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Preparation method and application of prodrug of endopeptidase activated doxorubicin

A technology of doxorubicin and endopeptidase, applied in the direction of peptide, drug combination, anti-tumor drug, etc., can solve the problems of low reaction rate, low product yield, stability and purity, long time consumption, etc. Efficacy of curative effect, simple and easy synthesis method and high yield

Active Publication Date: 2014-11-12
GUANGDONG PHARMA UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, in the existing research and development, the specificity, quantity, arrangement, antigenicity and effectiveness of modified peptides need to be solved urgently. Most of the preparation methods of complexes formed by Dox covalently coupled peptides take a long time and the reaction rate is not high. Product yield, stability and purity are relatively low

Method used

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  • Preparation method and application of prodrug of endopeptidase activated doxorubicin
  • Preparation method and application of prodrug of endopeptidase activated doxorubicin
  • Preparation method and application of prodrug of endopeptidase activated doxorubicin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Design and synthesis of N-benzyloxycarbonyl-alanyl-alanyl-asparagine modified doxorubicin prodrug (CBZ-AAN-Dox)

[0036] (1) Activation of N-benzyloxycarbonyl-alanyl-alanyl-asparagine (CBZ-AAN-OH):

[0037] Weigh 39.0mg (95μmol) CBZ-AAN-OH (Guangzhou Jietewei Biotechnology Co., Ltd.) into a 25mL round bottom flask, add 12.9mg (95μmol) HOBt and 54.0mg (95μmol) HBTU, add 1.0mL DMF, Stir in an ice bath for 30 minutes, and when the temperature of the system drops to -15 to 5°C, add 9.5 μL (95 μmol) of NMM and react for 15 minutes.

[0038] (2) Preparation of CBZ-AAN-Dox:

[0039] Add 50 mg (86 μmol) of doxorubicin hydrochloride to the system in step (1), and add 1.0 mL of DMF, and react at room temperature until the fluorescence intensity of the product point is no longer increased by thin-layer chromatography (TLC), stop the reaction, and extract with ether The complex of tripeptide covalently coupled with doxorubicin was obtained by rotary evaporation.

[00...

Embodiment 2

[0042] Example 2: Design and synthesis of N-benzyloxycarbonyl-prolyl-alanyl-asparagine modified doxorubicin prodrug (CBZ-PAN-Dox)

[0043] (1) Activation of N-benzyloxycarbonyl-prolyl-alanyl-asparagine (CBZ-PAN-OH):

[0044] Weigh 41.5mg (95μmol) of CBZ-PAN-OH (Guangzhou Jietewei Biotechnology Co., Ltd.) into a 25mL round bottom flask, add 12.9mg (95μmol) of HOBt and 54.0mg (95μmol) of HBTU, add 1.0mL of DMF, Stir in an ice bath, and when the temperature of the system drops to -15-5°C, add 20 μL (200 μmol) of NMM and react for 10 minutes.

[0045] (2) Preparation of CBZ-PAN-Dox:

[0046] Add 55mg (95μmol) doxorubicin hydrochloride to the system in step (1), and add 1.0mL DMF, react at room temperature, until the fluorescence intensity of the product point is no longer increased by thin layer chromatography (TLC), stop the reaction, diethyl ether The extract was subjected to rotary evaporation to prepare a tripeptide covalently coupled doxorubicin complex.

[0047] (3) Purif...

Embodiment 3

[0049] Example 3: Design and synthesis of N-benzyloxycarbonyl-threonyl-alanyl-asparagine modified doxorubicin prodrug (CBZ-TAN-Dox)

[0050] (1) Activation of N-benzyloxycarbonyl-threonyl-alanyl-asparagine (CBZ-TAN-OH):

[0051] Weigh 41.8mg (95μmol) of CBZ-TAN-OH (Guangzhou Jietewei Biotechnology Co., Ltd.) into a 25mL round bottom flask, add 12.9mg (95μmol) of HOBt and 54.0mg (95μmol) of HBTU, add 1.0mL of DMF, Stir in an ice bath, and when the temperature of the system drops to -15-5°C, add 50 μL (500 μmol) of NMM and react for 8 minutes.

[0052] (2) Preparation of CBZ-TAN-Dox:

[0053] Add 37 mg (63 μmol) of doxorubicin hydrochloride to the system in step (1), and add 1.0 mL of DMF, react at room temperature, until the fluorescence intensity of the product point is no longer increased by thin-layer chromatography (TLC), stop the reaction, and extract with ether The complex of tripeptide covalently coupled with doxorubicin was obtained by rotary evaporation.

[0054] (3...

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Abstract

The invention belongs to the technical field of biology and medicine, and discloses a preparation method of a prodrug of endopeptidase activated doxorubicin. The preparation method is characterized by comprising the following steps: step (1), N-carbobenzoxy-tripeptide is weighed, 1-hydroxyl benzotriazole, 2-(7-azo benzotriazole)-tetramethylurea hexafluoride phosphate, and N,N-dimethyl formamide are sequentially added to the N-carbobenzoxy-tripeptide, bathed in ice and mixed, and then N-methyl morpholine is added for a reaction; step (2), doxorubicin hydrochloride is added, the N,N-dimethyl formamide is replenished for the reaction at the room temperature, a thin-layer chromatography method is used for monitoring the fluorescence intensity of product points until the fluorescence intensity is no longer increased, and then the reaction stops; and step (3), a column chromatography method is used for purification. The prodrug of the endopeptidase activated doxorubicin prepared through the method is low in toxicity, high in purity and capable of being used in the anti-tumor field.

Description

technical field [0001] The invention belongs to the technical field of biology and medicine, and in particular relates to a preparation method of an endopeptidase-activated doxorubicin prodrug and an application of the prodrug in the antitumor field. Background technique [0002] Anthracycline antineoplastic drug doxorubicin (Dox) is a broad-spectrum powerful anticancer drug commonly used in clinical first-line chemotherapy, which is effective for about 70% of solid tumors, such as breast cancer, malignant lymphoma, lung cancer, acute leukemia, etc. But it has toxic side effects such as cardiotoxicity and bone marrow suppression. Therefore, reducing its toxicity and improving targeting, thereby enhancing drug efficacy, is of great significance for chemotherapy and improving the quality of life of cancer patients. [0003] In order to reduce or improve the toxic and side effects of doxorubicin and improve the curative effect, the design theory of prodrugs (referred to as pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/083C07K5/097C07K1/16A61P35/00
Inventor 陈宏远朱嘉雯李秀琼萧婉芬罗智杰高嘉文黄林玉李明哲
Owner GUANGDONG PHARMA UNIV
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