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Folic acid-benzaldehyde nitrogen mustard-HPMA macromolecule copolymer and preparation and application thereof

A polymer copolymer and technology of benzaldehyde nitrogen mustard, applied in the field of polymer chemistry, can solve problems such as inconvenient administration, poor water solubility of benzaldehyde nitrogen mustard, and side effects

Inactive Publication Date: 2014-07-16
NORTHWEST NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Due to the poor water solubility of benzaldehyde nitrogen mustard, it is necessary to use cosolvents (absolute ethanol, DMSO, etc.) during application, which will cause a variety of toxic and side effects in the body
In addition, after being diluted with water, it needs to be filtered through a 0.25μm microporous membrane, which makes the administration inconvenient

Method used

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  • Folic acid-benzaldehyde nitrogen mustard-HPMA macromolecule copolymer and preparation and application thereof
  • Folic acid-benzaldehyde nitrogen mustard-HPMA macromolecule copolymer and preparation and application thereof
  • Folic acid-benzaldehyde nitrogen mustard-HPMA macromolecule copolymer and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] (1) compound Preparation: Weigh folic acid (441.4 mg, 1.0 mmol), cyclohexylcarbodiimide (247.6 mg, 1.2 mmol) and N-hydroxysuccinimide (230.2 mg, 2.0 mmol), dissolve in 30 mL of di In methyl sulfoxide, react in the dark at 45~55°C for 6~8h. After all the folic acid is converted into folic acid activated ester, add 571.0 mg (10 mmol) of allylamine to the reaction solution, and keep it in the dark at -5~5°C. Light reaction 12~15h. Add acetone to precipitate, filter with suction, and dry in a vacuum oven to obtain the compound (321.2 mg, yield 65%).

[0046] 1 H NMR (400MHz, CDCl3): δ 1.93 (m, 2H, -CH(COOH)C H 2 CH 2 CO-), 2.23 (t, 2H, -CH(COOH)CH 2 C H 2 CO-), 3.42 (s, 2H, -NHC H 2 CH=CH 2 ), 4.20 (s, 2H, -NHC H 2 -Heterocyclic), 4.46 (t, 1H, -C H (COOH)CH 2 CH 2 CO-), 5.22 (dd, 2H, -NHCH 2 CH=C H 2 ), 5.89 (m, 1H, -NHCH 2 C H =CH 2 ), 6.63 (d, 2H, -NHC 6 H 2 h 2 CO-), 7.62 (d, 2H, -NHC 6 h 2 H 2 CO-), 8.6 (s, 1H, Heterocyclic).

[0047] (...

Embodiment 2

[0054] compound , , Preparation: with embodiment 1.

[0055] Preparation of copolymer: Weigh HPMA (0.218 g, 1.52 mmol, 90 mol%) into a Shleck bottle, heat to dissolve with 0.5 mL of DMSO, then add 0.5 mL of acetone; weigh the compound (0.044 g, 0.09 mol, 5 mol%) and compound (0.040 g, 0.09 mmol, 5 mol%) was added to the Shleck bottle, stirred until dissolved, and when it was cooled to room temperature, 0.024 g (8%, wt) azoisobutyronitrile (AIBN) was added, vacuumized and nitrogen cycled 3~5 times, keep the temperature at about 55°C after sealing, and react for 24 hours. Precipitate with a mixture of acetone and ether (volume ratio 7:3), filter and dissolve the precipitate with 1 mL of anhydrous methanol, centrifuge with an ultrafiltration concentration centrifuge tube with a molecular weight of 3000, remove small molecules, and obtain 0.22 g of polymer , yield 73%.

[0056] m n =2.4×10 4 , M w / M n =1.56. 1 H-NMR (400 MHz, DMSO, δ, ppm): 8.6 (Heterocyclic of ...

Embodiment 3

[0058] compound , , Preparation: with embodiment 1.

[0059] Preparation of copolymer: Weigh HPMA (0.218 g, 1.52 mmol, 84 mol%) into a Shleck bottle, heat to dissolve with 0.5 ml of DMSO, then add 0.5 mL of acetone; weigh the compound (0.066 g, 0.14 mmol, 8%) and compound (0.056 g, 0.14 mmol, 8%) was added to the Shleck bottle, stirred until dissolved, and when it was cooled to room temperature, 0.034 g (10%, wt) azoisobutyronitrile (AIBN) was added, vacuumized and nitrogen cycled for 3 ~5 times, keep the temperature at about 55°C after sealing, and react for 24 hours. Precipitate with a mixture of acetone and ether (volume ratio 7:3), filter and dissolve the precipitate with 1 mL of anhydrous methanol, centrifuge with an ultrafiltration concentration centrifuge tube with a molecular weight of 3000, remove small molecules, and obtain 0.246 g of polymer , yield 72%.

[0060] m n =2.6×10 4 , M w / M n =1.23. 1 H-NMR (400 MHz, DMSO, δ, ppm): 8.6 (Heterocyclic of ...

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Abstract

The invention provides a folic acid-benzaldehyde nitrogen mustard-HPMA macromolecule copolymer, which is prepared by bonding folic acid and benzaldehyde nitrogen mustard to N-(2-hydroxypropyl) methacrylate (HPMA) by virtue of covalent bonds and belongs to the field of macromolecular synthesis. According to the folic acid-benzaldehyde nitrogen mustard-HPMA macromolecule copolymer, antineoplastic activity of folic acid, benzaldehyde nitrogen mustard and N-(2-hydroxypropyl) methacrylate are overlapped, so that the inhibiting effect of the polymer on tumor is further improved, and the standing time of anti-cancer medicines on the tumor is greatly prolonged. An experiment proves that the copolymer has a function of targeting intelligent drug release and has the good inhibiting effect on cervical cancer cell HeLa; moreover, because of HPMA, the toxicity of anti-cancer medicines is also reduced, and the high biocompatibility is represented, so that the damage to normal tissues is reduced; therefore, the polymer has good prospect when the polymer used as an HeLa tumor cell inhibiting agent is applied to preparation of anti-tumor medicines.

Description

technical field [0001] The invention belongs to the field of macromolecular chemistry, and relates to a folic acid-benzaldehyde nitrogen mustard-HPMA macromolecule copolymer with targeted antitumor activity of intelligent drug release; the invention also relates to a preparation method of the copolymer; the invention also relates to The invention relates to the application of the polymer as an inhibitor of cervical cancer cell HeLa cells. Background technique [0002] Cancer has become one of the major threats to human health, and it is on the rise. The main methods of treating cancer today include radiotherapy, chemotherapy, surgical therapy and gene therapy. Among them, radiotherapy and chemotherapy are extremely important non-surgical treatments, but while killing tumor cells, radiotherapy and chemotherapy also cause serious damage to normal cells in the body. [0003] Nitrogen mustard compounds are alkylating agent antineoplastic drugs, but due to their high toxicity a...

Claims

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Application Information

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IPC IPC(8): C08F220/58C08F226/02C08F220/36A61K31/357A61K47/48A61P35/00
Inventor 袁建超许卫兵赵杰陈静静慕燕琼张正华
Owner NORTHWEST NORMAL UNIVERSITY
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