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Method for synthesizing doxorubicin-coupled targeting polypeptide

A technology for targeting peptides and synthesis methods, applied in the preparation methods of peptides, chemical instruments and methods, peptides, etc., can solve the problems of unclear target products, many side reactions, and complex final products, and reduce the formation of by-products. Opportunities, Yield Improvement, Effect of Increased Bonding

Pending Publication Date: 2019-10-29
苏州强耀生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, the linking method between doxorubicin and polypeptide is to use the 3-amino group of doxorubicin to use glutaraldehyde as the linking arm to couple the polypeptide, or to use the hydroxyl group of doxorubicin to form an esterification reaction with the polypeptide using a condensation reagent. There are multiple active sites such as amino groups, hydroxyl groups, and carboxyl groups, and multiple active sites of doxorubicin will react with the targeted polypeptide, and even form self-crosslinking of the polypeptide, resulting in complex final products, many side reactions, and unclear target products Shortcomings

Method used

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  • Method for synthesizing doxorubicin-coupled targeting polypeptide
  • Method for synthesizing doxorubicin-coupled targeting polypeptide
  • Method for synthesizing doxorubicin-coupled targeting polypeptide

Examples

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Embodiment 1

[0063] The invention discloses a method for synthesizing doxorubicin-coupled targeting polypeptide, which comprises the following steps:

[0064] S1, Preparation of Resin Peptide NH 2 -A 1 -A 2 -...-A n -Cys(Trt)-Resin;

[0065] Cys(Trt), A n , ... and A 1 Link to resin Resin in turn;

[0066] Among them, A n Is the amino acid -Ala-, -Met-, -Phe-, -Pro-, -Gly-, -Ile-, -Leu-, -Val-, -Arg(Pbf)-, -Lys(Boc)-, -Trp (Boc)-, -Ser(tBu)-, -Thr(tBu)-, -Tyr(tBu)-, -Asp(OtBu)-, -Glu(OtBu)-, -Asn(Trt)- or -Gln( Trt)-, n is a natural number not less than 1.

[0067] S2, preparation of polypeptide fragment NH 2 -A 1 -A 2 -...-A n -Cys-COOH;

[0068] NH 2 -A 1 -A 2 -...-A n -Resin and side chain protecting groups on Cys(Trt)-Resin are removed, purified to obtain NH 2 -A 1 -A 2 -...-A n - Pure Cys-COOH.

[0069] S3, preparing the intermediate doxorubicin-Mal;

[0070] The intermediate doxorubicin-Mal was prepared by using doxorubicin hydrochloride and BMPS.

[0071] S4...

Embodiment 2

[0095] S1, Preparation of Resin Peptides

[0096] NH 2 -Tyr(tBu)-Gly-Arg(Pbf)-Lys(Boc)-Lys(Boc)-Arg(Pbf)-Arg(Pbf)-Gln(Trt)-Arg(Pbf)-Arg(Pbf)-Arg (Pbf)-Cys(Trt)-2-Chlorotrityl Chloride resin;

[0097] a. Add 1g of 0.50mmol / g 2-Chlorotrityl Chloride resin to the reaction vessel, and add DCM, blow the 2-Chlorotrityl Chloride resin with nitrogen for 15 minutes to fully swell the 2-ChlorotritylChloride resin, and then pump it through the sand core Filter off the solvent;

[0098] b. Add 1.5mmol of protected amino acid Fmoc-Cys(Trt)-OH into the reaction vessel, first add DCM to dissolve, then add 10eq of DIEA, react for 60min, and block with methanol during the reaction to obtain Fmoc-Cys(Trt) -Resin;

[0099] c. Remove Fmoc group: Add 10ml of 20% piperidine / DMF solution to the reactor, stir the reaction for 5min under nitrogen protection, and remove the liquid; wash with 10ml DMF twice, then add 10ml eluent, and stir the reaction Extract after 10 minutes; wash with 10ml DMF, 1...

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Abstract

The invention discloses a method for synthesizing doxorubicin-coupled targeting polypeptide. The method comprises the following steps that S1, resin peptide NH2-A<1>-A<2>-...-A<n>-Cys(Trt)-Resin is prepared; S2, a polypeptide fragment NH2-A<1>-A<2>-...-A<n>-Cys-COOH is prepared from the resin peptide in the step S1; S3, an intermediate doxorubicin-Mal is prepared; S4, a NH2-A<1>-A<2>-...-A<n>-Cys(doxorubicin)-COOH crude product is prepared from the polypeptide fragment in the step S1 and doxorubicin-Mal in the step S3; and S5, a NH2-A<1>-A<2>-...-A<n>-Cys(doxorubicin)-COOH pure product is prepared. By-products can be greatly reduced, the reactive site is specific, and the yield is high.

Description

technical field [0001] The present invention relates to a method for synthesizing a polypeptide, in particular to a method for synthesizing a doxorubicin-coupled targeting polypeptide. Background technique [0002] Doxorubicin is an anti-tumor antibiotic, which can inhibit the synthesis of RNA and DNA. It has the strongest inhibitory effect on RNA and has a wide anti-tumor spectrum. Cyclic tumor cells have a killing effect. It is mainly applicable to acute leukemia, and is effective for both acute lymphoblastic leukemia and myeloid leukemia. It is generally used as a second-line drug, that is, it can be considered when the first-line drug is resistant. For malignant lymphoma, it can be used as the drug of choice for alternate use. It has a certain effect on breast cancer, sarcoma, lung cancer, bladder cancer and other cancers, and it is mostly used in combination with other anticancer drugs. [0003] The structure of doxorubicin is as follows: [0004] [0005] The tu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/04C07K1/06C07K1/113C07K1/20
CPCC07K7/08C07K19/00Y02P20/55
Inventor 李广欢卢然张中玉王钒钒
Owner 苏州强耀生物科技有限公司
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