Water-soluble pegylated niclosamide and its preparation method and application in antitumor therapy

A technology for pegylated niclosamide and polyniclosamide, which is applied in the field of biomedicine and can solve the problems of limiting the clinical application of antitumor drugs, being insoluble in water, not being absorbed, and the like

Active Publication Date: 2018-11-20
HARBIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recent studies have shown that niclosamide has anti-tumor effects, but mainly in vitro experiments; the disadvantage of niclosamide pharmacokinetics is that it is insoluble in water and cannot be absorbed after oral administration, so it is only suitable for anthelmintics and cannot be used in vivo Antitumor
Oral nonabsorption of niclosamide limits its further clinical application as an antineoplastic drug

Method used

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  • Water-soluble pegylated niclosamide and its preparation method and application in antitumor therapy
  • Water-soluble pegylated niclosamide and its preparation method and application in antitumor therapy
  • Water-soluble pegylated niclosamide and its preparation method and application in antitumor therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The preparation of embodiment 1 pegylated niclosamide

[0036]

[0037] Where n is 2-30.

[0038] (1) Dissolve 8.5g of niclosamide in 200ml of anhydrous tetrahydrofuran, add 5g of anhydrous potassium carbonate and 3ml of acryloyl chloride, react at 55°C for 16h, filter, wash with deionized water 3 times, and dry under vacuum at 50°C to obtain the product band Double-bonded niclosamide (NIO-AC);

[0039] (2) 3.5g niclosamide (NIO-AC) with a double bond and 0.5g carboxyl dithioester (shown in formula II) are dissolved in DMF (N,N-dimethylformamide), 5 mg of azobisisobutyronitrile was used as a catalyst, reacted at 70°C under nitrogen protection for 24 hours, dialyzed in ethanol for 3 hours with a dialysis bag with a molecular weight cut-off of 1000Da, precipitated with deionized water, and dried the product under vacuum at 50°C to obtain polynitrosalcyl with carboxyl group amine;

[0040]

[0041] (3) Add carboxyl-containing polyniclosamide and polyethylene glyco...

Embodiment 2

[0044] The preparation of embodiment 2 pegylated niclosamide

[0045] (1) Dissolve 7.9g of niclosamide in 200ml of anhydrous tetrahydrofuran, add 5g of anhydrous potassium carbonate and 2.8ml of acryloyl chloride, react at 55°C for 18h, filter, wash with deionized water 3 times, and dry under vacuum at 50°C to obtain the product NIO-AC;

[0046] (2) 4g niclosamide (NIO-AC) with a double bond and 0.8g carboxyl dithioester (shown in formula II) are dissolved in DMF (N,N-dimethylformamide), 6.2 mg of azobisisobutyronitrile as a catalyst, reacted at 75°C for 25h under nitrogen protection, dialyzed a dialysis bag with a molecular weight cut-off of 1000Da in ethanol for 3h, precipitated with deionized water, and dried the product in vacuum at 50°C to obtain polynitrosalk with carboxyl group amine;

[0047]

[0048] (3) Add carboxyl-containing polyniclosamide and polyethylene glycol (PEG5000) to DMF (N,N-dimethylformamide) at a molar ratio of 1:1, and add 5 times the number of m...

Embodiment 3

[0049] The preparation of embodiment 3 pegylated niclosamide

[0050] (1) Dissolve 8g of niclosamide in 200ml of anhydrous tetrahydrofuran, add 5.3g of anhydrous potassium carbonate and 3.3ml of acryloyl chloride, react at 50°C for 24h, filter, wash with deionized water three times, and dry under vacuum at 50°C to obtain the product NIO-AC;

[0051] (2) 3.5g niclosamide (NIO-AC) with a double bond and 0.3g carboxyl dithioester (shown in formula II) are dissolved in DMF (N,N-dimethylformamide), 10mg of azobisisobutyronitrile was used as a catalyst, reacted at 70°C for 24h under nitrogen protection, dialyzed in ethanol for 3h with a dialysis bag with a molecular weight cut-off of 1000Da, precipitated with deionized water, dried the product in vacuum at 50°C, and obtained polynitrochloride with carboxyl group amine;

[0052]

[0053] (3) Add carboxyl-containing polyniclosamide and polyethylene glycol (PEG5000) to DMF (N,N-dimethylformamide) at a molar ratio of 1:1, and add 5...

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Abstract

The invention discloses water-soluble pegylated niclosamide, a preparation method thereof and an application in anti-tumor therapy and belongs to the technical field of biological medicines. Niclosamide is an anthelmintic and has an inhibition effect on a variety of tumors, but the nicotinamide has the pharmacokinetic defects of being insoluble in water and non-absorbent by oral administration, thereby being only applicable to the in-vivo drug use anti-tumor mode which is used for expelling intestinal worms but having no clinical significances. The prepared water-soluble pegylated niclosamide can significantly improve the solubility of niclosamide and can be medicated in vivo; pegylated niclosamide has a significant in-vivo anti-tumor effect and can be used for treating a variety of tumors.

Description

technical field [0001] The invention relates to the preparation of an anti-tumor drug and its application in anti-tumor treatment, in particular to a preparation method of water-soluble pegylated niclosamide and its application in anti-tumor treatment, belonging to the technical field of biomedicine . Background technique [0002] Tumor is the most important disease that endangers human health. In my country, the morbidity and mortality have risen sharply, and it has become the most important disease that endangers the health of our people, and the social burden is huge. The development of new anti-tumor drugs is an important issue for medical workers. [0003] Niclosamide (Niclosamide) has a killing effect on snails, Schistosoma japonicum, snails, beef tapeworm, pork tapeworm, fish tapeworm Schizophrenia lata, short hymenoleta, cercariae, etc. Niclosamide is not absorbed orally, but it can maintain a high concentration in the intestine, so it is clinically used in the tre...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/334A61K31/795A61P35/00
CPCA61K31/795C08G65/3348
Inventor 董德利孙志洁
Owner HARBIN MEDICAL UNIVERSITY
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