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Photosensitive targeted antineoplastic prodrug for responding to glutathione to kill tumor cells and preparation method and application thereof

A technology of glutathione and tumor cells, which is applied in the direction of anti-tumor drugs, pharmaceutical formulas, medical preparations containing active ingredients, etc., can solve the problems of anti-tumor clinical application limitations, low treatment efficiency, and large toxic and side effects. To achieve the effect of improving adverse pharmacokinetics

Active Publication Date: 2017-10-10
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nitrogen mustards are a class of broad-spectrum antineoplastic drugs used in clinical practice. They have a strong ability to kill cancer cells. low) limitations, making it limited in the clinical application of anti-tumor

Method used

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  • Photosensitive targeted antineoplastic prodrug for responding to glutathione to kill tumor cells and preparation method and application thereof
  • Photosensitive targeted antineoplastic prodrug for responding to glutathione to kill tumor cells and preparation method and application thereof
  • Photosensitive targeted antineoplastic prodrug for responding to glutathione to kill tumor cells and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] The synthesis of embodiment 1 prodrug (CM-2)

[0041] Put compound 2-3 (100 mg) into a three-necked flask containing 30 mL of DCM, after it is completely dissolved, add 1.5 equivalents of DMAP, 2.5 equivalents of DCC, and after activating for 10 minutes, dissolve 2.2 equivalents of chlorambucil in a 5 mL DCM injection bottle , reacted overnight. Add 50mL DCM to the bottle, wash with water (3×30mL), wash with saturated sodium chloride (2×30mL), dry over anhydrous sodium sulfate, filter, and remove the organic solvent by rotary evaporation to obtain a crude product, which is separated by thin-layer chromatography to obtain The product is pure product CM-2, the developing solvent used is DCM(D) / MeOH(M)=15:1, and the yield is 83%. H NMR spectrum see figure 1 .

[0042] 1 H NMR (500MHz, CDCl 3 )δ7.85(d,J=8.1Hz,3H),7.42(dd,J=16.4,8.4Hz,6H),7.08(d,J=8.7Hz,4H),6.97–6.88(m,4H), 6.68–6.60(m,4H),6.33(s,2H),5.25(d,J=1.2Hz,4H),5.16(d,J=3.6Hz,4H),3.71(t,J=6.9Hz,8H ), 3.63(dd, ...

Embodiment 3

[0045] Synthesis of embodiment 3 reference compound K

[0046] Compound 3 (100 mg) was put into a three-neck flask containing 30 mL of DCM. After it was completely dissolved, 0.2 equivalents of DMAP and 1.2 equivalents of DCC were added for activation for 30 minutes. 1.2 equivalents of chlorambucil was dissolved in 10 mL of DCM and injected into the bottle, and the reaction 24 hours. Add 50mL DCM to the bottle, wash with water (3×30mL), wash with saturated sodium chloride (2×30mL), dry over anhydrous sodium sulfate, filter, and rotary evaporate to remove the organic solvent to obtain a crude product, which is separated by thin-layer chromatography to obtain the product For pure product K, the developing solvent used is DCM(D) / MeOH(M)=15:1-3, and the yield is 51%.

[0047] Example 4 The prodrug (CM-2) prepared in Example 1 was detected by the fluorescence spectrum of adding 0 mM and 100 μM glutathione aqueous solution concentration under the condition of pH 7.4.

[0048] Add gl...

Embodiment 12

[0063] Example 12 Effect diagram of confocal fluorescence imaging of prodrug (CM-2) in cervical cancer cells (HeLa).

[0064] Since the coumarin released after the action of glutathione and light is a strong fluorescent dye, we tried to observe the distribution of the drug in the tumor cells through a confocal microscope. The experimental results are as follows: Figure 9 shown. Among them, Figure A is the untreated control group, Figure B is the confocal cell imaging image after drug addition and incubation for 12 hours, and Figure C is the glutathione treatment for 30 minutes after drug addition and incubation for 12 hours. It can be seen from the figure that the compound can be taken up by cells, and whether chlorambucil is released can be judged by the cell morphology at this time.

[0065] Experiments have shown that when the concentration of glutathione increases, we can see that the fluorescent signal in the cells also becomes stronger. Explain that our substance resp...

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Abstract

The invention discloses design and application of a drug and fluorescence dual-release system based on glutathione and photo-stimulation and designs and synthesizes a glutathione and photo-stimulation-based drug and fluorescence dual-release system. The glutathione and photo-stimulation-based drug and fluorescence dual-release system takes target molecules released by the drug of glutathione and 2, 4-dinitrobenzene sulfonyl chloride as response groups. Detection of the fluorescence performance of a prodrug (CM-2) shows that the prodrug (CM-2) can well respond to the glutathione to release fluorescence; meanwhile, compared with other photosensitive drugs, the prodrug is higher in stability and targeting property; measurement of antineoplastic activity research through an MTT (3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) method shows that the antineoplastic activity of the compound (CM-2) is higher than that of chlorambucil and accordingly shows that the targeting property of the compound (CM-2) is higher than that of the chlorambucil; the drug ingestion situation of cells is researched according to the fluorescence characteristics of coumarins, and experimental results show that the prodrug can be ingested by cells. The glutathione and photo-stimulation-based drug and fluorescence dual-release system provides an effective research tool for drug release of cell research.

Description

technical field [0001] The invention relates to the release of light-sensitive targeted anti-tumor drugs, in particular to the design and application of glutathione-based, light-stimulated anti-tumor drug chlorambucil and fluorescent double release system. Background technique [0002] As an "inexhaustible and inexhaustible" external stimulus, light can control the release of active drugs from light-sensitive prodrugs at a specific time and space without depending on changes in the internal physiological environment of the body. One of the most favored stimuli in the field. In recent years, there have been more and more reports on the preparation of photosensitive prodrugs. Among them, the photosensitive group of coumarin has the advantages of easy synthesis, easy modification, easy detection, fast photolysis speed and clear photolysis mechanism, and has been widely recognized. application. Nitrogen mustards are a class of broad-spectrum antineoplastic drugs used in clinic...

Claims

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Application Information

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IPC IPC(8): C07D311/16A61K41/00A61P35/00G01N21/64
Inventor 朱勍刘跃顾晓旭董佳黄金涛朱伸邢超俊
Owner ZHEJIANG UNIV OF TECH
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