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Low-molecular-weight L-polyglutamine-mitomycin C as well as synthesis method and applications thereof

A technology of polyglutamic acid and mitomycin, applied in the direction of drug combination, sensory disease, etc., can solve the problems of low molecular weight, toxic and side effects, etc., and achieve the effect of improving drug efficacy and reducing side effects of the whole eye

Inactive Publication Date: 2015-03-25
XIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The purpose of the present invention is to provide a low molecular weight (1882-5792Da) L-polyglutamic acid-mitomycin C, which solves the problem that mitomycin C has serious toxic and side effects in the clinical application of pterygium

Method used

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  • Low-molecular-weight L-polyglutamine-mitomycin C as well as synthesis method and applications thereof
  • Low-molecular-weight L-polyglutamine-mitomycin C as well as synthesis method and applications thereof
  • Low-molecular-weight L-polyglutamine-mitomycin C as well as synthesis method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Take 20 g of polyglutamic acid (molecular weight of about 100,000 Daltons), dissolve it in water with pH=1, and stir it at 80°C for 8 hours; Polyglutamic acid with a molecular weight of 1500-2000, after freeze-drying, add 250ml of dioxane, 0.61g of N-hydroxysuccinimide, 1.10g of dicyclohexylcarbodiimide and 3ml of pyridine, and keep warm at 50°C After 10 hours, the solvent was evaporated, and the residue was dissolved in 100 ml of chloroform, washed with 10 ml of dilute hydrochloric acid, and the chloroform layer was evaporated to dryness. Mycin C 3.34g, during which 0.5mol / L sodium hydroxide or potassium hydroxide aqueous solution was added to maintain pH 7.4; then the reaction solution was concentrated to dryness after stirring for 12 hours, and the residue was separated by silica gel column chromatography (eluent was two A mixture of methyl chloride and methanol at a volume ratio of 10:1) to obtain a yellow to white product, namely low molecular weight L-polyglutamic...

Embodiment 2

[0053] Take 22g of polyglutamic acid (molecular weight: about 100,000 Daltons), dissolve it in water with pH=1.3, and stir at 90°C for 6 hours; Polyglutamic acid with a molecular weight of 1500-6000, after freeze-drying, add 250ml of dioxane, 0.82g of N-hydroxysuccinimide, 1-ethyl-3-(3-dimethylaminopropyl) carbon disulfide 1.08g of imide hydrochloride and 5ml of N-methylmorpholine were incubated at 40°C for 7 hours, the solvent was evaporated, and the residue was dissolved in 200ml of chloroform, washed with 20ml of dilute hydrochloric acid, and the chloroform layer was evaporated to dryness. Add to 30ml of 0.05mol / L HBS buffer (pH 7.4), add 1.67g of mitomycin C under stirring, add 0.7mol / L sodium hydroxide or potassium hydroxide to maintain the pH of the aqueous solution at 7.4; then stir for 12 hours After the reaction solution was concentrated to dryness, the residue was separated by silica gel column chromatography (the eluent was a mixture of dichloromethane and methanol ...

Embodiment 3

[0055] Take 24g of polyglutamic acid (molecular weight: about 100,000 Daltons), dissolve it in water with pH=2.5, and stir at 60°C for 12 hours; Polyglutamic acid with a molecular weight of 2000-3000, after freeze-drying, add 250ml of dioxane, 1.0g of N-hydroxysuccinimide, 0.51g of dicyclohexylcarbodiimide and 4ml of triethylamine, at 30°C Keep it warm for 6 hours, evaporate the solvent, dissolve the residue in 300ml chloroform, wash with 30ml of dilute hydrochloric acid, evaporate the chloroform layer to dryness, add the resultant to 40ml of 0.08mol / L HBS buffer solution (pH is 7.4), and add Mitomycin C 2.0g, during which 0.6mol / L sodium hydroxide or potassium hydroxide aqueous solution was added to maintain pH 7.4; then the reaction solution was concentrated to dryness after stirring for 12 hours, and the residue was separated by silica gel column chromatography (eluent It is a mixture of dichloromethane and methanol at a volume ratio of 10:1) to obtain a yellow to white pro...

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Abstract

The invention relates to a low-molecular-weight L-polyglutamine-mitomycin C with the structural formula shown in the specification and the molecular weight of 1882Da-5892Da, wherein n is equal to 1500-6000. A synthesis method comprises the following steps: dissolving polyglutamic acid into water, stirring and then separating with sephadex chromatography to take polyglutamic acid with molecular weight of 1500-6000, performing freeze-drying and then adding dioxane, N-hydroxysuccinimide, a condensing agent and an acid-binding agent, evaporating out solvents and dissolving chloroform, washing with diluted hydrochloric acid and then evaporating the chloroform layer to dryness, adding a product to HBS buffer, adding mitomycin C under stirring, and then stirring reaction liquid and concentrating to dryness, and separating by using silicon gel column chromatography to obtain the low-molecular-weight L-polyglutamine-mitomycin C. The mitomycin C is modified by utilizing low-molecular-weight L-polyglutamine, and cannot penetrate cornea due to large molecular weight; the low-molecular-weight L-polyglutamine-mitomycin C can be accumulated in pterygium tissues through EPR effect; and the release of mitomycin C can be mediated by cathepsin B enzyme in the pterygium tissues so as to achieve the treatment effect.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a low molecular weight L-polyglutamic acid-mitomycin C, and the invention also relates to a synthesis method of the low molecular weight L-polyglutamic acid-mitomycin C and application. Background technique [0002] Pterygium is a disease of local bulbar conjunctival fibrovascular tissue, named for its resemblance to insect wings, and is one of the most common clinical eye diseases. The incidence of pterygium tends to increase year by year with age, which seriously endangers the visual health of Chinese people: First, the growth and infiltration of pterygium into the cornea can lead to changes in the curvature of the cornea, resulting in varying degrees of astigmatism, eye movement disorders, and decreased vision, seriously affecting The quality of life of patients with pterygium is greatly improved; secondly, the pterygium tissue itself is easy to cause re...

Claims

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Application Information

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IPC IPC(8): C08G69/48A61P27/02
Inventor 陈卓石蕊孙艳平陈研明石一宁
Owner XIAN MEDICAL UNIV
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