A doxorubicin precursor compound with photoresponse degradation and its preparation and application

The technology of a precursor compound, doxorubicin, is applied to the preparation of sugar derivatives, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., which can solve the problem of incomplete release of doxorubicin preparations Unable to time, fixed-point release, toxic and side effects and other problems, to achieve the effect of large drug load, small volume and good biocompatibility

Active Publication Date: 2019-12-03
MENGCHAO HEPATOBILIARY HOSPITAL OF FUJIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a doxorubicin precursor compound with light-responsive release, a preparation method and its application, so as to solve the incomplete release and burst release of doxorubicin preparations in the prior art, which cannot be released at a fixed time and at a fixed point, thereby causing The problem of severe toxic side effects

Method used

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  • A doxorubicin precursor compound with photoresponse degradation and its preparation and application
  • A doxorubicin precursor compound with photoresponse degradation and its preparation and application
  • A doxorubicin precursor compound with photoresponse degradation and its preparation and application

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Embodiment 1: the preparation of prodrug intermediate 1 formula (II) compound

[0041] Dissolve 340mg (2mmol) of 5-hydroxy-2-nitrobenzyl ethanol, 733mg (2.4mmol) of hexadecane bromide in 20mL of DMF, add 424mg (4mmol) of NaCO 3 , 80°C for 24 hours. After the reaction, the DMF was distilled off under reduced pressure, and the crude product was vigorously stirred overnight with a mixed solvent of 50mL water and 50mL ethyl acetate. Anhydrous Na 2 SO 4 Let dry overnight. After filtration and concentration of the filtrate under reduced pressure, the product was separated by silica gel column chromatography to obtain a light yellow solid product. The eluent was ethyl acetate:petroleum ether, and the yield was 83%.

[0042] Intermediate 1 The structure of the compound of formula (II) was characterized by the results of NMR and C NMR, and the results are as follows figure 1 and figure 2 shown.

Embodiment 2

[0043] Embodiment 2: the preparation of prodrug intermediate 2 formula (Ⅲ) compound

[0044] Phenyl p-nitrochloroformate (148 mg, 0.73 mmol) was dissolved in 2 mL of tetrahydrofuran, and 148 mg (0.7 mmol) of intermediate 1 and 256 μL (1.47 mmol) of N,N-diisopropylethylamine were added to 2 mL of tris Chloromethane solution, reacted for 24 hours. Additional phenyl p-nitrochloroformate (148 mg, 0.73 mmol) and 4-dimethylaminopyridine (90 mg, 0.74 mmol) were added, and the reaction was continued for 4 hours. The solvent was removed under reduced pressure, 50 mL of ethyl acetate was added and dissolved in 50 mL of 1M H 3 PO 4 and saturated NaHCO 3 Washed twice successively, the organic layer was washed with anhydrous Na 2 SO 4 Let dry overnight. After filtration and concentration of the filtrate under reduced pressure, the product was separated by silica gel column chromatography to obtain a light yellow solid product. The eluent was ethyl acetate:petroleum ether, and the yie...

Embodiment 3

[0046] Embodiment 3: the preparation of doxorubicin precursor compound (DOC)

[0047]Doxorubicin hydrochloride (50 mg, 86.2 μmol) was dissolved in 6 mL of DMF, triethylamine (36 μL, 258 μmol) and intermediate 2 (49 mg, 86.8 μmol) were added. After reacting at room temperature in the dark for 36 hours, the solvent was removed under reduced pressure, and the residue was dissolved in 4 mL of a mixed solvent of 3% methanol / chloroform, separated by a silica gel column, and finally the product was obtained.

[0048] The structure of doxorubicin precursor compound was characterized by H NMR and C NMR results, the results are as follows Figure 5 and Figure 6 shown.

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Abstract

The invention relates to a doxorubicin precursor compound which can be released under photo-response, and a preparation method and an application of same. The doxorubicin precursor compound is represented as the formula (I) and has following advantages: the compound contains a photo-sensitive group, which is connected to a strong-hydrophobic group; and then with an amphiphilic polymer, polylactic acid-glycolic acid copolymer (PLGA), which has excellent biocompatibility, as a supporter, a hydrophobic photo-responding doxorubicin prodrug molecule (DOC) is embedded in a hydrophobic core of a nano-micelle, which is formed by the PLGA; under light irradiation, the hydrophobic prodrug molecule is degraded into hydrophilic doxorubicin, which is easy to escape from the nano-supporter PLGA, thus achieving the effects of the doxorubicin. The method achieves photo-controlled release of the medicine, and solves the problems of intensive toxic and side effects since the medicine cannot be released at certain time and certain points due to incomplete release and sudden release of a doxorubicin preparation in the prior art.

Description

[0001] (1) Technical field [0002] The invention relates to a doxorubicin precursor compound with photoresponse degradation, a preparation method and application thereof. [0003] (2) Background technology [0004] Doxorubicin (DOX) belongs to the anthracycline antibiotics. It has a broad antitumor spectrum and strong activity. It is currently a commonly used chemotherapeutic drug for the treatment of liver cancer. However, it has strong cardiotoxicity and bone marrow suppression, especially when the dose is large, it can cause irreversible heart failure, which greatly limits its application. How to improve the curative effect of traditional chemotherapeutic drugs and effectively reduce their side effects has become a hot spot in current research, and the nano-controllable drug release system provides a new means to achieve this goal. It can carry drug molecules to the tumor site and release them at an appropriate rate. The drug concentration can be controlled within the requ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/252C07H1/00A61K31/704A61P35/00A61K47/54A61K47/34A61K41/00
CPCA61K31/704A61K41/0042A61K47/34C07H1/00C07H15/252
Inventor 刘景丰刘小龙吴名曾永毅
Owner MENGCHAO HEPATOBILIARY HOSPITAL OF FUJIAN MEDICAL UNIV
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