Hypoxia activation doxorubicin prodrug and preparation method thereof

A doxorubicin and prodrug technology, applied in the field of hypoxia-activated doxorubicin prodrug and its preparation, can solve liver toxicity and side effects, lack of versatility and targeting of tumor treatment, and lack of tumor cell targeting of nitrogen-mediated drugs Sex and other problems, to improve the therapeutic effect and reduce the effect of side effects

Active Publication Date: 2018-08-14
GUANGZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the lack of targeting of tumor cells by nitrogen-mediated drugs, especially in the process of tumor treatment, it will cause serious toxic side effects to the liver
The drugs reported above all lack the versatility and targeting of tumor treatment, and cannot meet the needs of clinical use. Therefore, there is an urgent need for a tumor-specific drug to achieve safe and effective treatment of tumor diseases

Method used

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  • Hypoxia activation doxorubicin prodrug and preparation method thereof
  • Hypoxia activation doxorubicin prodrug and preparation method thereof
  • Hypoxia activation doxorubicin prodrug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the hypoxia shown in formula (II) activates the synthesis of doxorubicin prodrug

[0044]

[0045] (1) Synthesis of N,N-bis(2-chloroethyl)aniline:

[0046]

[0047] Phosphorus oxychloride (5 mL) was placed in a round-bottomed flask, and N,N-bis(2-hydroxyethyl)aniline (3.9 g) was slowly added to the round-bottomed flask with stirring at 0°C until the solid was dissolved Finally, the reaction solution was refluxed at 110°C for 1 hour, concentrated by rotary evaporation to obtain a crude product; the obtained crude product was dissolved in 200 mL of ethyl acetate, washed three times with pure water, and the organic phase was separated with Magnesium sulfate water was dried overnight, and the obtained product was concentrated by rotary evaporation, and then separated by column chromatography to obtain N,N-bis(2-chloroethyl)aniline, and the eluent was methanol-dichloromethane mixed solution (methanol and dichloromethane) The volume ratio of methyl chlori...

Embodiment 2

[0059] Mouse breast cancer cells (4T1) were treated with 1×10 5 Cells / well were seeded at a density of 37°C in 1 mL of culture medium. After 24 hours, dissolve doxorubicin hydrochloride and doxorubicin prodrug in the culture medium respectively, and add 1 mL containing doxorubicin hydrochloride (5 micromole / liter) or doxorubicin prodrug (20 micromol / liter) to 4T1 cells respectively. mol / L) culture medium. At the same time, the 4T1 cells added with doxorubicin prodrug were cultured under normoxic or hypoxic conditions, respectively. After 24 hours, the cells were washed three times with PBS, the nuclei were stained with Hoechst 33342, and the distribution of doxorubicin in the cells was observed with a confocal microscope.

[0060] The result is as figure 2 As shown, in the 4T1 cells cultured with doxorubicin hydrochloride, doxorubicin is mainly distributed in the nucleus of the 4T1 cells. In 4T1 cells cultured with doxorubicin prodrug under normoxia, the red fluorescence ...

Embodiment 3

[0062] Mouse melanoma cells (B16) were mixed with 1×10 5 Cells / well were seeded at a density of 37°C in 1 mL of culture medium. After 24 hours, the doxorubicin prodrug was dissolved in the medium, and 1 mL of the medium containing the doxorubicin prodrug (20 μmol / L) was added to the B16 cells. At the same time, the B16 cells added with doxorubicin prodrug were cultured under normoxic or hypoxic conditions. After 24 hours, the cells were washed three times with PBS, and after the nuclei were stained with Hoechst 33342, the distribution of doxorubicin in the cells was observed with a confocal microscope.

[0063] The result is as image 3 As shown, in the B16 cells cultured with doxorubicin prodrug under normoxia, the red fluorescence is mainly distributed in the cytoplasm of the cells. In B16 cells cultured with doxorubicin prodrug under hypoxic conditions, the red fluorescence was enriched to the nucleus. These results indicate that in B16 cells, hypoxic conditions can ind...

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Abstract

The invention discloses a hypoxia activation doxorubicin prodrug and a preparation method thereof. The doxorubicin prodrug is synthesized by modification of an amino group located at a 3' position ofdoxorubicin by an azo bond having a hypoxia activation effect and a response functional group having a self-occluded structure. The doxorubicin prodrug provided by the invention can effectively realize selective activation under a hypoxic environment, and can regulate and control growth activity of tumor cells by regulating subcellular organelle distribution of the doxorubicin in normoxia and hypoxic environments, thereby reducing toxic and side effects of a drug on normal cells, improving targeting efficiency of the drug on tumor treatment, and providing more novel ideas for development of antitumor drugs; and the synthetic method for the hypoxia activation doxorubicin prodrugs provided by the invention is simple, raw materials are cheap and easy to obtain, and the hypoxia activation doxorubicin prodrugs are convenient for industrialized production and clinical transformation.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and biomedicine, in particular to a hypoxia-activated doxorubicin prodrug and a preparation method thereof. Background technique [0002] Cancer (also known as malignant tumor) has become one of the major diseases threatening human health. According to data released by the World Health Organization, a total of 8 million people died of cancer in the world in 2012, and it is expected to reach 13 million in 2030. According to the "2017 China Cancer Registration Annual Report" released by the National Cancer Center, about 10,000 people are diagnosed with cancer every day in my country, which is equivalent to one person being diagnosed with cancer every 7 minutes. By the age of 85, the cumulative risk of a person suffering from cancer is as high as 36%, and it is developing towards a trend of high morbidity, high mortality, and rejuvenation. It is imminent to realize effective treatment of cancer. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/252C07H1/00A61K47/55A61K31/704A61K31/136A61P35/00
CPCA61K47/55A61P35/00A61K31/136A61K31/704C07H1/00C07H15/252A61K2300/00
Inventor 李仕颖江雪燕成红余细勇
Owner GUANGZHOU MEDICAL UNIV
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