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D-galactose/benzaldehyde nitrogen mustard/N-(2-hydroxypropyl) methacrylamide copolymer as well as preparation and application thereof

A technology of methacrylamide copolymer and methacrylamide, applied in the field of polymer chemistry, can solve the problems of inconvenient drug administration, poor water solubility of benzaldehyde mustard, toxic side effects and the like

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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] 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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  • D-galactose/benzaldehyde nitrogen mustard/N-(2-hydroxypropyl) methacrylamide copolymer as well as preparation and application thereof
  • D-galactose/benzaldehyde nitrogen mustard/N-(2-hydroxypropyl) methacrylamide copolymer as well as preparation and application thereof
  • D-galactose/benzaldehyde nitrogen mustard/N-(2-hydroxypropyl) methacrylamide copolymer as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] (1) compound Preparation: take benzaldehyde nitrogen mustard (1.0 g, 5.6 mmol, 1.0 equiv.), dissolve in 75 mL tetrahydrofuran, add 15-20 g molecular sieves, and add p-toluenesulfonic acid (0.13 g, 0.75 mmol, 0.13 equiv.), 1,1,1-trimethylolethane (1.45g, 16mmol, 3.0equiv.), reacted in an ice-water bath for 12-15 h; followed the reaction by thin-layer chromatography, and the benzaldehyde nitrogen After the mustard reaction is complete, add ammonia water to neutralize p-toluenesulfonic acid to pH = 7-8, filter out molecular sieves, concentrate the filtrate, dilute with dichloromethane, wash three times with phosphate buffer solution with pH = 8, and wash with anhydrous Sodium sulfate was dried for 12 hours, separated by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 101 (v / v)), the product components were collected, and the solvent was evaporated to obtain the compound (1.08g). Yield (78%).

[0051] 1 H NMR (400MHz, CDCl 3 ): δ7.61 (d, J = 7.2...

Embodiment 2

[0063] compound , , , , The preparation is with embodiment 1.

[0064] Preparation of copolymer: Weigh HPMA (0.159 g, 1.11 mmol, 82 mol%) into a Shleck bottle, heat to dissolve with 0.5 mL of DMSO, then add 0.5 mL of acetone; weigh the compound (0.038 g, 0.09 mmol, 7 mol%) and compound (0.023 g, 0.09 mmol, 7 mol%) was added to the Shleck bottle, stirred until dissolved, and when cooled to room temperature, 0.018 g (8%, wt) of azoisobutyronitrile (AIBN) was added, vacuumized and nitrogen cycled 3 to 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 1ml of anhydrous methanol, centrifuge with an ultrafiltration concentration centrifuge tube with a molecular weight of 3000, remove small molecules, and obtain 0.153g of polymer , yield 70%.

[0065] m n =2.4×10 4 , M w / M n =1.16. 1 H-NMR (400 MHz, DMSO, δ, ppm): δ 7.26 ...

Embodiment 3

[0067] compound , , , , The preparation is with embodiment 1.

[0068] Preparation of copolymer: Weigh HPMA (0.159 g, 1.11 mmol, 80 mol%) into a Shleck bottle, heat to dissolve with 0.5 mL of DMSO, then add 0.5 mL of acetone; weigh the compound (0.057g, 0.14 mmol, 10 mol%) and compound 5 (0.034 g, 0.14 mmol, 10 mol%) were added to the Shleck bottle, stirred until dissolved, and 0.025 g (10%, wt) di Nitrogen and isobutyronitrile (AIBN), vacuumize and nitrogen cycle 3 to 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 1ml of anhydrous methanol, centrifuge with an ultrafiltration concentration centrifuge tube with a molecular weight of 3000, remove small molecules, and obtain 0.16 g of polymer , yield 64%.

[0069] m n =2.6×104 , M w / M n =1.23. 1 H-NMR (400 MHz, DMSO, δ, ppm): δ 7.26 (–CHC 6 H 2 h 2 N(CH 2 CH 2 C...

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Abstract

The invention provides a D-galactose / benzaldehyde nitrogen mustard / N-(2-hydroxypropyl) methacrylamide copolymer, and belongs to the field of high polymer chemistry and application. The D-galactose / benzaldehyde nitrogen mustard / N-(2-hydroxypropyl) methacrylamide copolymer is a macromolecular copolymer which has good biocompatibility and is formed in the way that D-galactose and benzaldehyde nitrogen mustard are linked to N-(2-hydroxypropyl) methacrylamide (HPMA) through covalent bonds. An experiment proves that the D-galactose / benzaldehyde nitrogen mustard / N-(2-hydroxypropyl) methacrylamide copolymer has the function of intelligently releasing drugs in a targeting manner, and has excellent inhibiting effect on a liver cancer HepG2 tumor cell; besides the macromolecular copolymer is an effective drug delivery system; therefore, the copolymer has excellent prospect as being used as an inhibitor for the HepG2 tumor cell and the like to be applied to the preparation of anti-tumor drugs.

Description

technical field [0001] The invention belongs to the field of macromolecular chemistry, and relates to a D-galactose / benzaldehyde nitrogen mustard / N-(2-hydroxypropyl)methacrylamide copolymer with targeted anti-tumor activity of intelligent drug release; At the same time, it also relates to a preparation method of the copolymer; the invention also relates to the application of the polymer as an inhibitor of liver cancer HepG2 cells in the preparation of anticancer drugs. Background technique [0002] Nitrogen mustard compounds are alkylating agent antineoplastic drugs, but due to their high toxicity and side effects, there are certain limitations in clinical application. Currently, they are mainly used in the treatment of malignant lymphomas. According to the parent structure, nitrogen mustards can be divided into benzoate mustard, chlorambucil, benzaldehyde mustard and methyl mustard. Wherein the structural formula of benzaldehyde nitrogen mustard is as follows: [0003] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08F220/58C08F220/28C08F220/36A61K47/48A61K47/26A61K31/196A61P35/00
Inventor 袁建超许卫兵赵杰陈静静慕燕琼张正华
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