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Ortho-naphthaquinone derivative, and preparation method and medicinal application thereof

A technology of derivatives, o-naphthoquinone, applied in the field of medicinal chemistry, to achieve the effects of novel structure, easy availability of raw materials 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 o-naphthoquinone and thiadiazolo[3,2-a]pyrimidine, which has not yet been reported

Method used

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  • Ortho-naphthaquinone derivative, and preparation method and medicinal application thereof
  • Ortho-naphthaquinone derivative, and preparation method and medicinal application thereof
  • Ortho-naphthaquinone derivative, and preparation method and medicinal application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The synthesis of embodiment 1 compound

[0022] The reactants 1.74g 2-hydroxy-1,4-naphthoquinone, 1.20g 3-methylbenzaldehyde, 1.15g 5-methyl-2-amino-1,3,4-thiadiazole and 10mL dimethylformamide were added Into a 50mL round bottom flask, heat the reaction at 130°C for 5-8 hours. After the reaction was complete, the resulting mixture was cooled to room temperature, 50 mL of distilled water was added, precipitated and filtered, and purified by column chromatography to obtain the corresponding reddish-brown product 5-m-methylphenyl-2-methyl-5H-benzo[i] [1,3,4]Thiadiazolo[3,2-a]quinazoline-6,7-dione 1.16g, yield 31%.

[0023] 1 HNMR (400MHz, CDCl 3 )δ:8.37(d,1H,J=8.0Hz),8.10(d,1H,J=7.6Hz),7.72(t,1H,J=7.6Hz),7.56(t,1H,J=7.6Hz) ,7.29-7.10(m,4H),6.59(s,1H),2.54(s,3H),2.32(s,3H); 13 CNMR (100MHz, CDCl 3 )δ: 179.1, 175.9, 167.7, 154.2, 152.2, 140.2, 138.5, 134.6, 134.5, 131.1, 130.9, 129.7, 128.8, 128.7, 128.2, 126.7, 124.5, 111.8, 60.4, 21.5, 17.0 [M+Na] + :396.0773.

Embodiment 2

[0024] Embodiment 2 in vitro antitumor activity test

[0025] The antitumor activity of the target compounds was tested by MTT method. Human liver cancer cells HepG2 and colon cancer cells HCT116 were used as test cell lines, and adherent tumor cells in the logarithmic growth phase were selected, digested with trypsin, and formulated with RPMI1640 medium containing 10% calf serum to prepare 5000 cells / mL Cell suspension, seeded in 96-well culture plate, 200 μL per well, 37°C, 5% CO 2 Cultivate for 24h. 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 Cultur...

Embodiment 3

[0026] Embodiment 3NQO1 activity test

[0027] 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 5-m-methylphenyl-2-methyl -5H-Benzo[i][1,3,4]thiadiazolo[3,2-a]quinazoline-6,7-dione (25 μΜ). 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 1202±61 μmol reduced cytochrome c / min / μgNQOl.

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Abstract

The present invention relates to an ortho-naphthoquinone derivative, a preparation method and medical application thereof, and provides a compound with the structure shown as a formula I, a preparation method and application thereof in the manufacture of tumor medicaments. The compound of the invention has a hybrid structure of ortho -naphthoquinone with thiadiazole [3,2-a] pyrimidine, strong anti-cancer activity, metabolic stability and good selectivity. In vitro cytotoxicity and topoisomerase I inhibition tests show that the compound has strong inhibition on tested cancer cells and topoisomerase I; 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 drug or a lead compound for further development. The method of the present invention has the characteristics of greenness, environmental protection, easily available raw materials, simple operation, and high yield.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an o-naphthoquinone derivative, including a preparation method of the compound and its use as a medicine for treating malignant tumors. Background technique [0002] Malignant tumors are a serious threat to human health. Overcoming 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. NQO1 As an important phase II reaction enzyme in the body, it participates in the metabolic process of exogenous substances in the body through the deelectron reduction reaction. NQO1 is closely related to the detoxification of quinones, the biological activation of anticancer drugs, the regulation of p53 protein stability and the effect of TNF-α-induced apoptosis, thus playing an important role in cell transformation, apoptosis and prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61P35/00
CPCC07D513/04
Inventor 武利强张崇晁淑军
Owner XINXIANG MEDICAL UNIV
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