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F3 polypeptide-targeted doxorubicin prodrug with pH sensitivity and preparation method thereof

A doxorubicin and sensitivity technology, applied in the field of doxorubicin prodrug and its preparation, can solve the problems of low selectivity of doxorubicin, prominent toxic and side effects, etc., and achieve the effect of reducing toxic and side effects and avoiding release

Active Publication Date: 2020-06-19
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In view of this, the present invention aims to propose a F3 polypeptide-targeted and pH-sensitive prodrug of doxorubicin to solve the problem of low selectivity of existing doxorubicin, resulting in prominent toxic and side effects

Method used

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  • F3 polypeptide-targeted doxorubicin prodrug with pH sensitivity and preparation method thereof
  • F3 polypeptide-targeted doxorubicin prodrug with pH sensitivity and preparation method thereof
  • F3 polypeptide-targeted doxorubicin prodrug with pH sensitivity and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0030] A F3 polypeptide-targeted and pH-sensitive doxorubicin prodrug, composed of 6-maleimidocaproic acid hydrazide and doxorubicin linked by a pH-sensitive acylhydrazone bond, and then combined with the The mercapto group is prepared by Michael addition reaction, wherein the 6-maleimidocaproic acid hydrazide is prepared by hydrazide reaction of 6-maleimidocaproic acid.

[0031] The above-mentioned F3 polypeptide-targeted and pH-sensitive doxorubicin prodrug is specifically prepared by the following method:

[0032] 1) Preparation of 6-maleimide caproic acid hydrazide: Dissolve 400 mg of 6-maleimide caproic acid in anhydrous tetrahydrofuran, cool to 4°C, add 208 μL N-methylmorpholine, 257mg of isobutyl chloroformate, 250mg of tert-butyl carbazate was added after 5 minutes, and kept at 4°C for 30 minutes, then stirred at room temperature for 1 hour to carry out hydrazide reaction, after the hydrazide reaction was completed, filter, The solvent was evaporated, the residue was ...

Embodiment 2

[0041] A F3 polypeptide-targeted and pH-sensitive doxorubicin prodrug, composed of 6-maleimidocaproic acid hydrazide and doxorubicin linked by a pH-sensitive acylhydrazone bond, and then combined with the The mercapto group is prepared by Michael addition reaction, wherein the 6-maleimidocaproic acid hydrazide is prepared by hydrazide reaction of 6-maleimidocaproic acid.

[0042] The above-mentioned F3 polypeptide-targeted and pH-sensitive doxorubicin prodrug is specifically prepared by the following method:

[0043] 1) Preparation of 6-maleimide caproic acid hydrazide: Dissolve 400mg of 6-maleimide caproic acid in anhydrous tetrahydrofuran, cool to 4°C, add 270 μL N-methylmorpholine, 334mg of isobutyl chloroformate, after 5-10min, add 325mg of tert-butyl carbazate, and keep at 4°C for 40min, then, stir at room temperature for 1.5h, carry out hydrazide reaction, after the hydrazide reaction is completed , filtered, evaporated the solvent, and dissolved the residue in ethyl ac...

Embodiment 3

[0048] A F3 polypeptide-targeted and pH-sensitive doxorubicin prodrug, composed of 6-maleimidocaproic acid hydrazide and doxorubicin linked by a pH-sensitive acylhydrazone bond, and then combined with the The mercapto group is prepared by Michael addition reaction, wherein the 6-maleimidocaproic acid hydrazide is prepared by hydrazide reaction of 6-maleimidocaproic acid.

[0049] The above-mentioned F3 polypeptide-targeted and pH-sensitive doxorubicin prodrug is specifically prepared by the following method:

[0050] 1) Preparation of 6-maleimide caproic acid hydrazide: Dissolve 400 mg of 6-maleimide caproic acid in anhydrous tetrahydrofuran, cool to 4°C, add 312 μL N-methylmorpholine, 386mg of isobutyl chloroformate, 375mg of tert-butyl carbazate was added after 5-10min, and kept at 4°C for 50min, and then stirred at room temperature for 2h to perform hydrazide reaction. After the hydrazide reaction was completed, Filter, evaporate the solvent, and dissolve the residue in et...

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Abstract

The invention provides an F3 polypeptide-targeted doxorubicin prodrug with pH sensitivity and a preparation method thereof. The F3 polypeptide-targeted doxorubicin prodrug with pH sensitivity is prepared by connecting 6-maleimide hexanoic acid hydrazide to doxorubicin through a pH-sensitive acylhydrazone bond, then enabling the 6-maleimide hexanoic acid hydrazide and the doxorubicin to have a Michael addition reaction with a sulfydryl on an F3 peptide, wherein the 6-maleimide hexanoic acid hydrazide is prepared by subjecting 6-maleimide hexanoic acid to a hydrazide reaction. According to the invention, the 6-maleimide hexanoic acid is used as a drug carrier, the 13-carbonyl of doxorubicin is connected to the carrier through the acylhydrazone bond, the drug loading capacity is improved, andthe acylhydrazone bond is disconnected under a tumor acidic condition to release the doxorubicin; and the F3 polypeptide is subjected to Michael addition with maleimide groups of the 6-maleimido hexanoic acid hydrazide through sulfydryl on cysteine residues, so that the target of targeted accurate drug delivery is achieved.

Description

technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to an F3 polypeptide-targeted and pH-sensitive doxorubicin prodrug and a preparation method thereof. Background technique [0002] Doxorubicin (doxorubicin) belongs to the anthracycline anti-tumor antibiotics, since it has been on the market, it has been used in combination with other drugs to form a standard treatment method for various tumors. Clinically, it is mainly used to treat solid tumors, such as breast cancer, ovarian cancer, lung cancer, thyroid cancer, liver cancer, etc. However, its toxic and side effects are prominent, the main manifestations are: inhibition of bone marrow, resulting in cumulative cardiotoxicity, and even heart failure. Therefore, the biggest defect of traditional anticancer treatment methods is the lack of selectivity. [0003] The acylhydrazone bond is pH sensitive. The pH of normal human tissue cells and the blood environment is ab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61K47/64A61K31/704A61P35/00
CPCA61K31/704A61K47/545A61K47/64A61P35/00
Inventor 徐文瑨李勇曾雅文贺依明刘佳王昶旭
Owner WUHAN UNIV OF TECH
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