Beta-lapachone derivative, and preparation method and medicinal application thereof

A technology of derivatives and compounds, applied in the field of β-lapachone derivatives, to achieve the effect of novel structure, good selectivity and simple operation

Active Publication Date: 2016-05-04
XINXIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The innovation of the present invention lies in the synthesis of a hybrid of β-lapachone and pyrimidinethione, which has not yet been reported

Method used

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  • Beta-lapachone derivative, and preparation method and medicinal application thereof
  • Beta-lapachone derivative, and preparation method and medicinal application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] The synthesis of embodiment 1 compound

[0021] Under the protection of argon, the compound 4-amino-3-(aminoethyl)naphthalene-1-ol (940mg, 5.0mmol) was dissolved in 20mL of dichloromethane, and the solution was cooled to 0°C with an ice bath. A solution of thiocarbonyldiimidazole (978 mg, 5.5 mmol) dissolved in 20 mL of dichloromethane was added dropwise within 10 minutes. After the addition was completed, the temperature was raised to room temperature and reacted for 5 hours. After the reaction was completed, the solvent was evaporated and washed with a small amount of ethanol to obtain the corresponding pale yellow solid. Add 20 mL of acetone to dissolve, and cool the solution to 0°C with an ice bath. Dissolve in 200mL0.06MNaH 2 PO 4 3.34 g of Fermi salt was added dropwise to the reaction solution, and the temperature was controlled below 10°C to react for 2 hours, filtered, and washed with water to obtain 538 mg of orange-yellow red solid I, with a yield of 32%. ...

Embodiment 2

[0023] Embodiment 2 in vitro antitumor activity test

[0024] The antitumor activity of the target compounds was tested by MTT method. Human liver cancer cell HepG2 was used as the test cell line, and the adherent tumor cells in the logarithmic growth phase were selected. After digesting with trypsin, 5000 cells / mL cell suspension was formulated with RPMI1640 medium containing 10% calf serum, and inoculated Inoculate 200 μL per well in a 96-well culture plate at 37°C, 5% CO 2 Incubate for 24 hours. Set up a negative control group, a positive control group and an administration group. The experimental group was replaced with new media containing different concentrations of tested samples, the control group was replaced with media containing an equal volume of solvent, and the positive control group was given the positive control drug doxorubicin (diluted with complete media to a concentration of 10 μmol L -1 ), set 3-5 parallel wells for each group, 37°C, 5% CO 2 Culture fo...

Embodiment 3

[0025] Embodiment 3NQO1 activity test

[0026] 1mL reaction system contains 25mM Tris / HCl (pH7.4), 0.7mg / mL bovine serum albumin, 0.1% Tween-20, 200μM NADH, 77μM Cytochromec, 2μg recombinant human NQOl and 1,2,3,4-tetrahydro-2- Thiobenzo[h]quinazoline-5,6-dione (25 μM). Set the detection wavelength to 550nm, add NADH to start the reaction at room temperature, calculate the reduction rate from the initial linear part of the reaction curve, and convert the molar absorption coefficient of cytochrome c (21.1mM -1 cm -1 ), the results are expressed as μmol reduced cytochrome c / min / μgNQOl. The ability of the compound to generate active oxygen can be judged from the change of the amount of cytochrome c. The rate of the compound to generate active oxygen at the enzyme level is 1143±62μmol reduced cytochrome c / min / μgNQOl.

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Abstract

The invention provides a beta-lapachone derivative, and a preparation method and medicinal application thereof. The beta-lapachone derivativof the invention is a hybrid of beta-lapachone with dihydro-pyrimidine thione, and has strong anti-cancer activity, metabolic stability and good selectivity. In vitro cytotoxicity test shows that the compound has strong inhibition on tested cancer cells; and NQO1 activity test shows that the compound is an effective substrate for NQO1, and mediated by NQO1, the compound cycles by a redox reaction, produces a large amount of reactive oxygen to induce oxidative stress, and selectively kills tumor cells. The compound can be used as an anti-cancer lead compound of targeting NQO1 for further development. The preparation method of the invention has the advantage mild condition and easy operation.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a beta-lapachone derivative, including a preparation method of the compound and an application as an NQO1-targeted anticancer drug. Background technique [0002] Malignant tumors are a serious threat to human health. Conquering and curing malignant tumors has become one of the hotspots in drug research around the world. Finding highly efficient, low-toxic and specific anti-tumor drugs is still the main direction of anti-tumor drug research. Quinone oxidoreductase (NQO1) is an important phase II reaction enzyme in the body. It participates in the metabolic process of exogenous substances in the body through deelectron reduction reaction, and has chemical protection and biological activation. Due to the high expression of NQO1 in tumor cells and its bioactivation properties, it is considered as a potential molecular target for the treatment of various tumors. β-lapachone, chemic...

Claims

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Application Information

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IPC IPC(8): C07D239/70A61P35/00
CPCC07D239/70
Inventor 武利强王永学
Owner XINXIANG MEDICAL UNIV
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