrum and strong effect, and has synergistic effects with many anti-tumor drugs without cross-resistance. It has remarkable curative effect on ovarian cancer and testicular cancer. cure rate. However, severe adverse reactions (such as myelosuppression, leukopenia, oto...

Claims

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Application Information

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IPC IPC(8): C07F15/00A61P35/00
CPCA61P35/00C07F15/0093
Inventor 乔鑫徐靖源张振磊
Owner TIANJIN MEDICAL UNIV
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