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Polypeptide drug conjugate with tumor targeting, and preparation method of polypeptide drug conjugate

A technology of drug conjugates and tumor targeting, which is applied in the field of preparation of polypeptide drug conjugates, can solve the problems of difficulty in the research of anti-tumor polypeptide drug conjugates, and achieve the goal of overcoming toxic side effects and solving core technical problems Effect

Active Publication Date: 2021-02-23
辽宁医学诊疗科技研发中心有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the research on anti-tumor peptide drug conjugates is quite difficult, mainly reflected in the need for suitable linkers to ensure that the peptide moiety can be effectively coupled with cytotoxic drugs while having tumor targeting properties.

Method used

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  • Polypeptide drug conjugate with tumor targeting, and preparation method of polypeptide drug conjugate
  • Polypeptide drug conjugate with tumor targeting, and preparation method of polypeptide drug conjugate
  • Polypeptide drug conjugate with tumor targeting, and preparation method of polypeptide drug conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1 Synthesis of Fmoc-WA1-Wang resin.

[0059] Add Fmoc-Ala-Wang resin (degree of substitution 0.237 mmol / g, 0.711 mmol) to the solid phase reaction tube, then add 25 ml DMF to swell for 20 min. The reagent for removing the Fmoc protecting group was 20% Pip in DMF, and the amino acid condensing agent was HOAt (0.387 g, 2.844 mmol) and DIC (0.440 ml, 2.844 mmol). After adding Fmoc-Pro-OH (0.959 g, 2.844 mmol) to react for 2 h, DMF was washed 3 times to complete the extension of one amino acid. According to the above reaction cycle of amino acid condensation, Fmoc-Leu-OH (1.005 g, 2.844 mmol), Fmoc-Arg(pbf)-OH (1.845 g, 2.844 mmol), Fmoc-Thr(tBu )-OH (1.130 g, 2.844 mmol), Fmoc-Asn(Trt)-OH (1.697 g, 2.844 mmol), Fmoc-Trp(Boc)-OH (1.498 g, 2.844 mmol) were reacted and washed twice with DMF , and washed twice with DCM, and dried to obtain Fmoc-Trp(Boc)-Asn(Trt)-Pro-Leu-Leu-Leu-Thr(tBu)-Arg(pbf)-Leu-Leu-Pro-Ala-Wang , namely Fmoc-WA1-Wang resin.

Embodiment 2

[0060] Example 2 Synthesis of Fmoc-linker-WA1-Wang resin.

[0061] The obtained Fmoc-WA1-Wang resin was deprotected by 20% Pip in DMF, and then HOAt (0.387 g, 2.844 mmol), DIC (0.440 ml, 2.844 mmol) and Fmoc-Acp-OH (1.005 g, 2.844 mmol) was reacted in an ultrasonic reactor for 45 min, and the reaction end point was judged by Kaiser detection, the reaction solution was drained, and washed twice with DMF to obtain Fmoc-linker-WA1-Wang resin. (A small amount of product was treated with a peptide cleavage reagent to obtain WA1-lineker, which was detected by mass spectrometry, and the results are shown in figure 1 .

Embodiment 3

[0062] Example 3 Synthesis of PDC-WA1.

[0063] Also use 20% Pip in DMF solution to remove the Fmoc protecting group of Fmoc-WA1-Wang resin, add HOAt (0.387 g, 2.844 mmol), DIC (0.440 ml, 2.844 mmol) and chlorambucil (0.865 g, 2.844 mmol) mmol) were reacted in an ultrasonic reactor for 1 h, washed twice with DMF, and the resin was shrunk with methanol. Add peptide cleavage reagent 95% TFA aqueous solution, react under ice bath for 1.5h. Filter, add the filtrate to anhydrous ether, and centrifuge to obtain the crude peptide. The crude peptide was dissolved, purified by HPLC, and then freeze-dried to obtain a product of 0.449 g (yield: 35%), which was detected by mass spectrometry. The results are shown in figure 2 .

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Abstract

The invention discloses a preparation method and application of a polypeptide drug conjugate with tumor targeting. The polypeptide drug conjugate with the tumor targeting structurally comprises tumortargeting peptide WA1, a non-splitting connector and a cytotoxicity anti-tumor drug. The preparation method of the polypeptide drug conjugate (PDC-WA1) with the tumor targeting adopts a Fmoc solid-phase synthesis method and comprises the following main synthesis steps of: taking Fmoc-Ala-Wang resin as a raw material, after the tumor targeting peptide is synthesized, connecting the synthesized tumor targeting peptide with Fmoc-Acp-OH and chlorambucil in sequence, and carrying out purification by HPLC to obtain the polypeptide drug conjugate with the tumor targeting and anti-tumor activity. Thepreparation method has the advantages of low production cost, low environment pollution, few reaction by-products and low purification difficulty and is simple in reaction operation.

Description

technical field [0001] The invention relates to a preparation method of a polypeptide drug conjugate with tumor targeting. Background technique [0002] Peptide solid-phase synthesis technology and genetic engineering technology are developing rapidly, and the research and development of peptide drugs continues to heat up. There are more than 100 peptide drugs approved for marketing in the world, and about 200 peptides are in the clinical research stage. In the international research and development of peptide drugs, anti-tumor peptides account for about 21% of the market, while my country's peptide drugs are mainly concentrated in the fields of immune assistance and gastrointestinal hemostasis. Due to the high morbidity and mortality of tumors, targeted therapy has special significance for them. Peptide drugs have the characteristics of high selectivity, strong biological activity and low toxicity and side effects, so tumor peptide drugs will be an important part of anti-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K31/196A61P35/00
CPCA61K47/64A61K31/196A61P35/00Y02P20/55
Inventor 魏敏杰
Owner 辽宁医学诊疗科技研发中心有限公司
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