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DHA (docosahexaenoic acid)-MMC (mitomycin C) derivative and preparation method and application thereof

A technology of mitomycin and derivatives, which is applied in the field of pharmacy, can solve side effects and other problems, and achieve the effects of reducing intraocular side effects, tumor suppression and enhanced targeting

Inactive Publication Date: 2017-08-01
XIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the molecular weight of MMC is only 334, which can be absorbed into the eye through the cornea, causing side effects

Method used

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  • DHA (docosahexaenoic acid)-MMC (mitomycin C) derivative and preparation method and application thereof
  • DHA (docosahexaenoic acid)-MMC (mitomycin C) derivative and preparation method and application thereof
  • DHA (docosahexaenoic acid)-MMC (mitomycin C) derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Step 1, add 329mg (1mmol) of cis-4,7,10,13,16,19-docosahexaenoic acid and 173mg (1.5mmol) of N-hydroxysuccinimide to a 25ml round bottom bottle , 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride 574mg (3mmol) and 1.01g (10mmol) N-methylmorpholine, add dioxane 32.9g to dissolve after N 2 React at room temperature under protection for 48 hours, evaporate the solvent under reduced pressure, dissolve the residue in chloroform, wash with 30ml of 2N dilute hydrochloric acid, dry the chloroform layer and evaporate to dryness to obtain a yellow oil DHA-NHS, NHS 2 Store under protection.

[0054] Step 2, add the DHA-NHS 106.3mg (0.25mmol) that step 1 obtains in the 25ml round bottom bottle, 0.03mol / L HBS damping fluid (pH is 7.4) 10ml, add Mitomycin C 83.5mg (0.25 mmol), during which pH is monitored and 0.5mol / L aqueous sodium hydroxide solution is added as required to maintain pH 7.4; then the reaction solution is concentrated to dryness after stirring for 12 hour...

Embodiment 2

[0056] Step 1, add 329mg (1mmol) of cis-4,7,10,13,16,19-docosahexaenoic acid and 577mg (5mmol) of N-hydroxysuccinimide to a 25ml round bottom bottle, 957mg (5mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 2.02g (20mmol) of N-methylmorpholine, after adding 2.3g of dioxane to dissolve , at N 2 React at room temperature for 4 hours under protection, evaporate the solvent under reduced pressure, dissolve the residue with dichloromethane, wash with 40ml of 1N phosphoric acid, dry the dichloromethane layer and evaporate to dryness to obtain a yellow oil DHA-NHS, NHS 2 Store under protection.

[0057] Step 2, add the DHA-NHS 106.3mg (0.25mmol) that step 1 obtains in the 25ml round bottom bottle, 0.01M borax solution buffer (pH is 9) 10ml, add Mitomycin C 83.5mg (0.25mmol) under stirring ), during which pH is monitored and 0.01mol / L potassium hydroxide aqueous solution is added as required to maintain pH 9; then the reaction solution is concentrated to dry...

Embodiment 3

[0059] Step 1, add 329mg (1mmol) of cis-4,7,10,13,16,19-docosahexaenoic acid and 115mg (1mmol) of N-hydroxysuccinimide to a 25ml round bottom bottle, 191mg (1mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 101mg (1mmol) of N-methylmorpholine were added to dissolve in 15.0g of ether, and reacted for 96h. Evaporate the solvent under reduced pressure, dissolve the residue with carbon tetrachloride, wash with 20ml of 3N dilute phosphoric acid, dry the carbon tetrachloride layer and evaporate to dryness to obtain a yellow oil DHA-NHS, NHS 2 Store under protection.

[0060] Step 2, add DHA-NHS 106.3mg (0.25mmol) obtained in step 1 to a 25ml round bottom bottle, 0.025M potassium dihydrogen phosphate and disodium hydrogen phosphate mixed salt solution buffer (pH is 7) 10ml, add under stirring Mitomycin C 83.5mg (0.25mmol), during which pH was monitored and sodium carbonate powder was added as needed to maintain pH 7; then the reaction solution was stirred for...

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Abstract

The invention discloses a DHA (docosahexaenoic acid)-MMC (mitomycin C) derivative. A structure formula thereof is shown in the description. The invention also discloses application of the derivative in preparing medicines for resisting pterygium, and a preparation method of the derivative. The preparation method specifically comprises the following steps of mixing DHA-NHS and a buffer solution, stirring, adding MMC, concentrating to the dry state, and separating the remained matter by silica gel column chromatography. The preparation method has the advantages that the MMC and the DHA are prepared into the larger-molecule derivative, namely the DHA-MMC, by a chemical synthesizing method, so that the molecular weight of the medicine is increased from 334 (use of single MMC) to 649, the absorbing in eyes via cornea is difficult, and the side effect in eyes is reduced; after accumulating to the conjunctiva and pterygium tissues, the derivative is gradually hydrolyzed to release the MMC to take effect; by utilizing the tumor inhibiting property and targeting property of the DHA, the selectivity and inhibiting property of the pterygium tissue of the DHA-MMC are enhanced.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and specifically relates to a DHA-mitomycin C derivative, and also relates to the application and preparation method of the derivative in preparing medicine. Background technique [0002] Pterygium is one of the most common ocular surface diseases in the Northwest Territories. The ocular surface is subject to external stimuli for a long time, such as high ultraviolet rays, high wind and sand, and haze, etc., often easily cause fibrovascular tissue neoplastic lesions in the bulbar conjunctiva of the palpebral fissure. It is named pterygium because it resembles the wings of insects. Pterygium seriously endangers the vision health of Chinese people. Its growth and infiltration of cornea can cause astigmatism, inflammation, and even blindness. Pterygium is currently treated clinically with highly toxic antimetabolites such as Mitomycin C (MMC) to kill and inhibit the remaining fibroblasts on the oc...

Claims

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Application Information

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IPC IPC(8): C07D487/14A61K31/407A61P27/02
CPCC07D487/14
Inventor 陈卓谭李玉石蕊刘少静邬莉娜余丽丽张宇佳王婵李立
Owner XIAN MEDICAL UNIV
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