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Light-sensitive targeted anti-tumor predrug for killing tumor cells in response to hydrogen peroxide as well as preparation method and application of light-sensitive targeted anti-tumor predrug

A hydrogen peroxide, tumor cell technology, applied in anti-tumor drugs, chemical instruments and methods, pharmaceutical formulations, etc., can solve the problems of limited clinical application of anti-tumor, low treatment efficiency, poor selectivity, etc., to improve adverse pharmacokinetics. The effect of dynamics

Active Publication Date: 2017-10-20
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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  • Light-sensitive targeted anti-tumor predrug for killing tumor cells in response to hydrogen peroxide as well as preparation method and application of light-sensitive targeted anti-tumor predrug
  • Light-sensitive targeted anti-tumor predrug for killing tumor cells in response to hydrogen peroxide as well as preparation method and application of light-sensitive targeted anti-tumor predrug
  • Light-sensitive targeted anti-tumor predrug for killing tumor cells in response to hydrogen peroxide as well as preparation method and application of light-sensitive targeted anti-tumor predrug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] The synthesis of embodiment 1 prodrug (CM-1)

[0042] Compound 1-3 was put into a three-necked flask containing DCM, and after it was completely dissolved, DMAP (1.5 equivalents) and DCC (2.5 equivalents) were added successively. After activation for 10 min, 2.2 equivalents of chlorambucil was dissolved in 10 mL of DCM and Pour into the bottle, the whole reaction needs N 2 Protected and reacted overnight. Add 50mL DCM to the bottle, wash with water (7×50mL), wash with saturated sodium chloride (2×50mL), dry over anhydrous sodium sulfate, filter, and rotary evaporate to remove the organic solvent to obtain the crude product, which is separated by thin-layer chromatography to obtain the product For CM-1, the developer used was DCM(D) / MeOH(M)=15:1, and the yield was 83%. H NMR spectrum see figure 1 , see C NMR figure 2 .

[0043] 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...

Embodiment 2

[0044] The synthesis of embodiment 2 prodrugs (CM-1)

[0045] Compound 1-3 was put into a three-necked flask containing DCM. After it was completely dissolved, DMAP (0.1 equivalent) and DCC (1 equivalent) were added successively. After activation for 10 min, 1 equivalent of chlorambucil was dissolved in 10 mL of DCM and Pour into the bottle, the whole reaction needs N 2 Protected and reacted overnight. Add 50mL DCM to the bottle, wash with water (7×50mL), wash with saturated sodium chloride (2×50mL), dry over anhydrous sodium sulfate, filter, and rotary evaporate to remove the organic solvent to obtain the crude product, which is separated by thin-layer chromatography to obtain the product For CM-1, the developer used was DCM(D) / MeOH(M)=15:1, and the yield was 61%.

Embodiment 3

[0047] Compound 1-2 (100 mg) was added to a round bottom flask containing 10 mL of DMF, dissolved completely, and 1.2 equivalents of potassium carbonate solid was added, and 1.2 equivalents of 4-bromomethylbenzene was dissolved in 10 mL of DMF, and slowly added dropwise to the flask , react at room temperature for 2h. After the reaction, add 20mL DCM to the bottle, wash with water (7×50mL), take the organic phase and wash with saturated sodium chloride (2×50mL), dry over anhydrous sodium sulfate, filter, and remove the organic solvent by rotary evaporation to obtain the crude product. Compound 2 was separated by thin-layer chromatography, the developer used was D / M=10:1, and the yield was 78%.

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Abstract

The invention discloses a light-sensitive targeted anti-tumor predrug for killing tumor cells in response to hydrogen peroxide as well as a preparation method and application of the light-sensitive targeted anti-tumor predrug. A hydrogen peroxide-light stimulated drug and fluorescence double-release system is designed and synthesized by taking hydrogen peroxide as a target molecule released by the drug as well as boric acid ester as a response group. The determination of the fluorescence of the predrug (CM-1) finds that the predrug (CM-1) can well release fluorescence in response to hydrogen peroxide; meanwhile, compared with other light-sensitive drugs, the predrug has relatively good stability and targeting property; a research for determining the anti-tumor activity of the predrug by virtue of an MMT method finds that the compound (CM-1) has the anti-tumor activity higher than that of chlorambucil, namely that the targeting property of the compound (CM-1) is higher than that of chlorambucil; the intake condition of cells to the drug is explored according to the fluorescence characteristic of coumarin, and an experiment result shows that the predrug can be digested by cells. According to the predrug, an effectively research tool is provided for drug release in cell researches.

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 hydrogen peroxide-based, light-stimulated anti-tumor drug chlorambucil and a fluorescent dual-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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61K41/00A61P35/00
CPCA61K41/0057C07F5/02
Inventor 朱勍刘跃朱伸邢超俊顾晓旭董佳
Owner ZHEJIANG UNIV OF TECH
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