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Peptide-drug conjugate of target placenta-like chondroitin sulfate A, and preparation method and application of peptide-drug conjugate

A technology of chondroitin sulfate and drug conjugates, which is applied in the field of medicine, can solve the problems of no receptor delivery system reported in the literature, achieve the effects of prolonging the circulation time in the body, simple and easy preparation method, and avoiding side effects

Active Publication Date: 2019-04-05
SHENZHEN INST OF ADVANCED TECH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the specific receptor of pl-CSA is unknown, and there are no literature reports on receptors, delivery systems, etc. that can specifically bind to pl-CSA

Method used

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  • Peptide-drug conjugate of target placenta-like chondroitin sulfate A, and preparation method and application of peptide-drug conjugate
  • Peptide-drug conjugate of target placenta-like chondroitin sulfate A, and preparation method and application of peptide-drug conjugate
  • Peptide-drug conjugate of target placenta-like chondroitin sulfate A, and preparation method and application of peptide-drug conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Preparation of a polypeptide-drug conjugate targeting placenta-like chondroitin sulfate A (pl-CSA): first react doxorubicin hydrochloride with succinic anhydride to introduce a carboxyl group on the doxorubicin molecule; then carboxylate The doxorubicin and the polypeptide undergo amide reaction, so that the terminal amino group of the polypeptide fragment reacts with the carboxyl group on the carboxylated doxorubicin to generate a targeted polypeptide-drug conjugate. The reaction equation is as follows:

[0061]

[0062] Specifically, the following steps are included:

[0063] (1) Synthesis of Compound II

[0064] Add 1.0g (1.72mmol) doxorubicin hydrochloride, 0.52g (5.2mmol) succinic anhydride, 30mL tetrahydrofuran (THF) to the 50mL reaction flask, add dropwise 0.66g (5.12mmol) of N,N-diisopropylethyl Amine (DIEA), stirred at 27°C for 6 hours, evaporated to dryness to obtain a waxy substance, added water and stirred, a yellow solid precipitated, suction filtered,...

Embodiment 2

[0068] A preparation of a polypeptide-drug conjugate targeting pl-CSA. Firstly, paclitaxel is reacted with succinic anhydride to introduce a carboxyl group on the paclitaxel molecule; The amino group reacts with the carboxyl group on the carboxylated paclitaxel to generate a polypeptide-drug conjugate. The reaction equation is as follows:

[0069]

[0070] Specifically, its preparation process includes the following steps:

[0071] (1) Synthesis of compound III

[0072]Add 1.0g (1.72mmol) paclitaxel, 0.52g (5.2mmol) succinic anhydride, 30mL tetrahydrofuran (THF) to the 50mL reaction bottle, add dropwise 0.66g (5.12mmol) N, N-diisopropylethylamine (DIEA) , Stir at 27°C for 6h, evaporate the solvent to dryness to obtain a waxy substance, add water and stir, a yellow solid precipitates, filter with suction, wash twice with water, and dry to obtain 1.15g of a yellow solid.

[0073] (2) Synthesis of Compound IV

[0074] Add 0.22g (0.32mmol) compound III, 0.10g (0.31mmol) O-b...

Embodiment 3

[0076] A method for preparing a polypeptide-drug conjugate targeting pl-CSA, the difference from Example 1 is that this example uses 0.1 g of a polypeptide such as SEQUENCE NO.2 (EDVKDINFDTKEKFLAGCLIVSFHEGKC) to replace the one in Example 1 Peptides used.

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PUM

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Abstract

The invention provides peptide-drug conjugate of target placenta-like chondroitin sulfate A. The peptide-drug conjugate comprises a small molecule drug part, a peptide part and a connecting sub-part connected with the small molecule drug part and the peptide part, wherein peptide corresponding to the peptide part can target the placenta-like chondroitin sulfate A specifically, and the amino acid sequence of the peptide is selected from one or more of amino acid sequences shown as SEQ ID NO:1 to SEQ ID NO:3. The peptide-drug conjugate can target inappropriately-expressed target tissue of the placenta-like chondroitin sulfate A specifically, a drug is controlled to be released near the target tissue, and the toxic and side effects of the drug on normal tissue are reduced. The invention further provides a preparation method and application of the peptide-drug conjugate.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to a polypeptide drug conjugate targeting placenta-like chondroitin sulfate A and its preparation method and application. Background technique [0002] Malignant tumors seriously endanger human health. Among the anti-tumor drugs developed in recent years, although many new drugs have excellent drug activity, they have not passed the clinical stage due to poor stability and lack of targeting of tumor tissues. test. For these small molecular compounds with excellent activity and potential clinical application prospects but poor stability or lack of targeting, couple them with peptides with good therapeutic effect or targeting, and become a new type of peptide drug conjugates Peptide-drug conjugate (PDC), which can effectively enhance the stability and targeting of small molecule compounds. The development of PDC drugs has brought new hope for the diagnosis and treatment of tumors....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K45/00A61K49/00A61K49/04A61K49/14A61K49/22A61K31/337A61K31/704A61P35/00
CPCA61K31/337A61K31/704A61K45/00A61K49/0002A61K49/0056A61K49/04A61K49/14A61K49/22
Inventor 范秀军张保珍张键
Owner SHENZHEN INST OF ADVANCED TECH CHINESE ACAD OF SCI
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