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Water-soluble IDO (dioxygenase) inhibitor cisplatin and preparation method thereof

An inhibitor, water-soluble technology, applied in chemical instruments and methods, drug combinations, pharmaceutical formulations, etc., can solve problems such as poor water-soluble immunosuppression, and achieve the effect of maintaining the killing effect, increasing the effect of immunotherapy, and improving the environment of immunosuppression

Active Publication Date: 2017-11-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Objective: In order to overcome the deficiencies in the prior art, the present invention provides a water-soluble IDO inhibitor combined with platinum to solve the problem of poor water solubility of current IDO inhibitor drugs and the immunosuppressive problems in tumor immunotherapy

Method used

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  • Water-soluble IDO (dioxygenase) inhibitor cisplatin and preparation method thereof
  • Water-soluble IDO (dioxygenase) inhibitor cisplatin and preparation method thereof
  • Water-soluble IDO (dioxygenase) inhibitor cisplatin and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Weigh 200mg (0.53mmol) of Pt(1R,2R-DACH)Cl 2 , 88.47mg (0.52mmol) of silver nitrate and 151.53mg (0.54mmol) of NLG919 were dissolved in 20mL of anhydrous DMF, protected by argon, protected from light, and reacted at 55°C for 24h. After the reaction, the reaction solution was lowered to room temperature, centrifuged at room temperature 3000rpm for 5min, the supernatant was taken, concentrated to about 1mL by rotary evaporation, and column chromatography was carried out with chloroform:methanol:acetone:glacial acetic acid=10:0.5:4:0.1 , take compounds with Rf=0.2-0.3, combine and concentrate to obtain white or light yellow solid, dry in vacuum at 40°C, and weigh to obtain 145.55 mg of the product (yield 44.11%). And the product is soluble in water, the solubility can reach 2.85mg / mL.

[0023] The chemical structure of the compound synthesized in this example is shown in Formula 1.

[0024]

[0025] of the conjugates prepared in this example 1 H NMR spectrum as figu...

Embodiment 2

[0028] In the state of conductivity measurement, insert the clean and rinsed electrode and temperature sensor into 0.0100mol / L KCl solution (about 20mL), calculate according to the value, get the actual electrode constant value, and input the actual electrode constant value into the instrument middle. Take 20mL of distilled water in a 50mL beaker and measure its conductivity. Determination of Pt(1R,2R-DACH)Cl with different concentration gradients 2 , NLG919, [Pt(1R,2R-DACH)C 18 h 22 N 2 O]Cl NO 3 Conductivity, the concentration gradient is 5.22, 20.86, 74.72, 83.44, 166.88, 333.76, 667.52μM.

[0029] The molar conductivity-concentration data that the present embodiment measures is as image 3 shown.

Embodiment 3

[0031] Determination of [Pt(1R,2R-DACH)C by MTT method 18 h 22 N 2 O]Cl NO 3 For the inhibitory effect on tumor cell viability, the in vitro cell viability inhibition experiment was carried out in 4T1 cells and HeLa cells. The specific operation steps are as follows: first, 4T1 and HeLa cells in the logarithmic growth phase were added to 96-well plates, and the plating density per well was is 1×10 4 / 200μL, cultivated in the cell culture incubator for 24h. Then the oxaliplatin group, NLG919 group, [Pt(1R,2R-DACH)C 18 h 22 N 2 O]Cl NO 3group, oxaliplatin and NLG919 physical mixing group were diluted into a series of concentration gradients, and the cells that were not given drugs were used as the control group, and the cells that were only added with medium in the blank wells were used as the blank group. The drug concentrations administered to 4T1 and HeLa cells were 1, 1.6, 2.8, 4.7, 7.8, 13.0, 21.6, 36.0, 60.0, and 100.0 μM, respectively, based on oxaliplatin. Aspir...

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Abstract

The invention discloses a water-soluble IDO (dioxygenase) inhibitor cisplatin and a preparation method and application thereof. The water-soluble IDO inhibitor cisplatin medicine synthesized with the preparation method comprises a hydrophilic compound formed by the coordination of an IDO inhibitor, or the derivative of the IDO inhibitor and a platinum antitumor drug. Compared with other IDO inhibitors, the IDO inhibitor cisplatin prepared with the preparation method has good water solubility, and the problem of low solubility of the IDO inhibitor is solved. Meanwhile, the water-soluble IDO inhibitor cisplatin medicine keeps the activity of the IDO inhibitor, improves an immunosuppression environment, keeps the killing function of the platinum drug for tumor cells, accelerates the releasing of tumor antigens, and increases an immunotherapy effect to achieve a purpose of the collaborative treatment of tumors.

Description

technical field [0001] The invention relates to a water-soluble IDO inhibitor combined with platinum for treating tumors, a preparation method and application thereof, and belongs to the technical field of biomedicine. Background technique [0002] Malignant tumor is one of the main causes of human death, and its treatment remains one of the greatest challenges in the world today. At present, the clinical treatment of tumors still mainly relies on surgical intervention, radiotherapy, chemotherapy and immunotherapy. Since conventional treatments such as surgery, radiotherapy, and chemotherapy are not very effective in treating tumors, immunotherapy has become the most promising treatment. Although immunotherapy has a good application prospect, the strong immunosuppression in the tumor microenvironment makes many treatments unable to effectively alleviate the disease. Therefore, the release of the immunosuppression in the tumor microenvironment, combined with chemotherapy can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61K31/555A61K33/24A61P35/00A61K33/243
CPCC07F15/0093A61K33/243
Inventor 姜虎林邢磊朱勇
Owner CHINA PHARM UNIV
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